This is interesting - a week to get from SJW induction of 3A4 to return to steady state pre-induction levels of a 3A4 substrate. It suggests that week-on / week-off pulsing is a good bet for “tricking” the hepatic mixed oxidase system into maintaining steady levels of a 3A4 substrate in the setting of induction - for example artemsinin which induces its own clearance.

The recovery time-course of CYP3A after induction by St John’s wort administration.

Br J Clin Pharmacol. 2008 May;65(5):701-7

Authors: Imai H, Kotegawa T, Tsutsumi K, Morimoto T, Eshima N, Nakano S, Ohashi K

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: St John’s wort causes the induction of CYP3A. Little is known about how long the effect remains after cessation of St John’s wort. WHAT THIS STUDY ADDS: The in vivo CYP3A activity returns progressively to the basal level approximately 1 week after cessation of St John’s wort administration AIMS: To examine the recovery time course of CYP3A after enzyme induction by St John’s wort administration. METHODS: The subjects were 12 healthy men, aged 20-33 years. On the first day, they received an oral dose of midazolam 5 mg without St John’s wort (day -14). From the next day, they took St John’s wort for 14 days. On the last day of St John’s wort treatment (day 0) and 3 and 7 days after completion of St John’s wort treatment (days 3 and 7), they received the same dose of midazolam. On each day, blood samples were obtained until 8 h after midazolam administration. Plasma concentrations of midazolam were measured by HPLC. Pharmacokinetic parameters of midazolam were determined using noncompartmental analysis. RESULTS: Apparent oral clearance of midazolam was significantly increased after St John’s wort administration from 65.3 +/- 8.4 l h(-1) (day -14) to 86.8 +/- 17.3 l h(-1) (day 0). It returned to the control level 7 days after the completion of St John’s wort (day 7, 59.7 +/- 3.8 l h(-1)). No significant difference in the elimination half-life between the four periods of the study was observed. The changes in apparent oral clearance after St John’s wort discontinuation indicated that CYP3A activity recovers from enzyme induction with an estimated half-life of 46.2 h. CONCLUSIONS: CYP3A activity induced by St John’s wort administration progressively returns to the basal level after approximately 1 week. This finding may provide useful information to avoid clinically significant interactions of St John’s wort with CYP3A substrates.

PMID: 18294328 [PubMed - indexed for MEDLINE]

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Effects of rhubarb extract on radiation induced lung toxicity via decreasing transforming growth factor-beta-1 and interleukin-6 in lung cancer patients treated with radiotherapy. Yu HM, Liu YF, Cheng YF, Hu LK, Hou M, Lung Cancer. 2008 Feb;59(2):219-26

BACKGROUND: Radiation induced lung toxicity (RILT) is the main adverse effect in the radiation therapy of lung cancer. However, the optimal management of RILT has not been defined. In this paper, we investigated the effects of rhubarb extract on RILT, pulmonary function (PF), transforming growth factor-beta-1 (TGF-beta1), and interleukin-6 (IL-6) in lung cancer patients treated with radiotherapy. PATIENTS AND METHODS: We conducted a randomized, double-blind, placebo-controlled trial. Eighty consecutive patients were randomly enrolled into two groups: trial group and control group. The trial group received three-dimensional conformal radiation therapy (3D-CRT) plus rhubarb (at a dose of 20 mg kg(-1) once a day) for 6 weeks. The control group received 3D-CRT plus a placebo containing starch for 6 weeks. Plasma TGF-beta1 and serum IL-6 were measured in all patients before, every 2 weeks during, and at 6 weeks after the completion of the treatment. RILT and PF were evaluated at 6 weeks and 6 months after the end of the treatment, respectively. The differences of TGF-beta1, IL-6, RILT, and PF between the two groups were analysed. RESULTS: The incidence of RILT in the trial group was significantly lower than that in the control group at 6 weeks and 6 months after treatment (32.4% versus 56.7% at week 6, and 27.0% versus 52.8% at month 6, both P<0.05). The plasma TGF-beta1 levels in the trial group were significantly lower than that in the control group during and after the treatment (P<0.05 or 0.01, respectively). The serum IL-6 levels in the trial group were significantly lower than that in the control group during the treatment (all P<0.01). The forced vital capacity (FVC), forced expiratory volume at 1s (FEV1) at 6 weeks and the diffusion capacity for carbon monoxide (DLCO) at 6 months in the trial group were significantly improved compared to the control group (P<0.05 or 0.01, respectively). CONCLUSIONS: The rhubarb extract significantly attenuated RILT and improved PF, probably by decreasing the level of TGF-beta1 and IL-6. These results may be of value for the prophylaxis of RILT, but the exact mechanisms underlying these prophylactic effects remain to be further explored.

PMID: 17870203 [PubMed - indexed for MEDLINE]

(Via Herbal Science Research aggregator.)

(more…)

More on ginkgo and coagulation: trial evidence that finally knocks out the myth that ginkgo is likely to cause additive interaction of over-anticoagulation when combined with aspirin. Of especial interest is that the study population was OLDER adults, the higher risk group that are often on an rx of aspirin as well as ginkgo users.
Effect of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: a randomized clinical trial: Gardner CD, Zehnder JL, Rigby AJ, Nicholus JR, Farquhar JW, Blood Coagul Fibrinolysis. 2007 Dec;18(8):787-93

Several case reports have implicated Ginkgo biloba in clinically adverse bleeding disorders. Ginkgo biloba has been reported to increase pain-free walking distance among patients with peripheral artery disease (PAD). Standard PAD therapy includes 325 mg/day aspirin. The objective of this study was to examine potential adverse effects of concomitant aspirin and Ginkgo biloba on platelet function. Ginkgo biloba (EGb 761, 300 mg/day) was compared with placebo for effects on measures of platelet aggregation among adults consuming 325 mg/day aspirin in a randomized, double-blind, placebo-controlled, parallel design trial of 4-week duration. Participants were adults, age 69 +/- 10 years, with PAD or risk factors for cardiovascular disease. Outcome measures included platelet function analysis (PFA-100 analyzer) using ADP as an agonist (n = 26 placebo; n = 29 ginkgo), and platelet aggregation using ADP, epinephrine, collagen and ristocetin as agonists (n = 21 placebo; n = 23 ginkgo). Participants kept daily logs of bleeding or bruising episodes. There were no clinically or statistically significant differences between treatment groups for any agonists, for either PFA-100 analysis or platelet aggregation. Reports of bleeding or bruising were infrequent and similar for both study groups. In conclusion, in older adults with PAD or cardiovascular disease risk, a relatively high dose of Ginkgo biloba combined with 325 mg/day daily aspirin did not have a clinically or statistically detectable impact on indices of coagulation examined over 4 weeks, compared with the effect of aspirin alone. No adverse bleeding events were observed, although the trial was limited to a small sample size.

PMID: 17982321 [PubMed - indexed for MEDLINE]

Just in time - Christmas stocking addition for the favorite practitioners in your life…..900+ pages dealing with 30 herbs, and more nutrients (see list of contents below) and thousands of references on a CDROM. Forward by Tieraona Low Dog (MD). The herbs monographs were all authored by yours truly, and the book is a steal at 79.95USD. Indispensable…..

Herb, Nutrient & Drug Interactions: Elsevier US Link

Table of Contents

Interactions Probability, Significance and Source Strength Guides
Section I: Herbs Interacting with Drugs

Aloe (Aloe vera)
Astragalus (Astragalus membranaceus)
Bilberry (Vaccinium myrtillus)
Black Cohosh (Cimicifuga racemosa)
Cascara
Cayenne (Capsicum)
Dang Gui (Angelica sinensis)
Devil’s Claw (Harpagophytum procumbens)
Echinacea (Echinacea spp.)
Eleuthero (Eleutherococcus senticosus)
Ephedra (Ephedra sinica)
Feverfew (Tanacetum parth.)
Garlic (Allium sativum)
Ginger (Zingiber off.)
Ginkgo (Ginkgo biloba)
Ginseng, Chinese/Korean (Panax ginseng)
Gotu Kola (Centella asiatica)
Green Tea (Camellia sinensis)
Hawthorn (Crataegus)
Horse Chestnut (Aesculus hippocastanum)
Kava Kava (Piper methysticum)
Licorice Root (Glycyrrhiza glabra)
Milk Thistle Seed (Silybum marianum)
Red Clover (Trifolium pratense)
Reishi Mushroom (Ganoderma lucidum)
Saw Palmetto (Serenoa repens)
St. John’s Wort (Hypericum perforatum)
Turmeric/Curcumin (Curcuma longa)
Valerian (Valeriana off.)
Vitex/Chaste (Vitex agnus-castus)

Section II: Nutrients Interacting with Drugs and Drug-Induced Nutrient Depletions

A. Vitamins
Beta-Carotene
Folic Acid
Vitamin A / Retinol
Vitamin B1 / Thiamine
Vitamin B2 / Riboflavin
Vitamin B3 / Niacin/Niacinamide
Vitamin B6
Vitamin B12
Vitamin C / Ascorbic Acid
Vitamin D / Calciferol
Vitamin E
Vitamin K
B. Minerals
Boron
Calcium
Chromium
Copper
Iron
Magnesium
Potassium
Selenium
Zinc
C. Amino Acids
Arginine
Carnitine
Methionine
Phenylalanine
Tryptophan
Tyrosine
D. Nutriceuticals and Physiologics
5-HTP (5-Hydroxytryptophan)
Alpha Lipoic Acid
Chondroitin Sulfate
Coenzyme Q10
DHEA (Dehydroepiandrosterone)
Glucosamine sulfate
Inositol
Melatonin
Omega 3 Fatty Acids (including Fish Oils: DHA and EPA)
PABA (Para-aminobenzoic Acid)
Policosanol
Probiotic Intestinal Flora and Prebiotics
S-adenosyl Methionine (SAMe)

Section III: Cross Indexes

A. Drugs by Trade Names
B. Drugs by Generic Names
C. Drugs by Drug Classes
Index

Treading on the Tigers Tail is a detailed deconstruction of the myth that herbs negatively interact with cancer chemotherapy, with a detailed analysis of the so called interaction between St John’s Wort and CPT 11 or irinotecan. It includes an explanation of the origins of the myth that antioxidants are “bad” to combine with chemotherapy. Technical in parts, but worth a read.

HH3 is available as a pdf download from here.

Green tea polyphenols could be added to Rx (eg ginkgo, Urtica seed, Cordyceps) for antidoting chemo induced nephrotoxicity - according to this rodent study.

Reduction of ciclosporin and tacrolimus nephrotoxicity by plant polyphenols
Zhong Z, Connor HD, Li X, Mason RP, Forman DT, Lemasters JJ, Thurman RG.J Pharm Pharmacol. 2006 Nov;58(11):1533-43.

The immunosuppressants ciclosporin (cyclosporin A, CsA) and tacrolimus can cause severe nephrotoxicity. Since CsA increases free radical formation, this study investigated whether an extract from Camellia sinensis, which contains several polyphenolic free radical scavengers, could prevent nephrotoxicity caused by CsA and tacrolimus. Rats were fed powdered diet containing polyphenolic extract (0-0.1%) starting 3 days before CsA or tacrolimus. Free radicals were trapped with alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) and measured using an electron spin resonance spectrometer. Both CsA and tacrolimus decreased glomerular filtration rates (GFR) and caused tubular atrophy, vacuolization and calcification and arteriolar hyalinosis, effects that were blunted by treatment with dietary polyphenols. Moreover, CsA and tacrolimus increased POBN/radical adducts in urine nearly 3.5 fold. Hydroxyl radicals attack dimethyl sulfoxide (DMSO) to produce a methyl radical fragment. Administration of CsA or tacrolimus with (12)C-DMSO produced a 6-line spectrum, while CsA or tacrolimus given with (13)C-DMSO produced a 12-line ESR spectrum, confirming formation of hydroxyl radicals. 4-Hydroxynonenal (4-HNE), a product of lipid peroxidation, accumulated in proximal and distal tubules after CsA or tacrolimus treatment. ESR changes and 4-HNE formation were largely blocked by polyphenols. Taken together, these results demonstrate that both CsA and tacrolimus stimulate free radical production in the kidney, most likely in tubular cells, and that polyphenols minimize nephrotoxicity by scavenging free radicals.

PMID: 17132217 [PubMed - indexed for MEDLINE]

In all the hysteria about potential interactions between herbs and chemotherapy (which is entirely unsubstantiated by case reports of any such interactions at all) a study such as this is welcome. Medical marijuana use is not uncommon by cancer patients, both during chemo and otherwise, to help deal with a range of problems including nausea, anorexia, and pain control. The vast majority of data suggest that herbs can be used to reduce toxicity and increase efficacy of chemotherapy. The facts are the facts.

Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel.:

Oncologist. 2007 Mar;12(3):291-300. Engels FK, de Jong FA, Sparreboom A, Mathot RA, Loos WJ, Kitzen JJ, de Bruijn P, Verweij J, Mathijssen RH

Objective. To date, data regarding the potential of cannabinoids to modulate cytochrome P450 isozyme 3A (CYP3A) activity are contradictory. Recently, a standardized medicinal cannabis product was introduced in The Netherlands. We anticipated an increased use of medicinal cannabis concurrent with anticancer drugs, and undertook a drug-interaction study to evaluate the effect of concomitant medicinal cannabis on the pharmacokinetics of irinotecan and docetaxel, both subject to CYP3A-mediated biotransformation. Patients and Methods. Twenty-four cancer patients were treated with i.v. irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal cannabis (200 ml herbal tea, 1 g/l) for 15 consecutive days, starting 12 days before the second treatment. Blood samples were obtained up to 55 hours after dosing and analyzed for irinotecan and its metabolites (SN-38, SN-38G), respectively, or docetaxel. Pharmacokinetic analyses were performed during both treatments. Results are reported as the mean ratio (95% confidence interval [CI]) of the observed pharmacokinetic parameters with and without concomitant medicinal cannabis. Results. Medicinal cannabis administration did not significantly influence exposure to and clearance of irinotecan (1.04; CI, 0.96-1.11 and 0.97; CI, 0.90-1.05, respectively) or docetaxel (1.11; CI, 0.94-1.28 and 0.95; CI, 0.82-1.08, respectively). Conclusion. Coadministration of medicinal cannabis, as herbal tea, in cancer patients treated with irinotecan or docetaxel does not significantly influence the plasma pharmacokinetics of these drugs. The evaluated variety of medicinal cannabis can be administered concomitantly with both anticancer agents without dose adjustments. Disclosure of potential conflicts of interest is found at the end of this article.

PMID: 17405893 [PubMed - in process]

Well this is the study referred to in the (jackass) Lancet editorial. Here is the deal. We have no idea what herbs were used. Each patient was examined and assessed by a practitioner of CHM, using traditional methods and approaches (presumably = no labs or mainstream diagnostics) We do not know who the practitioners were, or whether they had any experience in the specialized area of botanicals in the oncology setting. We do not know how they were briefed, or if they knew what the patients a history and current chemotherapy assignment was. We simply know that they prescribed a bunch of herbs from a list of 250, made l to them in granular powder tea format by the triallists.

Hence the report title in the Lancet? The validity of Chinese herbal medicine questioned? Why?
Worse still - the conclusion of Ernst? “Individualized herbal prescriptions in general” are invalid. What?

When these sort of cheap attacks are made, the perpetrators demean themselves, keep the clock firmly set on neanderthal time, and do nothing but disservice to patients. Ernst, for reasons that are largely obscure to many is seen as an expert on CAM. He persistently uses this “expert status” to make pronouncements that are nothing more than his own bigoted opinions. The whole thing stinks, but is just one more example of the feeble attempts of the status quo to maintain its hegemonic “authority”.

Mok, T., W. Yeo, et al. (2007). “A double-blind placebo-controlled randomized study of Chinese herbal medicine as complementary therapy for reduction of chemotherapy-induced toxicity.” Ann Oncol. epub ahead of print

BACKGROUND: Chinese herbal medicine (CHM) is a common complementary therapy used by patients with cancer for reduction of chemotherapy-induced toxic effects. This study applied the highest standard of clinical trial methodology to examine the role of CHM in reducing chemotherapy-induced toxicity, while maintaining a tailored approach to therapy. PATIENTS AND METHODS: Patients with early-stage breast or colon cancer who required postoperative adjuvant chemotherapy were eligible for the study. Enrolled patients were randomly assigned to one of three Chinese herbalists who evaluated and prescribed a combination of single-item packaged herbal extract granules. Patients received either CHM or placebo packages with a corresponding serial number. The placebo package contained nontherapeutic herbs with an artificial smell and taste similar to a typical herbal tea. The primary end points were hematologic and non-hematologic toxicity according to the National Cancer Institute Common Toxicity Criteria Version 2. RESULTS: One hundred and twenty patients were accrued at the time of premature study termination. Patient characteristics of the two groups were similar. The incidence of grade 3/4 anemia, leukopenia, neutropenia, and thrombocytopenia for the CHM and placebo groups were 5.4%, 47.3%, 52.7%, and 1.8% and 1.8%, 32.2%, 44.7%, and 3.6%, respectively (P = 0.27, 0.37, 0.63, and 0.13, respectively). Incidence of grade 2 nausea was the only non-hematologic toxicity that was significantly reduced in the CHM group (14.6% versus 35.7%, P = 0.04). CONCLUSIONS: Traditional CHM does not reduce the hematologic toxicity associated with chemotherapy. CHM, however, does have a significant impact on control of nausea.

This jackass headline accompanies a piece by Angela Paolino reporting to Lancet Oncology readers (current issue) on a study by Mok et al, (from Annals of Oncology earlier this year January 17th) that is typical of the anti-herb propaganda and garbage that mainstream medicine endlessly serves up….it is almost beyond the point of being funny it so stupidly transparent. Are the readers of Lancet oncology really this dumb? Will all Chinese medicine practitioners kindly see the light and stop what they have been doing ( for the last few thousand years) now that Lancet Oncology has spoken in its profound wisdom, especially since the execrable Ernst endorses this headline, and indeed extends it to ALL of herbal medicine….
FWIW - the study in question compares two groups of cancer patients (resected breast and colon) undergoing chemotherapy (adriamycin/cytoxan) and 5FU/leucovorin) repsectively, with and without concomitant CHM (Chinese herbal medicine) Total n=111 for both groups. The verum groups were assigned to one of three “experienced Chinese herbalists” who assessed each patient on day 1 and day 14 of each cycle of chemo. The assessments were apparently “traditional”. The subjects were then prescribed “individualized herbal teas”. After the cycles of chemotherapy were completed the patients were evaluated for a range of chemotherapy induced toxicities compared to those that had received “placebo herbal teas” No significant differences were found between the control and herbal Rx groups of patients with respect to hematological toxicity (neutropenia and leukopenia) nor any other toxicity except nausea and vomiting for which the herbal treatment groups did better than controls.

We shall report the gory details of this study in the following post since it is bound to get a lot of attention but trust me for now, the study is flawed to the point of absurdity - but the point here, even if it were an intelligent study design, is that how come one negative finding calls ALL of Chinese herbal medicine into question??

The author of this piece and the Editor of the journal should apologize for such a low life attempt to rubbish something they know nothing about. But instead, the reporter wheels out our old friend Eddie Ernst, champion of evidence based CAM who says , this one study actually “questions the validity of all of individualized herbal treatment in general” .

Ernst is a fatuous fool for making such a remark, and the Editors of Lancet Oncology are moronic to print it.

The bigger and deeper tragedy is, that for the countless people with cancer facing the daunting prospect of toxic chemotherapy for advanced disease despite its pathetic cure rate, as well as the few herbal practitioners ( Chinese or Western) dedicated, thick skinned, or perhaps foolish enough to persist in attempting to help forge a more inclusive, integrative multidimensional model of cancer care, these kind of comments are not merely egregiously retarded, but they arguably harm patients as well as the emerging integrative approach which will inevitably supercede the current reductionist/materialist/toxic/and banalized model of cancer care promoted by pharmaceutical companies and the majority of mainstream oncology. Shame on you Lancet Oncology.

Of course we would rather no-one did tamoxifen, but this is relevant to those that find themselves in that situation

The combination of green tea and tamoxifen is effective against breast cancer. Sartippour MR, Pietras R, Marquez-Garban DC, Chen HW, Heber D, Henning SM, Sartippour G, Zhang L, Lu M, Weinberg O, Rao JY, Brooks MN; Carcinogenesis. 2006 Dec;27(12):2424-33

Epidemiologic data have suggested that green tea may prevent breast cancer. Studies in our laboratory have provided evidence that green tea extract inhibits breast cancer growth by a direct anti-proliferative effect on the tumor cells, as well as by indirect suppressive effects on the tumor-associated endothelial cells. In this study, we asked whether concurrent administration of green tea may add to the anti-tumor effects of standard breast cancer therapy. We observed that green tea increased the inhibitory effect of tamoxifen on the proliferation of the ER (estrogen receptor)-positive MCF-7, ZR75, T47D human breast cancer cells in vitro. This combination regimen was also more potent than either agent alone at increasing cell apoptosis. In animal experiments, mice treated with both green tea and tamoxifen had the smallest MCF-7 xenograft tumor size, and the highest levels of apoptosis in tumor tissue, as compared with either agent administered alone. Moreover, the suppression of angiogenesis in vivo correlated with larger areas of necrosis and lower tumor blood vessel density in treated xenografts. Green tea decreased levels of ER-alpha in tumors both in vitro and in vivo. We also observed that green tea blocked ER-dependent transcription, as well as estradiol-induced phosphorylation and nuclear localization of mitogen-activated protein kinase. To our knowledge, this study is the first to show the interaction of green tea with the ER pathway, as well as provide mechanistic evidence that the combination of green tea and tamoxifen is more potent than either agent alone in suppressing breast cancer growth. These results may lead to future improvements in breast cancer treatment and prevention.

PMID: 16785249 [PubMed - indexed for MEDLINE]