Herbal Supplements: Precautions and Safe Use.

The Food and Drug Administration (FDA) classifies herbal preparations as food supplements. New herbal supplements and products are not governed by the strict FDA drug approval process and there is no premarket approval required. The FDA prohibits manufacturers and distributors from marketing adulterated or misbranded products but does not rigorously define safe practices. Scientific evidence related to herbal supplements is limited. Herbal supplements have been associated with adverse reactions and herbal-drug interactions. Information and precautions for 20 common herbal supplements, including St. John's wort, ginseng, echinacea, and ginkgo, are reviewed. Resources for consumers and health care professionals are highlighted.

Analysis of spontaneous adverse drug reactions to echinacea, valerian, black cohosh and ginkgo in Australia from 2000 to 2015.

OBJECTIVE: Assessing adverse drug reactions (ADRs) is a proven method to estimate the safety of medicines. The ADRs to herbal medicines in Australia (and by inference, the safety of herbal medicines in Australia) remain unknown. This study examines spontaneous ADR cases to four of the most popular herbs in Australia from 2000 to 2015: echinacea (Echinacea purpurea), valerian (Valeriana officinalis), black cohosh (Actaea racemosa) and ginkgo (Ginkgo biloba). METHODS: ADRs of echinacea, valerian, black cohosh and ginkgo reported to the Australian Therapeutic Goods Administration (TGA) between 2000 and 2015 were obtained from the TGA database. Data were collated and analysed according to age, sex, severity, type of ADR and body system affected. Statistics were calculated using GraphPad Prism software. RESULTS: Most ADRs were mild or moderate. However, every herbal medicine was associated with life-threatening ADRs. In each life-threatening case, the herbal medicine was taken concomitantly with prescription medications. Black cohosh was associated with a significant number of severe ADRs (30.3% of the total), with 39.4% of these ADRs being associated with abnormal hepatic function, hepatitis or hepatotoxicity. CONCLUSION: This study highlights the lack of public awareness with regard to herb-drug interactions, since most of the severe ADRs involved a herb-drug interaction.

Possible Drug-nutraceutical Interaction leading to Unexpected Sequelae after Inguinal Hernia Repair.

BACKGROUND Nutraceutical formulations are an area in which physicians should be increasingly aware of their side effects. This case study shows the adverse effects that ginkgo biloba can have when combined with tadalafil following an inguinal hernia repair. CASE REPORT A 74-year-old male presented for repair of a recurrent inguinal hernia and for which the procedure was performed without complication. Upon follow-up, it was noted that he had significant ecchymosis not only in the inguinal region but in the ventral aspect of his penis. Upon further questioning, he reported that he had been taking ginkgo biloba that was stopped 5 days prior to the operation and restarted postoperative day 1. This, combined with tadalafil, was thought to be the reason for the unexpected induration and ecchymosis at the shaft of the penis. After discontinuing both medications, the ecchymosis and induration did resolve. CONCLUSIONS While ecchymosis and induration are expected in the inguinal region, the appearance of significant ecchymosis and induration down the shaft of the penis was unexpected in this case, and therefore we thought it could be due to nutraceutical use of ginkgo biloba combined with tadalafil, which were started postoperatively.

[Post-marketing study on clinical safety of ginkgo diterpene lactone meglumine injection in 6 300 patients with ischemic stroke].

To further evaluate the safety of ginkgo diterpene lactone meglumine injection in the clinical use in ischemic stroke patients. Clinical safety study was conducted in 82 clinical units and 6 300 cases were completed and included from June 2013 to December 2014 by using multicenter, prospective, open and uncontrolled design methods for clinical research. A total of 29 cases of adverse reactions were observed in the experiment. Adverse reaction ratio (ADR) was 0.46%, and about 86.21% (25 cases) of them was mild with transient response which could be alleviated or disappeared without intervention; about 13.79% (4 cases) was moderate, including 2 cases of headache, 1 case of dizziness and 1 case of rash; no serious adverse reactions were found. The adverse reactions occurred in this study were pre-known adverse reactions or common adverse reactions of Chinese medicine injection. The overall incidence of adverse reactions was low, and the risk was controllable.

Moderate doses of commercial preparations of Ginkgo biloba do not alter markers of liver function but moderate alcohol intake does: A new approach to identify and quantify biomarkers of 'adverse effects' of dietary supplements.

It is difficult to determine if certain dietary supplements are safe for human consumption. Extracts of leaves of Ginkgo biloba trees are dietary supplements used for various purported therapeutic benefits. However, recent studies reported they increased risk of liver cancer in rodents. Therefore, this study assessed the association between ginkgo consumption and liver function using NHANES 2001-2012 data (N = 29,684). Since alcohol is known to adversely affect liver function, association of its consumption with liver function was also assessed. Alcohol and ginkgo extract intake of adult consumers and clinical markers of liver function (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, bilirubin) were examined. Moderate consumers of alcohol (0.80 ± 0.02 drinks/day) had higher levels of aspartate aminotransferase and gamma glutamyl transferase than non-consumers (P < 0.001). There was no difference (P > 0.01) in levels of markers of liver function in 616 ginkgo consumers (65.1 ± 4.4 mg/day intake) compared to non-consumers. While moderate alcohol consumption was associated with changes in markers of liver function, ginkgo intake as typically consumed by U.S. adults was not associated with these markers. Biomarkers measured by NHANES may be useful to examine potential adverse effects of dietary supplements for which insufficient human adverse event and toxicity data are available. TRIAL REGISTRATION NUMBER: Not applicable, as this is secondary analysis of publicly released observational data (NHANES 2001-2012).

[Preventive and therapeutic effects of compound ginkgo extract in rats with nonalcoholic steatohepatitis induced by high-fat, high-fructose diet].

Objective: To establish a rat model of nonalcoholic steatohepatitis (NASH), and to investigate the preventative and therapeutic effects of compound ginkgo extract against NASH. Methods: A total of 60 male Sprague-Dawley rats were fed with high-fat feed and 10% fructose water for 24 weeks to establish the rat model of NASH. The general behaviors of the rats were observed, and the body weight was recorded. Blood samples from the inferior vena cava and the liver were collected after the last administration to measure serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), as well as liver function parameters. The liver index was calculated, HE staining was performed to observe liver histopathological changes, and the total lipase activity and the levels of TC, TG, and free fatty acid (FFA) in liver tissue were measured. Results: After 24 weeks, compared with the normal group, the model group had a significantly faster increase in body weight, significant increases in serum levels of TC (2.20±0.52 mmol/L), TG (0.87±0.22 mmol/L), LDL-C (1.22±0.50 mmol/L), alanine aminotransferase (ALT) (129.4±44.7 U/L), and aspartate aminotransferase (AST) (209.3±42.8 U/L), liver index (3.62%±0.28%), and the levels of TC (4.42±1.39 mmol/mg.prot), TG (0.85±0.11 mmol/mg.prot), and FFA (644.78±36.65µmol/L) in liver tissue, and significant reductions in serum HDL-C level (0.58±0.11 mmol/L) and the activity of lipoprotein lipase (LPL) (9.95±1.64 U/mg.prot) and hepatic lipase (HL) (9.91±1.03 U/mg.prot) (allP< 0.01). In addition, the pathological results showed severe hepatocyte steatosis, varying degrees of inflammatory cell infiltration, exudation in the portal area, and necrosis of liver cells in the model group. After the intervention with compound ginkgo extract, there were significant reductions in serum levels of TC (1.78±0.21 mmol/L), TG (0.58±0.07 mmol/L), LDL-C (0.84±0.19 mmol/L), and ALT (84.1±17.1 U/L), AST (155.4±20.9 U/L), liver index (2.71%±0.15%), and the levels of TC (2.24±1.02 mmol/mg.prot), TG (0.46±0.11 mmol/mg.prot), and FFA (580.56±50.63µmol/L) in liver tissue, as well as significant increases in serum HDL-C level (0.68±0.10 mmol/L) and the activities of LPL (15.54±2.21 U/mg.prot) and HL (11.92±1.87 U/mg.prot) (P< 0.05 orP< 0.01). At the same time, it significantly reduced hepatomegaly in rats and improved fatty degeneration and degree of inflammation in liver cells. Conclusion: Compound ginkgo extract can prevent and treat NASH by correcting dyslipidemia, improving liver function and fatty degeneration in hepatocytes, and reducing the degree of inflammation, and its mechanism of action may be associated with increasing total lipase activity, reducing FFA in the liver, increasing the decomposition of TG, and reducing the synthesis of TG.

Unexplained alveolar hemorrhage associated with Ginkgo and ginseng use.

The author presents a case of diffuse alveolar hemorrhage in a woman consuming Ginkgo biloba extract and ginseng. The patient had no illnesses or exposures that would predispose to diffuse alveolar hemorrhage, and an extensive evaluation revealed no etiology. The patient has had no further bleeding since discontinuing Ginkgo biloba extract and ginseng 1 year ago.

Ginkgo biloba extract for essential hypertension: a systemic review.

BACKGROUND: Ginkgo biloba extract (GBE), a traditional natural herbal product, is often used in the treatment of essential hypertension (EH) as complementary therapy in China and European countries. AIM: To critically assess the current clinical evidence of efficacy and safety of GBE for EH. METHODS: 7 electronic databases (Cochrane Library, PubMed, EMBASE, VIP, CBM, Wanfang data, and CNKI) were searched to identify randomized controlled trials (RCTs) of GBE for EH. Methodological quality was assessed independently using the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: A total of 9 RCTs with 1012 hypertensive patients were identified and reviewed. Most RCTs were of high risk of bias with flawed study design and poor methodological quality. 6 trials demonstrated potential positive effect of GBE as complementary therapy on BP reduction when compared with antihypertensive drug therapy; however, it was not associated with a statistically significant effect on both SBP and DBP reduction in 3 other trials. Despite the positive findings, there were so many methodological limitations and significant clinical heterogeneity. Most of the trials did not report adverse effects, and the safety of GBE is still uncertain. CONCLUSION: No confirmative conclusions on the efficacy and safety of GBE for EH could be drawn. More rigorous trials are warranted to support their clinical use.

Electrocardiographic profile of guinea pig heart submitted to Ginkgo biloba extract and its terpenoids / Perfil eletrocardiográfico do coração de cobaia submetido ao extrato de Ginkgo biloba e seus terpenóides

Electrocardiographic effects produced by Ginkgo biloba extract (EGb) and by ginkgolides A (GA) and B (GB), and bilobalide (BB) were investigated in guinea pig heart mounted in Langendorff apparatus (Tyrode, 34 ± 0.1 ºC, 95% O2, 5% CO2). Electrocardiographic parameters were evaluated in the conditions: 1) control with Tyrode and DMSO, 2) EGb (n=4), GA (n=5), GB (n=5) or BB (n=6), and 3) washout. The results showed that 0.1 and 1.0 mg/ml of EGb do not change the electrocardiographic parameters. However, 10 mg/ml of EGb increased the PR interval (PRi) at 21% (p<0.001). This increase was also observed for 50 mM GA (20%, p<0.001) and 70 mM BB (13%, p<0.001), which indicates Ca2+ channel block. However, the 50 mM GB reduced the PRi at 11 % (p<0.001). The GA (23%, p<0.001), GB (16%, p<0.001), and BB (40%, p<0.001) reduced the QT interval (QTi), which suggests the activation of the potassium channel. However, EGb increased QTi (6%, p<0.001). The EGb (28%, p<0.05) and GB (13%, p<0.05) reduced the heart rate. Atrioventricular (AV) block was observed with EGb, GA, and BB. We can conclude that EGb and its terpenoids alter the ECG parameters inducing AV block, which indicates possible arrhythmogenic potential.

Os efeitos eletrocardiográficos produzidos pelo extrato de Ginkgo biloba (EGb) e gingkolídeos A (GA) e B (GB), e bilobalide (BB) foram investigados em coração de cobaia montado sistema de Langendorff (Tyrode, 34 ± 0.1 ºC, 95% O2, 5% CO2). Os parâmetros do ECG foram avaliados nas condições: 1) Tyrode e DMSO, 2) EGb (n=4), GA (n=5), GB (n=5) ou BB (n=6) diluídos em DMSO e 3) washout. Os resultados demonstram que 0,1 e 1,0 mg/mL de EGb não alteraram os parâmetros eletrocardiográficos. Entretanto, 10 mg/ml de EGb aumentaram o intervalo PR (PRi) em 21% (p<0.001). Esse aumento também foi observado com GA a 50µM (20%, p<0,001) e BB a 70 mM (13%, p<0,001) indicando bloqueio de canais de cálcio. Por outro lado, GB reduziu o PRi (11%, p<0,001). O intervalo QT (QTi) foi reduzido por GA (23%, p<0,001), GB (16%, p<0,001) e BB (40%, p < 0.001) sugerindo uma ativação de canais de potássio. Entretanto, EGb aumentou o QTi (6%, p<0.001). A frequência cardíaca foi reduzida por EGb (28%, p<0.05) e GB (13%, p<0.05). Bloqueios átrio-ventriculares (BAV) foram observados com EGb, GA e BB. Podemos concluir que EGb e os terpenos alteram parâmetros eletrocardiográficos induzindo BAV e demonstrando possível potencial arritmogênico.

Reproductive and developmental toxicity of the Ginkgo biloba special extract EGb 761® in mice.

Extracts from leaves of Ginkgo biloba are among the most widely used and best investigated phytopharmaceuticals worldwide. Almost all clinical trials and the majority of preclinical studies have been performed with a specifically defined extract (EGb 761(®)) standardized to contain confined concentrations of active ingredients and limited quantities of potentially harmful substances. Besides pharmaceutical grade extracts poorly characterized Ginkgo preparations are now increasingly appearing on the market as nutraceuticals. While the safety of EGb 761(®) has been evaluated in an extensive set of toxicology studies, adverse effects of Ginkgo extracts of non-pharmaceutical quality on reproductive functions in mice have been reported in several publications in recent years. As this species has not previously been used in reproductive toxicity studies with EGb 761(®), the present investigation was conducted to examine the influence of EGb 761(®) (100, 350 and 1225mg/kg/day) on embryo-fetal development in mice during the critical period of organogenesis. During external and internal inspection of the fetuses as well as examination of skeletal and soft tissues no embryotoxic properties were noted. In particular, the incidence of malformations, variations or retardations was not increased and the general condition of dams was not influenced. Thus, the no-observed-effect level (NOEL) was above 1225mg/kg/day for the dams and the fetuses.

Acute hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency complicated by Ginkgo biloba.

We report on a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency who developed acute hemolytic anemia after having received an injection of Ginkgo biloba for dementia prophylaxis without medical advice. She suddenly developed general malaise, generalized yellowish skin color, and tea-colored urine. Intravenous fluid infusion and cessation of G. biloba quickly relieved her clinical symptoms. To the best of our knowledge, this is the first case report of G. biloba-induced acute hemolytic anemia in vivo.

[Ginkgo biloba--effect, adverse events and drug interaction]. / Ginkgo biloba--effekt, bivirkninger og interaksjoner.

Ginkgo is probably one of the most widely used medicinal herbs in Europe. In Norway products of ginkgo leaf extract have been approved by the Norwegian Medicines Agency for the following indication: traditionally used to improve blood circulation, for example, cold hands and feet. Elsewhere, ginkgo is used for cognitive impairment and dementia, acute ischaemic stroke, intermittent claudication, tinnitus and age-related macular degeneration. Evidence of the efficacy of ginkgo for these indications has previously been studied by the Cochrane Collaboration. In this update we have repeated all the searches in Medline and EMBASE exactly as described in the five Cochrane Systematic Reviews (last search date: 16.02.2011). We identified two new randomised and placebo-controlled studies on cognitive impairment and dementia (3187 patients) and one study on acute ischaemic stroke (3069 patients). The results of these studies gave no reason to change the conclusions of earlier reviews by the Cochrane Collaboration. There is no convincing evidence that ginkgo is effective for cognitive impairment or dementia, acute ischaemic stroke, intermittent claudication or tinnitus. There is still a lack of conclusive evidence for the effect on age-related macular degeneration. Ginkgo leaf extract appears to be safe to use, with no excess side effects compared with placebo. It can cause some minor side effects such as stomach upset, headache, dizziness, constipation, forceful heartbeat, and allergic skin reactions. There is some concern that ginkgo leaf extract might increase the risk of bruising and bleeding, and interactions with anticoagulants/antiplatelet drugs cannot be ruled out. As a general precaution, it is recommended withdrawing ginkgo two weeks before elective surgery.

Ginkgo biloba: an adjuvant therapy for progressive normal and high tension glaucoma.

Gingko biloba has been used for hundreds of years to treat various disorders such as asthma, vertigo, fatigue and, tinnitus or circulatory problems. Two of the main extracts are EGb761 and LI 1370. Most pharmacological, toxicological and clinical studies have focused on the neuroprotective value of these two main extracts. Neuroprotection is a rapidly expanding area of research. This area is of particular interest due to the fact that it represents a new avenue of therapy for a frustrating disease that may progress despite optimal treatment. One such disease is glaucoma.Glaucoma leads to the loss of retinal ganglion cells and their axons but also to tissue remodelling which involves both the optic nerve head and the retina. In the retina the astrocytes get activated. In addition, the optic nerve gets thinner and the cells of the lateral geniculate ganglion disappear partially. On average, ocular blood flow (OBF) is reduced in glaucoma patients in various tissues of the eye. Increased intraocular pressure (IOP) is a major risk factor for glaucomatous damage. Nevertheless, there is little doubt that other risk factors besides IOP are involved. One such risk factor is a primary vascular dysregulation (PVD) occurring in patients with a disturbed autoregulation, another risk factor is oxidative stress.

A potential drug-herbal interaction between Ginkgo biloba and efavirenz.

Efavirenz (EFV) is primarily metabolized by cytochrome P450 (CYP) 2B6 and to a lesser extent by CYP3A4. Drugs that significantly inhibit or induce these enzymes would then be expected to increase or lower the levels of EFV potentially resulting in toxicity or therapeutic failure, respectively. The constituents of Ginkgo biloba extract have been demonstrated to induce gene expression of the CYP450 enzymes. We report a case in which a potential drug-herb interaction may have led to virological breakthrough in a patient that was maintained on the same regimen for 10 years. Therefore, a drug-herbal interaction may be expected when these agents are taken concurrently, and we advise clinicians to avoid this combination when possible.