Herb-drug interactions: a literature review

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.
Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.
Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).
In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Comparable effects of nicotine in smokers and nonsmokers on a prospective memory task

In a double-blind placebo-controlled study, we examined the effect of nicotine, a cholinergic agonist, on performance of a prospective memory (ProM) task in young adult volunteers.

Volunteers were required to complete an ongoing lexical decision task while maintaining the ProM task (responding with a different button press to items containing particular target letters). Half of the volunteers were smokers, half were nonsmokers. Half of each group received a single dose (1 mg) of nicotine nasal spray before completing the task; the remaining volunteers received a matched inactive placebo spray.

Nicotine improved performance on the ProM task when volunteers were able to devote resources to that task. Under a variant procedure, where volunteers completed a concurrent auditory monitoring task, ProM performance was impaired under nicotine. Results are discussed in terms of the resource model of ProM, and the arousal model of drug effects.

Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs

Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches using in vitro, in silico and in vivo models can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (K(I)) and the maximal rate of inactivation at saturation (k(inact)).Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs.Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of its K(I), k(inact) and partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confounding in vitro-in vivo extrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.

Hormone replacement therapy and cardiovascular disease

The authors examine the most recent research concerning the risks and benefits of oestrogen or combined oestrogen-progestin therapy in postmenopausal women.

Antihypertensive treatments obscure familial contributions to blood pressure variation

The linkage and association between inherent blood pressure and underlying genotype is potentially confounded by antihypertensive treatment. We estimated blood pressure variance components (genetic, shared environmental, individual-specific) in 767 adult volunteer families by using a variety of approaches to adjusting blood pressure of the 244 subjects (8.2%) receiving antihypertensive medications. The additive genetic component of variance for systolic pressure was 73.9 mm Hg(2) (SE, 8.8) when measured pressures (adjusted for age by gender within each generation) were used but fell to 61.4 mm Hg(2) (SE, 8.0) when treated subjects were excluded. When the relevant 95th percentile values were substituted for treated systolic pressures, the additive genetic component was 81.9 mm Hg(2) (SE, 9.5), but individual adjustments in systolic pressure ranged from -53.5 mm Hg to +64.5 mm Hg (mean, +17.2 mm Hg). Instead, when 10 mm Hg was added to treated systolic pressure, the additive genetic component rose to 86.6 mm Hg(2) (SE, 10.1). Similar changes were seen in the shared environment component of variance for systolic pressure and for the combined genetic and shared environmental (ie, familial) components of diastolic pressure. There was little change in the individual-specific variance component across any of the methods. Therefore, treated subjects contribute important information to the familial components of blood pressure variance. This information is lost if treated subjects are excluded and obscured by treatment effects if unadjusted measured pressures are used. Adding back an appropriate increment of pressure restores familial components, more closely reflects the pretreatment values, and should increase the power of genomic linkage and linkage disequilibrium analyses.

Co-ingestion of energy drinks with alcohol and other substances among a sample of people who regularly use ecstasy

INTRODUCTION AND AIMS: Despite the potential harms of mixing unregulated drugs with energy drinks (ED), research to date has primarily been focused on EDs co-ingested with alcohol. Consequently, the aim of the present study was to explore the rate of use, harms and correlates of EDs co-ingested with alcohol and other drugs among a sample of people who regularly use illicit stimulant drugs. DESIGN AND METHODS: In 2010, 693 Australians who regularly used ecstasy completed a 1-h interview about their past six-month ED and drug use. RESULTS: Three-quarters of the sample (77%) had recently consumed EDs with other substances, primarily alcohol (70%) and ecstasy (57%). People who consumed ED with alcohol versus those who had consumed ED with ecstasy and with alcohol (only 8% reported only consuming ED with ecstasy) had similar profiles in regards to demographics, drug use, mental health and drug-related problems. Primary motives for consuming ED with alcohol included increased alertness (59%), the taste (25%), to party for longer (23%) and to combat fatigue (16%). One-half (52%) and one-quarter (27%) of participants who consumed EDs with alcohol and with ecstasy respectively had recently experienced adverse outcomes post-consumption, primarily headaches (24% and 11%) and heart palpitations (21% and 14%). DISCUSSION AND CONCLUSIONS: Co-ingestion of EDs with licit and illicit drugs is common among people who regularly use ecstasy and related drugs. Adverse outcomes of co-ingestion suggest that targeted education regarding negative interactive drug effects is crucial for harm reduction. [Peacock A, Sindicich N, Dunn M, Whittaker E, Sutherland R, Entwistle G, Burns L, Bruno R. Co-Ingestion of Energy Drinks with Alcohol and Other Substances among a Sample of People Who Regularly Use Ecstasy. Drug Alcohol Rev 2015].

A novel technique to investigate the effect of ageing on ventricular repolarization characteristics in healthy and LQTS subjects

Ventricular repolarization(VR) characteristics is affected by ageing alongside several other factors like Heart rate(HR),respiration, modulation of autonomic nervous system, different drug effects, genetical factors affecting the cardiac ion channel characteristics, gender etc. Therefore, total VR variability (i.e. QT interval variability in surface ECG) consists of two components: one dependent on HR variability (HRV) and another independent of HRV. Analysis of QT interval variability (QTV) is crucial for both healthy and pathological conditions as increase in VR variability measured by QTV increases cardiac repolarization instability, which might lead to arrhythmogenesis. Analyzing the effect of ageing using a widely used measure of QTV (i.e. QTVI) is reported inconsistently in Healthy subjects whereas the same for Long QT Syndrome (LQTS) subjects is not widely reported. In this study, we propose a novel time domain measure from beat-tobeat QT-RR distribution to analyze how ageing affects VR in both Healthy and a group of genotyped LQTS1 subjects. A total of 139 Healthy subjects and 134 LQTS1 subjects of three different age groups (i.e. Young: age 20-35, Middle-aged: 40-55 and Old: age<;60) were analyzed for this study. The proposed measure is also compared with other existing widely used measures of QTV like SDQT and QTVI in differentiating different age groups. The proposed measure stands out to be more discriminatory than other existing variability measures of QT interval.

Longitudinal effects of school drug policies on student marijuana use in Washington State and Victoria, Australia

OBJECTIVES: We examined the longitudinal effect of schools' drug policies on student marijuana use. METHODS: We used data from the International Youth Development Study, which surveyed state-representative samples of students from Victoria, Australia, and Washington State. In wave 1 (2002), students in grades 7 and 9 (n = 3264) and a school administrator from each participating school (n = 188) reported on school drug policies. In wave 2 (2003), students reported on their marijuana use. We assessed associations between student-reported and administrator-reported policy and student self-reported marijuana use 1 year later. RESULTS: Likelihood of student marijuana use was higher in schools in which administrators reported using out-of-school suspension and students reported low policy enforcement. Student marijuana use was less likely where students reported receiving abstinence messages at school and students violating school policy were counseled about the dangers of marijuana use. CONCLUSIONS: Schools may reduce student marijuana use by delivering abstinence messages, enforcing nonuse policies, and adopting a remedial approach to policy violations rather than use of suspensions.

The deleterious effects of oxidative and nitrosative stress on palmitoylation, membrane lipid rafts and lipid-based cellular signalling : new drug targets in neuroimmune disorders

Oxidative and nitrosative stress (O&NS) is causatively implicated in the pathogenesis of Alzheimer’s and Parkinson’s disease, multiple sclerosis, chronic fatigue syndrome, schizophrenia and depression. Many of the consequences stemming from O&NS, including damage to proteins, lipids and DNA, are well known, whereas the effects of O&NS on lipoprotein-based cellular signalling involving palmitoylation and plasma membrane lipid rafts are less well documented. The aim of this narrative review is to discuss the mechanisms involved in lipid-based signalling, including palmitoylation, membrane/lipid raft (MLR) and n-3 polyunsaturated fatty acid (PUFA) functions, the effects of O&NS processes on these processes and their role in the abovementioned diseases. S-palmitoylation is a post-translational modification, which regulates protein trafficking and association with the plasma membrane, protein subcellular location and functions. Palmitoylation and MRLs play a key role in neuronal functions, including glutamatergic neurotransmission, and immune-inflammatory responses. Palmitoylation, MLRs and n-3 PUFAs are vulnerable to the corruptive effects of O&NS. Chronic O&NS inhibits palmitoylation and causes profound changes in lipid membrane composition, e.g. n-3 PUFA depletion, increased membrane permeability and reduced fluidity, which together lead to disorders in intracellular signal transduction, receptor dysfunction and increased neurotoxicity. Disruption of lipid-based signalling is a source of the neuroimmune disorders involved in the pathophysiology of the abovementioned diseases. n-3 PUFA supplementation is a rational therapeutic approach targeting disruptions in lipid-based signalling.

An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice

The aim of this study was to investigate the effect of modification processes on physical properties and explain the mechanism of sustained drug release from modified rice (MR). Various types of Vietnamese rice were introduced in the study as the matrices of sustained release dosage form. Rice was thermally modified in water for a determined temperature at different times with a simple process. Then tablets containing MR and isradipine, the model drug, were prepared to investigate the capability of sustained drug release. Scanning electron microscopy (SEM) was used to determine different morphologies between MR formulations. Flow property of MR was analyzed by Hausner ratio and Carr's indices. The dissolution rate and swelling/erosion behaviors of tablets were evaluated at pH 1.2 and pH6.8 at 37±0.5°C. The matrix tablet containing MR showed a sustained release as compared to the control. The SEM analyses and swelling/erosion studies indicated that the morphology as well as swelling/erosion rate of MR were modulated by modification time, drying method and incubation. It was found that the modification process was crucial because it could highly affect the granule morphologies and hence, leading to the change of flowability and swelling/erosion capacity for sustained release of drug.

What do we know about preventing drug-related harm through social developmental intervention with children and young people

This chapter examines the evidence for the effectiveness of interventions aiming to reduce drug-related harm by improving conditions for healthy develeopment in the earliest years through adolescence. Of the interventions beginning prior to birth, there is efficacy evidence that family home visitation is a feasible strategy for implementation with disadvataged families and can reduce risk factors for early developmental deficits and thereby improve childhood development outcomes. There is efficacy evidence for strategies such as parent education and school preparation through the pre-school age period. Some of the strongest evidence for efficacy in reducing developmental pathways to drug-related harm comes from interventions delivered through the early school years to improve educational environments. Of the interventions targeting the high school age period, school drug education has been the most commonly evaluated. The evidence suggests that short term reduction in both drug use and progression to frequent drug use may be achievable through this strategy, but the prospects for longer-term and population-level behaviour change is still unclear. In overview, a range of prevention strategies have been developed and evaluated. Most of the exisiting evidence is restricted to efficacy studies and there are future challenges to progress evaluation through to studies of effectiveness. In general, prevention programmes appear more successful where they maintain intervention activities over a number of years and incorporate more than one strategy. Much of the existing research has been based in North America and evaluates discrete programmes. Future research should test effects in other countries, in different social contexts and seek to better understand the interrelated effects of combining interventions within the community. Developmental prevention programmes target different age periods and social settings, hence communities have the challenge of coordinating a mixture of programmes that address the local conditions that adversely influence child and youth development. There are opportunities in this work to coordinate prevention activities using funding from different jurisdictions (e.g., crime prevention, health promotion, mental health, education, substance abuse prevention).

School, parent, and student perspectives of school drug policies

Background: Schools use a number of measures to reduce harmful tobacco, alcohol, and drug use by students. One important component is the school's drug policy, which serves to set normative values and expectations for student behavior as well as to document procedures for dealing with drug-related incidents. There is little empirical evidence of how policy directly or indirectly influence students' drug taking. This study compares how effectively schools communicate school drug policies to parents and students, how they are implemented, and what policy variables impact students' drug use at school and their perceptions of other students' drug use at school.

Methods: Data were obtained from 3876 students attending 205 schools from 2 states in the United States and Australia, countries with contrasting national drug policy frameworks. School policy data were collected from school personnel, parents, and students.

Results: Schools' policies and enforcement procedures reflected national policy approaches. Parents and students were knowledgeable of their school's policy orientation.

Conclusions: When delivered effectively, policy messages are associated with reduced student drug use at school. Abstinence messages and harsh penalties convey a coherent message to students. Strong harm-minimization messages are also associated with reduced drug use at school, but effects are weaker than those for abstinence messages. This smaller effect may be acceptable if, in the longer term, it leads to a reduction in harmful use and school dropout within the student population.

The effects of the opioid pharmacotherapies methadone, LAAM and buprenorphine, alone and in combination with alcohol, on simulated driving

While methadone is currently the primary pharmacotherapy used in the treatment of heroin dependence in Australia, levo-alpha-acetyl-methodol (LAAM) and buprenorphine are new pharmacotherapies that are being examined as alternatives to methadone maintenance treatment. The aim of this research is to consider the effects of the methadone, buprenorphine and LAAM, as used in maintenance pharmacotherapy for heroin dependence, upon simulated driving. Clients stabilised in methadone, LAAM and buprenorphine treatment programs for 3 months, and a control group of non-drug-using participants, took part in this study which involved operating a driving simulator over a 75 min period.