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Journal: Basic & clinical pharmacology & toxicology


Cross-neutralisation has been demonstrated for haemorrhagic venoms including Echis spp. and Cerastes spp. and for Australia elapid procoagulant toxins. A previous study showed that commercial tiger snake antivenom (TSAV) was able to neutralise the systemic effects of the Egyptian cobra, Naja haje, in vivo but it is unclear if this was true cross-neutralisation. The aim of the current study was to determine whether TSAV can neutralise the in vitro neurotoxic effects of N. haje venom. Both Notechis scutatus (10 μg/ml) and N. haje (10 μg/ml) venoms caused inhibition of indirect (supramaximal V, 0.1 Hz, 0.2 msec.) twitches of the chick biventer cervicis nerve-muscle preparation with t(90) values (i.e. the time to produce 90% inhibition of the original twitch height) of 26 ± 1 min. (n = 4) and 36 ± 4 min.; (n = 4). This effect at 10 μg/ml was significantly attenuated by the prior addition of TSAV (5 U/ml). A comparison of the reverse-phase HPLC profiles of both venoms showed some similarities with peak elution times, and SDS-PAGE analysis elucidated comparable bands across both venoms. Further analysis using Western immunoblotting indicated TSAV was able to detect N. haje venom, and enzyme immunoassay showed that in-house biotinylated polyclonal monovalent N. scutatus antibodies were able to detect N. haje venom. These findings demonstrate cross-neutralisation between different and geographically separated snakes supporting potential immunological similarities in snake toxin groups for a large range of snakes. This provides more evidence that antivenoms could be developed against specific toxin groups to cover a large range of snakes.

Concepts: Toxin, Venom, Snake, Antivenom, Neurotoxin, Elapidae, King Cobra, Tiger snake


Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men; an effect that may be inherent in sex differences in propofol metabolism.

Concepts: Male, Sexual dimorphism, Sexual selection, Gender, Sex, Sexual reproduction, Mating, Operational sex ratio


Oseltamivir, an anti-influenza virus drug, has strong antipyretic effects in mice (Ono et al., 2008) and influenza patients. In addition, hypothermia has been reported as an adverse event. The prodrug oseltamivir is converted to oseltamivir carboxylate (OC), an active metabolite of influenza virus neuraminidase. In this study, core body temperature was measured in mice, and oseltamivir and OC were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p). Low i.c.v. doses of oseltamivir and OC dose-dependently produced hypothermia. Zanamivir (i.c.v.), another neuraminidase inhibitor, did not produce hypothermia. These results suggested that the hypothermic effects of oseltamivir (i.p. and i.c.v.) and OC (i.c.v.) are not due to neuraminidase inhibition. OC (i.p.) did not lower body temperature. Although mecamylamine (i.c.v.) blocked the hypothermic effect of nicotine administered i.c.v., the hypothermic effects of oseltamivir and OC (i.c.v.) were not blocked by mecamylamine (i.c.v.). The effect of oseltamivir (i.p.) was markedly increased by s.c.-preadministered mecamylamine and also hexamethonium, a peripherally acting ganglionic blocker, suggesting their potentiating interaction at peripheral sites. The hypothermic effect of nicotine (i.c.v.) was decreased by lower doses of oseltamivir (i.c.v.), suggesting the anti-nicotinic action of oseltamivir. These results suggest that oseltamivir (i.p.) causes hypothermia through depression of sympathetic temperature regulatory mechanisms via inhibition of nicotinic receptor function and through unknown central mechanisms.

Concepts: Hypothermia, Influenza, Acetylcholine, Nicotinic acetylcholine receptor, Oseltamivir, Neuraminidase, Viral neuraminidase, Mecamylamine


Epidemiological data, including prevalence, for cannabinoid hyperemesis syndrome (CHS) remain largely unknown. Without these data, clinicians often describe CHS as “rare” or “very rare” without supporting information. We seek to estimate the prevalence of CHS in a population of patients presenting to a socioeconomically and racially diverse urban Emergency Department of a public hospital. This study consisted of a questionnaire administered to a convenience sample of patients presenting to the ED of the oldest public hospital in the United States. Trained Research Associates (RAs) administered the questionnaire to patients between the ages of 18-49 years who reported smoking marijuana at least 20 days per month. The survey included questions related to CHS symptoms (nausea and vomiting) and Likert scale rankings on eleven symptom relief methods, including “hot showers.” Patients were classified as experiencing a phenomenon consistent with CHS if they reported smoking marijuana at least 20 days per month and also rated “hot showers” as five or more on the ten-point symptom relief method Likert scale for nausea and vomiting. Among 2,127 patients approached for participation, 155 met inclusion criteria as smoking 20 or more days per month. Among those surveyed, 32.9% (95% CI, 25.5% - 40.3%) met our criteria for having experienced CHS. If this is extractable to the general population, approximately 2.75 million (2.13 - 3.38 million) Americans may have suffered from a phenomenon similar to CHS. This article is protected by copyright. All rights reserved.

Concepts: Disease, Hospital, United States, Symptoms, Symptom, Vomiting, Nausea, Copyright


A novel antihypertensive drug, LCZ696 (Entresto(®) ), has recently been introduced, which combines the action of an antagonist of the renin-angiotensin-aldosterone-system (RAAS), effectively decreasing the blood pressure, with an inhibition of neprilysin, which is responsible for metabolizing natriuretic peptides exerting anti-hypertensive and anti-fibrotic effects. In this MiniReview, we describe the pharmacokinetics and -dynamics, efficacy and side effects of the combined angiotensin receptor antagonist and neprilysin inhibitor LCZ696. We summarize the effect of LCZ696 treatment of patients suffering from hypertension and heart failure (HF) and further highlight the role of this new drug as a treatment option in the future. In the earlier stages of the treatment of patients with heart failure, LCZ696 was superior in lowering the blood pressure compared to olmesartan, while the effect on blood pressure at long-term treatment was comparable for the two drugs. The numbers of adverse effects were comparable. LCZ696 was superior to enalapril in reducing mortality, hospitalizations and HF symptoms. Adverse effects were reduced with a slower up-titrating regimen of 6 weeks. The current results are promising and suggest that LCZ696 will be a new candidate for first-line treatment of HF. However, it needs to be explored whether LCZ696 is safe in pregnant women, what are the effects of long-term LCZ696 treatment on survival, and whether the anti-fibrotic effects can be of major benefit in e.g. HF with preserved ejection fraction. This article is protected by copyright. All rights reserved.

Concepts: Pharmacology, Myocardial infarction, Hypertension, Blood pressure, Renin-angiotensin system, Angiotensin II receptor antagonist, Antihypertensive drug, Antihypertensive agents


While the harmful effects of alcohol during pregnancy are well established, the consequences of alcohol intake during lactation have been far less examined. We reviewed available data on the prevalence of alcohol intake during lactation, the influence of alcohol on breastfeeding, the pharmacokinetics of alcohol in lactating women and nursing infants, and the effects of alcohol intake on nursing infants. A systematic search was performed in PubMed from origin to May 2013, and 41 publications were included in the review. Approximately half of all lactating women in Western countries consume alcohol while breastfeeding. Alcohol intake inhibits the milk ejection reflex, causing a temporary decrease in milk yield. The alcohol concentrations in breastmilk closely resemble those in maternal blood. The amount of alcohol presented to nursing infants through breastmilk is approximately 5-6% of the weight-adjusted maternal dose, and even in a theoretical case of binge drinking, the children would not be subjected to clinically relevant amounts of alcohol. Newborns metabolise alcohol at approximately half the rate of adults. Minute behavioural changes in infants exposed to alcohol-containing milk have been reported, but the literature is contradictory. Any long-term consequences for the children of alcohol-abusing mothers are yet unknown, but occasional drinking while breastfeeding has not been convincingly shown to adversely affect nursing infants. In conclusion, special recommendations aimed at lactating women are not warranted. Instead, lactating women should simply follow standard recommendations on alcohol consumption. This article is protected by copyright. All rights reserved.

Concepts: Infant, Milk, Breastfeeding, Oxytocin, Lactation, Breast milk, Drinking culture, Breast pump


Delta-9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, may inhibit the cytochrome P450 enzyme CYP2C9. Consequently, cannabis use might infer a risk of drug-drug interaction with substrates for this enzyme, which includes drugs known to have a narrow therapeutic window. In this study, we describe a case report of a 27-year-old man treated with warfarin due to mechanical heart valve replacement who presented with elevated international normalized ratio (INR) value (INR = 4.6) following recreational cannabis use. We conducted a review of the available literature, using the PubMed and EMBASE databases while following PRISMA guidelines. Following screening of 85 articles, three eligible articles were identified, including one in vitro study and two case reports. The in vitro study indicated that THC inhibits the CYP2C9-mediated metabolism of warfarin. One case study reported of a man who on two occasions of increased marijuana use experienced INR values above 10 as well as bleeding. The other case study reported of a patient who initiated treatment with a liquid formulation of cannabidiol (CBD) for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic INR values. The available, although sparse, data suggest that use of cannabinoids increase INR values in patients receiving warfarin. Until further data are available, we suggest patients receiving warfarin be warned against cannabis smoking. This article is protected by copyright. All rights reserved.


At the time that Paracelsus coined his famous dictum, “What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison,” embryonic toxicology was a fairly focused discipline that mainly dealt with occupational poisonings and side effects of pharmaceuticals, such as mercury. While Paracelsus paved the way for the modern threshold concept and the no-adverse effect level, modern-day toxicology is now tussling with highly complex issues, such as developmental exposures, genetic predisposition and other sources of hypersusceptibility, multiple causes of underestimated toxicity, and the continuous presence of uncertainty, even in regard to otherwise well-studied mercury compounds. Further, the wealth of industrial chemicals now challenges the “untested-chemical assumption,” that the lack of documentation means that toxic potentials can be ignored. Unfortunately, in its ambition to provide solid evidence, toxicology has been pushed into almost endless replications, as evidenced by the thousands of toxicology publications every year that focus on toxic metals, including mercury, while less well-known hazards are ignored. From a public health viewpoint, toxicology needs to provide better guidance on decision-making under ever-present uncertainty. In this role, we need to learn from the stalwart Paracelsus the insistence on relying on facts rather than authority alone to protect against chemical hazards. This article is protected by copyright. All rights reserved.

Concepts: Chemical element, Metal, Toxicology, Mercury, Toxicity, Poison, All rights reserved, Copyright


Due to the risk of hepatotoxicity when excessive amounts of paracetamol are consumed, Poisons Information Centers (PICs) frequently receive paracetamol-related enquiries. This study examined how widely pack size restrictions of paracetamol sold over-the-counter have been implemented in Europe and also availability of paracetamol through non-pharmacy outlets and their possible associations with frequency of poisoning enquiries. A cross-sectional European multicentre questionnaire study was performed using a questionnaire to identify the extent and nature of paracetamol pack size restrictions, non-pharmacy outlet sales and the frequency of paracetamol-related enquiries to PICs. In total, 21 European countries participated. All PICs provided telephone hotline services. In 14 (67%) countries, pack size restrictions had been implemented in pharmacies (range: 8-30 grams). No significant difference (median difference 0.7%, p-value=0.36) was found when comparing median frequencies of paracetamol-related enquiries in countries with pack size restriction to countries without restrictions. A significantly lower median frequency of paracetamol-related enquiries was found in countries without non-pharmacy outlet sales compared to those with such sales (median difference 2.2%, p = 0.02). Pack size restrictions on pharmacy sales of paracetamol have been implemented in two thirds of examined countries. There was no difference in the proportion of paracetamol-related enquiries to PICs among countries with and without pack size restrictions. However, a lower rate of paracetamol-related enquiries was noted in countries where paracetamol was not available in non-pharmacy outlets. This article is protected by copyright. All rights reserved.

Concepts: Europe, Paracetamol, Frequency, Poison, Pharmacy, All rights reserved, Copyright, Note


In this MiniReview, we provide general considerations for the planning and conduct of pharmacoepidemiological studies of associations between drug use and cancer development. We address data sources, study design, assessment of drug exposure, ascertainment of cancer outcomes, confounder adjustment and future perspectives. Aspects of data sources include assessment of complete history of drug use and data on dose and duration of drug use, allowing estimates of cumulative exposure. Outcome data from formal cancer registries are preferable, but cancer data from other sources, e.g., patient or pathology registries, medical records or claims are also suitable. The two principal designs for observational studies evaluating drug-cancer associations are the cohort and case-control designs. A key challenge in studies of drug-cancer associations is the exposure assessment due to the typically long period of cancer development. We present methods to examine early and late effects of drug use on cancer development and discuss the need for employing ‘lag-time’ in order to avoid reverse causation. We emphasize that a new user study design should always be considered. We also underline the need for ‘dose-response’ analyses, as drug-cancer associations are likely to be dose-dependent. Generally, studies of drug-cancer associations should explore risk of site-specific cancer, rather than cancer overall. Additional differentiation may also be crucial for organ-specific cancer with various distinct histological subtypes (e.g., lung or ovary cancer). We also highlight the influence of confounding factors and discuss various methods to address confounding, while emphasizing that the choices of methods depend on the design and specific objectives of the individual study. In some studies, use of active comparator(s) may be preferable. Pharmacoepidemiological studies of drug-cancer associations are expected to evolve considerably in the coming years, due to the increasing availability of long-term data on drug exposures and cancer outcomes, the increasing conduct of multinational studies, allowing studies of rare cancers and subtypes of cancer, and methodological improvements specifically addressing cancer and other long-term outcomes. This article is protected by copyright. All rights reserved.

Concepts: Scientific method, Experimental design, Epidemiology, Cancer, Confounding, Case-control study, All rights reserved, Copyright