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.

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.

Bivariate variance-component analysis, with application to systolic blood pressure and total cholesterol levels in the Framingham Heart Study

Background :
The correlations between systolic blood pressure (SBP) and total cholesterol levels (CHOL) might result from genetic or environmental factors that determine variation in the phenotypes and are shared by family members. Based on 330 nuclear families in the Framingham Heart Study, we used a multivariate normal model, implemented in the software FISHER, to estimate genetic and shared environmental components of variation and genetic and shared environmental correlation between the phenotypes. The natural logarithm of the phenotypes measured at the last visit in both Cohort 1 and 2 was used in the analyses. The antihypertensive treatment effect was corrected before adjustment of the systolic blood pressure for age, sex, and cohort.
Results :
The univariate correlation coefficient was statistically significant for sibling pairs and parent-offspring pairs, but not significant for spouse pairs. In the bivariate analysis, the cross-trait correlation coefficients were not statistically significant for all relative pairs. The shared environmental correlation was statistically significant, but the genetic correlation was not significant.
Conclusion :
There is no significant evidence for a close genetic correlation between systolic blood pressure and total cholesterol levels. However, some shared environmental factors may determine the variation of both phenotypes.

Physical activity for cancer survivors : a meta-analysis of randomised controlled trials

Objective To systematically evaluate the effects of physical activity in adult patients after completion of main treatment related to cancer. Design Meta-analysis of randomised controlled trials with data extraction and quality assessment performed independently by two researchers. Data sources Pubmed, CINAHL, and Google Scholar from the earliest possible year to September 2011. References from meta-analyses and reviews. Study selection Randomised controlled trials that assessed the effects of physical activity in adults who had completed their main cancer treatment, except hormonal treatment. Results There were 34 randomised controlled trials, of which 22 (65%) focused on patients with breast cancer, and 48 outcomes in our meta-analysis. Twenty two studies assessed aerobic exercise, and four also included resistance or strength training. The median duration of physical activity was 13 weeks (range 3-60 weeks). Most control groups were considered sedentary or were assigned no exercise. Based on studies on patients with breast cancer, physical activity was associated with improvements in insulin-like growth factor-I, bench press, leg press, fatigue, depression, and quality of life. When we combined studies on different types of cancer, we found significant improvements in body mass index (BMI), body weight, peak oxygen consumption, peak power output, distance walked in six minutes, right handgrip strength, and quality of life. Sources of study heterogeneity included age, study quality, study size, and type and duration of physical activity. Publication bias did not alter our conclusions. Conclusions Physical activity has positive effects on physiology, body composition, physical functions, psychological outcomes, and quality of life in patients after treatment for breast cancer. When patients with cancer other than breast cancer were also included, physical activity was associated with reduced BMI and body weight, increased peak oxygen consumption and peak power output, and improved quality of life.

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.

Individual boldness traits influenced by temperature in male Siamese fighting fish.

Temperature has profound effects on physiology of ectothermic animals. However, the effects on temperature variation on behavioral traits are poorly studied in contrast to physiological endpoints. This may be important as even small differences in temperatures have large effects on physiological rates including overall metabolism, and behavior is known to be linked to metabolism at least in part. The primary aim of this study was to determine the effects of ambient temperature on boldness responses of a species of fish commonly used in behavioral experiments, the Siamese fighting fish (Betta splendens). At 26°C, subjects were first examined for baseline behaviors over three days, using three different (but complementary) 'open field' type assays tested in a fixed order. Those same fish were next exposed to either the same temperature (26°C) or a higher temperature (30°C) for 10days, and then the same behavioral assays were repeated. Those individuals exposed to increased temperatures reduced their latency to leave the release area (area I), spent more time in area III (farthest from release area), and were more active overall; together we infer these behaviors to reflect an increase in general 'boldness' with increased temperature. Our results add to a limited number of studies of temperature effects on behavioral tendencies in ectotherms that are evident even after some considerable acclimation. From a methodological perspective, our results indicate careful temperature control is needed when studying behavior in this and other species of fish.

Prescribed fluid consumption and its effects on the physiology and work behaviour of Australian wildland firefighters

The present study examined firefighters' ability to consume a prescribed fluid volume (1200 ml · h-1) during a wildland fire suppression shift and compare the effect of this additional fluid prescription with self-paced drinking on firefighters' hydration status and plasma sodium concentration post shift and their heart rate, core temperature and physical activity during their shift. Thirty-four firefighters were evenly divided into two drinking groups: self paced and prescribed. Prescribed drinkers did not meet the required 1200 ml·h-1 intake, yet they consumed twice the fluid drank by the self-paced group. No differences were noted between groups in plasma sodium levels or hydration status before or after their shift. Prescribed fluid consumption resulted in significantly lower core temperature between two and six hours into the shift. This did not coincide with lower cardiovascular strain, greater physical activity when compared to the self-paced drinking group. Additional fluid consumption (above self-paced intake) did not improve firefighter activity or physiological function (though it may buffer rising core temperature). It seems that wildland firefighters, at least in mild to warm weather conditions, can self-regulate their fluid consumption and work behaviour to leave the fireground hydrated at the conclusion of their shift.

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.