Journal impact factors: a 'bioequivalence' issue?

AIMS: Journal impact factors (IMFs) are used increasingly by institutions as performance indicators of the quality of 'individual research output'. Although the need for discretion when using the numbers has been emphasized, there has been little formal analysis of the issues. We therefore investigated citation profiles for three clinical pharmacology journals to assess the validity of using IMF as a measure of 'individual research'. METHODS: We compared the pattern of individual citations for random samples of 120 papers published in Clin Pharmacol Ther (CPT), Br J Clin Pharmacol (BJCP) and Eur J Clin Pharmacol (EJCP) in 1981, 1991, 1995 and 1996. Using an analogy between citation-time profiles of papers and concentration-time profiles of drugs, it was possible to define 'lag-time', Cmax, tmax, t(1/2) and AUC(t), and to investigate 'bioequivalence'. RESULTS: Citation distributions for individual publications were widely variable and skewed (skewness = 1.47, 2.16 and 1.37 for CPT, BJCP and EJCP, respectively). The 90% CI values for the IMF of a publication in each journal (i.e. 90% CI for an observation as opposed to 90% CI for the mean) were 0.24-16.94, 0.08-10.3 and 0.09-5.68. CONCLUSIONS: IMF does not represent the impact of an individual paper. Furthermore, if the comparison of journals is treated as a bioequivalence issue, the citation data should be log transformed prior to calculating IMF such that they represent the likelihood of citation for the median article. After such transformation, absolute differences between the IMF of clinical pharmacology journals become much smaller.     

Thalidomide: a new anticancer drug?

Experimental studies have demonstrated that thalidomide (Thal), a drug developed as a sedative, has antitumoural properties. The possible antitumour mechanisms of action involve: inhibition of angiogenesis, cytokine-mediated pathways, modulation of adhesion molecules, inhibition of cyclooxygenase-2 and stimulation of immuno response. Therefore, Thal is under clinical evaluation in oncology. This paper provides an overview of the data currently available in literature regarding, in terms of activity and toxicity, the use of Thal in cancer patients. Multiple myeloma is so far the most responsive malignancy. A moderate activity has been documented in certain solid tumours: glioblastoma multiforme, renal cell carcinoma and malignant melanoma. Tolerability is generally satisfactory with peripheral neuropathy being the most relevant dose-dependent toxicity. The more frequent, but moderate side effects are: somnolence, constipation, dizziness and fatigue. More studies are needed to properly evaluate the anticancer activity of Thal alone or in combination with other anticancer treatments. Preliminary studies suggest promising results of Thal in combinations with corticosteroids and cytotoxic drugs as front-line therapy of multiple myeloma. Regarding therapy of solid tumours in the adult, combination with chemotherapy, radiation therapy and molecular-targeting compounds are under investigation.     

What makes a good drug target?

Novel therapeutics in areas with a high unmet medical need are based on innovative drug targets. Although 'biologicals' have enlarged the space of druggable molecules, the number of appropriate drug targets is still limited. Discovering and assessing the potential therapeutic benefit of a drug target is based not only on experimental, mechanistic and pharmacological studies but also on a theoretical molecular druggability assessment, an early evaluation of potential side effects and considerations regarding opportunities for commercialization. This article defines key properties of a good drug target from the perspective of a pharmaceutical company.     

Is ecstasy a drug of dependence?

This paper examines the evidence for an MDMA or “ecstasy” dependence syndrome. Animal evidence suggests that MDMA may be a less potent reinforcer than other drugs, but that it does have dependence potential. This suggests that (a) ecstasy dependence might be less likely than dependence upon other drugs; and (b) factors related to the behavioural and psychological aspects of reward and dependence may make a relatively greater contribution for ecstasy than for other drugs, where physically centred (and better understood) features of dependence may be more salient. Human evidence supports this proposition. Some people report problems with their use, but the literature suggests that physical features play a more limited role than psychological ones. Tolerance is apparent, and withdrawal is self-reported, but it is unclear whether these reports distinguish sub-acute effects of ecstasy intoxication from symptoms reflective of neuroadaptive processes underlying a “true” withdrawal syndrome. Studies examining the structure of dependence upon ecstasy suggest it may be different from drugs such as alcohol, methamphetamine and opioids. Consistent with studies of hallucinogens, a two-factor structure has been identified with factors suggestive of “compulsive use” and “escalating use”. Regardless of the nature of any dependence syndrome, however, there is evidence to suggest that a minority of ecstasy users become concerned about their use and seek treatment. Further controlled studies are required to investigate this phenomenon.     

Transfollicular drug delivery--is it a reality?

Once regarded as merely evolutionary remnants, the hair follicles and sebaceous glands are increasingly recognised as potentially significant elements in the percutaneous drug delivery paradigm. Interest in pilosebaceous units has been directed towards their use as depots for localised therapy, particularly for the treatment of follicle-related disorders such as acne or the alopecias. Furthermore, considerable attention has also been focused on exploiting the follicles as transport shunts for systemic drug delivery. This paper reviews various key facets of this field including; relevant aspects of pilosebaceous anatomy and physiology, the design and efficacy of follicle-targeting formulations and the emergence of quantitative modeling systems. Several novel developments in this area promise to greatly expand our understanding of this field in the near future.     

Benzylpiperazine: a drug of abuse?

N-benzylpiperazine (BZP) is the active ingredient in recreational 'party' or 'p.e.p.' pills, which are used to provide a stimulant, euphoric effect akin to that of methylenedioxymethamphetamine (MDMA, 'ecstasy'). BZP predominantly affects dopamine neurotransmission in a similar fashion to known 'drugs of abuse', such as methamphetamine and cocaine, which strongly suggests BZP has abuse liability. BZP is illegal in many countries including the United States of America and Australia, yet it remains legal in the United Kingdom, Canada and New Zealand. There has been little research, to date, on the neurological consequences of high dose or chronic exposure of BZP. Here we provide a comprehensive review of the information currently available on BZP and suggest a need for further research into the mechanisms of action, long-term effects and potentially addictive properties of BZP.     

The importance of drug–drug interactions as a cause of adverse drug reactions: a pharmacovigilance study of serotoninergic reuptake inhibitors in France

Purpose  

To quantify the importance of drug–drug interactions (DDIs) in the occurrence of adverse drug reactions (ADRs) reported with serotoninergic reuptake inhibitors in a pharmacovigilance database.     

Proteomics： a new approach for drug discovery

Proteomics is a bridge that crosses genome to drug discovery. Proteomic studies will provide possible targets for therapeutic usage and moreover increase the efficiency of the downstream of drug discovery process. By using the 2-D electrophoresis combining with MS technology, which is most preva-lent techniques of proteome, we have identified more than 20     

What makes a good anti-inflammatory drug target?

This review focuses on the major, 'successful' target families in inflammation and attempts to identify some of the key features of what makes a good anti-inflammatory target. The review is based on a systematic analysis of approved anti-inflammatory drugs grouped according to their drug-target family. The cytokine family is a drug-dense area. They have yielded and continue to yield a rich stream of drugs. As in other therapeutic areas, G-protein-coupled receptors (GPCRs), also known as seven-transmembrane pass receptors, have provided significant drug targets. In addition, the superfamilies of cell adhesion molecules and co-stimulatory molecules, which have special relevance to immune processes, have begun to provide the first approved drugs and might yield many more. The recent, rapid increase in the number of defined targets in the immune system -- leukocyte surface antigens, cytokines, GPCRs, adhesion molecules and co-stimulatory molecules -- will ensure a rich stream of future anti-inflammatory drug targets.     

Biotransformation and in vitro assessment of metabolism-associated drug–drug interaction for CRx-102, a novel combination drug candidate

CRx-102 is an oral synergistic combination drug which contains the cardiovascular agent, dipyridamole (DP) and a very low dose of the glucocorticoid, prednisolone (PRED). CRx-102 works through a novel mechanism of action in which DP selectively amplifies the anti-inflammatory activity of PRED without replicating its side effects. CRx-102 is in clinical trials for the treatment of osteoarthritis. Here we delineate the in vitro metabolism and explore the potential for a drug–drug interaction between the active agents in CRx-102. Our study using human hepatocyte suspensions showed that both DP and PRED were metabolized by CYP3A4 isozymes, resulting in the formation of diverse arrays of both oxidative and oxidative-reduced metabolites. Within phase 1 biotransformation, CYP3A4 was one of the pathways responsible for the metabolism of PRED, while phase 2 biotransformation played a significant role in the metabolism of DP. Glucuronidation of DP was substantial and was catalyzed by many UGT members, specifically those in the UGT1A subfamily. Based on the tandem mass (MS/MS) product ion spectra (PIS) acquired, the major metabolites of both agents, namely, monooxygenated, mono-N-deethanolaminated, dehydrogenated and O-glucuronidated metabolites of DP and the monooxygenated (e.g., 6-hydroxyl), dehydrogenated (prednisone) and reduced (20-hydroxyl) metabolites of PRED, were identified and elucidated. The affinities for DP biotransformation, including CYP3A4-mediated oxidative pathways and UGT-mediated O-glucuronidation, appeared high (K_m < 10 μM), as compared with the modest affinities of PRED biotransformation catalyzed by CYP3A4 (K_m ∼ 40–170 μM). DP, but not PRED, exerted a minimal inhibitory effect on the drug-metabolizing CYP isoforms, including CYP3A4, which was determined using a panel of CYP isoform-preferred substrate activities in pooled human liver microsomal (HLM) preparations and microsomal preparations containing the recombinant enzymes (K_i ∼ 2–12 μM). Using the DP maximal plasma concentration (C_max) observed in the clinic and a predictive mathematical model for metabolism-associated drug–drug interaction (DDI), we have demonstrated that there is little likelihood of a pharmacokinetic interaction between the two active agents in CRx-102.     

Donepezil in a chronic drug user—a potential treatment?

The objective of the current study was to explore the potential cognitive benefits of an anticholinesterase inhibitor, donepezil, in a former chronic drug user. A neuropsychological test battery composed of the vocabulary and matrix reasoning subtests of the Wechsler adult intelligence scale-III, measures of everyday executive functioning (behavioural assessment of the dysexecutive syndrome [BADS]), and verbal learning and memory tasks (California verbal learning test-II; Rivermead behavioural memory test) was completed at baseline, at 3 months after introducing donepezil, and at 3 months after donepezil was discontinued. After donepezil treatment, substantial improvements were found on tasks of nonverbal fluid reasoning (i.e. matrix reasoning) and other executive functioning tests (i.e. BADS). At entry into the study, poor academic performance and subjective problems with memory and concentration were reported, particularly after amphetamine use (i.e. MDMA and crystal methamphetamine); after donepezil treatment, dramatic increases in memory, concentration and academic achievement were observed. The finding of improvements in tests of executive functioning and in academic performance in this case study, together with the minimal adverse side effects of donepezil, warrants the investigation of controlled studies of cholinergic enhancement in chronic amphetamine and other drug users.