Current Drug Therapy (v.4, #1)

Editorial by Joachim Wernicke (1-1).
On starting a new year, one usually reflects upon the recent past. Perhaps in more than many other years, changes, some good and some not so good, appeared to be the hallmark of 2008. One of the good changes, often overlooked, is the accrual of knowledge. In few areas, this is more important than the medical sciences. Although there is much to do and the number of questions seems to be growing rather than becoming smaller, much has been learned, and there has been a lot of progress. Current Drug Therapy is pleased to participate in the dissemination of information about this progress. In keeping with the tradition of providing readers an array of informative review articles and reports of original research, this issue contains papers on a variety of topics, briefly summarized here in the order in which they appear. All drugs have unwanted effects. Strategies to minimize these side effects are being developed, as exemplified by the paper describing the antioxidant properties of cephalospirins used in conjunction with aminoglycosides. In the area of neuropsychopharmacology, we have a review of paliperidone, which is the active metabolite of respiridone. Although not a truly new drug, patients respond differently, and having more treatment options are of value. Advances in understanding of ion channels have led to safer and more effective therapies for patients with cornonary artery disease. Ivabradine, an If channel blocker, lowers heart rate by selective action at the sinoatrial node. In the area of oncology, we have a comprehensive review of mechanisms of platinum resistance. Understanding of how cancer cells resist chemotherapeutic agents, allows the development of new treatment strategies. Understanding of biochemical processes involved in carcinogenesis will likely to lead to the development of new treatments. In this regard, work on the role of mRNA translation in tumor cells provides insight into how inhibition of these processes may lead to the control of tumor growth. Phototherapy, use of drugs in conjunction with light has been hampered by increased risk of skin malignancies. Development of drugs which do not cross link DNA may reduce this risk. Patients suffering with myocardial infarctions may develop arrhythmias, which may themselves be fatal. QT dispersion has been reported to be predictive of ventricular arrhythmias. Trimetazidin is reported to reduce QT dispersion and the frequency of ventricular arrhythmias. One of the cardinal features of Alzheimer's disease is death of cholinergic neurons, leading to decreased acetylcholine mediated neural transmission. Inhibitors of cholinesterases, which metabolize this neurotransmitter have been used in the symptomatic treatment of dementias, but may also modify the pathologic processes involved.

Anti Oxidant Property of New Cephalosporin-Aminoglycoside Fixed Dose Combination by Manu Chaudhary, Arvind Soni, Vivek Dwivedi, Rajesh Sehgal (2-6).
Aminoglycosides are known to cause oxidative stress related toxicities and tissue injuries. Present study was planned to evaluate the effect of aminoglycosides on blood oxidative stress parameters in mice and free radical scavenging potential of cephalosporins, when combined as a single injection with aminoglycosides using chemical vector mediated technology. Mus musculus mice were divided into five groups: Control group animals (treated with normal saline), amikacin treated group, tobramycin treated group, cefepime + amikacin treated group and ceftazidime + tobramycin treated group. A significant improvement in superoxide dismutase (SOD), catalase activities, along with malonaldialdehyde (MDA) levels and creatinine levels were observed in fixed dose combination of cephalosporins and aminoglycosides treated groups as compared to aminoglycosides alone (amikacin and tobramycin) treated groups. These findings indicate that on combining cephalosporins with aminoglycosides using chemical vector mediated technology prevents oxidative stress related tissues injury induced by aminoglycosides.

Paliperidone: A Clinical Review by Ben Green (7-11).
Paliperidone is an antipsychotic recently made available in the US and UK in a special oral extended release form. Paliperidone is a modified form of risperidone namely 9-hydroxyrisperidone, (itself the active metabolite of risperidone). Since risperidone has been available for many years some argue that paliperidone is not a novel antipsychotic but a newly marketed variant. An injectable form, paliperidone palmitate is being trialled. Paliperidone is mainly excreted renally and there is only limited hepatic metabolism. Paliperidone works by partially blocking D2 dopamine receptors and fully blocking serotonin. The normal dosing range for paliperidone is 3-12 mg daily. Efficacy studies with paliperidone indicate that it is effective against schizophrenia and also has a similar side effect profile compared to other antipsychotics. There is an absence of effects on glucose and lipids in comparison with olanzapine. Symptom reduction in schizophrenia occurs as soon as day four of treatment with paliperidone. Clinical experience with risperidone over many years suggests that paliperidone would have a valuable role as an antipsychotic. The entity is not truly novel, but rather than being a variant existing purely for marketing purposes, should be regarded as an upgrade.

Sinus Node If Channel Inhibition - A New Therapeutic Approach to Heart Rate Lowering by Anne Scott, Kirsten Kruszewski, Stephen Leslie (12-18).
Heart rate lowering has an important role in the treatment of coronary artery disease. Lower heart rates extend diastolic filling, facilitating improved myocardial perfusion and reduced myocardial oxygen demand. This has traditionally been achieved with beta-blockers or calcium-channel blockers. Unfortunately both these classes of drugs have sideeffects in a significant minority of patients. The recent development of ivabradine, which acts specifically on the sinoatrial node, offers promise in achieving heart rate reduction without major side effects. Ivabradine selectively and specifically inhibits the If channel which is integral to the generation of the pacemaker current in the sinoatrial node. Initial studies utilising ivabradine show improvements in exercise tolerance and time to developing ischaemia during exercise in patients with chronic stable angina. Ivabradine has no negative inotropic effects and does not appear to have any major side-effects. It has been shown to have similar antianginal and anti-ischaemic effects to atenolol and amlodipine. Animal studies have suggested that ivabradine may have beneficial effects in chronic heart failure leading to improvements in left ventricular function. In humans with stable coronary artery disease, left ventricular dysfunction and heart rates of 70bpm or more, ivabradine appears to reduce rates of revascularisation and hospitalisation for myocardial infarction.

This review article is devoted exclusively to DNA repair and acquired resistance to platinum compounds, with an emphasis on research needs and clinical application. It focuses on the role of genetic variants (gene mutations and SNPs) and epigenetic alterations (methylation and acetylation). Four major DNA repair pathways and one enzymecorrection mechanism are presented: Base Excision Repair, Nucleotide Excision Repair, DNA Double-Strand Break Repair, Mismatch Repair and Direct Damage Reversal. It is suggested that one cause of platinum resistance is more accurately described as alterations of DNA repair system rather than activation of DNA repair mechanism, as this cause of resistance is brought about by changes in genetic and epigenetic regulation. Given what is known, research on DNA repair and platinum resistance might best be directed at 1) transcriptional cis-elements (activators/repressors) within promoters of essential DNA repair genes, 2) effects of epigenetic alterations, and 3) connections between gene expression and DNA methylation or protein acetylation. Special attention should be directed at three interrelationships: between the different DNA repair pathways; between DNA methylation and protein acetylation; and between DNA repair pathways and DNA methylation or protein acetylation. Improved clinical outcomes may be achieved by restoring wild type p53 with small molecule drugs, the use of gene demethylation strategies, individual-targeted treatment of BRCA mutation carrier, and combining platinum compounds with molecularly-targeted drugs such as EGFR inhibitors.

Promising targets for cancer drugs are translation initiation factors. mRNA translation is regulated in many cancers via a combination of protein overexpression and defects in the pathways that signal the translation machinery. Previously, we reported evidence that human RNA structure-modifying helicase rck/p54, a member of DEAD-box family, was highly expressed in most of the malignant cell lines tested and that this expression was linked to the maintenance of growth in cancer cells. In cell growth and differentiation induced by external stimuli, the level of rck/p54 expression was up-regulated during cell proliferation and down-regulated during differentiation. The knockdown of rck/p54 by using siRNA of RCK induced cell growth inhibition through cell cycle arrest at the S phase in HeLa cells. Immunoprecipitation using anti-rck/p54 antibody in HeLa cells demonstrated the co-precipitation of rck/p54 with eIF4E, which is well known to bind to the 5'cap-structure and to be a rate-limiting factor in the initiation of translation. On the other hand, by use of cell and cell free systems we found that rck/p54 acts as a translation repressor of mRNAs such those of as c-myc and hepatitis C virus, which have an internal ribosomal entry site structure. The results of our recent study indicated that rck/p54 contributes to the suppression of the expression of let-7 which targets RAS. These data altogether suggest that rck/p54 positively affects cell growth probably by playing a role in the selection and quantity control of mRNAs at the translational level, leading to the fidelity of desirable gene expression for cell proliferation in cancer cells, which is a newly defined mechanism leading to carcinogenesis.

Natural and Synthetic Furanocoumarins as Treatment for Vitiligo and Psoriasis by Filomena Conforti, Mariangela Marrelli, Federica Menichini, Marco Bonesi, Giancarlo Statti, Eugenio Provenzano, Francesco Menichini (38-58).
Phototherapy has been used for centuries to treat various skin disorders. Numerous inflammatory skin diseases, such as atopic dermatitis and pigment disorders like vitiligo and psoriasis, benefit from ultraviolet light treatment. Psoralen-containing plants have been used for centuries in popular medicine to treat vitiligo, a skin disease characterized by lack of pigmentation. Further advancement in treatments using different psoralen molecules should strive to decrease the possibility of long-term side effects such as cutaneous malignancies. One of the directions for continued refinement of photochemotherapy in the future, as well as one of the new paradigms associated with photochemotherapy itself, is development of other psoralen molecules that do not form bifunctional adducts, which provide a basis for the DNA crosslinking. One such class of furanocoumarins is the methylangelicins (angular furanocoumarins) which only forms monofunctional adducts. There is clearly a theoretical basis that monofunctional adducts would less likely promote cutaneous malignancies as compared to bifunctional adducts. In this review we wish to present recent pharmacological approaches of furanocoumarins, particularly angular furanocoumarins, and a detailed investigation on the photocytotoxicity exerted by these compounds. Furthermore the edible vegetables and fruits which contain these compounds are showed.

Trimetazidine: Does it Actually Reduce QT Dispersion After First Acute Myocardial Infarction? by Khaled El-Meniawy, Hanan Hafez, Hala Bamatraf, Wail Nammas (59-64).
We sought to explore whether trimetazidine addition reduces QT dispersion early after acute myocardial infarction. Prospectively, we randomized 60 consecutive patients with first acute ST elevation myocardial infarction to receive either trimetazidine 20 mg tid (trimetazidine group 30 patients), or placebo (placebo group 30 patients). QT dispersion and corrected QT dispersion were measured on day 3 and day 7 of admission. Patients were followed during hospitalization for the occurrence of ventricular arrhythmias (sustained ventricular tachycardia or ventricular fibrillation). QT dispersion and corrected QT dispersion were significantly lower in trimetazidine group in both days, compared to control group: day 3, 58and#xB1;5 msec versus 78and#xB1;6 msec, and 69and#xB1;11 msec versus 91and#xB1;10 msec, respectively, p andlt; 0.001 for both; day 7, 41and#xB1;7 msec versus 60and#xB1;8 msec, and 47and#xB1;9 msec versus 69and#xB1;6 msec, respectively, p andlt; 0.0001 for both. This finding was consistent in all prespecified subgroups. During hospital stay, 3 patients (10and#x25;) of the placebo group developed sustained ventricular tachycardia and 2 (6.6and#x25;) died of ventricular fibrillation, but no one in the trimetazidine group had such arrhythmias. Conclusion: In patients with first acute myocardial infarction, the addition of trimetazidine significantly reduced both QT dispersion and corrected QT dispersion and reduced the occurrence of ventricular arrhythmias throughout hospitalization.

Since damage to cholinergic neurons was found widely and severely in the brain of Alzheimer's disease (AD) patients in 1970s, many clinical trials of several kinds of cholinomimetics have been actively undertaken to stimulate the central cholinergic system which might be involved in cognitive function. Although there are various drug targets to activate the cholinergic system, only cholinesterase inhibitors prevailed in the clinical trials with regard to AD. At present, three cholinesterase inhibitors donepezil, galantamine, and rivastigmine are prescribed as a symptomatic treatment for AD. This class of drugs inhibits cholinesterase which breaks down acetylcholine), thus raising the level of acetylcholine in the synaptic clefts, activating central cholinergic function and finally leading to improvement of cognitive function, as well as other symptoms associated with AD. Clinical studies revealed that cholinesterase inhibitors reliably improved clinical rating scales of the two co-primary endpoints, typical cognition measured by ADAS-cog (Alzheimer's Disease Assessment Scale cognitive subscale) and global function assessed by CIBIC-plus (Clinician's Interview-Based Impression of Change), in mild-to-moderate AD patients. Furthermore, clinical evidence has accumulated to show efficacy in other states of dementia as well, namely dementia with Lewy bodies and severe AD. In addition to their symptomatic effects in AD, recent pharmacological studies showed that some cholinesterase inhibitors displayed certain disease modifying characteristics, namely interaction with the amyloid processing pathway, neuroprotection and enhancement of adult brain neurogenesis.

In Vitro Microbial Efficacy of Sulbactomax: A Novel Fixed Dose Combination of Ceftriaxone Sulbactam and Ceftriaxone Alone by Sanjay Shrivastava, Sandeep Saurabh, Dharmendra Rai, Vivek Dwivedi, Manu Chaudhary (73-77).
Microorganism susceptible to beta lactam antibiotics are fastly becoming resistant because of production of beta lactamase by microorganisms. This study is aimed at evaluating microbial efficacy of Sulbactomax drug, a novel fixed dose combination of beta lactam antibiotic Ceftriaxone and beta lactamase inhibitor Sulbactam drugs. Efficacy was evaluated on the basis of Minimum Inhibitory Concentration (MIC) and time kill curve analysis in Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Klebsiella pneumoniae. The MIC for Sulbactomax in E. coli was 0.0625 mg/l whereas Ceftriaxone alone showed MIC of 0.25 mg/l. In case of S. aureus and P. aeruginosa MIC were found to be 1 mg/l for Sulbactomax and 2 mg/l for Ceftriaxone. There was significant reduction of MIC values to 8 mg/l of Sulbactomax from 32mg/l of Ceftriaxone in B. subtilis and 2mg/l of Sulbactomax from 16mg/l of Ceftriaxone. In all organisms under study, time-kill curve analysis demonstrated bacterial maximum killing at 6 hours. Sulbactomax demonstrated better bactericidal activity than Ceftriaxone alone. In conclusion, Sulbactomax was found to have more bacterial inhibiting properties than Ceftriaxone alone in in vitro analysis.