My Thoughts: Leukemia, Blood, T-Cells, Soft Tissue Injuries and Stem Cells

One of the factors in my disorder is that the locations of tumors on my body were located at the sites of prior soft tissue injury.

If Leukemia is a cancer of the blood, would an injury also facilitate the growth of another tumor at some point following the injury at that site?

And at this point which kind of stem cells would be the ones at work to form a cancerous tumor?

Stem Cell Information – Are Stem Cells Involved in Cancer?

Cancer: Impact and Challenges

Data from 2007 suggest that approximately 1.4 million men and women in the U.S. population are likely to be diagnosed with cancer, and approximately 566,000 American adults are likely to die from cancer in 2008.1 Data collected between 1996 and 2004 indicate that the overall 5-year survival rate for cancers from all sites, relative to the expected survival from a comparable set of people without cancer, is 65.3%.1 However, survival and recurrence rates following diagnosis vary greatly as a function of cancer type and the stage of development at diagnosis. For example, in 2000, the relative survival rate five years following diagnosis of melanoma (skin cancer) was greater than 90%; that of cancers of the brain and nervous system was 35%. Once a cancer has metastasized (or spread to secondary sites via the blood or lymph system), however, the survival rate usually declines dramatically. For example, when melanoma is diagnosed at the localized stage, 99% of people will survive more than five years, compared to 65% of those diagnosed with melanoma that has metastasized regionally and 15% of those whose melanoma has spread to distant sites.2

The term “cancer” describes a group of diseases that are characterized by uncontrolled cellular growth, cellular invasion into adjacent tissues, and the potential to metastasize if not treated at a sufficiently early stage. These cellular aberrations arise from accumulated genetic modifications, either via changes in the underlying genetic sequence or from epigenetic alterations (e.g., modifications to geneactivation- or DNA-related proteins that do not affect the genetic sequence itself).3,4Cancers may form tumors in solid organs, such as the lung, brain, or liver, or be present as malignancies in tissues such as the blood or lymph. Tumors and other structures that result from aberrant cell growth, contain heterogeneous cell populations with diverse biological characteristics and potentials. As such, a researcher sequencing all of the genes from tumor specimens of two individuals diagnosed with the same type of lung cancer will identify some consistencies along with many differences. In fact, cancerous tissues are sufficiently heterogeneous that the researcher will likely identify differences in the genetic profiles between several tissue samples from the same specimen. While some groupings of genes allow scientists to classify organ-or tissue-specific cancers into subcategories that may ultimately inform treatment and provide predictive information, the remarkable complexity of cancer biology continues to confound treatment efforts.

Once a cancer has been diagnosed, treatments vary according to cancer type and severity. Surgery, radiation therapy, and systemic treatments such as chemotherapy or hormonal therapy represent traditional approaches designed to remove or kill rapidly-dividing cancer cells. These methods have limitations in clinical use. For example, cancer surgeons may be unable to remove all of the tumor tissue due to its location or extent of spreading. Radiation and chemotherapy, on the other hand, are non-specific strategies—while targeting rapidly-dividing cells, these treatments often destroy healthy tissue as well. Recently, several agents that target specific proteins implicated in cancer-associated molecular pathways have been developed for clinical use. These include trastuzumab, a monoclonal antibody that targets the protein HER2 in breast cancer,5 gefitinib and erlotnib, which target epidermal growth factor receptor (EGFR) in lung cancer,6 imatinib, which targets the BCR-ABL tyrosine kinase in chronic myelogenous leukemia,7 the monoclonal antibodies bevacizumab, which targets vascular endothelial growth factor in colorectal and lung cancer,8 and cetuximab and panitumumab, which target EGFR in colorectal cancer.8 These agents have shown that a targeted approach can be successful, although they are effective only in patients who feature select subclasses of these respective cancers.

All of these treatments are most successful when a cancer is localized; most fail in the metastatic setting.9–11 This article will discuss the CSC hypothesis and its supporting evidence and provide some perspectives on how CSCs could impact the development of future cancer therapy.

Defining The “Cancer Stem Cell”

A consensus panel convened by the American Association of Cancer Research has defined a CSC as “a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor.”12 It should be noted that this definition does not indicate the source of these cells—these tumor-forming cells could hypothetically originate from stem, progenitor, or differentiated cells.13 As such, the terms “tumor-initiating cell” or “cancer-initiating cell” are sometimes used instead of “cancer stem cell” to avoid confusion. Tumors originate from the transformation of normal cells through the accumulation of genetic modifications, but it has not been established unequivocally that stem cells are the origin of all CSCs. The CSC hypothesis therefore does not imply that cancer is always caused by stem cells or that the potential application of stem cells to treat conditions such as heart disease or diabetes, as discussed in other chapters of this report, will result in tumor formation. Rather, tumor-initiating cells possess stem-like characteristics to a degree sufficient to warrant the comparison with stem cells; the observed experimental and clinical behaviors of metastatic cancer cells are highly reminiscent of the classical properties of stem cells.9

The CSC Hypothesis And The Search For CSCs

The CSC hypothesis suggests that the malignancies associated with cancer originate from a small population of stem-like, tumor-initiating cells. Although cancer researchers first isolated CSCs in 1994,14 the concept dates to the mid-19th century. In 1855, German pathologist Rudolf Virchow proposed that cancers arise from the activation of dormant, embryonic-like cells present in mature tissue.15 Virchow argued that cancer does not simply appear spontaneously; rather, cancerous cells, like their non-cancerous counterparts, must originate from other living cells. One hundred and fifty years after Virchow’s observation, Lapidot and colleagues provided the first solid evidence to support the CSC hypothesis when they used cell-surface protein markers to identify a relatively rare population of stemlike cells in acute myeloid leukemia (AML).14 Present in the peripheral blood of persons with leukemia at approximately 1:250,000 cells, these cells could initiate human AML when transplanted into mice with compromised immune systems. Subsequent analysis of populations of leukemia-initiating cells from various AML subtypes indicated that the cells were relatively immature in terms of differentiation.16 In other words, the cells were “stem-like”—more closely related to primitive blood-forming (hematopoietic) stem cells than to more mature, committed blood cells.

The identification of leukemia-inducing cells has fostered an intense effort to isolate and characterize CSCs in solid tumors. Stem cell-like populations have since been characterized using cell-surface protein markers in tumors of the breast,17 colon,18 brain,19 pancreas,20,21 and prostate.22,23 However, identifying markers that unequivocally characterize a population of CSCs remains challenging, even when there is evidence that putative CSCs exist in a given solid tumor type. For example, in hepatocellular carcinoma, cellular analysis suggests the presence of stem-like cells.24Definitive markers have yet to be identified to characterize these putative CSCs, although several potential candidates have been proposed recently.25,26 In other cancers in which CSCs have yet to be identified, researchers are beginning to link established stem-cell markers with malignant cancer cells. For instance, the proteins Nanog, nucleostemin, and musashi1, which are highly expressed in embryonic stem cells and are critical to maintaining those cells’ pluripotency, are also highly expressed in malignant cervical epithelial cells.27 While this finding does not indicate the existence of cervical cancer CSCs, it suggests that these proteins may play roles in cervical carcinogenesis and progression.

Do CSCs Arise From Stem Cells?

Given the similarities between tumor-initiating cells and stem cells, researchers have sought to determine whether CSCs arise from stem cells, progenitor cells, or differentiated cells present in adult tissue. Of course, different malignancies may present different answers to this question. The issue is currently under debate,9,12 and this section will review several theories about the cellular precursors of cancer cells (see Fig. 9.1).


Figure 9.1. How Do Cancer Stem Cells Arise? The molecular pathways that maintain “stem-ness” in stem cells are also active in numerous cancers. This similarity has led scientists to propose that cancers may arise when some event produces a mutation in a stem cell, robbing it of the ability to regulate cell division. This figure illustrates 3 hypotheses of how a cancer stem cell may arise: (1) A stem cell undergoes a mutation, (2) A progenitor cell undergoes two or more mutations, or (3) A fully differentiated cell undergoes several mutations that drive it back to a stem-like state. In all 3 scenarios, the resultant cancer stem cell has lost the ability to regulate its own cell division.

© 2009 Terese Winslow

Hypothesis #1:

Cancer Cells Arise from Stem Cells. Stem cells are distinguished from other cells by two characteristics: (1) they can divide to produce copies of themselves, or self-renew, under appropriate conditions and (2) they are pluripotent, or able to differentiate into most, if not all, mature cell types. If CSCs arise from normal stem cells present in the adult tissue, de-differentiation would not be necessary for tumor formation. In this scenario, cancer cells could simply utilize the existing stem-cell regulatory pathways to promote their self-renewal. The ability to self-renew gives stem cells long lifespans relative to those of mature, differentiated cells.30 It has therefore been hypothesized that the limited lifespan of a mature cell makes it less likely to live long enough to undergo the multiple mutations necessary for tumor formation and metastasis.

Several characteristics of the leukemia-initiating cells support the stem-cell origin hypothesis. Recently, the CSCs associated with AML have been shown to comprise distinct, hierarchically-arranged classes (similar to those observed with hematopoietic stem cells) that dictate distinct fates.31 To investigate whether these CSCs derive from hematopoietic stem cells, researchers have used a technique known as serial dilution to determine the CSCs’ ability to self-renew. Serial dilution involves transplanting cells (usually hematopoietic stem cells, but in this case, CSCs) into a mouse during a bone-marrow transplant. Prior to the transplant, this “primary recipient” mouse’s natural supply of hematopoietic stem cells is ablated. If the transplant is successful and if the cells undergo substantial self-renewal, the primary recipient can then become a successful donor for a subsequent, or serial, transplant. Following cell division within primary recipients, a subset of the AML-associated CSCs divided only rarely and underwent self-renewal instead of committing to a lineage. This heterogeneity in self-renewal potential supports the hypothesis that these CSCs derive from normal hematopoietic stem cells.31 It should be noted, however, that the leukemia-inducing cells are the longest-studied of the known CSCs; the identification and characterization of other CSCs will allow researchers to understand more about the origin of these unique cells.

Hypothesis #2: Cancer Cells Arise from Progenitor Cells.

The differentiation pathway from a stem cell to a differentiated cell usually involves one or more intermediate cell types. These intermediate cells, which are more abundant in adult tissue than are stem cells, are called progenitor or precursor cells. They are partly differentiated cells present in fetal and adult tissues that usually divide to produce mature cells. However, they retain a partial capacity for self-renewal. This property, when considered with their abundance relative to stem cells in adult tissue, has led some researchers to postulate that progenitor cells could be a source of CSCs.32,33

Hypothesis #3: Cancer Cells Arise from Differentiated Cells.

Some researchers have suggested that cancer cells could arise from mature, differentiated cells that somehow de-differentiate to become more stem celllike. In this scenario, the requisite oncogenic (cancer causing) genetic mutations would need to drive the de-differentiation process as well as the subsequent self-renewal of the proliferating cells. This model leaves open the possibility that a relatively large population of cells in the tissue could have tumorigenic potential; a small subset of these would actually initiate the tumor. Specific mechanisms to select which cells would de-differentiate have not been proposed. However, if a tissue contains a sufficient population of differentiated cells, the laws of probability indicate that a small portion of them could, in principle, undergo the sequence of events necessary for de-differentiation. Moreover, this sequence may contain surprisingly few steps; researchers have recently demonstrated that human adult somatic cells can be genetically “re-programmed” into pluripotent human stem cells by applying only four stem-cell factors (see the chapter, “Alternate Methods for Preparing Pluripotent Stem Cells” for detailed discussion of inducing pluripotent stem cells).28,29

How Cancer Stem Cells Could Support Metastasis

Metastasis is a complex, multi-step process that involves a specific sequence of events; namely, cancer cells must escape from the original tumor, migrate through the blood or lymph to a new site, adhere to the new site, move from the circulation into the local tissue, form micrometastases, develop a blood supply, and grow to form macroscopic and clinically relevant metastases.9,34,35 Perhaps not surprisingly, metastasis is highly inefficient.9 It has been estimated that less than 2% of solitary cells that successfully migrate to a new site are able to initiate growth once there.34,36,37 Moreover, less than 1% of cells that initiate growth at the secondary site are able to maintain this growth sufficiently to become macroscopic metastases.36These observations suggest that a small, and most likely specialized, subset of cancer cells drives the spread of disease to distant organs.

Some researchers have proposed that these unique cells may be CSCs.9,30,32,33,38 In this hypothesis, metastatic inefficiency may reflect the relative rarity of CSCs combined with the varying compatibilities of these cells with destination microenvironments. Researchers have demonstrated that stem cells and metastatic cancer cells share several properties that are essential to the metastatic process, including the requirement of a specific microenvironment (or “niche”) to support growth and provide protection, the use of specific cellular pathways for migration, enhanced resistance to cell death, and an increased capacity for drug resistance.9There is emerging, albeit limited, evidence that these properties may also hold for CSCs.9 Metastatic sites for a given cancer type could therefore represent those tissues that provide or promote the development of a compatible CSC niche, from which CSCs could expand through normal or dysregulated cellular signaling. Moreover, normal stem cells tend to be quiescent unless activated to divide.39 If the CSC hypothesis holds true, then undifferentiated, dormant CSCs would be relatively resistant to chemotherapeutic agents, which act mainly on dividing cells.10 As such, this subpopulation could form the kernel of cells responsible for metastasis and cancer recurrence following treatment and remission.

How The CSC Model Could Affect Cancer Therapy

As noted previously, most contemporary cancer treatments have limited selectivity — systemic therapies and surgeries remove or damage normal tissue in addition to tumor tissue. These methods must therefore be employed judiciously to limit adverse effects associated with treatment. Moreover, these approaches are often only temporarily effective; cancers that appear to be successfully eliminated immediately following treatment may recur at a later time and often do so at a new site. Agents that target molecules implicated in cancer pathways have illustrated the power of a selective approach, and many researchers and drug developers are shifting toward this paradigm. If the CSC hypothesis proves to be correct, then a strategy designed to target CSCs selectively could potentially stop the “seeds” of the tumor before they have a chance to germinate and spread.

The CSC hypothesis accounts for observed patterns of cancer recurrence and metastasis following an apparently successful therapeutic intervention. In clinical practice, however, some cancers prove quite aggressive, resisting chemotherapy or radiation even when administered at relatively early stages of tumor progression. These tumors therefore have an increased likelihood of metastasizing, confounding further treatment strategies while compromising the cancer patient’s quality of life. The presence of CSC in some malignancies may account for some of these metastases. So why do some tumors succumb to therapy, while others resist it? Some scientists have suggested that the tumor aggressiveness may correlate with the proportion of CSCs within a corresponding tumor.40–42 In this scenario, less aggressive cancers contain fewer CSCs and a greater proportion of therapy-sensitive non-CSCs.9

There is also some evidence to suggest that CSCs may be able to selectively resist many current cancer therapies, although this property has yet to be proven in the clinic.9 For example, normal stem cells and metastatic cancer cells over-express several common, known drug-resistance genes.43 As a result, breast cancer CSCs express increased levels of several membrane proteins implicated in resistance to chemotherapy 17 These cells have also been shown to express intercellular signaling molecules such as Hedgehog and Bmi-1,44 which are essential for promoting self-renewal and proliferation of several types of stem cells.45 Moreover, experiments in cell lines from breast cancer46 and glioma40 have shown that CSCs (as identified by cell-surface markers) are more resistant to radiotherapy than their non-CSC counterparts. In the face of radiation, the CSCs appear to survive preferentially, repair their damaged DNA more efficiently, and begin the process of self-renewal.

These discoveries have led researchers to propose several avenues for treating cancer by targeting molecules involved in CSC renewal and proliferation pathways. Potential strategies include interfering with molecular pathways that increase drug resistance, targeting proteins that may sensitize CSCs to radiation, or restraining the CSCs’ self-renewal capacity by modifying their cell differentiation capabilities.9 In each case, successful development of a therapy would require additional basic and clinical research. Researchers must characterize the CSCs associated with a given tumor type, identify relevant molecules to target, develop effective agents, and test the agents in pre-clinical models, such as animals or cell lines. However, by targeting fundamental CSC cellular signaling processes, it is possible that a given treatment could be effective against multiple tumor types.


Cancer represents a major health challenge for the 21st century. Governed by an intricate, complex interplay of molecular signals, cancers often resist systemic treatments. Yet the uncontrolled cellular growth that characterizes cancers may paradoxically hold the key to understanding the spread of disease. It has long been postulated that tumors form and proliferate from the actions of a small population of unique cells. The observation that metastatic cancer cells exhibit experimental and clinical behaviors highly reminiscent of the classical properties of stem cells has led researchers to search for and to characterize “cancer stem cells” believed to be implicated in the cancer process.

The discovery of CSCs in some tumor types has ushered in a new era of cancer research. Cancer stem cell science is an emerging field that will ultimately impact researchers’ understanding of cancer processes and may identify new therapeutic strategies. However, much remains to be learned about these unique cells, which as of yet have not been identified in all tumor types. At present, evidence continues to mount to support a CSC Hypothesis—that cancers are perpetuated by a small population of tumor-initiating cells that exhibit numerous stem cell-like properties. Whether or not the Hypothesis ultimately proves true in all cases, understanding the similarities between cancer cells and stem cells will illuminate many molecular pathways that are triggered in carcinogenesis. Thus, the question, “Are stem cells involved in cancer?” has no simple answer. However, the characterization of CSCs will likely play a role in the development of novel targeted therapies designed to eradicate the most dangerous tumor cells, that may be resistant to current chemotherapy regimens, thereby providing researchers and clinicians with additional targets to alleviate the burden of cancer.


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The Pharmacological Potential of Rutin

~Content Source


The contemporary scientific community has presently recognized flavonoids to be a unique class of therapeutic molecules due to their diverse therapeutic properties. Of these, rutin, also known as vitamin P or rutoside, has been explored for a number of pharmacological effects. Tea leaves, apples, and many more possess rutin as one of the active constituents. Today, rutin has been observed for its nutraceutical effect. The present review highlights current information and health-promoting effects of rutin. Along with this, safety pharmacology issues and SAR of the same have also been discussed.

Keywords: Anticancer, Antidiabetic, Antimicrobial, Organ protection, Rutin

1. Introduction

Medicinal plants are an integral part of traditional medicine since ancient era. Drug discovery process has witnessed phytochemicals for discovery of new leads (). Flavonoids, polyphenolic compounds, are one of the important classes of plant derived chemicals that contain benzopyrone moiety. About 4000 types of flavonoids have been reported to be present in plants ().

Rutin (3,3′,4′,5,7-pentahydroxyflavone-3-rhamnoglucoside, Fig. 1) is a flavonol, abundantly found in plants, such as passion flower, buckwheat, tea, and apple. It is a vital nutritional component of food stuff (). Rutin, also called as rutoside, quercetin-3-rutinoside, and sophorin is a citrus flavonoid glycoside found in buckwheat (). The name ‘rutin’ comes from the plant Ruta graveolens, which also contains rutin. Chemically it is a glycoside comprising of flavonolic aglycone quercetin along with disaccharide rutinose. It has demonstrated a number of pharmacological activities, including antioxidant, cytoprotective, vasoprotective, anticarcinogenic, neuroprotective and cardioprotective activities ().

2. Pharmacological actions

2.1. Central nervous system

2.1.1. Prevention of neuroinflammation

Rutin has demonstrated the neuroprotective effect on brain ischemia. Administration of rutin caused attenuation of ‘ischemic neural apoptosis’ due to the embarrassment of p53 expression and lipid peroxidation along with increment in ‘endogenous antioxidant defense enzymes’ (). It has been found to be useful in hypoxic, glutamate and oxidative stress (). Reduction of ‘neuroinflammation’ in rat model of ‘sporadic dementia of Alzheimer type’ () and neuroprotective effects in ‘dexamethasone-treated mice’ () were observed on rutin administration.

2.1.2. Promotion of neural crest cell survival

The neural crest is progenitor comprising of neural and mesenchymal potentials. Treatment of rutin to trunk neural crest cells increased their viability without altering cell differentiation and proliferation which could be due to modulation of ERK2 and PI3K pathways ().

2.1.3. Sedative activity

CNS and behavioral activity of rutin were on hole board, thiopental-induced sleeping time and locomotor activity tests in mice. Rutin, given by intraperitoneal route caused a depressant action on the CNS. Research confirmed the CNS depressant activity of rutin was unlikely due to the involvement of GABAA receptor ().

2.1.4. Anticonvulsant activity

Rutin also possesses anticonvulsant activity and seems to be safe for patients with epilepsy as it does not alter the activity of any of the administered antiepileptic drugs nor demonstrates any adverse effects ().

2.1.5. Anti-Alzheimer activity and treatment of hyperkinetic movement disorder

Rutin suppressed activity of proinflammatory cytokines by diminishing TNF-α and IL-1β production in microglia. Such an effect seems to be useful in the treatment of Alzheimer’s disease as evident by prevention of β-amyloid oligomeric cytotoxicity (). Rutin caused attenuation of streptozotocin-induced inflammation by decreasing the activity of the glial fibrillary acidic protein, interleukin-8, cyclooxygenase-2, inducible nitric oxide synthase and nuclear factor-kB and thereby prevented gross anatomical changes in rat hippocampus. Such an effect could be useful in averting cognitive deficits and proves to be beneficial in the treatment of ‘sporadic dementia of Alzheimer type’ ().

‘Tardive dyskinesia’ is a motor disorder of the orofacial region raised due to chronic treatment with neuroleptic drugs, and is considered as a chief clinical concern in the treatment of schizophrenia. In a study, in haloperidol-induced orofacial dyskinesia, rutin treatment reversed behavioral changes such as orofacial dyskinetic movements, stereotypic rearing, locomotor activity, and percent retention along with restoration of biochemical and neurochemical parameters. Thus, rutin seems to be a lead molecule in the treatment of hyperkinetic movement disorder ().

2.1.6. Antidepressant effects

Forced swimming test and tail suspension test in mice were utilized to analyze ‘antidepressant-like effects’ of rutin isolated from Schinus molle. There was a reduction in the immobility time in the tail suspension test. There was no alteration in locomotor activity. Studies demonstrated the antidepressant-like effect of rutin mediated due to increasing the availability of serotonin and noradrenaline in the synaptic cleft ().

2.1.7. Stroke

Stroke could be regarded as a decisive public health issue that seems to be an important cause of fatality and disability in adults globally (). Oxidative stress and inflammation are two of the pathological events observed after ‘ischemic injury’ in the brain (). Protective effect of rutin an animal model of focal cortical ischemia induced by unilateral thermocoagulation of superficial blood vessels of the motor (M1) and somatosensory (S1) primary cortices was studied. Rutin administration significantly promoted recovery of sensorimotor loss which was observed due to the reduction of neurodegeneration in the periphery of cortical injury ().

2.2. Analgesic and antiarthritic activities

2.2.1. Analgesic and antinociceptive effects

Analgesic effect of rutin was studied by hot plate test on swiss albino mice whereby the analgesic effect of rutin was established (). Further, it was also confirmed that rutin exhibited peripheral and central antinociceptive activities ().

2.2.2. Antiarthritic effects

Animals treated with rutin were observed with significant decrement in rheumatoid arthritis and Fanconi anemia by inhibiting ‘oxygen radical overproduction’ (). In adjuvant arthritis rat model, rutin inhibited acute and chronic phases of inflammation. Rutin was the most active in the chronic stage of inflammation (). Due to antifungal and anti-arthritic effects, rutin has a therapeutic effect on septic arthritis caused by Candida albicans (). Further in an independent study, rutin slowed down inflammatory and catabolic cartilage markers in osteoarthritic lesions in the Hartley guinea pig ().

2.3. Endocrine system

2.3.1. Antidiabetic effects

Streptozotocin is a toxic chemical known to deplete levels of insulin by destroying pancreatic islets. Streptozotocin selectively assaults pancreatic β-cells by generating free radicals of oxygen and nitrogen monoxide along with reducing levels of NAD and NADP. Excessive production of glucose and its decreased utilization by tissues serve as the fundamental bases of hyperglycemia (). In a study, chronic administration of rutin in streptozotocin-induced diabetic rats caused a decrement in plasma glucose, augmentation in insulin levels, and restitution of glycogen content and glycolytic enzymes. Significant rejuvenation of pancreatic islets along with diminished fatty infiltrate was observed in rutin-treated diabetic rats (). Diminution of fasting plasma glucose, glycosylated hemoglobin, C-peptide, and malondialdehyde levels was observed in rutin treated streptozotocin diabetic rats (). Rutin averted the levels of enzymes viz. ALT, AST, and LDH in the serum, liver, and heart demonstrating a protective effect on hepatic () and cardiac toxicity () associated due to streptozotocin. Alteration in the activity of matrix metalloproteinase and protection to kidney against streptozotocin-induced damage was observed (). Rutin stimulated glucose uptake in the soleus muscle, and effect was thought to be mediated through extracellular calcium and calcium-calmodulin-dependent protein kinase II activation. Increase in intracellular calcium concentration is involved in DNA activation which was mediated by rutin (). Rutin added for glycemic control via enhancement of insulin receptor kinase activity, thus aided in promoting ‘insulin signaling pathway’ that caused increased GLUT4 translocation and augmented glucose uptake ().

2.3.2. Anti-hypercholesterolemic effects

Rutin is a ‘selective and non-toxic modulator’ of hypercholesterolemia. In a study conducted on diet-induced hypercholesterolemic Golden Syrian hamster model, rutin significantly reduced plasma triglyceride levels in experimental animals (). Along with this, rutin also caused a decrement in levels of total cholesterol and HDL cholesterol ().

In a high-cholesterol diet fed male wistar rats, rutin administration demonstrated protective effect against the hepatotoxicity as evident by decrement of the plasma level of alanine transaminase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL) (). In another study, it was established that chronic consumption of flavonoids such as rutin could be favorable to cardiovascular health ().

2.3.3. Thyroid uptake promotion

‘Thyroid iodide uptake’ mediated via sodium-iodide symporter plays a pivotal role in thyroid hormone biosynthesis and also plays a key role in diagnosis and treatment of various thyroid diseases. However, some of the patients with thyroid cancer are obstinate to radioiodine therapy, which reduced iodine uptake ability, that remarkably reduces the probability of endurance. Thus, it becomes necessary to search for natural agents that aid in the uptake of thyroid iodide.

In a study, rutin caused a minor reduction in levels of serum T4 and T3 without changing serum thyrotropin. There was a significant increase in hypothalamic, pituitary and brown adipose tissue type 2 deiodinase along with the diminution of liver type 1 deiodinase activities. Administration of rutin was observed with increment in thyroid iodide uptake that could be due to an elevation in the activity of sodium-iodide symporter. The study demonstrates the effectiveness of rutin as an adjuvant in radioiodine therapy ().

2.4. Cardiovascular system

2.4.1. Hypertension

Buckwheat, a rich source of rutin is found to prevent oxidative damage in ‘aortic endothelial cells’ by lowering nitrotyrosine immunoreactivity. Germinated extract of buckwheat demonstrated antihypertensive effect and possibly shelter ‘arterial endothelial cells’ by detrimental effects of oxidative stress (). Reduction in oxidative stress due to rutin, when administered by oral route, is the key reason for the restoration of ‘impaired baroreflex sensitivity’ and ‘vascular reactivity’ in hypertensive rats (). By augmenting NO production in human endothelial cells, rutin improved endothelial functions ().

2.4.2. Blood coagulation

 attempted to study effects of the rutin on the anticoagulant activity of oral warfarin and the protein binding along with pharmacokinetics of its enantiomers in rats. Rutin enhanced the in vitro serum protein binding of S- and R-warfarin. Rutin treatment significantly decreased the elimination half-life of S-warfarin by 37% as a result of the 69% increase in unbound clearance of the S-enantiomer. In a nutshell, concomitant administration of rutin possibly reduces the anticoagulant effect of racemic warfarin ().

2.4.3. Antiplatelet aggregatory effect

Rutin in vitro caused concentration-dependent inhibition of platelet activating factor induced washed rabbit platelet aggregation, and intra-platelet free calcium concentration elevation was induced by platelet activating factor which was inhibited by rutin in a dose-dependent manner ().

2.5. Gastrointestinal system

2.5.1. Antiulcer effects

A peptic ulcer is infirmity that influences the substantial population in the world. Ulcers are observed when disparity occurs among ‘aggressive’ and ‘protective’ factors at the luminal surface of the gastric epithelium. HCl, pepsins, nonsteroidal anti-inflammatory drugs, Helicobacter pylori, bile acids, ischemia, hypoxia, smoking, alcohol, etc. include dynamic features whereas defensive factors comprise of bicarbonate, a mucus layer, mucosal blood flow, PGs and growth factors ().

Ethanol is ill-reputed agent known to produce damage to gastric mucosa in animal and clinical studies. Ethanol in a concentration higher than 400 ml/l causes significance in gross morphology of stomach which is observed by mucosal hyperemia, necrosis, edema and mucosal or submucosal hemorrhage (). Oxygen-derived free radicals could be regarded as a key reason for the formation of lesions (). Rutin pretreatment before administration of ethanol afforded significant protection against necrosis. Restoration in the levels of glutathione peroxidase along with ‘anti-lipoperoxidant effect’ was observed (). Similarly in an indomethacin-induced model of ulcers, rats pretreated with rutin caused reestablishment of altered oxidative stress and biochemical parameters possibly due to neutrophil infiltration, suppression of oxidative stress generation and replenishing nitrite/nitrate levels. Protective effects are also evident by histopathological investigations ().

Another investigation provides insight into the molecular mechanism of action of rutin over gastric proton pumps. Rutin demonstrated concentration-dependent inhibition of goat gastric ATPase, with IC50 = 36 μg/ml, making it that rutin exerts an antiulcer effect by inhibiting the gastric proton pump ().

2.6. Respiratory system

2.6.1. Antiasthmatic activity and other associated effects

The antiasthmatic activity of rutin was studied in ovalbumin-sensitized conscious guinea pigs challenged with aerosolized ovalbumin where airway resistance during the immediate phase response and late-phase response was determined. Rutin significantly inhibited specific airway resistance and immediate-phase response along with reticence of histamine, phospholipase A2, and eosinophil peroxidase. There was reduced conscription of neutrophils and eosinophils into the lung (). Use of rutin was also suggested in whooping cough along with vitamins C and K (). In cats and whippets, rutin has been effectively used in the management of idiopathic chylothorax ().

2.7. Bones

2.7.1. Antiosteoporotic and antiosteopenic effect

Osteoporosis is a skeletal disorder observed by a decrement in bone strength, that is associated with augmented risk of fracture (). This condition is affecting elderly citizens globally and seems to be budding health predicament. Osteoporosis is observed in the case when bone resorption by osteoclasts surpasses bone formation by osteoblasts (). All therapeutic strategies for treatment of osteoporosis emphasize inhibition of ‘osteoclast-mediated bone resorption’. Parathyroid hormones are only classes of agents that ‘stimulate bone formation’ (). In osteogenic-related assays, rutin caused proliferation and differentiation of human osteoblast-like MG-63 cells. There was also increase in the activity of alkaline phosphatase, expression of collagen type I and degree of mineralization (). Similar effects have been observed with rat calvarial osteoblast cells (). Rutin inhibits osteoclast formation by decreasing oxygen reactive species and TNF-alpha by inhibiting activation of NF-kappaB (). Rutin inhibits ovariectomy-induced osteopenia in rats by slowing down resorption and increasing osteoblastic activity (). Thus, rutin can also be regarded as ‘osteoblast stimulant’.

2.8. Eye

2.8.1. Anticataract and ophthalmic effect

Formation of advanced glycation end products (AGE) is associated with cataract, a diabetic complication. Thus, inhibition of such glycation could be a useful strategy to prevent such complication. In this study, rutin caused embarrassment of glycation of proteins, chelation of metal complexes and partly inhibiting post-Amadori formation (). In another study in wistar rat pups, selenium was used to induce cataract and protective effect of rutin in retarding cataractogenesis was investigated. Eye lens of rats treated with rutin were observed with restoration of lenticular antioxidant enzymes along with decrement in malondialdehyde formation. Experimental outcomes suggest that rutin prevented cataractogenesis possibly due to antioxidant mechanism ().

Oral administration of rutin has been observed with an improved reduction in intraocular pressure (). Involvement of vitamins B1, B2, forskolin, and rutin demonstrates ‘defending effect’ on the ocular surface which aids to re-establish a ‘normal equilibrium’ of the tear film altered due to toxins ().

2.9. Excretory system

2.9.1. Diuretic effect

Quercetin, a metabolite of rutin, which is abundantly found in Hibiscus sabdariffaLinn acted on vascular endothelium causing nitric oxide release, leading to increasing renal vasorelaxation by increasing kidney filtration ().

2.10. Reproductive system

2.10.1. Effect on sperm quality and male reproductive organs

Rutin, in a study, afforded protective effect on damage to human sperm induced by lipid peroxidation (). Rutin also demonstrated possible protection to testicular tissue and reproduction from oxidative stress observed in type 1 diabetes mellitus () along with amelioration of cyclophosphamide-induced reproductive toxicity () and testicular ischemia–reperfusion-induced oxidative stress in rats ().

2.11. Anticancer effects

Cancer includes a group of diseases that are characterized by the abnormal growth of cells that latently assault or spread to other parts of the body (). Flavonoids are known to demonstrate an extensive assortment of biological effects, comprising of ‘antioxidant and radical-scavenging activities’. Reactive oxygen species have been associated with the pathogenesis of several diseases such as atherosclerosis and certain cancers.

Rutin has been extensively studied for anticancer/antineoplastic effects. In a study, human leukemia HL-60 cells were implanted in a murine model, and rutin (dose 120 mg/kg) caused a significant reduction in tumor size justifying antileukemic potential (). In an independent study, rutin when administered to SW480 tumor cell lines (human colon cancer cell lines), was observed with less detrimental effects on the body and relative organ weight in mice along with an increment of mean survival time of 50 days (). Chem et al., demonstrated anti-neuroblastoma effect of rutin, where, rutin significantly inhibited the growth of LAN-5 cells and chemotactic ability. The study demonstrated that rutin could decrease BCL2 expression and BCL2/BAX ratio along with a reduction in levels of MYCN mRNA level and the secretion of TNF-α (). Rutin is also known to inhibit cancer cell growth by cell cycle arrest and/or apoptosis, along with inhibition of proliferation, angiogenesis, and/or metastasis in colorectal cell lines (). Rutin analog, quercetin, is studied against the proliferation of the ovarian cancer cell line OVCA 433, where dose-related inhibition was observed (). In another study, quercetin augmented apoptosis and barred metastasis in a model of pancreatic cancer (). Rutin also seems to be useful as an adjuvant in radioiodine therapy ().

2.12. Chemotherapeutic activity

2.12.1. Antibacterial activity

Rutin is extensively studied for antimicrobial activity against various strains of bacteria. It has demonstrated a profound degree of inhibition on growth of bacteria Escherichia coli (). Rutin, quantified in honey has shown inhibitory effects over Proteus vulgarisShigella sonnei and Klebsiella sp. (). Antimicrobial activity against Pseudomonas auruginosssa and Bacillus subtilis has also been documented (). In situ antimicrobial activity of rutin and other polyphenols in the food system has been studied, and the results demonstrate a promising involvement of flavonoids in the preservation of food ().

Bernard et al., demonstrated that rutin by inhibiting DNA isomerase IV demonstrated antibacterial activity against Ecoli (). In a study, rutin synergistically enhanced antibacterial activity of other flavonoids against Bacillus cereus and Salmonella enteritidis. Minimum inhibitory concentration value for kaempferol was remarkably decreased by the addition of rutin ().

2.12.2. Antifungal activities

Rutin demonstrated antifungal activity against the strain of Candida gattiiwith a minimum inhibitory concentration of 60 μg/ml (). It was suggested that chemical modification in rutin by the introduction of substitute group may alter physicochemical properties such as electron density, hydrophobicity and steric strain that may prove to be fruitful regarding increment of antifungal activity. Use of rutin in treatment of septic arthritis caused by C. albicans has also been suggested ().

2.12.3. Antimycobacterial activity

In a study, flavonoids rich extract containing rutin demonstrated antimycobacterial activity against Mycobacterium smegmatis ().

2.12.4. Larvicidal activity

In a study, rutin significantly inhibited growth and propagation of larvae of S. aegypti where maximum mortality of larvae was observed at 72 h ().

2.12.5. Antimalarial activity

Antimalarial effect of rutin in association with chloroquine was observed on white leghorn chickens infected with Plasmodium (Bennettinia) juxtanucleare (). In another study, biochemical mechanism of the antimalarial activity of Azadirachta indica leaf extract revealed the presence of an abundant amount of quercetin, an active metabolite of rutin (). Recently, the antiplasmodial activity of quercetin is documented against Plasmodium falciparum().

2.12.6. Antiretroviral activity

In a study, sodium rutin sulfate, a sulfated rutin analog, was investigated for anti-HIV activity against HIV-1 X 4 viruses IIIB, HIV-1 R5 isolates Ada-M and Ba-L strains. The mechanism by which sodium rutin sulfate demonstrated antiretroviral effect was a blockade of viral entry and virus-cell fusion which was mediated via interaction with HIV-1 envelope glycoprotein ().

2.12.7. Antiviral activity

Antiviral agents for the treatment of infections caused by retroviruses, orthomyxoviruses, herpes viruses, hepatitis B virus and hepatitis C virus are widely available (). Owing to the high incidence of viral infections along with no precise treatment for ‘appearance of new resistant viral strains’, its seems to be necessary to develop novel antiviral drugs.

Rutin has been tested against vesicular stomatitis virus on mouse fibroblasts and protected cells for about 24 h (). In the case of canine distemper virus infection, rutin affords immense viral embarrassment when added at the times of adsorption and penetration in the viral replicative cycle (). Rutin a chief constituent of Capparis sinaica Veill demonstrated profound antiviral effect against avian influenza strain H5N1 using plaque inhibition assay in the Madin-Darby canine kidney ().

2.13. Hair

Apoptosis of hair follicular cells is a leading cause of hair follicle degeneration. In a study, apoptosis of human follicular dermal papilla cells was observed after treatment with staurosporine; this event was completely introverted by exposure to rutin, spermidine, and zeaxanthin. There was the preservation of expression of anti-apoptotic molecules such as Bcl-2, MAP-kinases and their phosphorylated forms, which concludes the use of rutin in the prevention of apoptosis of hair follicular cells, one of the leading causes of baldness ().

2.14. Skin

2.14.1. Sunscreen effects

The desire for having healthy, beautiful and disease free skin is being observed from the eternal era. History of cosmetics and skin care product dates back in ancient Greek, Roman and Egyptian civilization. Advances in sciences and technology along with the development of modern chemistry have made this dream easy (). Exposure to ultraviolet B radiations produces ‘oxidative and inflammatory skin damage’ and augments jeopardy of skin ‘carcinogenesis. Rutin has been studied to explore the effects of rutin on UVB-induced inflammation in mouse skin in vivo. Topical application of rutin on mice skin 30 min before UVB irradiation reduced epidermal hyperplasia and the levels of proteins. There was also significant inhibition of UVB-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) which could be due to inhibition of p38 MAP kinase and JNK that caused diminution UVB-induced expression of COX-2 in mouse skin (). In a study conducted by , rutin when incorporated in oil-in-water emulsions (concentration 10% w/w), sun protection factor (SPF) values comparable to ‘homosalate’ were observed. Along with TiO2, SPF values approached to 30.

2.14.2. In atopic dermatitis

In an atopic dermatitis model in BALB/c mice by repeated local exposure of house dust mite (Dermatophagoides farinae) extract (DFE) and 2,4-dinitrochlorobenzene (DNCB) to the ears, rutin treatment caused suppression of interleukin (IL)-4, IL-5, IL-13, IL-31, IL-32 and interferon (INF)-γ in the tissue. In 2,4-dinitroflourobenzene-sensitized a local lymph node assay for allergic contact dermatitis, rutin caused suppression of allergic contact dermatitis based on ear thickness and lymphocyte proliferation, serum IgG2a levels, and expression of INF-γ, IL-4, IL-5, IL-10, IL-17 and tumor necrosis factor-α in allergic contact dermatitis ears. This study signifies anti-atopic dermatitis and allergic contact dermatitis activity of rutin (). Rutin has also demonstrated anti aging effects on the skin (). Thus, rutin could be regarded as most effective topically applied compound given its antioxidant activity and skin penetration profile ().

2.15. Immune effects

Vibrio alginolyticus challenge was studied based on immune and physiological response to rutin in white shrimp. In this study, physiological, innate non-specific immune responses, respiratory bursts and superoxide dismutase activity against the pathogen were analyzed. Rutin from Toona sinensis was administered to shrimp. In brief, shrimps treated with rutin maintained lower glucose, lactate, and lipid levels in response against the pathogen. Survival rates of shrimps treated with rutin were more (). Another study demonstrates promotion of the activity of macrophage phagocytosis in cells ().

2.16. Body strength

2.16.1. Anti fatigue activity

Fatigue is an indication which is associated with person’s health. Fatigue is related to deterioration in ‘physical performance’. Extreme exercise is associated with accretion of surplus reactive free radicals that leads to an oxidative stress injury to the body. Depletion of energy along with the accumulation of excess metabolite is the key reasons for fatigue (). Rutin administration in mice prevented depletion of superoxide dismutase and reduced glutathione. After seven days of treatment with rutin, mice were sacrificed and analyzed for soleus muscle and brain for peroxisome proliferator-activated receptor-α coactivator and sirtuin one mRNA expression. Up-regulation of the CB1 cannabinoid receptor-interacting protein 1, myelin basic protein, Rho GDP dissociation inhibitor (GDI) alpha, and TPI indicated that rutin treatment inhibited condition anxiety via up-regulation of the expression of anxiety-associated proteins () and hence in nutshell it can be regarded as treatment with rutin improves the various mutilations allied with physical fatigue.

2.17. Organ protective effects

2.17.1. Neuroprotective activity

In mice model, rutin inhibited oxaliplatin-induced chronic painful peripheral neuropathy. Oxaliplatin is one of the most important platinum compounds used in colorectal cancer chemotherapy. However, it suffers from a drawback of peripheral which seems to be difficult to treat. Rutin significantly decreased oxaliplatin-induced peroxidative changes in the spinal cord and lipid peroxidation along with inducible nitric oxide ().

2.17.2. Retinoprotective activity

Effect of rutin on ocular blood flow by ‘colored microsphere technique’ was determined. Electroretinography was used to determine the b-wave recovery which is a tool for estimation of retinal function recovery. Rutin increased ocular blood flow and demonstrated a remarkable effect on retinal function recovery ().

2.17.3. Protective effect on lung tissue

Acute lung injury is severe disease observed with ‘high mortality and morbidity.’ Till date, there is no therapeutic stratagem established. Rutin demonstrated protective effects on histopathological changes in lung tissue along with prevention of ‘infiltration of polymorphonuclear granulocytes in bronchoalveolar lavage fluid’. There was also a reduction in secretion of lipid peroxidation and proinflammatory cytokines. The activity of antioxidant enzymes such as catalase, glutathione peroxidase, superoxide dismutase, and heme oxygenase-1 caused by lipopolysaccharide was reversed by rutin (). Pretreatment of rutin caused inhibition of lipopolysaccharide-induced arterial blood gas exchange and neutrophils infiltration in the lungs. There was suppression of macrophage inflammatory protein-2 and matrix metalloproteinase-9 (). Another study demonstrated that rutin effectively inhibited vascular cell adhesion molecule-1 and inducible nitric oxide synthase (). There is also evidence that rutin prevented early adult respiratory distress syndrome possibly due to inhibition of lipid peroxidation ().

2.17.4. Cardioprotective effects

Ischemic heart disease is one of the primary reasons for ‘morbidity and mortality’ all along the globe. The pathophysiology underlying damage at a cellular level raised due to ischemia is multifaceted. ‘Reactive oxygen species’ are identified to participate and play a key task in the pathogenesis of several diseases (). It is well known that ischemic tissues produce ‘oxygen-derived free radicals’ that are known to cause oxidative damage to membrane lipids, proteins, and carbohydrates that predispose to ‘qualitative and quantitative alterations’ of the myocardium (). Rutin was studied for cardioprotective effect by ischemia–reperfusion-induced myocardial infarction in normal and streptozotocin diabetic rats. Rutin administration significantly offered cardioprotection and restricted infracts size in normal and diabetic rats (). The mechanism lying behind this protection could be attenuation of lipid peroxidation in myocardial tissues ().

Isoproterenol is β-adrenergic agonist used to treat bradycardia and heart block (). However, frequent administration of it may lead to cardiac toxicity observed by an increase in the activity of serum cardiac marker enzymes viz lactate dehydrogenase, aspartate transaminase, creatine kinase, and alanine transaminase along with significant decrease in the activity of these enzymes in the heart. Rutin restored the levels of cardiac marker enzymes along with a reduction in lipid peroxidation. The study suggests the cardioprotective effect is due to the virtue of the antioxidant effect of rutin ().

Repression of isoproterenol-induced increase in angiotensin II and aldosterone in plasma was observed after administered by rutin. Along with this, overexpression of transforming growth factor β1, connective tissue growth factor, and excessive deposition of extracellular matrix in isoproterenol-treated myocardial tissues was observed in the group of animals treated with rutin ().

2.17.5. Prevention of splenocyte apoptosis

Rutin is known to alter the viability and function of mitogen-stimulated splenocytes and thymocytes compared with non-stimulated cells. In a study, when splenocytes were cultured with mitogens, it was observed that there was a decrease in interferon-gamma production along with decrement in splenocyte apoptosis ().

2.17.6. Hepatoprotective activity

Cirrhosis is the destruction of hepatocytes and following substitution with ‘scar tissue’ which alter the flow of blood through liver leading to the death of hepatocytes and n function of the liver (). The event of liver damage is followed by ‘hepatic fibrosis’ whereby regeneration of apoptotic cells is observed after ‘repeated injury’ (). In the event, when the death of regenerating cells occurs, deposition of extracellular matrix is observed, which leads to deposition of ‘fibrillar collagen’ (). Such pathology is difficult to treat. The effectiveness of treatment with colchicines, interferons, penicillamine and corticosteroids are contradictory and seem to be questionable. As oxidative stress is one of the causes beneath cirrhosis, use of antioxidants could be a unique strategy for treatment. Rutin is extensively studied for hepatoprotective activity in experimental animals.  evaluated the protective effect of rutin in carbon tetrachloride (CCl₄)-induced liver injuries in rats. Administration of rutin caused a decrement in levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase in serum raised due to carbon tetrachloride. The level of cholesterol in blood was regulated whereas the level of endogenous liver antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glutathione was increased, whereas lipid peroxidation was decreased in a dose-dependent manner. Along with this, the activity of p53 and CYP2E1 was restored by treatment with rutin. In an independent study in BALB/c mice, rutin treatment allayed oxaliplatin-induced hepatotoxicity and neurotoxicity. Prevention of mechanical allodynia along with histopathological observations suggested the protective role of rutin in the prevention of hepatotoxicity ().

2.17.7. Nephroprotective activity

Nephropathy is one of the most encountered pathogenesis observed in the populace all over the world regardless of age, caste, creed, race and environment. The reasons behind this condition result from anomalies rose due to different metabolic and physiological disturbances. Nephropathy is among the ten primary causes of death all along the globe (). Gentamicin (), ecstasy (), cisplatin (), and carbon tetrachloride () are some of the compounds known to demonstrate nephrotoxicity.

In a study, rutin demonstrated protective activity against oxonate-induced hyperuricemia and renal dysfunction in mice. Administration of rutin resulted in a the decrement in levels of serum urate, creatinine and blood urea nitrogen, serum and kidney uromodulin levels, and increased urine uromodulin, urate and creatinine excretion in hyperuricemic mice. There was a significant downregulation of mRNA and protein levels of mouse glucose transporter 9 and urate transporter 1, along with upregulation of mRNA and protein levels of organic anion transporter 1 and organic cation/carnitine transporters in the kidney of hyperuricemic mice. In a fructose-fed rat model for hyperuricemia, rutin blocked the NOD-like receptor three inflammasome activation and aided in the improvement in the signaling and reduced lipid accumulation in the kidney of rats () along with reversal of dysregulation of renal transporters (). Inhibition of inducible nitric oxide synthase activity and reduction in 3-nitrotyrosine formation () along with inhibition of reactive oxygen species () in the kidneys seem to be an important approach to prevent renal ischemia/reperfusion injury.

In cisplatin-treated wistar rats, rutin pretreatment caused restoration of kidney function and oxidative stress biomarkers (). It partially inhibited effect on NFκB and TNF-α pathway mediated inflammation, caspase-3 mediated-tubular cell apoptosis, along with re-establishment of histopathological changes due to cisplatin administration (). Rutin also demonstrated protective effects against potassium bromate-induced nephrotoxicity in rats. The decrement in DNA fragmentation, upregulation in the activity of antioxidant enzymes viz. catalase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, and reduced glutathione along with a reduction in lipid peroxidation were observed ().

2.17.8. Protective effect on blood vasculature

Rutin was found to resist damages in vascular beds due to a disturbance in myocardium supply leading to initial damage, however in a chronic model of ‘stenocardia in dogs,’ therapeutic effect of rutin is up to a limited extent ().

2.18. Protective effects on wounds

2.18.1. Wound healing activity

Rutin, formulated as hydrogel, when applied to skin lesions of rats, caused a decrease in wound area as compared to control hydrogels. There was a reduction in oxidative stress in wound area as signified by a reduction in lipid peroxidation and protein carbonyl content along with increased catalase activity (). Rutin-releasing chitosan hydrogels as injectable dressings for dermal wound healing have been formulated. These hydrogels promoted defined formation of neo-epithelium and thicker granulation, which is closer to the original epithelial tissue ().

2.19. Radio modulatory effects

Radiation therapy is one of the principal strategies in anticancer therapy for treatment of various cancers; however, due to ill effects on normal tissues, its use is restricted. Ionizing radiations predispose to the generation of free radicals that damages DNA; cell death follows this event. Thus along with cancerous cells, the damage is observed with normal cells also. Some ‘radioprotectors’ have been screened; still, their clinical effectiveness is restricted due to toxicity with the frequent administration. In a study, rutin has been investigated for potential radioprotective effects. Rutin was administered to Swiss albino mice to assess its impact on ‘radiation-induced sickness along with the survival analyses’. Rutin at the dose of 10 mg/kg optimally demonstrated radioprotective effects. There was an increment in radiation tolerance and levels of antioxidant enzymes were restored along with a decrease in lipid peroxidation in liver (). Similar protection by rutin against gamma radiations was also observed ().

2.21. Drug interaction

Absorption of paclitaxel is increased when concurrently administered with rutin (). Rutin treatment cause increased the body’s resistance to drugs due to induction of the drug metabolizing enzymes in the liver; such an action has about the same magnitude with that of phenobarbital and pregnenolone-16 alpha-carbonitrile ().

2.22. Safety pharmacology

Rutin has been studied for carcinogenicity and results have demonstrated practically and significantly no carcinogenic potential in non-inbred golden hamsters ().

2.23. Structure–activity relationship

  • • 4-Oxo group and the 2,3 double bond in the C ring in rutin may be related by its neuroprotective action ().
  • • The presence of sugar moiety (O-rha-glu) has no significant effect on the ileum, which indicates that presence of sugar substitution diminishes the biological activity of the flavonoids ().
  • • Hydroxyl group in 5-position as well as the double bond and the double-bonded oxygen in the oxane ring is all necessary for the overall ability of flavonoids to inhibit phospholipase A2 activity, and that the hydroxyl groups in 3’- and 4’-position are required for selective inhibition of phospholipase A2-II ().
  • • Polyhydroxylated substitutions on rings A and B, a 2,3-double bond, a free 3-hydroxyl substitution and a 4-keto moiety, confer antiperoxidative properties to rutin ().
  • • Catechol group in the B-ring, a double bond between C2 and C3 at the C-ring, and ketone group in C4 at the C-ring are necessary for inhibitory effect on angiotensin-converting enzyme activity ().
  • • Rutin, whose C-3 position is glycosylated has a less free radical neutralizing activity that is aglycone quercetin ().
  • • The glycosylation decreases the AChE inhibitory activities of flavonoids and lowers the affinities for AChE by 1–5 times depending on the conjunction site and the type of sugar moiety ().
  • • The presence of a phenolic group in rutin is known to add hydrogen donation for scavenging the radiation-induced radicals, and to inhibit radiation-induced oxidative stress ().
  • • The presence of a glycosylation group in rutin greatly reduces vascular relaxation effect in porcine coronary artery ().

3. Conclusion

As evident from aforesaid facts, rutin is phytochemical with multiple pharmacological activities. An ancient saying ‘an apple a day, keeps doctor away’ seems to be true as rutin, one of the important constituents of apples, has a wide array of biological activities. Hence, rutin can be regarded as a ‘vital phytochemical’ which is needed to be studied extensively to establish effective safety profile in human to get therapeutic benefits.


Peer review under responsibility of King Saud University.


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Outline of the Organon

~Content Source

This outline was prepared by Julian Winston for the students of the Wellington College of Homeopathy. It was printed in the USA in Homeopathy Today.

It was taken from the 5th edition, translated by Dudgeon (1893), with additions (where needed) by Boericke (1922) from the 6th edition, and cross referenced with the Kunzli translation of the 6th.

When substantial changes were made between the 5th edition of 1833 and the 6th edition of 1842, the 5th will be in italic type and the 6th will be in plain type.

An asterisk ( *) indicates a footnote well worth reading.

Paragraph 1-9: Basic postulates about disease and what Healing is about.

1. The physician’s only mission is to cure the sick; it is not to speculate on the nature of disease.*
2. The ideal cure is rapid, gentle, permanent and removes the whole disease in the shortest, least harmful way, according to easily comprehensible principles.
3. If the physician understands what is curable in disease, and understands what is curative in medicines, and understands how to apply the medicines (according to well defined principles) to the disease, and knows how to remove conditions which prevent the patient from getting well, he is a true physician.
4. The need to recognize and remove the maintaining causes
5. Pay attention to the exciting cause AND the fundamental cause (which is usually a chronic disease) including the patient’s character, activities, way of life, habits, etc.
6. There is no need for metaphysical speculation. Diseases are the totality of the perceptible symptoms *
7. To cure, you only need to treat the totality [NOT symptomatic palliation; a single symptom is not the disease] *
8. If the symptoms are removed, the disease is eradicated
9. The physician want to make people healthy so they can use their body to get on with the higher purposes of their existence.

10-18: The concept of vital force and its relation to disease

10. Without the vital spirit (force), the organism is dead
11. In diseases, it is the vital force that is deranged. *
12. The vital force produces the disease THEREFORE if the vital force is cured, the disease is cured. [how it does so is of no concern to the physician]
13. Diseases are not peculiar or distinct entities. It is absurd to think so. Only materialistic minds think so. It is this thinking that has pushed conventional medicine along, making it mischievous (an art of darkness), incapable of healing.
14. Everything morbid is curable
15. The diseased vital force and the symptoms of the disease are the same
16. Since diseases are, therefore, spirit-like, you need spirit-like medicines to be effective against them.
17. The physician only needs to eliminate the totality of symptoms, which will remove the inner alteration
18. The TOTALITY is the only guide to the remedy

19-21: The need for provings (determine the nature of medicine)

19. Medicines cannot cure unless they can cause derangement
20. The power of medicines can be discovered only by their effects– not by reason.
21. Symptoms of provings are the only way of learning their power. Pure experiment will reveal nothing. Remedies cure only because of their ability to alter human health by causing characteristic symptoms.

22-27: The principle of similars

22. The curative powers of medicines exist only because they can produce symptoms in the healthy and remove them from the sick. Medicines can be similar or opposite to the disease. Which to use is revealed by experience. [description of allopathic medicine]
23. But experience shows that anti-pathic drugs don’t cure; the symptoms return with renewed intensity
24. Therefore homeopathy is the system of choice.
25. This can be learned by pure experiment [not the kind of experiment which is conducted by the regular physician, which is like looking into a kaleidoscope] *
26. A weaker dynamic affliction is extinguished by a stronger IF it is similar in nature.
27. Curative powers depend upon the symptoms they produce being similar to the symptoms of the disease, but stronger.

28- 29: HOW IT WORKS (attempt) rewritten in the 6th.

28. Scientific explanations of how it works are of little importance, there is no value in attempting one. Nevertheless…
29. The artificial disease of the remedy overpowers the weaker natural disease. When the force of the artificial disease is spent, the body returns to normal health. This is a most probable explanation.

30-69: Lays out the philosophy of the system

30. The human body is more disposed to let it’s state of health be altered by drugs than by nature.
31. Disease agents do not affect everyone. We fall ill only when susceptible. [SUSCEPTIBILITY]
32. Medicinal agents can affect all people.
33. The body is, therefore, more susceptible to medicinal forces.
34. The artificial disease does not only have to be stronger, but it has to be most similar. [the vital principle is instinctive, unreasoning, and without memory]. Nature cannot cure an old disease by adding a new dissimilar one.
35. Consider when two dissimilar diseases meet in the same person [examples are given in paragraphs 36-40]
36. Old diseases keep away new dissimilar diseases.
37. Chronic diseases are not affected by non-homeopathic treatment.
38. New, stronger diseases can suppress old disease but will never remove it
39. Allopathic treatment suppresses the disease, then the chronic disease returns when the medication is withdrawn.
40. New diseases can join older diseases and become complex. Neither removes the other
41. Heavy drugging with allopathic medicines leads to an artificial drug disease and makes it into a chronic problem
42. Two dissimilar diseases can exist in the body at the same time
43. But when two similar diseases meet we can observe how cure takes place.
44. Two similar diseases cannot suspend, ward off, or exist at the same time.
45. Two similar diseases will destroy each other in the organism.
46. Examples of the above.
47. It should be convincingly clear that this is how to cure according to natural law.
48. Dissimilar diseases don’t cure.
49. Nature is poor in remedial homeopathic diseases, so we do not notice them often.
50. And those that can cure, bring other problems, often because the dose cannot be controlled.
51. But the physician has many medicines available

52-56 have been totally re-written in the 6th edition

52. By looking at nature, the physician will learn to treat only by homeopathy.
52. there are two methods: allopathic and homeopathic. Each opposes the other. To practice both at the whim of the patient, is criminal

53. Mild cures can happen ONLY through homeopathy. It should be the first mode of employing medicines
53. True, gentle cures, can only be homeopathic

54. The homeopathic way is the only one.
54. allopathic practice is based on conjecture

55. the 2nd mode is allopathic
55. the only reason people stuck by allopathy is that it afforded palliative relief

56. the 3rd mode is anti-pathic or palliative
56. Patients were deceived by quick improvement, but this method is fundamentally harmful.

57. Examples of treating a single symptom with a contrary remedy
58. Why anti-pathic is bad. Directed against a single symptom: a short amelioration followed by a long aggravation
59. Examples of injurious effect of anti-pathic medicine
60. Increasing doses of a palliative medicine never cures
61. Physicians (if they had been capable of reflecting upon the sad results) should see the result of applying contrary medicines and understand that the homeopathic way is better and the only way to cure
62. The reason palliation is dangerous is explained in paragraphs 63-69.
63. The primary action of the medicine and the secondary reaction of the vital force or counter reaction).
64 Explanation of primary and secondary reactions.
65. Examples of primary and secondary effects as stated in paragraph 64.
66 In a healthy body, one does not notice the secondary reaction to homeopathic doses, but the primary action of some of these remedies is perceptible to a good observer.
67. These TRUTHS explain why homeopathy is good. [long footnote condemning those of the “mongrel sect” who claim to be homoeopaths but use palliation to avoid looking for the correct remedy] *
68. In homeopathy, experience shows that a small dose of medicine will extinguish the natural disease.
69. Exactly the opposite happens in anti-pathic treatment. The disease becomes worse when the palliation wears off.

70: Summary of all that has been said so far

71. All diseases are groups of symptoms that can be cured by similar remedies. There are three points for curing: investigate the disease, investigate the remedies, learn how to employ them. (see Para. 3)

72-81: Acute and Chronic diseases

72. Diseases–definition of acute and chronic
73. Discussion of acute disease
74. The worst Chronic diseases are produced by unskilled physicians using allopathic medicines
75. These diseases are the most incurable.
76. Homeopathy can cure natural diseases. The debilitations of allopathic care can only be removed over time by the vital force itself (with treatment of any miasm that is in the background).
77. Some diseases are called “chronic” but are not– addictions and indispositions. Remove the cause and remove the disease
78. Real chronic diseases arise from the chronic miasms
79. Syphilis and sycosis
80-81. psora (read Chronic Diseases, published in 1828)

82-104: CASETAKING (how to elicit the information)

82. In trying to cure these diseases, the case is to be conducted carefully
83. Requisites for understanding the picture of the disease: Freedom from prejudice and sound sense. The individualizing examination of a case of disease (general directions)
84. Patient talks. Physician keeps quiet. Do not interrupt. Write it all down.
85. Start a new line for every symptom
86. When patient finishes, ask for particulars
87. Don’t ask “yes” or “no” questions
88. Ask about other parts of he body not mentioned
89. The physician should then ask more special detailed questions
90. The physician notes what he observes in the patient
91. In chronic cases, understand what the symptoms are before the medicines were taken. Ask to discontinue to see the real disease.
92. In diseases of rapid course (acute) forget the other medicines. Do what you can to sort it out
93. See what the friends say about the patient
94. In cases of Chronic Disease, ask about habits, diet, and domestic situation to be able to remove the maintaining causes
95. In cases of Chronic Disease, the most minute peculiarities are attended to
96. Some patients might exaggerate their symptoms
97. Others have false modesty and allege that their symptoms are of no consequence
98. Attach credence to the patient’s own expressions
99. Acute diseases are of short duration and easy to treat. There is less to inquire into and are often spontaneously detailed

100-102: epidemic diseases

100. Investigating epidemic diseases.
101. It takes time to see the totality of the epidemic disease
102. You see the characteristics of the disease through several patients

103- 104 : chronic diseases

103. Chronic disease must be carefully investigated. You must see the totality of the patient.
104. Once the totality is sketched, the most difficult part is done. The physician has a picture of the disease. To see the effect of the medicine, just ask how the patient is, and cross out the symptoms that have been cured

105- 120: The effects of the remedies

105. The second point is to know the remedies
106. The pathological effects of several medicines must be known, so we can select among them
107. You can’t learn much about the effects of medicines by giving them to sick people, because the symptoms of the medicine will be mixed up with the symptoms of the natural disease
108. You must do provings to find out the medicinal effects
109. I was the first to suggest this method
110. All those who have seen the effect of poisons could have never understood that the morbid lesions were simply the clues to the curative powers of the drugs. It can’t be learned by a priori speculation, nor by the senses.
111. I have observed pure effects of the medicines– without any reference to therapeutic object– and they produce certain, reliable disease symptoms, each according to its own peculiar character.
112. Dangerous effects are seen at the termination of symptoms when given in large doses. This recalls the primary actions (Para. 63) and secondary action (Para. 62-7). The human organism reacts as much as is needed to raise the health to a normal healthy state.
113. The only exception is narcotic medicines, where the secondary action produces greater irritation and sensitivity.
114. With the exception of the narcotics, we observe the primary action when given in moderate doses to healthy people
115. Certain symptoms which are opposite are not secondary but, rather, alternating actions
116. Some symptoms are produced frequently, and others rarely or in few persons
117. The rarely produced symptoms are idiosyncrasies– the substances produce seemingly no impression in others. But when used homeopathically they can heal ALL individuals
118. Every medicine has a unique action
119. Each substance cannot be confused with another
120. Therefore, all medicines must be carefully distinguished from each other, so the physician can choose the correct remedy.

121-142: Conducting provings

121. Strong substances produce effects in small doses, weak substances produce effects in larger doses, and the mildest must be tested on very sensitive people
122. The medicines used in provings must be pure and well known
123. They must be taken in a pure form
124. They should not be mixed with other substances
125. The diet of the provers should be strictly regulated and simple. No stimulating drinks. [footnote giving specific restrictions]
126. The prover must be trustworthy and devote himself to observation. He must be in good health and intelligent enough to be able to describe sensations accurately
127. The provings should be done by both sexes
128. Provers should take 4-6 globules of the 30th daily for several days
129. If effects are slight, then take a few more globules. Start with a small dose and increase daily
130. If the first dose produces symptoms, then the experimenter can learn the order of succession of the symptoms– which is useful to learn the primary and alternating actions. The duration of action can be found only after a comparison of several experiments
131. If you have to give the medicine for several days, you can’t learn about the order of symptoms. One dose might act curatively of symptoms caused by the previous dose. Record these symptoms in brackets until further experiments show if they are secondary action or alternating action.
132. But if you are just interested in symptoms and not in the order, give it every day.
133. You must learn the exact character of the symptoms–the modalities are most important
134. Not all symptoms will be seen in one person
135. The whole picture of the remedy can be understood through a study of all the provings. The substance is thoroughly proved when no new symptoms are seen
136. Although only certain people are susceptible to remedies when healthy, ALL people are susceptible to the simillimum when sick
137. With mild doses in sensitive people, the primary effects can be observed. But excessively large doses will lead to a mixture of primary and secondary effects in “hurried confusion.”
138. All symptoms during a proving are symptoms of the medicine even though the prover may have experienced them before
139. The prover must note all details and the physician should question the exact circumstances
140. If the person can’t write, he should talk to the physician every day
141. The best provings are done by the physician upon himself. Experience shows that continued provings lead to robust health.
142. In practice, judgement is always needed to separate the symptoms of the remedy from the symptoms of the malady

143- 145: The formation of the materia medica

143. If we collect all the symptoms produced, we have a true materia medica
144. Nothing conjectural, imaginary, or mere assertion should be included in the book
145. If the symptoms are accurately stated, we now have a curative substance for every disease

146-171: The application of the medicine to the disease

146. The third point concerns the use of the medicines. The physician must be judicious in his use of these agents
147. The most similar must be used

[the following two paragraphs were re-written in the 6th edition; although the explanation changes, the content is the same]
148. An explanation of how homeopathy probably works.
149. Acute diseases can respond quickly, but chronic diseases take longer to treat.

150. trivial symptoms of short duration are indispositions and can be cured by diet and regimen
151. More violent sufferings will provide, upon investigation, a complete picture of the disease
152. The numerous striking symptoms will lead to a homeopathic remedy
153. The striking, singular, uncommon, and peculiar signs and symptoms are the most important. The general symptoms are observed in every disease and from almost every drug
154. If the striking symptoms of the medicine match those of the disease, and the disease is not one of long standing, it will be removed by the first dose, without “considerable disturbance.”
155. The other symptoms of the disease (“which are very numerous”) are not part of the case and are not “called into play.”
156. If the patients are very sensitive they MIGHT produce a “trifling” new symptom. (it is impossible that the disease and the remedy cover each other like identical triangles) but this symptom is not perceptible in patients not “excessively delicate.”
157. But in certain cases [6th ed. when the dose is not sufficiently small .], there might be an aggravation for the first hour or so. This is nothing but the medicinal disease exceeding the strength of the original disease.
158. This “aggravation” is a sign that the remedy was correctly chosen.
159. The smaller the dose [6th ed. in the treatment of acute diseases ] the less the aggravation
160. The dose can’t ever be made small enough to not relieve, so any dose, if not the smallest possible, will produce an aggravation
161. During chronic treatment, there may also be an aggravation, but not as immediate [6th ed. in chronic diseases where the smallest dose is dynamized between doses (LM) aggravations appear at the end when the cure is almost quite finished ]
162. Since we don’t know ALL medicines, we often have to give the one which is closest.
163. If we do, we can’t expect a complete cure. We might see new symptoms which are not part of the disease, but of the medicine.
164. A small number of symptoms is no obstacle to cure IF the symptoms are peculiarly distinctive (characteristic)
165. If you prescribe on non-characteristic symptoms, and can find no remedy more appropriate, the physician cannot “promise himself any immediately favorable result.”
166. These cases are rare, since we know more and more remedies. When they do happen, the selection of a subsequent, more accurate remedy is needed
167. So in acute diseases, if the wrong remedy is given, and you see new symptoms in the case, give the correct (new) remedy now seen.
168. Give the best remedy, re-study the case, give the best remedy. [zig-zag] (because we don’t know all the remedies)
169. If two remedies are close, give the closest one. Do not give the other without re-examining the case– because the case may change and there might be a more appropriate selection. [6th ed. never give two remedies together ]
170. When re-examining a case, if the next best remedy is clearly indicated, give it.
171. In non-venereal diseases (psora) we often need several remedies to cure– each chosen [after the completion of the action of the previous remedy] and selected on the symptoms remaining.

172-184: one sided cases

172. A similar difficulty occurs when there are too few symptoms. These cases deserve our careful attention
173. There are certain chronic diseases that have few symptoms. These are “one sided” cases.
174. The complaint may be internal or external (local maladies)
175. In the first kind it might just be the lack of discernment on the part of the practitioner
176. Still, there might be just one or two symptoms after a well taken case
177. In these VERY RARE cases, we should give the remedy that is homeopathically indicated
178. Sometimes, this will cure the case– especially if the symptoms are characteristic
179. More frequently, the medicine will cover the case only partially
180. This leads to a new array of symptoms, some of the disease itself, which have never before been noticed
181. These new symptoms, while they might owe their origin to the remedy, are the symptoms of the disease– and we should direct further treatments accordingly.
182. The imperfect selection of the remedy, in these cases, opens the case to the discovery of the more accurate remedy.
183. When the first dose ceases action, the second remedy can be selected.
184. Keep taking the case after each new remedy until recovery is complete.

185-203: local diseases

185. Local maladies appear on external parts of the body. That they stand alone is absurd.
186. Problems which are “local” and have been produced from without have great effect on the whole living organism. When mechanical aid is needed, then surgery is required (setting bones, bringing skin together, extracting foreign objects, etc.) but the whole living organism requires dynamic aid to accomplish the work of healing.
187. But “local” manifestations that are not produced by external injury have their source within the body. To see them and treat them as external is as absurd as it is pernicious.
188. It is absurd to think that living organisms know nothing of these external problems.
189. All external maladies (except injuries) come about as a result of an internal diseased state.
190. All treatments, therefore, must be directed against the whole.
191. This is confirmed through experience.
192. All changes, not just the local affliction, must be taken into account when determining the remedy.
193. When the dose is taken, the general morbid state of the body is cured, and with it, the local affliction– which was an inseparable part of the whole disease.
194. In local diseases it is of no use to apply remedies locally for the topical affliction, even if it is the same remedy that is used internally. If the vital force was not competent to restore full health, then the acute disease was a manifestation of latent psora which has now burst forth.
195. To cure such cases (which are not rare), give the anti-psoric remedy after the acute stage has subsided. This is all that is required in non-venereal cases.
196. It might seem that cure would be hastened by the application of the remedy locally as well as internally.
197. This should not be done. In diseases where there is a local affliction, the application of the remedy to the surface may annihilate the local symptoms before the internal disease, and this may seem to be a cure but isn’t.
198. The use of topical applications alone is inadmissible. If you only remove the local symptoms, it is often hard to see the more obscure inner symptoms (which may be slightly characteristic and difficult to see)
199. If the external symptoms have been removed (by surgery, etc.) the remaining internal symptoms might be too vague to discover the remedy because the external symptoms can no longer be seen.
200. If it hadn’t been removed, the remedy of the whole disease would have been found and would have resulted in a perfect cure.
201. The vital force, when expressing a chronic disease keeps the disease on the surface, and therefore not threaten life itself. But since the external manifestation is a part of the general disease, as the disease gets worse the external manifestation gets worse– so it can still be a substitute.
202. If the external disease is now destroyed, nature will make up the loss by increasing the internal disease. This is incorrectly referred to as being “driven back into the system.”
203. Removing the external without treating the internal is a criminal procedure.

204-209: Introduction to the treatment of chronic disease

204. If we exclude all chronic diseases that are caused by unhealthy living (Para. 77) and all medicinal diseases (Para. 74), most of the remainder of chronic diseases, WITHOUT EXCEPTION, are caused by the three miasms, sycosis, syphilis, and a greater proportion, psora.
205. The homoeopath will never treat the primary symptoms, but only cures the underlying miasm. Refer to Chronic Diseases.
206. When taking the chronic case, make a careful investigation if the patient ever had venereal disease. Two miasms might be present, but, frequently, psora is the sole fundamental cause of all chronic disease.
207. Find out what kind of allopathic treatment had been had, to understand how the disease has changed
208. The patients age, mode of living and diet, occupation, domestic position, social relation, etc. must be taken into consideration, as well as the state of the mind and the disposition.
209. Trace the picture of the disease, and get the patient to tell the most striking and peculiar symptoms.

210-230: mental diseases

210. All one-sided diseases are psoric. Mental diseases are not a separate class, since in all diseases the mind is altered
211. The disposition of the patient often determines the selection of the remedy– because they are often characteristic symptoms which “can least of all remain concealed from the accurately observing physician.”
212. The Creator of healing forces also thinks highly of this as all medicines (which he created) affect the mind
213. We can’t cure diseases if we do not observe the disposition and the state of mind.
214. Mental diseases are to be cured the same was as all other diseases
215. All mental diseases are physical ones, where the physical symptoms are so slight as to make the disease seem to be one-sided
216. Many physical ailments of an acute character, transform into insanity whereupon the physical symptoms cease.
217. In such cases we must look to the whole phenomenon– the physical and mental
218. The symptoms include previous physical symptoms– which may be learned from friends or relations
219. Those symptoms will be found to be still present, though obscured
220. The complete picture of the disease can then be prescribed upon– usually an anti-psoric remedy
221. When insanity comes on acutely after a fright, etc., it should not be treated with anti-psorics (although it arises from an inner psoric state bursting forth), but with the other class of proved remedies (Aconite, Belladonna, Stramonium, etc.) until the patient returns to his latent state.
222. But such patients are not cured. They should be “freed completely” by anti-psoric treatment.
223. If this is not done, the patient will have recurring attacks, each brought on by a slighter cause.
224. If it is not certain that the mental disease arose from physical illness rather than from “faults in education, bad practices, corrupt morals, superstition or ignorance”, see if it can be improved by “friendly exhortations, consolatory arguments, serious representations, and sensible advice.” Real disease will be speedily aggravated by such a course.
225. There are some emotional illnesses that will, if left alone, destroy the physical health.
226. These may be treated, in an early stage, by “displays of confidence, friendly exhortations, sensible advice, and often by well-disguised deception.”
227. But the underlying cause is a psoric miasm (which is not fully developed) and must be treated.
228. With mental diseases that come from physical maladies, we must also treat the patient well and “not reproach him for his acts” or use punishment or torture. The only reason coercion is justified is the giving of the remedy– but it could be given in a drink without the patient’s knowledge.
229. The physician and the keeper must always pretend to believe them to be possessed of reason
230. If anti-psorics are used than the case can be cured [confidently assert]

231-244: intermittent diseases

231. Intermittent diseases are those that recur at certain periods and states which alternate at intervals
232. Alternating diseases are numerous and belong to the class of chronic disease. They are, generally, a manifestation of chronic psora. Read Chronic Diseases.
233. In the typical intermittent disease, the same state returns at fixed periods
234. The non-febrile intermittent diseases are, mostly, purely psoric and seldom complicated with syphilis, but sometimes they need a small dose of Cinchona to completely extinguish them.
235. In intermittent fevers, when the symptoms alternate, the remedy should produce similar alterations.
236. The best time to give the medicine is soon after the paroxysm
237. But if the state of no fever is short, give the remedy when perspiration begins to abate
238. The remedy can be repeated if the symptoms return and have the same picture. If the fever is brought on by marshy districts, then permanent restoration can only be had by getting away from the causative factors.
239. All fevers may be cured with homeopathic remedies
240. If cure is not possible, it must always be because of the psoric miasm, which must be treated
241. Epidemics of intermittent fevers are of the nature of chronic diseases. Each epidemic is of a uniform character which will reveal the common totality– which will lead to the (specific) remedy for all cases.
242. If the person is very weakened, then an anti-psoric remedy would be needed, generally a minute and rarely repeated dose of Sulphur or Hepar sulphuricum in a high potency
243. If a single person is attacked, find the totality and give the remedy. If cure is not complete, give an anti-psoric.
244. Persons who can’t be cured by a few doses of cinchona, have psora at the root of the malady, which needs to be treated.

245-263: how to use the remedies

245. We will now talk about how to use remedies and the diet and regimen during their use

Paragraphs. 246-248 are totally re-written in the 6th edition

246. The best selected remedies should be repeated at suitable intervals
246. Don’t repeat as long as there is amelioration (in acute disease). In chronic disease this may also be the case at times. But this is rare. If the medicine is well selected, highly potentized, dissolved in water, and given properly (that the degree of each dose is changed), a cure will result. [footnote describing the new method]

247. Smallest doses may be repeated
247. The remedy must be changed in potency each time it is given

248. The dose may be repeated until action is exhausted
248. How to do it. The instructions for changing the potency each time. Aggravation comes at the end. Even a one dram vial of alcohol with one globule that is used for olfaction must be succussed 8-10 times before each dose.

249. If new and troublesome symptoms are produced by the remedy, it is not homeopathic and should be neutralized and/or the next remedy be given immediately to take the place f the improperly selected one.
250. When you see the wrong remedy is given, find and give the right one!
251. Some medicines have alternating actions. If you give one (Ignatia, Bryonia, Rhus tox) and no improvement follows, give it again
252. If nothing happens after the most suitable remedy is given, there is an obstacle to cure in their mode of life
253. In acute diseases the first positive changes are usually mental– a freedom of mind, higher spirits. The opposite is seen in an aggravation.
254. The observing physician will note these changes while the patient might not
255. If you go through the case point by point and notice no changes in symptoms, but the patient’s disposition is better, the medicine might just need more time to act, there might be an obstacle to cure, or the dose was not small enough
256. If the patient has new symptoms– signs that the medicine was not correct– but says he feels good, we must not believe it.
257. Do not make any remedies “your favorites” because you will neglect many others, perhaps better, remedies.
258. If you avoid some remedies because you have bad results with them (through your own fault), remember that ALL remedies are useable when the similarity to the totality is matched and “no paltry prejudices should interfere with this serious choice.”
259. Because the doses are so small, anything which has medicinal action must be removed from the diet and regimen.
260. In chronic diseases this is even more important (followed by a list of things to avoid)
261. The best thing in chronic diseases is to remove the obstacles to recovery, and encourage recreation, exercise, and good food
262. In acute diseases, the patient should be allowed to eat what he wants
263. The desires are to be granted within moderate bounds, the room and temperature should be controlled as the patient wishes

264-271: the medicines

264. The physician should have pure medicines to use
265. The physician should see that the patient takes the right medicine (6th ed. prepared by the physician himself)
266. Animal and vegetable remedies are most perfect in their raw state
267. Instructions for making extracts
268. With materials that are not supplied fresh, you must be convinced that they are genuine
269. Description of potentization [conceptual]
270. Description of making centesimal potencies (6th ed: LM potencies)
271. Description of trituration (6th ed: the physician should do it himself)

272-279: administering the remedies

272. In no case is it needed to give more than one remedy at a time (6th ed: one globule is OK, but dissolved in water and stirred well will touch many more nerves)
273. How can one not understand that one remedy at a time is the only way (6th ed: It is absolutely not allowed in homeopathy to give the patient at one time two different remedies)
274. Single remedies are proven and have totalities. If you give two you can’t evaluate the results
275. You must control the size of the dose as well
276. Even if the remedy is homeopathic it can do harm in too large a dose and more harm the higher the potency. “Too large doses too frequently repeated bring trouble.”
277. If the dose is sufficiently small it will have salutary and gentle remedial effect.
278. How small must it be? Theories and speculation are not the answer. Careful observation and accurate experience alone determines this.
279. Experience shows that a selected and highly potentized dose of the homeopathic remedy can never be too small to overpower a natural disease

280-to end: more on dosages and allied practices (mesmerism, baths, etc.)


280. Materialistic people don’t understand this. 
280: The dose should be gradually ascending as long as there is general improvement, followed by a mild return of old complaints. This indicates an approaching cure.

281: Everyone, especially in a diseased state, is capable of being influenced by the simillimum. Mere theoretical scepticism is ridiculous.
281. To be convinced, just give the patient placebo and watch him get better at this point

282. The dose can produce aggravation in the parts already affected. The artificial diseases substitutes for the natural disease.
282: if the dose is too large, the first dose produces an aggravation, especially in chronic diseases

283. The true healing artist prescribes his well selected remedy only in a minute dose. If it is the wrong medicine, the smallness of the dose will prevent injury
283: The true healing artist prescribes his well selected remedy only in a minute dose to avoid the homeopathic aggravation. If it is the wrong medicine, the smallness of the dose will prevent injury

284: The action of the dose does not diminish with quantity. Eight drops are not four times as strong as two drops
284: The nose and respiratory organs are receptive to the action of the medicines. The whole skin is also adapted to the action of medicinal solutions, especially when used with an internal remedy

285: The diminution of the dose is essential, as is the diminishing of the volume, i.e., a single globule
285: In very old diseases, the remedy may be rubbed on the back, arms, and extremities, while being given internally

286: The greater the quantity of fluid the dose is dissolved in, the better, since it comes into contact with more surface area
286: The dynamic forces of mineral magnets, electricity, and galvanism act upon the life principle. We don’t know enough about them to use them homeopathically. The positive, pure actions upon the body have not been tested.

287: By diluting it further the effect is changed. Each person must judge for himself how to diminish the dose to make them suitable for sensitive patients
287: The powers of the magnet for healing purposes is outlined in the Materia Medica Pura.

288. The actions of the medicines in liquid form are certainly spirit-like in power. (footnote describing the effectiveness of olfaction)
288: Mesmerism and animal magnetism are also priceless gifts

289: Every part of the body that possess the sense of touch is capable of receiving the medicines.
289: Discussion of positive and negative mesmerism

290: The interior of the nose, rectum, and genitals are also sensitive to the medicinal agents
290: Advantages of massage in the cases of a chronic invalid

291: Even organs which have lost their sense (i.e., sense of smell) will be susceptible to the remedy
291: Discussion of hydrotherapy.

292: Even the external parts of the body would be susceptible, especially if the remedy is in liquid form

293: A reference to Mesmer and the powers of “animal magnetism” and the curative effects of hypnosis

294: Continued discussion of “positive” and “negative” mesmerism, in light of the vital force

What is Cutaneous T-Cell Lymphoma

~Content Source


Cutaneous T-cell lymphoma (CTCL), also known as mycosis fungoides, is a rare type of lymphocytic cancer in which certain cells of the lymphatic system, called T-lymphocytes or T-cells, become cancerous (malignant) and affect the skin.


The lymphatic system is part of the immune system. It is made up of tiny tubes that branch, like blood vessels, into all parts of the body, including the skin.

These vessels, called lymph vessels, carry lymph (a milky body fluid that contains lymphocytes, proteins and fats) into and out of the lymph nodes (lymph glands) which are located in the underarm, pelvis, neck and abdomen.

The lymph nodes’ main function is to act as a barrier to the spread of infection and destroy or filter out bacteria before it can pass into the bloodstream. Within the lymph nodes are lymphocytes (white blood cells) whose purpose is to ambush and destroy the foreign bacteria.

There are two types of lymphocytes: B-lymphocytes (B-cells) and T-lymphocytes (T-cells). B-cells work chiefly by secreting antibodies into the body’s fluids. T-cells destroy the abnormal cells.

There are two types of T-cells: helper T-cells and killer T-cells. Helper T-cells enhance the activities of the killer T-cells, as well as regulate the antibody production of the B-cells. Killer T-cells attack and destroy infected or cancerous cells.

CTCL is the result of an uncontrolled growth of helper T-cells.

Clinically, patients with CTCL fall into three prognostic groups: good risk, intermediate risk and poor risk.

Good risk (median survival over 12 years): Only patch or plaque skin lesions and no lymph node, blood or internal organ involvement.

Intermediate risk (median survival about five years): Skin tumors, plaques or abnormal redness over a large portion of the body, with affected lymph node and blood involvement, but no internal organ has succumbed to the disease.

Poor risk (median survival about two to four years): Internal organs and lymph nodes affected.


Genetic predisposition is the main cause, but other causative agents such as long-term exposure to industrial or environmental metals, organic solvents, chemical carcinogens, pesticides and herbicides are also under consideration from the research community.


Patients with CTCL can take many years to progress through the three cancerous phases of CTCL. These three phases are listed below:

Premycotic and patch phase: can last between a few years and several decades. The first symptoms are usually a generalized itching (pruritus) and patches of raised, reddened skin that can appear anywhere on the body. This reddened skin often closely resembles benign inflammatory skin problems such as eczema (itching skin disease), psoriasis (a chronic skin condition characterized by red, scaly skin patches), drug reactions, fungal infections or parapsoriases (a group of slowly developing, persistent, red, scaly elevated skin lesions), or poikiloderma (a condition characterized by pigmentary and atrophic changes in the skin, giving it a mottled appearance).

Infiltrative plaque phase: during this phase the patches of skin present in the premycotic and patch phase become elevated, thicker, denser, darker red, and develop into horseshoe or bizarre patterns. Itching persists, as well as hair loss, in the areas of and surrounding the patches. These patches of skin are now called plaques, because they have gone from surface lesions to raised lesions.

Tumor phase: during this phase, the patches and plaques present in the prior two phases become massive (mushroom in appearance) and spread. These tumors tend to ulcerate and appear on the skin as an open sore. As more and more of the skin becomes ulcerated, the skin may become infected. Additionally, the disease can spread to lymph nodes, causing them to become enlarged, or to other organs in the body, such as the spleen, lungs or liver. When large number of tumor cells are found in the blood, the condition is called Sezary Syndrome.


It is hard to diagnosis CTCL early in its development because the skin lesions closely mimic skin conditions, such as eczema and psoriasis. Therefore, physicians may have to wait years until the condition is more discernible.

However, if parapsoriasis appears as faint pink to yellowish tan patches with scaling and wrinkling, or poikiloderma appears as large, flat pinkish brown patches with spider-like tendencies, the doctor may suspect the onset of CTCL.

Conditions such as follicular mucinosis, lymphomatoid papulosis, Schamberg’s disease or Woringer-Kolopp disease can also be precursors to CTCL.

If CTCL is suspected, the doctor will do a skin biopsy (a diagnostic test in which tissue or cells are removed from the body for examination under a microscope), a whole body mapping of skin lesions, a complete medical history and a physical examination, as well as complete blood count (CBC) testing, serum chemistries (including liver and renal function tests, calcium, phosphorus and uric acid) and a chest x-ray.


If the CTCL is in the premycotic and patch-phase, bland emollients, gentle skin care, topical antipruritic agents and gradual exposures to sunlight will help.

In the infiltrative plaque phase, topical mustard applications (mechlorethamine HCl) is applied daily or if PUVA photochemotherapy is suggested. PUVA therapy involves taking a drug called psoralen and then being exposed to ultraviolet A light. The drug makes the cancer cells sensitive to light and in turn, the light kills the cancer cells.

In another type of phototherapy, called extracorporeal photochemotherapy, a drug called 8-methoxypsoralen is taken, then some of the blood cells are taken from the patient’s body, put under a special UVA light and put back into the patient’s body.

In the tumor stage, a cyclic treatment method is done. In the first treatment method, a total skin electron beam (TSEB) radiation therapy is done. TSEB radiation therapy uses special high-energy rays of tiny electron particles to kill the cancer cells. The effects of this therapy will kill the existing tumors and allow the healing of the ulcerations. This therapy usually lasts only a few months. During this remission period, a second treatment method of topical chemotherapy (skin drugs) is introduced.

The condition will reoccur as either the premycotic and patch phase or infiltrative plaque phase. As stated above, the third treatment method will be bland emollients, gentle skin care, topical antipruritic agents, and gradual exposures to sunlight if the patch phase is present, or topical mustard applications and PUVA photochemotherapy if the plaque phase is present. As the condition progresses, the treatment starts all over again.

Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

~Content Source-National Institutes for Health

Hypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

Vit D3 and Colorectal Cancer

~Content Source-WeeksMD

Dr. Weeks’ Comment: Inexcusably, when patients are referred or self-refer to me from nationally renown cancer  cancer centers like Mass General, Johns Hopkins, MD Anderson etc  over the past 20 years,  the oncologists there NEVER did a 25-OH D3 test.  How many peer-reviewed scientific articles at PubMed teach about the causal relationship between low vitamin D3 and Cancer?  Only 10,369!

Vitamin D Deficiency Elevates Colorectal Cancer Risk

David A. Johnson, MD

November 15, 2018

Hello. I’m Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. Welcome back to another GI Common Concerns.

How many of you talk to your patients about vitamin D as a supplement? My message for you today is that I think we should. I certainly have changed my practice to reflect that.

We traditionally recognize vitamin D as the key vitamin for regulation of bone metabolism and homeostasis, but I want you to think out of the box here. This is incredibly important because vitamin D has a profound effect on the immune system and the intestinal barrier function. We know that vitamin D receptors regulate an active metabolite of vitamin D highly expressed in both the small and large bowel. It’s critical to regulatory actions in the gut, as it relates to proliferation and differentiation, intestinal barrier function, innate immunity, and host response. We know that vitamin D expression declines in particular as it relates to late-stage colon cancer, and it’s absent in colorectal cancer metastasis.[1,2]

Vitamin D affects the microbiome. There’s a mechanistic role in T-cell trafficking and a significant effect as it relates to the immune function. Regarding the potential for promotion of synthesis and the bad things that upregulate cancers and inflammation, we know that vitamin D actually inhibits the response of tumor necrosis factor-alpha. There’s an anti-inflammatory response with cytokine interleukin-10.[1,2]

In mouse models with vitamin D receptor overexpression, you actually can reduce the animal-related colitis.[3] If you knock out that receptor, they get spontaneous enterocolitis. If you see this knockout in humans, they really don’t respond well to any therapy other than stem cell transplant.

Vitamin D Levels and Colorectal Cancer

I wanted to share with you an article[4] that is going to be published in the Journal of National Cancer Institute in 2019, but I think it’s ready for primetime and needs to be understood now. It relates to the risk reduction for vitamin D and potential for vitamin D replacement.

This new study supports the idea that vitamin D deficiency makes a difference. Researchers pooled data from 17 study cohorts (5706 colorectal cancer patients and 7107 controls) to determine colorectal cancer risk at various ranges of vitamin D. They used the traditional measure for vitamin D deficiency of < 30 nmol/L. The threshold for sufficient bone health is around 50 to < 62.5 nmol/L. Vitamin D levels in this range were associated with a risk reduction for colorectal cancer of 19%, while those in the range of 87.5 to < 100 nmol/L were associated with a 27% risk reduction.

The results essentially show that the more vitamin D you get, the better. However, there seemed to be a plateau effect at 100 nmol/L. It didn’t mean that more was better forever; there wasn’t a linear relationship. Nonetheless, it raises the bar for vitamin D supplementation in our patients.

Putting It Into Practice

I’ve also used supplementation in patients with diverticulitis, which we know to occur more frequently in patients with lower vitamin D. When you get into some of the anti-inflammatory effects of vitamin D on proliferation, differentiation, barrier function, and immune response, it makes sense to start looking at this in inflammatory/infectious disease as well.

In summary, vitamin D is really essential in homeostasis and signaling. It affects the microbiome and has a direct effect on host intestinal inflammation. We do know that this certainly plays out in inflammatory bowel disease.[5]

It remains to be determined whether supplementation makes a big difference as far as clinical outcomes. However, to me, there’s clear evidence that it modulates inflammation, maintains epithelial integrity, and reduces intestinal proliferation. In my practice, it’s ready for primetime. I think it should be in yours as well.

Start to look at supplementation; perhaps measure the patient’s vitamin D levels, and monitor and target it in patients—particularly those at risk. I do think this represents translational, bench-to-bedside research that is ready for primetime now.

I hope this leads you in the next discussion with your patients about ways to use vitamin D beyond bone homeostasis.

Saccharomyces cerevisiae vaccines against Cancer

~Content Source-WeeksMD

Dr. Weeks’ Comment: Therapeutic vaccines using a common yeast (used in brewing and baking) are being developed for the treatment of people with cancer and other infectious diseases. Here is an update.

“…Yeast is thus able to activate and inducing maturation of DCs, leading to the generation of antigen-specific CD4+ and CD8+ T-cell responses capable of killing virally infected or malignant cells…”

Vaccines based on whole recombinant Saccharomyces cerevisiae cells

  1. Andressa Ardiani,
  2. Jack P. Higgins,
  3. James W. Hodge

Article first published online: 5 NOV 2010 Journal compilation © 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. No claim to original US government works

FEMS Yeast Research

Special Issue: Yeasts as a Model for Human Diseases    Volume 10, Issue 8, pages 1060-1069, December 2010



The ultimate goal of therapeutic vaccines is to activate and exploit the patient’s own immune system to vigorously and dynamically seek and eradicate established malignant or virally infected cells. Therapeutic vaccines also offer the potential for preventing disease recurrence. Saccharomyces cerevisiae-based vaccines, where the yeast is engineered to express viral or tumor antigens, represent an ideal therapeutic approach due to their ability to stimulate tumor- or viral-specific CD4+ and CD8+ T-cell responses that are capable of reducing disease burden. This review describes preclinical and clinical studies supporting the development of S. cerevisiae-based therapeutic vaccines for the treatment of cancer and viral diseases, as well as multimodal strategies in which therapeutic vaccines are combined with cytotoxic drugs to achieve a greater clinical response.


Saccharomyces cerevisiae, commonly known as baker’s yeast, is a nonpathogenic yeast strain mainly used in the making of beer and bread. It is the first eukaryotic organism whose genome was sequenced and has since become a preclinical model and valuable tool for unraveling the fundamental cellular processes in higher eukaryotes (Galao et al., 2007). Saccharomyces cerevisiae is an effective vector in therapeutic vaccines. Stubbs et al. (2001) have demonstrated that whole recombinant S. cerevisiae expressing foreign antigens can activate dendritic cells (DCs), elicit robust antigen-specific cytotoxic T lymphocyte (CTL) responses, and confer protective cell-mediated immunity against tumor challenge in mice (Stubbs et al., 2001). Lu et al. (2004) demonstrated that a yeast-based vaccine can generate antigen-specific immune responses independent of the viability of the yeast itself. Additionally, it has been demonstrated that heat-killed and live yeast elicit equivalent protective immunity (Franzusoff et al., 2005). These findings, and further studies performed by our laboratory and others, make heat-killed S. cerevisiae an attractive vaccine vehicle, offering many key benefits such as: (1) the ability to express one or more antigens; (2) cost-effectiveness in large-scale manufacturing; (3) expression of cell-surface ligands (”˜danger signals’) that lead to DC maturation without the need for additional adjuvants; (4) efficient antigen presentation via major histocompatibility complex (MHC) class I and class II pathways, generating antigen-specific T-cell immune responses; (5) lack of yeast-induced host-neutralizing immune responses, allowing multiple vaccinations; and (6) the ability to mount immune responses and protective immunity similar to those of live yeast, eliminating the potential safety risks associated with the use of live cells, especially in immunocompromised patients (Franzusoff et al., 2005; Munson et al., 2008). Here, we review multiple preclinical and clinical studies supporting the use of heat-killed whole recombinant S. cerevisiae (hereafter referred to simply as yeast) as a therapeutic vaccine to treat cancer and infectious diseases.

Therapeutic vaccines

The goal of prophylactic vaccines is to prevent infectious diseases by activating humoral immune responses and subsequently producing neutralizing antibodies capable of blocking pathogens from infecting host cells. In contrast, therapeutic vaccines seek to eliminate abnormal cells (such as virally infected or malignant cells) by generating T-cell-mediated immunity. Elimination of established abnormal cells via a therapeutic vaccine is largely dependent on cell-mediated cytotoxicity executed by CD8+ CTLs. Ideally, however, a therapeutic vaccine must also be able to induce CD4+ T helper responses, because CD4+ T cells can release numerous immunomodulatory cytokines to further drive the generation and proliferation of the robust CD8+ CTL responses essential to the efficacy of a therapeutic vaccine.

Although it is nonpathogenic, yeast has been shown to induce immunologic responses in mammals and is avidly taken up by DCs and macrophages (Fig. 1) (Stubbs et al., 2001; Heintel et al., 2003). The phagocytosis of yeast by DCs is driven by the immunogenicity of yeast cell-wall components, such as β-1,3-d-glucan and mannan, that can transmit ”˜danger signals’ normally associated with microbial infection. These components have strong adjuvant properties and can be detected by pattern recognition receptors such as Toll-like receptors and mannan receptors on DCs (Munson et al., 2008). DCs are the most efficient antigen-presenting cells (APCs). Their unique ability to efficiently process antigens to MHC class I and class II pathways through cross-presentation makes them crucial for initiating both humoral responses and cell-mediated cytotoxicity. Therefore, once inside the host, yeast expressing viral or tumor antigen is easily recognized and subjected to receptor-mediated phagocytosis by DCs for presentation to both MHC class I and class II pathways.

Figure 1. ”‚Proposed mechanism of action of the yeast-CEA vaccine. After injection, yeast-CEA is avidly taken up by DCs and macrophages, driven by the immunogenicity of yeast cell-wall components that transmit ”˜danger signals’ normally associated with microbial infection. The DCs efficiently process antigens to MHC class I and class II pathways through cross-presentation and initiate T cells involved in cell-mediated cytotoxicity. Adapted from GlobImmune, Inc., Louisville, CO.


Yeast expressing tumor or viral antigens can be degraded in proteasomes, presented through MHC class I, and recognized by CD8+ CTLs. This subsequently induces the proliferation, maturation, and activation of antigen-specific CD8+ CTLs. Yeast can also be degraded in endosomes, presented to MHC class II, and recognized by CD4+ T helper cells. Engagement of the T-cell receptor and the peptide-MHC complex is the first signal necessary to activate T-cell immunity. The second signal involves the interaction of DC costimulatory molecules with their ligands expressed on the T cell. Yeast vaccine enhances both signals, as increased expression of both MHC class I and class II molecules and increased expression of costimulatory molecules on DCs have been observed (Bernstein et al., 2008; Remondo et al., 2009). In sum, the use of yeast-based vaccines leads to the recruitment and activation of antigen-specific CD4+ and CD8+ T cells (Stubbset al., 2001; Franzusoff et al., 2005; Munson et al., 2008).

The activation of CD4+ and CD8+ T cells is required to induce the therapeutic immune responses needed to treat malignant or virally infected cells. Specifically, CD4+ T cells release immunostimulatory Th-1 type inflammatory cytokines, such as interleukin-2 (IL-2), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), that further induce the activation and proliferation of CD8+ CTLs. These CD8+CTLs kill abnormal cells via two main mechanisms of action. The first is the release of the cytotoxins perforin and granzymes. Perforin forms holes in the target cell’s plasma membrane, allowing granzymes to enter and kill the target cell. Granzymes activate caspase enzymes and induce the production of reactive oxygen species, both of which lead to cell death. Secondly, CD8+ CTLs kill target cells through the interaction of surface protein Fas ligands on activated CTLs and Fas receptors on target cells, which also induces apoptotic cell death (Stenger et al., 1998). Yeast is thus able to activate and inducing maturation of DCs, leading to the generation of antigen-specific CD4+ and CD8+ T-cell responses capable of killing virally infected or malignant cells.

Yeast-based vaccines for cancer immunotherapy

For a therapeutic yeast-based vaccine to effectively generate the CD8+ CTLs necessary to recognize and kill malignant cells, the yeast must be engineered to express the tumor-specific or tumor-associated antigens selectively expressed or overexpressed on malignant cells. Numerous tumor antigens are currently being investigated in preclinical and clinical studies. However, the yeast-based cancer vaccines reviewed here target two main tumor antigens: yeast-ras targets ras oncogenes and yeast-carcinoembryonic antigen (CEA) targets oncofetal CEA.


Ras, a family of genes that activates the signaling pathway for cell proliferation, acts downstream of receptor tyrosine kinases such as epidermal growth factor receptor (Lu et al., 2004). Ras activation leads to cell proliferation, differentiation, and survival. Mutations in the ras proto-oncogene family, such as K-, H-, or N-ras, are common and are consistently expressed in many types of solid tumors, including pancreatic (90-100%), colorectal (30-50%), ovarian (20-25%), melanoma (50%), and nonsmall-cell lung (20-30%) cancers (Franzusoff et al., 2005).

In 2004, Lu and colleagues generated whole recombinant yeast-ras vaccines expressing mammalian mutant K-ras proteins and tested their ability to generate the immune responses required for tumor killing in carcinogen-induced lung tumors in mice. Mice exposed to urethane, a chemical carcinogen, develop single amino acid mutations in codon 61 in the ras oncoprotein. Following urethane exposure, lung hyperplasias occur within 2 weeks, adenomas occur in approximately 5 weeks, adenocarcinomas by 16 weeks, and death from respiratory failure within 12 months (Forkert et al., 1992; Horio et al., 1996; Lu et al., 2004). Studies have been conducted with yeast vaccines expressing different mammalian ras proteins, representing some of the most frequent mutations responsible for the constitutive activation of ras oncoprotein. The use of these vaccines to immunize mice in a carcinogen-induced lung tumor model led to two important findings (Bos, 1989; Lu et al., 2004): (1) yeast-ras vaccines can generate regression of established ras mutation-bearing lung tumors in a dose-dependent and antigen-specific manner and (2) dosing regimens that include multiple boosts lead to optimum tumor killing (Lu et al., 2004; Franzusoff et al., 2005). The safety of the yeast-ras vaccine was further evaluated in five preclinical toxicity studies in a rabbit model. Rabbits were injected weekly with 0.5-100 yeast units (YU) for up to 13 weeks. Histopathologic analyses revealed no major side effects in the rabbits. Increased levels of circulatory neutrophils were observed, along with minor injection-site reactions that resolved on their own after 2 weeks (Munson et al., 2008).

These preclinical findings led to the initiation of an open-label, dose-escalation, phase I clinical trial of monotherapy with yeast-ras. The trial enrolled 33 patients with advanced ras mutation+ pancreatic, colorectal, and nonsmall-cell lung cancer (NSCLC). All patients underwent ras genotyping to match each patient’s individual mutation with the appropriate yeast-ras vaccine. Most patients had metastatic disease at the time of enrollment and had received an average of three previous therapy regimens before participating in this phase I trial. Subjects received 0.1, 1, 5, 10, 20, or 40 YU of the mutation-matched yeast-ras vaccine (Q61R+Q61L+G12V or Q61R+Q61L+G12C or Q61R+Q61L+G12D), administered subcutaneously for 5 weeks. The overall safety, injection-site reactions, and antigen-specific immune responses were monitored. After 5 weeks of yeast-ras vaccine therapy, no dose-limiting toxicities, therapy-related serious adverse events, or clinically significant laboratory abnormalities were observed at any of the dose levels tested. Approximately 90% of subjects exhibited ras-specific T-cell responses, as demonstrated by lymphocyte proliferation and/or intracellular cytokine staining assays (Franzusoff et al., 2005; Munson et al., 2008).


Oncofetal CEA, the first cell-surface tumor-associated antigen to be described (Gold & Freedman, 1965; Huang & Kaufman, 2002), is a 180-kDa glycoprotein normally expressed in limited areas of the adult human body. However, CEA is overexpressed in nearly 50% of all human tumor types and 80-90% of most colorectal cancers. In cancer patients, significantly elevated cell-surface expression of CEA is associated with more advanced disease and with increased rates of recurrence compared with patients with lower levels of CEA expression. Additionally, upon transformation of epithelial cells, CEA can lose its apical polarity on the cell surface and thus be secreted into the capillaries. It can then be used as a serologic circulating tumor marker in certain cancers (Huang & Kaufman, 2002).

CEA is an attractive target for immunotherapy because it is expressed minimally in normal tissues, but overexpressed in a wide variety of malignant epithelial tissues. Our laboratory has recently developed a recombinant yeast vaccine expressing human CEA antigen (yeast-CEA) (Bernstein et al., 2008).

Yeast vaccine combined with chemotherapy

In recent years, the field of cancer immunotherapy has achieved several significant milestones due to the success of trials of the cancer vaccines sipuleucel-T and PROSTVAC-VF. Sipuleucel-T is an autologous DC-based vaccine. In a recent phase III clinical trial, patients with advanced prostate cancer (n=225) randomized to receive sipuleucel-T demonstrated a 33% reduction in the risk of death and a significant increase in the median survival of 4.3 months compared with patients receiving placebo (23.2 vs. 18.9) (Higano et al., 2009). PROSTVAC-VF is a viral-based vaccine composed of two recombinant viral vectors, each encoding transgenes for prostate-specific antigen, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Recently published data from PROSTVAC-VF phase II trials in metastatic castration-resistant prostate cancer (n=125) demonstrate that this vaccine is well tolerated and is associated with a 44% reduction in the death rate and an 8.5-month improvement in the median overall survival compared with placebo (Kantoff et al., 2010).

Although both the sipuleucel-T and the PROSVAC-VF clinical trials have yielded significant clinical benefits, a mounting body of evidence suggests that cancer vaccines would probably be of the greatest benefit in the adjuvant or the neoadjuvant setting and/or where tumor burden is minimal (Schlom et al., 2007; Gulley et al., 2009). Large tumors have multiple, often redundant pathways to escape immune surveillance and mediate immune suppression, making them poor targets for immunotherapy. There is thus increasing interest in combining cancer vaccines with conventional standard-of-care (SOC) therapies, such as chemotherapy, that directly reduce tumor burden (Emens & Jaffee, 2005; Gulley et al., 2009). Chemotherapeutic agents are known to be immunosuppressive; therefore, the traditional thinking has been that chemotherapy and immunotherapy would not be an effective combination. Yet, while counterintuitive, recent evidence suggests that some chemotherapeutic agents can work synergistically to augment the antitumor effect of some immunotherapeutic agents, and thus generate superior antitumor activity than either modality alone (Zitvogel et al., 2008; Gulley et al., 2009; Higgins et al., 2009). The induction of tumor-cell apoptosis by certain cytotoxic agents not only activates DCs but also provides them with an increased supply of tumor-specific antigens for presentation and cross-presentation to T cells. Additionally, several other immunostimulatory properties of cytotoxic drugs can work with immunotherapeutic agents to generate more robust immune-mediated cytotoxicity against malignant cells (Lake & Robinson, 2005). Furthermore, chemotherapy drugs are metabolized and eliminated, while the tumor-specific immunity induced by a therapeutic cancer vaccine is active, dynamic, and, more importantly, able to persist long after vaccination. Cancer vaccines thus have tremendous potential to confer protection against tumor recurrence. Altogether, the combination of chemotherapy and immunotherapy (particularly cancer vaccines) has many attractive benefits (Lake & Robinson, 2005; Higgins et al., 2009). Ultimately, optimal dosage and scheduling of immunotherapy and chemotherapy are pivotal to the success of this multimodal therapy.

Yeast-ras and gemcitabine

Gemcitabine, a nucleoside analog, has been SOC for patients with advanced, inoperable pancreatic cancer for the last decade. Importantly, gemcitabine has been shown to modulate immune responses by reducing the frequency of myeloid suppressor cells and enhancing DC-dependent cross-presentation of tumor antigens to T cells (Nowak et al., 2003a; Zitvogel et al., 2008). The immunostimulatory benefits of gemcitabine have been demonstrated by enhanced tumor-specific CTLs and overall improvement in objective response rates in patients with pancreatic cancer, NSCLC, and colon cancer who received a combination of vaccines and recombinant IL-2 and granulocyte-macrophage colony-stimulating factor (Nowak et al., 2003b; Levitt et al., 2004; Plate et al., 2005; Zitvogel et al., 2008). Ongoing phase II clinical trials are evaluating the effect of combining yeast-ras and chemotherapy. A phase II double-blind, placebo-controlled, multicenter trial comparing yeast-ras vaccine plus six cycles of gemcitabine adjuvant vs. gemcitabine alone in patients with nonmetastatic, resected, ras-mutation+ pancreatic cancer is ongoing and carrying out recruitment (NCI Clinical Trial 00300950, An important enrollment criterion is that patients’ tumor resection status must either be R0 (resection margin completely free of microscopic disease) or R1 (evidence of microscopic disease at the resection margin, but no macroscopic disease). This small tumor burden provides more time for both chemotherapy and immunotherapy to be efficacious. Prospective ras genotyping is performed to identify and match a patient’s specific ras mutation with a yeast-ras vaccine. After tumor resection and before the initiation of gemcitabine therapy, patients receive three weekly doses of mutation-matched yeast-ras vaccine or placebo. Patients then receive six cycles of gemcitabine, with monthly injections of yeast-ras vaccine or placebo administered between gemcitabine cycles. The primary endpoint of this trial is recurrence-free survival, with overall survival as a key secondary endpoint (Brittonet al., 2009). This trial will determine whether gemcitabine and the yeast-ras vaccine can work synergistically to provide a meaningful clinical benefit to patients with ras+ pancreatic cancers.

Yeast-CEA and cisplatin/vinorelbine

Cisplatin is a platinum-based chemotherapy drug that causes DNA cross-linking, interferes with mitosis, and results in apoptosis. It is used to treat various types of cancers, including NSCLC. Vinorelbine is another antimitotic chemotherapeutic drug used in NSCLC. Combinations of both drugs have been used as adjuvant chemotherapy following surgery in patients with NSCLC and have been shown to increase 5-year survival by 10-15% compared with no chemotherapy treatment (Gameiro et al., 2008). A recent preclinical study in our laboratory demonstrated that appropriate scheduling of yeast-CEA and cisplatin/vinorelbine administration is crucial in this multimodal therapy (Gameiro et al., 2008). The study showed that the yeast-CEA vaccine was most effective when not administered concurrently with cisplatin and vinorelbine, as both drugs can modulate the expression of immune cells. In particular, the study demonstrated a significant reduction in the population of CD4+ and CD8+ T cells, natural killer (NK) cells, and B cells 2 days after the administration of cisplatin/vinorelbine, compared with control-treated groups. However, after about 4 days, cell populations returned to baseline, indicating that this effect is transient and that these cells proliferated around 3 or 4 days after drug administration. The population of T-regulatory cells (Tregs), a subpopulation of T cells that suppresses the activation of the immune system and thereby maintains immune system homeostasis and tolerance to self-antigens, was also significantly reduced 2 days after the administration of cisplatin/vinorelbine. Interestingly, it appeared that the Treg population was more adversely affected by these drugs, because the cells did not return to baseline on day 4. This result demonstrated that appropriate scheduling is important for both the yeast-CEA vaccine and chemotherapeutic drugs. Clearly, the first yeast-CEA vaccination should be administered before chemotherapy is initiated, to prime and activate the immune system. A second booster injection of yeast-CEA should be administered along with cisplatin/vinorelbine to take advantage of the approximately 3- to 4-day window when CD4+ and CD8+ T cells, NK cells, and B cells are proliferating and the Treg population is reduced. Using this scheduling strategy in an NSCLC mouse model demonstrated that the combination of cisplatin/vinorelbine and yeast-CEA vaccination was superior to either modality alone. Given this encouraging result, a phase II trial of yeast-CEA in combination with cisplatin/vinorelbine in patients with NSCLC is being planned. Patients with stages I-III NSCLC will undergo resection, and then receive three cycles of yeast-CEA during the 6-week rest period before adjuvant cisplatin/vinorelbine regimens. Patients will receive a yeast-CEA boost once a month during or between cisplatin/vinorelbine regimens for the duration of this trial. The primary endpoint is time to progression, with a secondary endpoint of overall survival and CEA-specific T-cell responses.

Yeast vaccine for infectious diseases

Yeast has also been used to produce proteins for vaccines to prevent infectious diseases caused by the hepatitis B and human papilloma viruses (McAleer et al., 1984; Schiller et al., 2008)……



While prophylactic vaccines provide protection against infectious diseases, therapeutic vaccines seek to eliminate established infected or malignant cells and prevent future recurrence. Yeast is a promising therapeutic vaccine vehicle due to its ability to generate robust cellular immune responses against malignant or virally infected cells. This review looked at two cancer vaccines that use yeast: yeast-ras and yeast-CEA. The yeast-ras vaccine demonstrated preclinical antitumor activity and induction of ras-specific T-cell responses in a majority of patients in a phase I trial (Franzusoff et al., 2005; Munson et al., 2008). A phase II trial of the combination of yeast-ras and gemcitabine is ongoing (Munson et al., 2008). Similarly, preclinical data on yeast-CEA led to the initiation of a phase I clinical trial evaluating the yeast-CEA vaccine in patients with CEA+ tumors. A phase II trial of yeast-CEA plus cisplatin/vinorelbine in patients with NSCLC is ongoing and recruiting patients (Gameiro et al., 2008). Additionally, vaccination of HCV-infected patients with yeast-HCV led to the induction of HCV-specific T-cell responses (Schiff et al., 2007; McHutchison et al., 2009). Together, these data demonstrate that yeast can direct a therapeutic immune response to potentially improve outcomes for patients with cancer or chronic infections.

Future perspectives

In the future, therapeutic yeast vaccines may be used to target other cancers or infectious diseases, such as melanoma and HIV (Barron et al., 2006; Riemann et al., 2007). As SOC treatments for cancers and infectious diseases change, there is a rationale for the strategic combination of treatments such as small molecule inhibitors, radiotherapy, antiangiogenesis, and hormone therapy with yeast vaccine to optimize clinical outcomes (Reits et al., 2006; Arlen et al., 2007; Chakraborty et al., 2008a, b; Hodge et al., 2008; Ferrara et al., 2009; Higgins et al., 2009; Kamrava et al., 2009). In addition, it has been shown that concurrent administration of yeast- and viral-based vaccines targeting the same antigen induces a more diverse T-cell population that leads to enhanced antitumor efficacy. This provides the rationale for future clinical studies investigating the concurrent administration of different vaccine platforms targeting a single antigen to enhance antigen-specific immune responses (Boehm et al., 2010). Finally, accumulating evidence suggests that using a cancer vaccine in the early stages of disease is much more effective at inducing antitumor immune responses and improving the overall survival compared with the use of vaccine in later-stage disease (Gulley et al., 2009). Given the favorable safety profile of yeast, treatment of cancer patients at earlier stages of disease would appear to be a reasonable approach.

Cutaneous t-cell lymphoma.

NIH-cutaneous t-cell lymphoma-Non-Hodgkin’s lymphoma – Mycosis Fungoids

Mycosis fungoides was first described in 1806 by French dermatologist Jean-Louis-Marc Alibert. The name mycosis fungoides is very misleading—it loosely means “mushroom-like fungal disease”. The disease, however, is not a fungal infection but rather a type of non-Hodgkin’s lymphoma. It was so named because Alibert described the skin tumors of a severe case as having a mushroom-like appearance. ~Content Source


Biofilm: What is it and how to get rid of it.

~Content Source

Most bacteria are present in biofilms, not as single-acting cells

The popular image of bacteria depicts single cells floating around, releasing toxins and damaging the host. However, most bacteria do not exist in this planktonic form in the human body, but rather in sessile communities called biofilms. To form a biofilm, bacteria first adhere to a surface and then generate a polysaccharide matrix that also sequesters calcium, magnesium, iron, or whatever minerals are available.

Within a biofilm, one or more types of bacteria and/or fungi share nutrients and DNA and undergo changes to evade the immune system. Since it requires less oxygen and fewer nutrients and alters the pH at the core, the biofilm is a hostile community for most antibiotics. In addition, the biofilm forms a physical barrier that keeps most immune cells from detecting the pathogenic bacteria (12).

The current model of care misses the mark

The current model of care usually assumes acute infections caused by planktonic bacteria. However, since the vast majority of bacteria are hidden in biofilms, healthcare providers are treating most illnesses ineffectively. According to the NIH, more than 80 percent of human bacterial infections are associated with bacterial biofilm (3). While planktonic bacteria can become antibiotic resistant through gene mutations, a biofilm is often antibiotic resistant for many reasons—physical, chemical, and genetic. Treating illnesses associated with biofilms using antibiotics is an uphill battle. For example, in patients suffering from IBD, antibiotics appear initially to work, only to be followed by a “rebound,” where the symptoms again flare up, presumably due to bacteria evading the antibiotic within a biofilm (4).

According to the NIH, more than 80% of human bacterial infections are associated with biofilms.

Biofilms are hidden in the nasal passageways and GI tract

Biofilms are well-known problems associated with endoscopic procedures, vascular grafts, medical implants, dental prosthetics, and severe dermal wounds. Biofilms found along the epithelial lining of the nasal passageways and GI tract are less understood.

The GI tract is an ideal environment for bacteria, fungi, and associated biofilms because of its huge surface area and constant influx of nutrients (4). For protection, the GI epithelium is lined with viscoelastic mucus, but it can be damaged in patients with excessive inflammation, IBD, and other conditions. This creates an opportunity for bacteria to attach to the surface and begin their biofilm construction. The epithelium to which it is attached is altered and often damaged (56).

Biofilms are difficult to diagnose

A number of problems make biofilms difficult to detect.

  • First, bacteria within the biofilm are tucked away in the matrix. Therefore, swabs and cultures often show up negative. Stool samples usually do not contain the biofilm bacteria, either.
  • Second, biofilm samples within the GI tract are difficult to obtain. The procedure would require an invasive endoscope and foreknowledge of where the biofilm is located. What’s more, no current procedure to remove biofilm from the lining of the GI tract exists.
  • Third, biofilm bacteria are not easily cultured. Therefore, even if you are able to obtain a sample, it may again test negative because of the microbes’ adapted lower nutrient requirements, rendering normal culture techniques null (7).
  • Fourth, biofilms might also play a role in the healthy gut,making it difficult to distinguish between pathogenic and healthy communities (47).

Although a culture might come back negative, the microbes in a biofilm could still be pumping out toxins that cause illness. Some clinicians look for mycotoxins in the urine to identify biofilms (8), but I am not impressed by the research behind it yet. Because the bacteria sequester minerals from the host, mineral deficiency is probably associated with the presence of biofilms, although mineral deficiencies are all too common in the general population to use this alone as a diagnostic criterion.

Biofilms in the background of many diseases

The medical community is increasingly dealing with antibacterial-resistant infections, with evidence of a biofilm at work behind the scenes:

  • Up to one-third of patients with strep throat, often caused by pyogenes, do not respond to antibiotics (9). In one study, all 99 strep throat-causing bacterial isolates formed biofilms (9).
  • Ten to 20 percent of people infected with Lyme disease, caused by burgdorferi, have prolonged symptoms, possibly due to antibiotic resistance and/or biofilm presence (1011).
  • Lupus flare-ups are induced by infection, inflammation, or trauma. In this autoimmune disease, cell death by NETosis instead of apoptosis turns the immune system against itself (12). Biofilms are suspected to be involved (13).
  • For chronic rhinosinusitis (CRS), “topical antibacterial or antifungal agents have shown no benefit over placebo in random controlled trials” (14). Bacterial and fungal biofilms are consistently found in these patients’ nasal passageways (1415).
  • Antibiotic treatment of irritable bowel disease (IBD) can work for a time, but flare-ups generally continue throughout a person’s life. Biofilms have been linked to both Crohn’s disease and ulcerative colitis (161718).

Biofilms have also been implicated in chronic ear infections, chronic fatigue syndrome, multiple sclerosis, and acid reflux (41920).

Peta Cohen, a pioneer in treating autism with a biomedical and nutritional approach, has found evidence of biofilms in autistic patients. When she disrupts the biofilm in these patients, she sees a huge “offload” of heavy metals in the urine and stool. Autistic individuals often have elevated mercury and lead levels (21). Bacteria aren’t choosy about which minerals they sequester during biofilm construction, and so Dr. Cohen’s explanation is that these patients also suffer from GI biofilms loaded with mercury and other heavy metals. Her experiences are as of yet only anecdotal; a PubMed search for “autism and biofilm” yields zero results. Check out my podcast here for what I believe are underlying causes of autism.

How to treat biofilms

Antibiotic after antibiotic for IBD. Corticosteroids for CRS. If a biofilm is at work, these standard “treatments” aren’t curing anything. Clinicians instead need to break down the biofilm, attack the pathogenic bacteria within, and mop up the leftover matrix, DNA, and minerals.

Biofilm disruptors are the first course of action. Enzymes such as nattokinase and lumbrokinase have been used extensively as coatings on implants to fight biofilms (2223). Cohen’s protocol recommends half a 50mg capsule of nattokinase and half of a 20mg capsule of lumbrokinase for small children with chronic strep throat and autism. Other promising enzymes include proteases, plasmin, and streptokinase (24).

Mucolytic enzyme N-acetylcysteine (NAC) is a precursor of glutathione and an antioxidant. Effective against biofilms on prosthetic devices, in vitro biofilms, and chronic respiratory infections (25262728), NAC is recognized as a “powerful molecule” against biofilms (29).

Lauricidin (other forms: monolaurin, lauric acid, and glycerol monolaurate) is a natural surfactant found in coconut oil that helps inhibit the development of biofilms (30). In my practice, I also use it as an option for a gentler antimicrobial agent.

Colloidal silver is effective at treating topical biofilms, such as in wound dressings (31,  32). Applications in vivo are still under research. Although used successfully to treat a sheep model of bacterial sinusitis (33), colloidal silver did not show the same effectiveness in a small human trial (3435).

I recommend Klaire Labs InterFase Plus and Kirkman Biofilm Defense, two commercial products formulated to effectively disrupt biofilm.

Antimicrobial treatments follow biofilm disruptors. When necessary, I do use pharmaceutical antibiotics, but mixtures of herbal antimicrobials can be effective:

  • berberine
  • artemisinin
  • citrus seed extract
  • black walnut hulls
  • Artemisia herb
  • echinacea
  • goldenseal
  • gentian
  • fumitory
  • galbanum oil
  • oregano oil

Once the biofilm is destabilized and microbes are treated, binders help clean up the mess. EDTA disrupts biofilms and also chelates minerals in the matrix (3637). Chitosan and citrus pectin are two other options.

I can’t stress enough how important probiotics and prebiotics are in healing the gut and maintaining a healthy GI tract. Probiotics reduce pathogenic bacteria and have even been shown to disrupt the growth, adhesion, and activity of biofilms (3839). I recommend Primal Probiotics and Prebiogen or potato starch for prebiotics.

Hopefully the medical community will soon recognize biofilms as factors in many diseases and properly treat recalcitrant infections and illnesses.