A contribution to a new test method for dandruff-inhibiting and “keratolytic” action of drugs

Summary Free cholesterol in lipids from the scalp and hair is predominantly a constituent of epidermal lipids. Therefore, a reduction in cholesterol content induced by a drug indicates a reduction in cell turnover in the epidermis. As, according to the literature, increased cell turnover in the epidermis results in formation of dandruff, a reduction in the proportion of cholesterol should indicate inhibition of the formation of dandruff. Conversely, an increase in free cholesterol should generally indicate a keratolytic effect. So unequivocal an interpretation has not so far been possible in persons with dandruff, as it was not known whether free cholesterol was increased or decreased. In addition, this interpretation was not possible after use of antimicrobial substances, as in vitro investigations had failed to exclude microbial esterification of cholesterol on the scalp. The present investigation has shown that correlation of free cholesterol level with cell turnover is permissible in patients with dandruff, even if antimicrobial drugs are being tested.     

Orphan drugs for rare diseases: is it time to revisit their special market access status?

Orphan drugs are intended for diseases with a very low prevalence, and many countries have implemented legislation to support market access of orphan drugs. We argue that it is time to revisit the special market access status of orphan drugs. Indeed, evidence suggests that there is no societal preference for treating rare diseases. Although society appears to assign a greater value to severity of disease, this criterion is equally relevant to many common diseases. Furthermore, the criterion of equity in access to treatment, which underpins orphan drug legislation, puts more value on health improvement in rare diseases than in common diseases and implies that population health is not maximized. Finally, incentives for the development, pricing and reimbursement of orphan drugs have created market failures, including monopolistic prices and the artificial creation of rare diseases. We argue that, instead of awarding special market access status to orphan drugs, there is scope to optimize research and development (R&D) of orphan drugs and to control prices of orphan drugs by means of, for example, patent auctions, advance purchase commitments, pay-as-you-go schemes and dose-modification studies. Governments should consider carefully the right incentive strategy for R&D of orphan drugs in rare diseases.     

Do ethnicity and gender moderate the influence of posttraumatic stress disorder on time to smoking lapse?

Background

Following a smoking cessation attempt, smokers with posttraumatic stress disorder (PTSD) experience smoking relapse at a higher and faster rate. Black ethnicity and female gender are also associated with lower success rates following smoking cessation. No study to date has prospectively examined how ethnicity and gender may moderate the effect of PTSD on smoking relapse. It was hypothesized that female gender and Black ethnicity would significantly predict early lapse after quitting; further, it was predicted that ethnicity and gender would moderate the effect of PTSD on relapse rate.

Methods

Smokers with PTSD (n = 48) and without PTSD (n = 56) completed ecological momentary assessment (EMA) the week after a quit date, and self-initiated EMA entries after smoking lapse. Smoking abstinence was biologically verified. The sample included Black (62%) and White (38%) participants, and was 50% female. Study hypotheses were tested with Cox proportional hazards regression modeling time to first smoking lapse.

Results

Study results confirmed the main hypothesis, with a significant PTSD × Ethnicity interaction emerging. The effect of PTSD on smoking relapse was significant for White participants but not for Black participants. No significant gender moderation was found.

Conclusion

Taken together, study results support previous research, and suggest that the relationship between smoking and PTSD is stronger for White smokers than for minorities. This study has significant implications for research in smoking and mental disease, as well as for smoking cessation treatments for Black smokers.     

Antiplatelet drugs and platelet reactivity: is it time to halt clinical research on tailored strategies?

Personalized medicine of antiplatelet drugs in cardiovascular patients has led to a significant enthusiasm. Indeed, numerous longitudinal studies showed an association between high platelet reactivity and the recurrence of ischemic events. The first small randomized trials of P2Y₁₂ blockers tailored to each patient’s platelet reactivity yielded encouraging reductions of coronary stent thrombosis in high-risk populations. The discovery of genetic variants contributing to the pharmacodynamic effect of clopidogrel has then paved the way toward a personalized antiplatelet therapy based on reliable and stable genetic tests. This enthusiasm was soon tempered by large interventional trials demonstrating that a platelet function testing-based strategy did not improve clinical outcome and that genetic variants discovered up to now only explained a small part of the pharmacodynamic effect of clopidogrel, thus limiting its clinical use. Looking back to the most recent trials, their target populations and the type of clinical setting, it seems that the one-size-fits all policy regarding antiplatelet drugs may be well acceptable for low-risk patients. On the contrary, integration of the clinical setting as well as other risk factors may help to identify subgroups of patients who could derive a benefit from a truly personalized management of antiplatelet therapy.     

Where to for tobacco regulation: time for new approaches?

From a public health perspective, tobacco remains the number one drug problem facing most countries, even countries such as Australia, which has made considerable headway in reducing tobacco use and associated harm. Clearly more needs to be done, but is it the case that more of the same will be sufficient? In this Harm Reduction Digest based in part on a presentation at the 'International Research Symposium Preventing Substance Use, Risky Use and Harm: What is Evidence-Based Policy?' held in Fremantle, Western Australia in February 2003, the author proposes a new regulatory framework through which to further reduce tobacco-related harm. The paper challenges whether the current profit motive is an appropriate driver of the tobacco industry and suggests a new model of tobacco regulation.     

Use of mode of action data to inform a dose–response assessment for bladder cancer following exposure to inorganic arsenic

In the recent National Research Council report on conducting a dose–response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose–response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose–response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose–response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7–43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies.     

Targeting invasion and egress: from tools to drugs?

A recent resurgence in the use of compounds to study essential biological processes raises important questions concerning the link between fundamental research and drug development. This article discusses many of the issues involved, in the context of host cell invasion and egress by parasites of the Phylum Apicomplexa. In addition, an overview of the key steps in invasion and egress is provided with a particular emphasis on potential parasite protein drug targets.     

Are chemically reactive metabolites responsible for adverse reactions to drugs?

Low molecular weight organic chemicals can be transformed by normal drug-metabolising systems into short-lived metabolites that are inherently reactive towards cellular macromolecules. There is direct evidence that the formation of such chemically reactive metabolites may lead to mutagenesis, carcinogenicity, apoptosis and necrosis in both cell and animal models. A number of drugs associated with non-pharmacological drug toxicities in man have been shown to undergo bioactivation either in vivo or in vitro. We have therefore examined the evidence for the role of reactive metabolites in the three most common drug-induced toxicities: hepatotoxicity, skin reactions and blood dyscrasias.     

AMPA receptor antagonists with additional mechanisms of action: new opportunities for neuroprotective drugs?

Ischaemic stroke of the brain accounts for about one third of all deaths in industrialized countries. Many of the patients who survive are severily impaired. Thus, there is an enormous need for pharmacotherapy for the treatment of ischaemic stroke. Why is such a treatment not available yet? Are the pathophysiological sequelae of brain ischaemia not well understood? Have there been no attempts for clinical development of neuroprotective drugs? Everyone who is engaged in stroke research knows that the opposite is true: The cellular processes occuring after brain ischaemia have been studied for a long time, and we have a thorough understanding of the cellular processes which are involved. Many compounds underwent clinical trials, but most of them failed. One hypothesis to explain this disappointing fact might be that the cellular consequences of stroke are manyfold, but that the clinically tested compounds were selective for only one molecular mechanism. The aim of this review is to give a summary of the pathophysiological mechanisms which occur during and after an ischaemic stroke, and to comment on the preclinical studies where multiple disease-related mechanisms were targeted pharmacologically. Moreover, a novel class of neuroprotective compounds, the oxadiazole derivatives, will be presented. Compounds of this chemical class target two key mechanisms which are important for the pathophysiology of stroke, namely voltage-gated sodium channels, as well as glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype.     

Adolescent sexual activity and cancer risk: physicians’ duty to inform?

Yearly, 33,000 cancer diagnoses in the US are attributed to human papillomavirus (HPV), with cervical cancer the most common. HPV is transmitted through sexual contact; HPV types 16 and 18 cause the majority of ano-genital cancers in men and women. HPV causes ～100% of cervical cancers, ～90% of anal cancers, and ～50% of vaginal, vulvar, and penile cancers. HPV is also involved in ～70% of oropharyngeal cancers (OPCs) in the US. The CDC recommends routine administration to all female (bivalent or quadrivalent vaccine) and male (quadrivalent vaccine) patients at 11–12 years of age; the series may be started as early as 9 years of age. Recent evidence suggests physicians do not universally recommend the vaccine to all adolescents. Additionally, parents may refuse the vaccine due to safety concerns as well as religious and moral beliefs related to onset of sexual debut. It has been suggested physicians should consider discussing HPV vaccine as a cancer prevention tool only, with less focus on the fact that transmission is caused by sexual activity. In this commentary we suggest physicians have a duty to warn parents and adolescents that OPCs may be transmitted through oral sex, which is often perceived as not constituting sexual activity.