Biopsy assessment of drug efficacy in the gastrointestinal tract

When using biopsy pathology in clinical pharmacology to assess drug efficacy in the gastrointestinal tract, a number of questions must be answered: Is the biopsy necessary or more effective than macroscopic views by endoscopy? Can we extract maximal information from the specimen? Are there surrogate serum or other markers that give an overall measure of disease and/or improvement? Indeed, clinicopathological correlation is of paramount importance. If biopsy is to be used, it is important to utilize appropriate scoring systems. Many grading systems use continuous spectra, which are ordinal categorical variables and therefore a grading system of assigned 'numbers' which cannot be used in processes that require continuous variables such as linear regression. The use of grading vs a 'true' score with real numbers must be carefully considered, the site and number of biopsies must be precisely chosen and interobserver reproducibility of results evaluated before undertaking drug trials. Immunocytochemistry and in situ hybridization, however, can provide quantifiable molecular information related to mechanisms of drug action. The biopsy is of significant value as it is a true in vivo assessment if the above caveats are taken into account. However, further work is needed to determine sound histological criteria to assess the efficacy of drugs for use in gastrointestinal disease.     

Endocannabinoids and the gastrointestinal tract: what are the key questions?

Cannabinoid (CB1) receptor activation acts neuronally, reducing GI motility, diarrhoea, pain, transient lower oesophageal sphincter relaxations (TLESRs) and emesis, and promoting eating. CB2 receptor activation acts mostly via immune cells to reduce inflammation. What are the key questions which now need answering to further understand endocannabinoid pathophysiology? GPR55. Does this receptor have a GI role? Satiety, Nausea, Vomiting, Gastro-Oesophageal Reflux, Gastric Emptying. Endocannabinoids acting at CB1 receptors can increase food intake and body weight, exert anti-emetic activity, reduce gastric acid secretion and TLESRs; CB2 receptors may have a small role in emesis. Question 1: CB1 receptor activation reduces emesis and gastric emptying but the latter is associated with nausea. How is the paradox explained? Q2: Do non-CB receptor actions of endocannabinoids (for example TRPV1) also modulate emesis? Q3: Is pathology necessary (gastritis, gastro-oesophageal reflux) to observe CB2 receptor function? Intestinal Transit and Secretion. Reduced by endocannabinoids at CB1 receptors, but not by CB2 receptor agonists. Q1: Do the effects of endocannabinoids rapidly diminish with repeat-dosing? Q2: Do CB2 receptors need to be pathologically upregulated before they are active? Inflammation. CB1, CB2 and TRPV1 receptors may mediate an ability of endocannabinoids to reduce GI inflammation or its consequences. Q1: Are CB2 receptors upregulated by inflammatory or other pathology? Pain. Colonic bacterial flora may upregulate CB2 receptor expression and thereby increase intestinal sensitivity to noxious stimuli. Q1: Are CB2 receptors the interface between colonic bacteria and enteric- or extrinsic nerve sensitivity? Relevance of endocannabinoids to humans. Perhaps apart from appetite, this is largely unknown.     

Is sibutramine more than a slim hope?

Sibutramine (Reductil-Abbott Laboratories), an orally active monoamine re-uptake inhibitor, is marketed in the UK for treating overweight adults. The company claims that it "helps obese patients control their eating". Is the drug worth prescribing?     

Baseline Observation Carry Forward: Reasoning,Properties, and Practical Issues

In some longitudinal drug studies, regulatory agencies suggest baseline observation carry forward (BOCF) as a method of handling patient dropout, despite the existence of many criticisms to BOCF. The reason for using BOCF is not clear to many users who either treat BOCF as an imputation method or consider BOCF to be “conservative” in the sense that it allows treatment effect to be evaluated with a severe penalty for dropouts. In this article we address the following questions and issues: What is the reason for using BOCF? Is BOCF a conservative approach to assessing drug efficacy? Is BOCF reasonable? If not, what are the alternatives? Our discussions are based on both theoretical and practical viewpoints.     

siRNA and the lung: research tool or therapeutic drug?

Oligonucleotide-based therapeutics have been hailed as 'the next great wave of the biotechnology revolution' starting with antisense oligonucleotides (ASOs) nearly 20 years ago to RNA interference (RNAi) currently. Is RNAi just the latest research tool or does it have real potential as a therapeutic drug modality? As a research tool, it is evident that RNAi has revolutionized the biological sciences by allowing selective silencing of messenger RNA (mRNA) expression. With the advent of the postgenomic era, RNAi offers a therapeutic platform on which to identify potential picomolar active drug candidates to any target, including those that are conventionally undruggable. In this review, we will discuss the progress made in developing RNAi therapeutics for the treatment of respiratory diseases.     

Adaptive regression

Adjustment for prognostic covariates is recommended in clinical trials because relative to a t-test, it improves precision and adjusts for treatment imbalances caused by an "unlucky" randomization. But, inclusion of too many covariates can be counterproductive. In the quest to strike a balance between inclusion of all important variables and not going overboard, people have proposed methods such as stepwise regression, whereby the decision to include a covariate depends on post-randomization data. Covariate inclusion decisions are typically based on either the strength of its correlation with the outcome or the degree of treatment imbalance. Are these methods valid? Is there a valid way to analyze such data? These are some of the questions we address.     

Pupillometry in psychopharmacologic experiments

Considering data of various clinical pharmacological studies, in which computer-assisted pupillometry was utilized, we investigated the following questions: What are the effects of drugs of 7 psychopharmacological classes on the human pupil? Do dose-efficacy and time-efficacy curves based on pupillary variables provide cues about pharmacodynamic properties of psychotropic substances? Is there a relationship between pupillometric and critical flicker frequency measures? Is there a relation between pupillometric and quantitative electroencephalographic changes? Are there correlations between static pupillometric and pharmacokinetic (e.g. blood levels) variables? Our investigations demonstrated that static pupillometry-utilized in the described manner and under certain experimental conditions - provide valuable information about effects of psychotropic drugs on the central and autonomous nervous system.     

Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015

Introduction: There are dozens of drugs in development for AD with billions of dollars invested. Despite the massive investment in AD drugs and a burgeoning pipeline, there have been more setbacks and failures than treatment successes.

Areas covered: The classes of drugs that have failed to date include the monoclonal antibodies, the gamma secretase inhibitors, dimebon, neurochemical enhancers, and one tau drug. Data for these compounds were sought through a PubMed search and a clinicaltrials.gov search.

Expert opinion: The obvious question to be posed is: Why are they failing? Is the treatment of symptomatic dementia too late? Are the therapeutic targets incorrect? Are the clinical methodologies imprecise, misleading, or inaccurate? This review summarizes the drugs that have failed during 2010–2015 and offers possible theories as to why they have failed.     

Some Ethical Considerations and the Status of Dietary Advice

Dietary guide-lines are currently given to whole populations whether the recipients have asked for it or not, and this raises ethical and practical problems. If we have not been asked for advice, what right do we have to tell people what they “ought” to eat? Are we sufficiently sure of the benefits of following our advice? Could we, in fact, be wrong about it? Are we sure of the absence of "side effects" of our advice? If not, are we sure that the balance between risk and benefit is favourable? Might our advice, in fact, do more harm than good? Would it not be better to restrict our advice to those at high risk of diet- related cancer? These issues are all discussed. Furthermore, the conclusions from the European Cancer Prevention (ECP) symposium and workshop on public education on diet and cancer are presented. The major conclusion is that the concept of general guide-lines should be abandoned in favour of guide-lines targeted to specific groups. In addition, it is concluded that the recent evidence had led to considerable confusion regarding dietary fibre and cancer, and also regarding dietary fat and cancer. The recent evidence strengthens the association between high intake of fresh fruit and vegetables and low risk of cancers at a number of sites.     

Effects of acarbose on food intake,body weight and fat depots in lean and obese rats

Effects of dietary acarbose at 0, 5, 15 and 50 mg per 100 g diet on food intake and body weight were studied for two months in female rats. The relationships between diet composition, the drug dose and the type of obesity were examined. In lean rats receiving the drug in a high carbohydrate diet (70 Cal.%), mean food intake was similar to control at 5 and 15 mg dietary levels, but was significantly increased at 50 mg. Body weight was significantly reduced only at the 15 mg level. In VMH obese rats receiving the drug in a high carbohydrate diet, it resulted in significant reductions in food intake at the 15 and 50 mg drug levels and in significant reductions in body weight at all three drug levels. In dietary obese rats receiving the drug in a high carbohydrate diet and also in a 32% sucrose drinking solution, food intake and body weight were significantly reduced at each of the drug levels. In dietary obese rats receiving the drug in a high fat diet (70 Cal.%), acarbose at all levels resulted in only small and usually not significant changes in either food intake or body weight. Weight of fat depots were significantly reduced at the 50 mg dietary level in all instances where a high carbohydrate diet was used while at the 5 mg level, fat depots were reduced only in the VMH obese, with the sucrose obese showing a trend for reduced depots. Acarbose in the high fat diet resulted in no significant changes in weight of fat depots. These data indicate that acarbose in a high carbohydrate diet is effective in reducing weight of rats, and that obese usually show a greater reduction in food intake and body weight than lean rats.     

Analysis and design of repeated measures in clinical trials using summary statistics

ABSTRACT

Adjustment for prognostic covariates is recommended in clinical trials because relative to a t-test, it improves precision and adjusts for treatment imbalances caused by an “unlucky” randomization. But, inclusion of too many covariates can be counterproductive. In the quest to strike a balance between inclusion of all important variables and not going overboard, people have proposed methods such as stepwise regression, whereby the decision to include a covariate depends on post-randomization data. Covariate inclusion decisions are typically based on either the strength of its correlation with the outcome or the degree of treatment imbalance. Are these methods valid? Is there a valid way to analyze such data? These are some of the questions we address.     

Serological biochemical markers of surrogate efficacy and safety as a novel approach to drug repositioning

How do pharmaceutical companies find new uses for old or failed drugs? Is there a way to 'manage serendipity' at the very first stage of identifying compounds that could be developed into new drugs? Several approaches are now being pursued by various companies that are dedicated to drug repositioning cross a spectrum of technologies and scientific bases. Biochemical markers could provide significant shortcuts for drug development. In this review, we introduce drug repositioning, approaches to it and their associated challenges. We also highlight a novel class of serological biomarkers, namely neo-epitopes, which have proven successful in repositioning drugs in clinical settings.     

Ghrelin and energy balance: focus on current controversies

Ghrelin is an enteric peptide that is the only known circulating appetite stimulant. This feature of the hormone has garnered widespread attention, as reflected by more than 1000 scientific papers featuring ghrelin that have been published since the first reports of its orexigenic actions, approximately four years ago. In this review, we discuss data that support roles for ghrelin in the short-term regulation of pre-meal hunger and meal initiation, functioning as a unique orexigenic counterpart to short-acting gastrointestinal satiation factors, such as cholecystokinin (CCK). We also highlight evidence indicating that ghrelin satisfies recognized criteria to be viewed as a participant in long-term body-weight regulation--a potential anabolic counterpart to the traditional adiposity hormones, leptin and insulin. We then discuss the following controversial questions in ghrelin research and offer our opinions regarding these debates. (1) Is ghrelin synthesized within the brain? (2) How does ghrelin increase food intake? (3) Does des-acyl ghrelin have a physiologic function? (4) Are there receptors for ghrelin other than GHS-R1a? (5) Does ghrelin regulate insulin secretion? (6) Does ghrelin regulate gastrointestinal motility? (7) Can ghrelin or ghrelin-receptor agonists be used to treat wasting conditions? Finally, we offer a speculative model of ghrelin as a thrifty gene product that evolved to help animals consume and store fat well, thereby increasing their chances of survival during times of famine. We suggest that ghrelin is a "saginary" hormone, from the Latin, saginare, which means, "to fatten".     

Recognition and activation of ryanodine receptors by purines

Ryanodine receptor (RyR) is a tetrameric, high molecular weight protein that functions as a calcium release channel. It plays a key role in phenomena such as signal transduction, excitation-contraction and excitation-secretion coupling. Hyperthermia maligna, central core disease and myocardial infarction have been related with RyR dysfunction. RyR is present as three isoforms in vertebrates: RyR 1 mainly localized in skeletal muscle, RyR 2 in cardiac muscle, and RyR 3 in nervous system. RyR is regulated by a number of physiological and pharmacological factors. Main physiological modulators: calcium, kinases and phosphatases, redox state and energy charge. Main pharmacological regulators: caffeine, dantrolene, ruthenium red, heavy metals and ryanodine. Purines have to do with both, physiological and pharmacological regulation of the RyR activity. So far, the mechanisms of RyR activation by ATP and caffeine have been described in detail using [3H]-ryanodine binding assays and unitary channel activity recorded in planar lipid bilayers. However, some questions remain to be addressed and are at present aim of active scrutiny: How many sites for purines are present in the RyR? Is the same site recognized by nucleotides and methylxanthines? What differences exist among the interaction between RyR and purine bases, nucleosides and nucleotides? Are the phosphate groups important for the recognition of nucleotides? Is the sugar moiety important for the recognition of nucleosides? The review article will examine the most recent specialized literature about the mechanism of activation of RyR by purines with emphasis on reports with approaches of structure-function and structure-activation.     

Challenges and opportunities with modelling and simulation in drug discovery and drug development

The benefits of modelling and simulation at the pre-clinical stage of drug development can be realized through formal and realistic integration of data on physicochemical properties, pharmacokinetics, pharmacodynamics, formulation and safety. Such data integration and the powerful combination of physiologically based pharmacokinetic (PBPK) with pharmacokinetic-pharmacodynamic relationship (PK/PD) models provides the basis for quantitative outputs allowing comparisons across compounds and resulting in improved decision-making during the selection process. Such PBPK/PD evaluations provide crucial information on the potency and safety of drug candidates in vivo and the bridging of the PK/PD concept established during the pre-clinical phase to clinical studies. Modelling and simulation is required to address a number of key questions at the various stages of the drug-discovery and -development process. Such questions include the following. (1) What is the expected human PK profile for potential clinical candidate(s)? (2) Is this profile and its associated PD adequate for the given indication? (3) What is the optimal dosing schedule with respect to safety and efficacy? (4) Is a food effect expected? (5) How can formulation be improved and what is the potential benefit? (6) What is the expected variability and uncertainty in the predictions?     

Early drug safety evaluation: biomarkers, signatures, and fingerprints

When target organ toxicity arises in animal models during routine drug safety evaluation, it raises several key questions: Is this target organ toxicity related to the pharmacology? What is the mode of action (MOA)? Is the target organ toxicity relevant to humans? Pathology or prior knowledge of the compound class may provide clues on a possible MOA for toxicity. However, if this deductive approach yields no results, the inductive approach offered by new technologies can generate novel research leads. For example, toxicogenomics can generate a gene expression profile of the toxicity that can be compared with reference compounds or with other candidate drugs. Similarly, proteomic analysis of the protein profile at the toxic vs. the efficacious dose can provide clues on MOA for the toxicity and may allow differentiation of the pathways of the toxic response from those required for pharmacological activity.     

Challenges and opportunities with modelling and simulation in drug discovery and drug development

The benefits of modelling and simulation at the pre-clinical stage of drug development can be realized through formal and realistic integration of data on physicochemical properties, pharmacokinetics, pharmacodynamics, formulation and safety. Such data integration and the powerful combination of physiologically based pharmacokinetic (PBPK) with pharmacokinetic–pharmacodynamic relationship (PK/PD) models provides the basis for quantitative outputs allowing comparisons across compounds and resulting in improved decision-making during the selection process. Such PBPK/PD evaluations provide crucial information on the potency and safety of drug candidates in vivo and the bridging of the PK/PD concept established during the pre-clinical phase to clinical studies. Modelling and simulation is required to address a number of key questions at the various stages of the drug-discovery and -development process. Such questions include the following. (1) What is the expected human PK profile for potential clinical candidate(s)? (2) Is this profile and its associated PD adequate for the given indication? (3) What is the optimal dosing schedule with respect to safety and efficacy? (4) Is a food effect expected? (5) How can formulation be improved and what is the potential benefit? (6) What is the expected variability and uncertainty in the predictions?     

Regulatory perspectives on multiplicity in adaptive design clinical trials throughout a drug development program

A clinical research program for drug development often consists of a sequence of clinical trials that may begin with uncontrolled and nonrandomized trials, followed by randomized trials or randomized controlled trials. Adaptive designs are not infrequently proposed for use. In the regulatory setting, the success of a drug development program can be defined to be that the experimental treatment at a specific dose level including regimen and frequency is approved based on replicated evidence from at least two confirmatory trials. In the early stage of clinical research, multiplicity issues are very broad. What is the maximum tolerable dose in an adaptive dose escalation trial? What should the dose range be to consider in an adaptive dose-ranging trial? What is the minimum effective dose in an adaptive dose-response study given the tolerability and the toxicity observable in short term or premarketing trials? Is establishing the dose-response relationship important or the ability to select a superior treatment with high probability more important? In the later stage of clinical research, multiplicity problems can be formulated with better focus, depending on whether the study is for exploration to estimate or select design elements or for labeling consideration. What is the study objective for an early-phase versus a later phase adaptive clinical trial? How many doses are to be studied in the early exploratory adaptive trial versus in the confirmatory adaptive trial? Is the intended patient population well defined or is the applicable patient population yet to be adaptively selected in the trial due to the potential patient and/or disease heterogeneity? Is the primary efficacy endpoint well defined or still under discussion providing room for adaptation? What are the potential treatment indications that may adaptively lead to an intended-to-treat patient population and the primary efficacy endpoint? In this work we stipulate the multiplicity issues with adaptive designs encountered in regulatory applications. For confirmatory adaptive design clinical trials, controlling studywise type I error and type II error is of paramount importance. For exploratory adaptive trials, we define the probability of correct selection of design features, e.g., dose, effect size, and the probability of correct decision for drug development. We assert that maximizing these probabilities would be critical to determine whether the drug development program continues or how to plan the confirmatory trials if the development continues.     

Stereochemical aspects of narcotic and psychotropic drug action]

Medicinal drugs are predominantly, whereas narcotic and psychotropic drugs are exclusively exogenous compounds. Three further fundamental properties of the narcotic/psychotropic compounds of significant abuse potential is that they all are of natural (plant or microbial) origin, they contain a large number of chiral atoms, and they influence the neurotransmission processes in the central nervous system. For some of them, the existence of corresponding endogenous ligands have recently been reported. Since exogenous compounds and their endogenous ligands are assumed to bind the same target moiety of the receptor, several fundamental questions arise: To what extent can stereochemical relationships be established between the exogenous compound and its endogenous counterpart? Do they have superimposable moieties? Are the corresponding chiral atoms of the same configuration? Is there a chiral-genetic relationship between the exogenous and endogenous compound? Theoretical aspects and answers to all these questions are sought for morphine, cocaine, LSD, tetrahydrocannabinol, amphetamine and related molecules.     

Lost Opportunities? Prison Needle and Syringe Exchange Schemes

Community needle and syringe exchange schemes (CNSES) have become an established part of harm reduction strategies in the UK. However, prison needle and syringe exchange schemes (PNSES) have not been afforded the same attention. This article explores some of the pertinent issues that surround PNSES debates. The focus is on the UK, although it draws on international sources as the issues presented transcend international borders. To represent the range of considerations that surround PNSES debates the following six questions will be addressed: Are PNSES unrealistic and unpopular? Do PNSES conflict with the duties and principles of the prison service and its staff? Do PNSES affect levels of drug use and drug injection in prison? Would PNSES affect levels of infections? Will drug injectors use PNSES? Will PNSES affect safety and security? The article concludes with a call for a much fuller debate on the issue of PNSES.