Lipophilicity in Drug Development: Too Much or Not Enough?

A round table discussion was held during the AAPS Annual Meeting on October 27, 2015, with the somewhat provocative topic of whether we need more or less lipophilic compounds in drug development. The session was attended by more than 250 participants, and the feedback was very positive as this round table became a forum for the exchange of ideas from scientists within the academia and industry. Most importantly, the discussion highlighted the difference in approaches to compound selection and development strategies in various companies and organizations. As moderators of this session, we are writing this report to highlight the points and counterpoints made at the session and to bring the importance of the dialogue and debate to the forefront of discussions on how to select the best drug development candidates to enable efficient delivery and, hence, treatment of diseases.     

Drug samples: friend or foe?

The common practice of drug manufacturers in providing 'free' samples to physicians has influenced the business of medicine in several ways. This article analyzes some of the pros and cons of drug sampling, including from professional, societal, economical, legal, and practical perspectives, and provides suggestions on how to dispense with some of the problems inherent in the current system.     

Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both?

Six severe epileptic patients developed stuporous encephalopathy with marked cognitive impairment when topiramate (TPM) and sodium valproate (VPA) were coprescribed for five patients, and when monotherapy with TPM was introduced for one patient. In four patients, ammonaemia increased and then returned to normal after TPM or VPA withdrawal. This severe potential side effect must be recognized. Moreover two distinct mechanisms might explain this toxicity: (1). a pharmacokinetic interaction between VPA and TPM, leading to hyperammonaemia, (2). a pharmacodynamic mechanism due to a direct toxicity of TPM in at-risk epileptic patients.     

Drug development in the light of translational science: shine or shade?

Approximately a decade ago, translational medicine was invented both as a catchword and as a novel approach to improve success in drug development and ameliorate the low-output syndrome from collapsing pipelines. However, no major breakthroughs regarding rates of expensive late attrition or market approvals have been detected, and drug industry condensation continues to accelerate. Here, I discuss what went wrong: namely the fact that the concept does not exist apart from general claims and attributes, and no robust structures, such as toolboxes, algorithms, reproducible standards and procedures, and assessment tools have been developed and/or implemented. Translational medicine might be a clue to the survival of biomedical research, but it needs to be filled with scientific and operational substance.     

Drug release in vitro--an aid in clinical trials?

The topic of this article is biopharmacy. Using delayed release tablets with the active ingredient theophylline as a practical example, it was demonstrated that prior to clinical trials, galenical preparations can be characterized according to drug release in vitro and, that profiles of in vitro drug release can be compared with each other (LEVY-plot). Drug release from the retard tablets was examined following the Cube Root Law which describes the dependency of release rate on surface and agitation. Comparing profiles of in vitro release to a hypothetical or even known profile of in vivo release, produce results that are open to interpretation (LEVY-plot). A postulated correlation between the nonanalogous parameters, relative bioavailability and the mean in vitro dissolution time was confirmed. Due to established in vitro/in vivo correlations, we can in our case, predict the hypothetical in vivo release profiles for tablets showing more or less retarded release profiles in vitro and the relative bioavailability can be estimated. In addition, prediction of blood level is possible. In vitro/in vivo correlations can also provide information about residence times of the delayed release tablets in components of the gastrointestinal tract (stomach, small bowel and large bowel). Thus, using these methods, delayed release tablets (with the active ingredient theophylline) can be optimized for their use in clinical trials.     

Drug hybridization strategies: before or after lead identification?

The molecular hybridization approach is one of the most valuable structural modification tools useful for the discovery of ligands and prototypes presenting either optimized affinity for one bioreceptor or the ability to modulate more than one bioreceptor associated with the target disease. The growing efforts to discover hybrid drugs resulting from the combination of pharmacophoric moieties of different known lead compounds have brought a new hope for the treatment of multifactorial diseases in recent years. This editorial describes possible ways of exploring molecular hybridization strategies to plan new effective dual or symbiotic drug candidates.     

Inflamed psoriatic plaques: Drug toxicity or disease exacerbation?

We are presenting a case of Methotrexate treated stable plaque psoriasis, in whom inflamed psoriatic plaques of drug toxicity were misdiagnosed as disease exacerbation. Erosive psoriatic plaques were present in the absence of biochemical or hematological derangements. Ulceration of psoriatic plaques in the presence of disturbed hematological profile is well described as a harbinger of methotrexate toxicity, but this kind of erosions in the absence of any systemic involvement is the first report of its kind.KEY WORDS: Methotrexate toxicity, myelosuppression, psoriasis exacerbation     

Drug Discovery in Academia- the third way?

As the pharmaceutical industry continues to re-strategise and focus on low-risk, relatively short term gains for the sake of survival, we need to re-invigorate the early stages of drug discovery and rebalance efforts towards novel modes of action therapeutics and neglected genetic and tropical diseases. Academic drug discovery is one model which offers the promise of new approaches and an alternative organisational culture for drug discovery as it attempts to apply academic innovation and thought processes to the challenge of discovering drugs to address real unmet need.     

Fragment-Sized Thiazoles in Fragment-Based Drug Discovery Campaigns: Friend or Foe?

Thiazoles exhibit a wide range of biological activities and therefore represent useful and attractive building blocks. To evaluate their usefulness and pinpoint their liabilities in fragment screening campaigns, we assembled a focused library of 49 fragment-sized thiazoles and thiadiazoles with various substituents, namely amines, bromides, carboxylic acids, and nitriles. The library was profiled in a cascade of biochemical inhibition assays, redox activity, thiol reactivity, and stability assays. Our study indicates that when thiazole derivatives are identified as screening hits, their reactivity should be carefully addressed and correlated with specific on-target engagement. Importantly, nonspecific inhibition should be excluded using experimental approaches and in silico predictions. To help with validation of hits identified in fragment screening campaigns, we can apply our high-throughput profiling workflow to focus on the most tractable compounds with a clear mechanism of action.     

Vessel pruning or healing: endothelial metabolism as a novel target?

Introduction: Antiangiogenic drugs were originally designed to starve tumors by cutting off their vascular supply. Unfortunately, when these agents are used as monotherapy or in combination with chemotherapy, they provide only modest survival benefits in the order of weeks to months in most cancer patients. Strategies normalizing the disorganized tumor vasculature offer the potential to increase tumor perfusion and oxygenation, and to improve the efficacy of radio-, chemo- and immunotherapy, while reducing metastasis.

Areas covered: This review discusses tumor vascular normalization (TVN) as an alternative strategy for anti-angiogenic cancer treatment. We summarize (pre)-clinical strategies that have been developed to normalize tumor vessels as well as their potential to enhance standard therapy. Notably, we describe how targeting endothelial cell metabolism offers new possibilities for antiangiogenic therapy through evoking TVN.

Expert opinion: Several drugs targeting VEGF signaling are now clinically used for antiangiogenic cancer treatment. However, excessive blood vessel pruning impedes perfusion and causes tumor hypoxia, known to promote cancer cell dissemination and impair radio-, chemo- and immunotherapy. Normalized vessels lessen tumor hypoxia, impair cancer cell intravasation and enhance anticancer treatment. New data indicate that targeting endothelial cell metabolism is an alternative strategy of antiangiogenic cancer treatment via promotion of TVN.     

Effects of the Amazonian psychoactive beverage Ayahuasca on binocular rivalry: interhemispheric switching or interhemispheric fusion?

An early theoretical analysis supposed changes in hemispheric integration as the basis of altered state of consciousness induced by psychoactive drugs. Brain imaging studies revealed right cortical activation after administration of hallucinogens. Recent studies on binocular rivalry suggest that interhemispheric switching is the neural substrate of the perceptual oscillations observed during dichoptic stimulus presentation. The current study tested perceptual alternation in ceremonial participants, who ingested the South American hallucinogenic beverage ayahuasca, to examine the claim that there might be changes in interhemispheric function under the influence of hallucinogens. Ingestion of ayahuasca resulted in a decrease of rivalry alternation rates, increased length of one percept and there was evidence of phenomenal fusion. The findings are in line with results of brain activation studies and support the concept of interhemispheric fusion in altered states of consciousness.     

Drug Use–Chronic and Relapsing or a Treatable Condition?

It is argued that the term “chronic relapsing disorder,” which is used frequently to characterize drug use, does not capture the complexity of drug treatment evaluation findings and thereby limits an understanding and appreciation of the accomplishments of drug treatment. Specifically, it is noteworthy that a substantial minority (19%) of treated drug users have been found to maintain abstinence over a 6-year period posttreat-ment, and that the three major multisite treatment evaluations sponsored by NIDA have all found that overwhelming majorities of treated drug users do not revert to the levels of drug use (or criminal activity) shown pretreatment. Thus, the view of inevitable and continuing adoption of pretreatment behaviors, i.e., chronic relapse, gives undeserved comfort to those who deny the utility of drug treatment, and does so at a time when changes in the health care industry threaten the integrity of that treatment.