Current Clinical Pharmacology - Volume 1, Issue 3, 2006

Photodynamic therapy (PDT) involves the administration of a photosensitizer followed by light irradiation with a specific wavelength, giving rise to irreversible tissue destruction. Hypericin, a herbal extract derived from Hypericum perforatum or St. John's Wort, has minimal toxicity but exhibits potent photo-damaging effects in the presence of light. Hypericin is known to generate a high yield of singlet oxygen and other reactive oxygen species that are associated with photo-oxidative cellular damage. The application of PDT with hypericin for the treatment of cancers such as recurrent mesothelioma and skin cancer has been validated in clinical trials. This mini-review focuses on the investigative studies of hypericin as a potential photodynamic agent in the treatment of nasopharyngeal cancer (NPC) in in vitro and in vivo models. NPC is an enigmatic tumor with a multifactorial etiology and a high incidence in the populations of Southern China.

Sorafenib (BAY 43-9006) is a novel oral bis-aryl urea compound originally developed as an inhibitor to RAF kinase for its anti-proliferative property. It also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-2/3, Flt-3/ and PDGFR-β. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Phase I studies demonstrated that sorafenib was well tolerated, and the recommended phase II dose was 400 mg twice daily continuously. Common toxicities included skin toxicity (rash and hand-foot syndrome), gastrointestinal toxicities (nausea and diarrhea) and fatigue. Anti-tumor activities were observed in multiple tumors types including renal cell carcinoma and hepatocellular carcinoma. Randomized phase III studies in these tumor types are ongoing, and results are eagerly waited.

Cerebral inflammation is a common phenomenon during the progression of neurodegenerative diseases. In general, neurodegenerative diseases have unpredictable clinical courses and timely effective treatment is not available. For effective clinical trials on new drugs, suitable surrogate markers to monitor disease progression are required. The extent of cerebral inflammation could be such a surrogate marker. Nuclear imaging techniques, like positron emission tomography (PET) and single photon emission computed tomography (SPECT), have been applied to monitor inflammatory processes in patients. Neuroinflammation is accompanied by a variety of physiological changes, such as changes in cerebral glucose metabolism and perfusion, cyclooxygenase-2 overexpression and microglia activation. Nuclear imaging has utilized these physiological changes to visualize the inflammatory process in various chronic or acute neurodegenerative diseases. Expression of the peripheral benzodiazepine receptor in activated microglia proved a suitable specific marker to detect neuroinflammation. Currently, radiolabeled COX-2 inhibitors are under investigation for this purpose. The causative of neuroinflammation is often unknown, but the herpes simplex virus (HSV), for example, has been implicated in several neurodegenerative diseases. Recently, antiviral agents and antibiotics have been prepared that might be applicable to discriminate specific viral or bacterial infections. These radiolabeled compounds could also be used to monitor the drug pharmacokinetics noninvasively with PET. This review summarizes the progress that has been made in nuclear imaging of neuroinflammation in neuropsychiatric diseases.

Rapid (premature) ejaculation (RE) is defined as persistent or recurrent ejaculation with minimal sexual stimulation before, upon, or shortly after penetration and before it is wished by the man or his partner. RE is the most frequently encountered sexual complaint of men and couples. Estimates suggest that as many as one third of all sexually active men suffer from RE. RE has been treated with various modalities. These include behavioral therapy, topical applications, oral pharmacotherapy and intracavernosal vasoactive drug injection. The success rates of these modalities are variable, however, to date an approved treatment does not exist. In this article, we review the evidence surrounding the pharmacological management of RE. The search included (i) a MEDLINE search from 1980 through August 2005 limited to Englishlanguage medical literature; (ii) relevant abstracts from 2003, 2004, and 2005; and (iii) a pipeline search for therapeutics in development. The review does not include behavioral therapy. The distinct feature of this review is that the level of evidence supporting each treatment will be discussed in details. Results showed that there is consistent evidence which supports the daily use of paroxetine, clomipramine, sertraline and fluoxetine for the treatment of RE. There is no strong evidence suggesting the use of these previous drugs on an as-needed basis. There is strong evidence to suggest the use of dapoxetine on an as-needed in RE. Available evidence indicates that topical anesthetic agents such as prilocaine-lidocaine and SS-cream appears to be effective in treatment of RE. There is no strong evidence to suggest that PDEI5 could prolong IELT in RE when used on-demand. In conclusion, based on literature data, although some drugs may be effective in treatment of RE, more extended multi-center prospective double-blind, placebo-controlled stopwatch studies on the benefits of SSRIs, SNRIs and PDEI5 in RE are required.

Conventional pharmacokinetic trials in oncology measure the total amount of drug and its metabolites in the plasma of patients. These total drug concentrations are then correlated with clinical parameters such as toxicity and/or drug efficacy. However, total drug concentrations in plasma are often not directly related to tumor or tissue concentrations and the kinetics in (tumor) tissue may be very different from the kinetics of the drug in plasma. As only the unbound fraction of drugs can passively diffuse or can be actively transported across the cell membrane of endothelial cells and penetrate the tissues and tumor cells, binding of drugs to plasma components may, in part, be responsible for the variability in clinical outcomes. Also, variation in binding to cellular components may be important. As an overall consequence, in in vivo models high inter-individual variabilities of drug concentrations in the tumor have been observed, which affected drug activity. Many current cancer drug-therapies aim for a clinical benefit at the edge of acceptable toxicity, without paying attention to (variability in) plasma and tumor or tissue pharmacokinetics. This review discusses the potential applicability of microdialysis, a minimally invasive method used to determine the unbound fraction of drugs in blood or in the interstitial fluid of tissues, in clinical oncology. Although faced with some methodological challenges, the technique offers many advantages over others, and enables direct tumor assessment for pharmacokinetics and even pharmacodynamics.

Chronobiology studies the phenomenon of rhythmicity in living organisms. Circadian rhythms are genetically determined and are regulated by external synchronizers (i.e. light/day cycle). Several biological processes involved in the pharmacokinetics and pharmacodynamics of drugs are subject to circadian variations. Chronopharmacology studies how biological rhythms impact on drug pharmacokinetic (chronokinetics), pharmacodynamics (chronoesthesy) and toxicity and determines whether time of day administration modifies drug's pharmacological characteristics. Chronotherapy applies chronopharmacological studies to clinical treatments, determining the best biological time for its dosing, i.e. when beneficial effects are maximal and incidence and /or intensity of related side-effects and toxicity are minimal. Significant variations in the pharmacokinetics and toxicity of antibiotics (aminoglycosides, beta-lactams and fluoroquinolones) related to administration time are well known. The aims of this review are to discuss, briefly, the currently accepted model of the circadian system that substantiates endogenous rhythmicity and to provide an update on the knowledge of circadian rhythms applied to drugs used as medicines, with a special mention to the possible impact on antimicrobial treatments. It is concluded that the dosing time of an antimicrobial agent might be clinically relevant in some treatments, thus, clinicians should be aware that the dosing time might affect the clinical response of a drug.

This review describes the mechanisms of drug resistance of the most clinically relevant mycobacteria and the methods that have been used for studying drug susceptibility (pnenotype, genotype and in vivo tests) and it describes the more important resistance mechanisms to the drugs. Also, this review describes the relationship between microbiological and pharmacological data and the importance of latency -stationary phase- in mycobacteria. Current clinical guidelines on the treatment of tuberculosis (populations of Mycobacterium tuberculosis within the host, drugs and duration, importance of HIV infection in the treatment of tuberculosis, and treatment of latent tuberculosis) and other diseases caused by mycobacteria (specially associated a Mycobacterium kansasii, Mycobacterium avium complex, Mycobacterium fortuitum and Mycobacterium chelonei) are commented in view of drug resistance information, including the more commonly accepted treatments to these diseases. In addition, the impact of pharmacological studies in predicting response to therapy is reviewed. Finally, it describes the new methods of susceptibility testing and the new antituberculous drugs.

The idea that the liver enzyme cytochrome P450 2A6 (CYP2A6), known also as nicotine C-oxidase, is one of the determinants of smoking addiction and smoking behavior is primarily based on its role in nicotine metabolism and disposition. The results of studies linking the CYP2A6 genetic polymorphism with smoking dependence and smoking behavior however remain controversial. The most likely causes of the controversies appeared to be consideration given to a few allelic variants coupled with the uses of the CYP2A6 alleles lacking in vivo phenotypic validation. In the present review, we summarize research findings on biological significance of CYP2A6 and gene polymorphisms together with a discussion on CYP2A6 inhibitors that hold the promise of uses in smoking cessation. In addition, we provide the phenotype/ genotype information derived from our systematic investigation on the relationship between CYP2A6 genotypes, smoking habits and coumarin metabolism phenotypes in a group of 393 normal adults (197 women and 196 men), 16 to 60 years of age, whose exposure to cadmium and lead were also determined, enabling us to assess the CYP2A6 phenotypic variability associated with CYP2A6 genotypes and environmental exposure. The results indicate that the phenotype of CYP2A6 enzyme in liver is an outcome of interactions between the CYP2A6 gene, cadmium, nicotine and possibly its metabolites.

Irinotecan (CPT-11) significantly improves the efficacy of colorectal cancer treatment, demonstrating a superior efficacy with respect to leucovorin-modulated 5-fluorouracil (5-FU), also in fluoropyrimidine-resistant neoplasms. Preclinical studies demonstrated the inhibition of topoisomerase I by CPT-11 active metabolite 7-ethyl-10- hydroxycamptothecin (SN-38), and the possible synergistic interaction with other drugs effective against colorectal cancer, including 5-FU and oxaliplatin. Because of the occurrence of toxicities due to the large interpatient variability in drug metabolism, irinotecan is a candidate for therapeutic drug monitoring and pharmacokinetic optimisation. New schedules of drug administration (i.e. prolonged infusion) have led to improved cytotoxic effect of irinotecan, which resulted in improved overall survival and time to relapse together with reduced toxicity in comparison with 5-FU-based regimens. Furthermore, the analysis of the conversion of irinotecan into SN-38 by carboxylesterase, the detoxification of irinotecan and SN-38 by CYP3A4 and UDP-glucuronosyl transferases, and the activity of excretory systems (i.e., cMOAT, P-gp and MRP) seems able to predict the interindividual variability in pharmacokinetics and pharmacodynamics, being possible to predict untolerable toxicities. Finally, pharmacogenetics may elucidate drug interaction and gene expression modulation by irinotecan, while pharmacokinetic/pharmacodynamic models represent a valuable approach to further define the pharmacologic profile of irinotecan and improve its therapeutic index.