Structure-based vaccine design in HIV: blind men and the elephant?

Traditional vaccine approaches have failed for HIV and novel strategies are now being sought to develop immunogens designed to elicit specific activity against known broad neutralization epitopes. Structure-based vaccine design has great potential but, thus far, remains a largely unproven concept. Further structural information for the envelope (Env) glycoproteins, gp120 and gp41, is needed, particularly for understanding trimer-specific antibodies and their epitopes and to clarify atomic details of the structural elements responsible for masking crucial epitopes and for mediating the conformational rearrangements undertaken during the process of receptor-binding and membrane fusion.     

Improvement in the handling of drug–drug interactions

Approximately one in 200 hospitalised patients has a serious adverse drug effect caused by drug–drug interactions (DDIs). Such adverse effects should be avoidable, but current information provided on DDIs is often incomplete and difficult or even impossible to translate into true risk and appropriate tangible action. Clinicians need to know the mean and maximal expected effect of a DDI on clinical endpoints, any dose adjustments required, and how to monitor tolerability and efficacy in patients subject to a DDI. To this end, improved study designs should take the objective of improving treatment explicitly into account, and any existing DDI data should be publicly accessible. Modelling needs to be used more extensively in order to quantitatively predict the effects of DDIs on clinical endpoints in patients and to relate clinical endpoint effects considered as acceptable to respective changes in experimental and clinical studies. Computer-based expert systems will be required to convert such DDI data into recommendations applicable to the individual patient. Therefore, the incorporation of DDIs in a more general procedure for personalisation of drug therapy is desirable.     

Potential drug–drug interactions in medical intensive care unit of a tertiary care hospital in Pakistan

Background Patients admitted to intensive care unit (ICU) present with severe and life-threatening illnesses. Most of them suffer from various comorbidities. They usually receive complex pharmacotherapy with large number of medicines which increase the risk of drug–drug interactions (DDIs). Objective The present report aimed to investigate prevalence and levels of potential DDIs (pDDIs) in medical ICU. Methods Medications profiles of 416 patients were checked for pDDIs using Micromedex Drug-Reax^®. Prevalence, levels of severity and levels of documentation were reported. Results Of total 416 patients, 310 were exposed to pDDIs (overall prevalence = 74.5 %). Likewise, a prevalence rate of 13.9 % was recorded for contraindicated pDDIs, 52.2 % for major pDDI and 58.4 % for moderate pDDI. This study reported 740 interacting drug pairs that were presented in total 1686 pDDIs. Of 1686 pDDIs, 4.3 % were of contraindicated severity, 33.8 % of major severity and 49.6 % of moderate severity, whereas 45.5 % were of fair scientific evidence and 41.4 % of good scientific evidence. Conclusion In this study, pDDIs were found highly prevalent in ICU patients at a rate of 74.5 %. Most of the pDDIs had moderate severity; however, substantial number of interactions (38.1 %) had major and contraindicated severity.     

An open future? The principle of autonomy within medical ‘codes of conduct’ versus the heteronomy effects of predictive medicine

Traditionally, the average code of conduct within Western health care starts from the autonomy of the patient. In addition, medicine today is ‘evidence based’ and the patient is an ‘informed consent’. Yet, the individual autonomy of the patient in health care is not simply enhancing today. Quite a few fundamental changes have and are currently at work within health care, which I will summarize here with the paradigm of predictive medicine. One of the characteristics of this paradigm is the increase of medical consults which are not autonomously chosen by an individual. For reasons of public health and diminishing of health risks or for reasons of prevention, on one hand we are dealing with ethical codes centered around the autonomy of patients and the face-to-face relations with health care workers, on the other, we are dealing with a society that takes an increasingly greater medical initiatives. Therefore, the question arises if predictive medicine confronts us with the limits of an ethical code as we know it today. Is there not an urgent need for a political code of conduct in health care?     

“Quite a Profoundly Strange Experience”: An Analysis of the Experiences of Salvia divinorum Users

Salvia divnorum (an intense hallucinogen) is currently illegal in New Zealand under the 2014 Psychoactive Substances Amendment Act. Despite this, there is a scarcity of research surrounding Salvia divinorum and its effects in a New Zealand context. To explore the experiences of Salvia divinorum users, an anonymous questionnaire was advertised through flyers placed in locations where young adults congregate. A total of 393 people took part in the online questionnaire in 2010–2011, while salvia was legally available in New Zealand; 167 respondents had used salvia. Thematic analysis was used to analyze the resulting open-ended questionnaire data and three key themes were identified: the effects of salvia; the importance of set and setting; salvia use and pleasure/not-pleasure. Recreational use of salvia was situated within a broader drug landscape, with participants being drug experienced and “drug wise” (Measham, Aldridge, and Parker 2001). Use of salvia also appeared to be intermittent, with its use referred to as a novel experience. Thus, the recent criminalization of salvia under the 2014 Act may see a significant decline in use as experienced drug users look elsewhere for novel drug experiences.     

Iboga interactions with psychomotor stimulants: panacea in the paradox?

Currently, no effective therapy has been approved for the treatment of addiction to stimulant drugs (e.g., cocaine, amphetamine and its methylated derivatives). However, preclinical studies indicate that the naturally-occurring indole alkaloid, ibogaine, and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), attenuate stimulant self-administration in laboratory animals. The in vivo pharmacological interactions between iboga agents and stimulant drugs are unclear. Ibogaine enhances the increase in accumbal dopamine produced by the acute administration of stimulant drugs. Consistent with these data, both ibogaine and 18-MC potentiate the expression of stimulant-induced motor behaviors in acute and chronic stimulant-treated animals. To account for the paradox between their effects on self-administration and motor behavior, we proposed that iboga agents interfere with stimulant self-administration by increasing sensitivity to their psychomotor-activating effects. However, this interpretation is contradicted by very recent observations that 18-MC is without effect on the dopamine response to acute cocaine and that both ibogaine and 18-MC block the expression of sensitized levels of dopamine in the nucleus accumbens produced by chronic cocaine administration. Thus, a positive relationship exists between the effects of iboga pretreatment on stimulant-induced dopamine sensitization and stimulant self-administration behavior. These data indicate that iboga agents might attenuate stimulant self-administration by reversing the neuroadaptations theoretically implicated in drug craving and compulsive drug-seeking behavior.     

An update on the potential role of intestinal first-pass metabolism for the prediction of drug–drug interactions: the role of PBPK modeling

Introduction: The intestinal absorption process is a combination of several events that are governed by various factors. Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes. The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs. Many studies have provided clear evidence on the significant role of intestinal first-pass metabolism on drug bioavailability and degree of drug–drug interactions (DDIs).

Areas covered: This review provides an update on the role of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs. It also provides a comprehensive overview and summary of the latest update in the role of physiologically based pharmacokinetic models modeling in prediction of intestinal metabolism and DDIs in humans.

Expert opinion: The contribution of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs has become more evident over the last few years. Several in vitro, in situ, and in vivo models have been developed to evaluate the role of first-pass metabolism and to predict DDIs. Currently, physiologically based pharmacokinetic modeling is considered the most valuable tool for the prediction of intestinal first-pass metabolism and DDIs.     

An investigation of the use of Nile Red as a long-wavelength fluorescent probe for the study of α1-acid glycoprotein-drug interactions

Spectrofluorimetry in the long-wavelength region of the electromagnetic spectrum (600–1000 nm) is a fairly recent development in photoluminescence spectroscopy, which has numerous advantages over measurements in the more conventional ultraviolet and visible spectral region. 9-Diethylamino-5H-benzophenoxazine-5-one (Nile Red) is an unchanged, hydrophobic molecule, and long-wavelength fluorescence of which is strongly influenced by the polarity of its environment. When Nile Red was added to solutions of α₁-acid glycoprotein (Orosomucoid. OMD), it showed an enhancement in fluorescence intensity and a shift to blue in emission wavelength, suggesting it was binding hydrophobically to a non-polar site on the protein. The association constant (12 261 000 ± 900 000 M⁻¹) and number of binding sites (0.746 ± 0.044) were calculated for the probe. Upon addition of both acidic and basic drugs, the Nile Red fluorescence reverted to its unbound form, indicating that OMD probably has one high-affinity, wide and flexible binding area for such drugs. Possible enantiomeric selectivity was shown with ephedrine, and the association constant determined for a racemic mixture of propranolol was found to be comparable to other values obtained with alternative, more conventional techniques.     

An update on the advancements in the treatment of agitation in Alzheimer’s disease

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks safe and effective long term interventions. Nonpharmacological interventions are suggested as first-line treatment, but aren’t effective for every patient, resulting in pharmacological interventions for some patients, consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; where efficacy doesn’t necessarily outweigh associated risks.

Areas covered: Gains in understanding neurobiological mechanisms underlying agitation have fueled several recent clinical trials. This article updates our review published in 2014. Comprehensive literature search for published articles from January 2014 to December 2016 evaluating pharmacologic interventions for agitation in AD was done. A review of several clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, citalopram, escitalopram, pimavanserin, ITI-007, ORM-12741 show promise in treating agitation.

Expert opinion: Neurobiological findings, innovative trials designs, statistical approaches, and preliminary paths for regulatory agency acceptance have re-ignited the area of pharmacological treatment of NPS. Though further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to find effective treatments for neuropsychiatric symptoms such as agitation in patients with dementia is well underway.     

Psychoneuroimmunology: An area of interest for the psychopharmacologist?

Anecdotal evidence suggesting a causal relationship between psychiatric illness, environmental stress and a malfunctioning immune system goes back to antiquity. Recently, clinical and experimental studies have established the interrelationship between neuro- endocrine regulation, the immune system and abnormalities in central neurotransmission which may be deranged as a consequence of stressful events. This short review is an attempt to assess the evidence implicating altered immune responsiveness in depression and to consider the impact of different types of environmental stress in triggering the immune malfunction. While these findings are of considerable biological importance, it is presently unclear whether the immunological changes are primary or secondary to the disease states.     

Drug interactions and protease inhibitors used in the treatment of hepatitis C: How to manage?

Purpose

The first-generation protease inhibitors (PI) boceprevir and telaprevir combined with pegylated interferon have revolutionized the treatment of type-1 hepatitis C by increasing the rates of sustained virologic response. However, they induce drug interactions, and their clinical relevance is difficult to predict. This review compiles available data on drug–drug interactions (DDI) based on their pharmacokinetic and pharmacodynamic properties with the aim of assisting clinicians in managing DDI

Methods

PubMed, drug interaction databases and hepatology and infectious disease conference abstracts were systematically searched using the key search terms “interaction”, “hepatitis C”, “telaprevir” and “boceprevir”. All known interactions were compiled and reclassified according to their pharmacokinetic and pharmacodynamic mechanisms. The state of knowledge of interaction mechanisms are reported and a therapeutic approach is proposed.

Results

Boceprevir and telaprevir are both substrates and potent inhibitors of cytochrome P450 3A4 and the drug transporter P-glycoprotein. They induce overdosage but can sometimes decrease the effect of other drugs by inducing other cytochromes. Overdosage or low dosage mainly affects drugs with a narrow therapeutic range, such as immunosuppressants or antiretrovirals. The distribution and elimination of PI are unaffected by interactions. In terms of pharmacodynamic interactions, PI can trigger drug-induced QT interval prolongation, which means that clinicians should manage such risk factors as potassium/magnesium levels or avoid other QT-prolonging drugs.

Conclusions

Management of hepatitis C therapy is complex. The key to interpreting DDI data is a solid understanding of the pharmacokinetic and pharmacodynamic profiles of the drugs involved. Their ability to inhibit cytochrome P450 3A4 and prolong the QT interval can have significant clinical consequences. This review provides a practical guide to the safe and effective management of therapy with boceprevir and telaprevir.     

Novel oral anticoagulants in the treatment of acute coronary syndromes: is there any room for new anticoagulants?

Thrombosis plays a key role in the pathophysiology of acute coronary syndromes (ACS). The management of patients with ACS includes interventional procedures and use of antithrombotic agents acutely, and dual antiplatelet therapy (aspirin and a P2Y12 receptor antagonist) for secondary prevention. However, patients with recent ACS remain at a substantial residual risk for recurrent ischemic events or death. The idea of follow-up treatment with an oral anticoagulant on top of standard therapy seems promising. Warfarin was the first oral anticoagulant thoroughly investigated in this direction, but the widespread long-term use of warfarin in ACS has been limited by challenges associated with pharmacodynamic/pharmacokinetic deficiencies of the drug and the risk of bleeding. Novel oral anticoagulants, such as direct thrombin inhibitors (DTIs) and FXa inhibitors overcome the downsides of VKAs. Ximelagatran was the first DTI, investigated and proven to be effective in prevention of recurrent ischemic events in ACS patients, but the drug association with hepatotoxicity prompted its withdrawal. Dabigatran etexilate, apixaban, darexaban (YM150) and TAK-442 were studied in phase II dose-escalation trials in order to determine the balance between clinical effectiveness and bleeding risk in daily use with dual antiplatelet therapy, with both positive and negative results. Rivaroxaban is the only agent that completed a phase III trial, showing reduction in recurrent ischemic events rate and death from cardiovascular causes as well as all-cause death. This review summarizes the data from completed and ongoing clinical trials of the new oral anticoagulants in patients with ACS.     

An analysis of media framing of and by Cannabis Social Clubs in Belgium: making the news?

Abstract

Aims: Cannabis Social Clubs (CSCs) are non-profit organizations that supply cannabis among their adult members. The goal of this paper is twofold: (1) to understand how Belgian CSCs have attempted to frame public debate through the media, and (2) to examine the ways in which the Belgian CSCs have been framed by that same domestic print media. Methods: We draw on semi-structured interviews with 15 CSC directors and a qualitative content analysis of Belgian print media (2006–2016), including 164 media articles. This dataset is complemented by a review of various Belgian CSCs’ internal documents. Findings: Most Belgian CSCs engaged with the domestic media. While the framing of the CSC model often focussed on legal issues, the news articles offered also some detail on CSCs’ functioning, in line with their self-defined practices. We noted a subtle shift in the framing over time. Conclusions: CSCs’ efforts in engaging with the media seem to have been somewhat successful, as they were able to contribute to the news production about the model. The media reporting was also generally less biased than previously anticipated. However, a public or political debate on the CSC model does not seem to have yet been initiated in Belgium.     

Quō vādis? Short-term medical missions in a globalized world and the role of pharmacy

Short-term medical missions (STMMs) have evolved in the past few decades to provide non-emergent care including routine and follow-up primary care for acute and chronic conditions, along with treatment of neglected tropical diseases. Many STMMs operate outside the local health care infrastructure and may have limited local partnerships. STMM outcomes in improving local population health are often inferred but not well documented. Concerns such as ethical conduct, provider bias, and lack of adequate training and preparation continue to be raised. When disruptions occur (e.g., the COVID-19 pandemic), STMMs need to develop and prepare for challenges such as the inability to travel and provide care. Pharmacists as health professionals play a unique role when volunteering in STMMs. However, pharmacists’ roles in STMMs need further development along with a framework to guide STMM work. Often driven by a few dynamic individuals, STMMs need to be aware of local geo-socio-political issues and develop local partnerships toward a meaningful legacy of building sustaining, long-lasting systems that will continue to serve others beyond the life of the STMMs and their founders.