Current Clinical Pharmacology - Volume 1, Issue 2, 2006

Programmed cell death also called apoptosis plays a pivotal role in many physiological and pathological conditions. In the multi-step process of drug development, a number of medications are being designed to target strategic checkpoints of the apoptotic cascade either to induce or to inhibit programmed cell death. Conceptually, the assessment of programmed cell death in response to various therapeutic interventions appears to be critical for evaluating the efficacy of many drugs that act through apoptotic pathways. In the last decade, nuclear medicine techniques provided proofs of principle for the imaging of apoptosis both in vitro and in vivo. The purpose of this article was to review current knowledge on the imaging of apoptosis with radiolabelled annexin A5 in various pre-clinical and clinical models, and beyond that, to assess the potential integration of such a dedicated technology into translational research.

The Angiotensin II receptor blockers (ARBs) have been efficacious and safe drugs for the treatment of hypertension, heart failure, diabetic nephropathy and stroke from several short and long term clinical trials. The ARBs exert their effects through selective blockade of the angiotensin II (Ang-II) subtype 1 (AT1) receptor and quite possibly through stimulation by Ang-II of the unoccupied subtype 2 (AT2) receptor. The ARBs are equipotent to other antihypertensive drugs with respect to their effect on blood pressure, heart failure or diabetic nephropathy. They appear to be superior to the other drugs with respect to their stroke protective effect. They exert their stroke protective effect by a dual action, selectively blocking the action of Ang-II on the AT1 receptors, while allowing Ang-II to stimulate the unoccupied AT2 receptors. This dual action is unique to ARBs and results in vasodilation and increase in blood flow to the ischemic zone of the brain leading to improvement and prevention of its extension. All these actions of the ARBs will be discussed in this comprehensive review.

The potential marketplace for biotech-derived products from different bioprocess modifications looms large. However, there is the widespread view that, for biopharmaceuticals, the process makes the product. The current practice includes the physic-chemical and biological tests required to demonstrate structural equivalence of both products, the assessment of the potential impact of process changes on the biological quality of the products, along with their comparability in terms of safety and efficacy endpoints. Interestingly, these procedures were developed to facilitate changes in the processes applied by originators, but at present they have been extended to compare multi-source biopharmaceuticals developed by different manufacturers. Although, we must realize that, as written, the existing recommendations leave substantial room for interpretation. No universally applicable rules have been proposed, so each product must be reviewed on a case by case basis. In this context, the regulatory authorities worldwide have become increasingly aware of such a critical situation associated with this regulatory void surrounding the comparability of complex molecules. This review describes the current state of the art in comparability testing. In addition, the point that any change in process, methods, or specifications would preclude any comparability will also be addressed.

Grapefruit juice (GFJ) interacts with a number of drugs, and can alter pharmacokinetics parameters of the drugs. As for these interactions, most reports have focused on the elevation of drug bioavailability by GFJ, but a few recent reports have indicated that GFJ reduced the absorption of drugs not metabolized by cytochrome P450 (CYP). The predominant mechanisms of GFJ-drug interaction are thought to be due primarily to the inhibition of intestinal CYP3A4 activity without an apparent inhibition of hepatic CYP3A4. GFJ is also an inhibitor of P-glycoprotein, an efflux pump in intestinal cell wall enterocytes, although clinical support for this mechanism remains unclear. In addition, GFJ has recently been shown to be a potent in vitro inhibitor of the organic anion-transporting polypeptides (OATP) 1A2, intestinal uptake transporters of structurally anionic drugs. It is therefore noteworthy that intestinal OATPs-mediated drug uptake are reduced by GFJ. The furanocoumarins, major active ingredients in relation to GFJ-drug interaction, were detected in fresh grapefruit, commercial GFJ and seville orange juice. However, the specific furanocoumarins responsible for the inhibition of CYP3A4 activity in in vitro study have yet to be fully determined and corresponded with GFJ effects in in vivo study. This article summarizes our data concerning GFJ-drug interaction and many GFJ-drug effects, and reviews the mechanism of this interaction, possible active ingredients and clinical implications.

Microdialysis has been developed during the last 25 years by several authors primarily to study brain function and changes in levels of endogenous compounds such as neurotransmitters or metabolites in different laboratory animals. However, in the last ten years microdialysis sampling has been introduced as a versatile technique in the clinical setting. Although, microdialysis sampling has been extensively used for metabolic monitoring in patients, it was also employed for the study of distribution of different therapeutic agents especially anti-infective and antineoplasic drugs. In addition, clinical effect of drugs in patients could be also determined by means of microdialysis. So, this article reviewed the vast applications of the microdialysis technique for the study of pharmacokinetic and pharmacodynamic properties of drugs in the clinical setting.

Selecting, evaluating and applying biomarkers in drug discovery and exploratory drug development do substantially shorten the time to reach a critical decision point. Biomarkers are most useful in the early phase of clinical development when measurement of clinical endpoints or true surrogates may be too time-consuming or cumbersome to provide timely proof of principle or dose-ranging information. The use of biomarkers in early drug development helps to streamline clinical development by determining whether the drug is reaching and affecting the molecular target in humans, delivering findings that are comparable to preclinical data, and by providing a measurable endpoint that predicts desired or undesired clinical effects. Critical decisions such as candidate selection, early proof of mechanism or proof of concept, dose ranging and patient stratification as well as the assessment of development risks regarding safety, toxicity and drug interactions can be based on measurement of appropriate biomarkers that are biologically and/or clinically validated. Preclinical and phase I development plans can be focused to support an early s.d. or m.d. biomarker study in healthy volunteers or mildly diseased patients, thus saving both resources and time. Dose estimates and patient stratification may reduce the size and duration of clinical studies in later phases of development, and safety and toxicity biomarkers may help to stop or continue a programme early on. Even if a biomarker fails in the validation process there may still be a benefit of having used it as more knowledge about pathophysiology of the disease and the drug may be obtained. Thus, appropriateness of biomarkers depends on the stage of development, development strategy and the medical indication. Examples of biomarkers in exploratory clinical development are given for the development of new drugs in various indications.

In male Sprague-Dawley rat model of acute renal failure induced by uranyl nitrate (rat model of U-ARF), the expression of CYP2C11 decreased by 20% of control, whereas that of CYP2E1 and 3A1(23) increased 2-4 and 4 times, respectively, as compared with controls. The expressions of CYP1A2 and 2B1/2 were not changed by U-ARF. The mRNA level of CYP2E1 increased 3 times and that of CYP2C11 decreased to 25% of controls. However, those of CYP1A2, 2B1, 2B2, and 3A2 were comparable to controls. These results of Northern blot analysis were consistent with those of Western blot analysis. Interestingly, however, the mRNA level of CYP3A23 did not increase in rat model of UARF. Hence, the induction of CYP3A23 expression by U-ARF may result from protein stabilization (i.e., a decrease in protein turnover). Hence, in this review, the changes in pharmacokinetics of drugs in rat model of U-ARF [especially the total area under the plasma concentration-time curve from time zero to time infinity (AUC) changes of metabolite(s)] reported from the literatures were tried to be explained in terms of CYP isozyme changes in rat model of U-ARF. Otherwise, the time-averaged nonrenal (Clnr) or total body (Cl) clearance, or AUC of parent drugs were compared.

The diagnosis of drug-induced liver injury is often one of exclusion with initial suspicion based on circumstantial evidence. The natural history, characteristics and limitations of this exclusion process are revised. Also, the numerous published attribution algorithms for evaluation of drug-related liver abnormalities are described and their characteristics and differences are illustrated with true patients from our clinical experience. Situations that complicate the diagnosis such as age, sex, concomitant use of other drugs, genetic polymorphism in metabolic pathways involved in activation or disposition of therapeutic drugs and drug-drug interactions are described. Finally, developing approach to diagnosis of drug-induced liver injury, different of attribution algorithms, are evaluated and explained using a new method based in a Bayesian approach developed and published by the authors. The authors' vision of all these potential advances and their clinical utility is provided.