Current Clinical Pharmacology - Volume 4, Issue 1, 2009
Volume 4, Issue 1, 2009
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Rosuvastatin Induced Rhabdomyolysis in a Low Risk Patient: A Case Report and Review of the Literature
Authors: Fahmi Y. Khan and Wael IbrahimWe report a case of rosuvastatin induced rhabdomyolysis in a low risk patient, who presented with five-day history of generalized muscle pain, weakness and easy fatigability associated with passing dark urine. Initial investigations showed creatinine 140μmol/L, creatine kinase (CK) 4566 U/L and serum myoglobin 2694 ng/ml with a significant increase in urine myoglobin. Although there were no obvious risk factors, the patient was diagnosed with rosuvastatin induced rhabdomyolysis. The drug was stopped on the first day of admission and the patient was initiated on intravenous fluid with cautious monitoring of serum electrolytes. On the following days the level of creatine kinase and serum myoglobin returned toward normal and consequently he was discharged without statins but on dietary therapy. On follow-up evaluation, the patient was symptom free his serum creatinine was 106μmol/L, whereas his LDL cholesterol was 2.1mmol/L. The rosuvastatin induced rhabdomyolysis is discussed and the danger of its use in low risk patients is emphasized.
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State of the Art Clinical Efficacy and Safety Evaluation of N-Acetylcarnosine Dipeptide Ophthalmic Prodrug. Principles for the Delivery, Self-Bioactivation, Molecular Targets and Interaction with a Highly Evolved Histidyl-Hydrazide Structure in the Treatment and Therapeutic Management of a Group of Sight-Threatening Eye Diseases
Authors: Mark A. Babizhayev and Anne Kasus-JacobiFull text svailable
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Evaluation of Human Plasma Protein Binding of Trabectedin (Yondelis™, ET-743)
Authors: Jan H. Beumer, L. Lopez-Lazaro, Jan H.M. Schellens, Jos H. Beijnen and Olaf van TellingenTrabectedin (ET-743, Yondelis™) is a novel anticancer drug with impressive activity in soft tissue sarcoma with a manageable, non-cumulative toxicity profile. Protein binding can be a major determinant of unbound concentration, volume of distribution, renal and hepatic clearance, and the half-life of a drug. Human plasma protein binding of trabectedin has not previously been reported. Using ultrafiltration techniques, we determined the human plasma protein binding of trabectedin at a clinically relevant concentration. Experiments with a panel of co-medications representing all known protein- binding sites showed that the concentration of unbound trabectedin could be increased by high concentrations of phenytoin. The other tested co-medications, at concentrations covering their respective therapeutic ranges, did not displace trabectedin from its plasma protein binding. This suggests that trabectedin binds to albumin site I (total protein binding of 94.2 ±0.6 %) displaying an association constant of 2.6 ±0.2 104 M-1. Because trabectedin is an intermediate-to-high hepatic extraction drug, changes in unbound fraction will not have a major impact on elimination processes. The high protein binding may have implications for the interpretation of in vitro data, which are usually performed in the presence of low protein levels. We can conclude that the studied co-medications are unlikely to have clinically relevant effects on trabectedin binding to plasma proteins at therapeutic concentrations.
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Anti-Cancer Properties of Nigella spp. Essential Oils and their Major Constituents, Thymoquinone and β-Elemene
By Amr E. EdrisEssential oils are the volatile fraction of aromatic and medicinal plants after extraction by steam or water distillation. They have been used for their pharmaceutical potential since early times, and even now are still subject to a great deal of attention, as is clear from the increasing number of publications each year on this subject. This review presents both fundamental and recent studies concerned with the role of Nigella species essential oils and their major constituents, thymoquinone and β-elemene, as potential chemotherapeutic and chemopreventive anti-cancer agents. The mechanism of action and the factors which determine the concentrations of these major constituents in the essential oil are also reviewed.
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Novel Options for the Pharmacological Treatment of Chronic Anal Fissure - Role of Botulin Toxin
Authors: Mariusz Madalinski and Leszek KalinowskiA chronic anal fissure (CAF) is commonly referred to as an ischemic ulcer. For many years it was thought that sphincteroctomy produces anal sphincter relaxation, enhances microcirculation and promotes CAF healing. The latest studies have shown that fissure healing does not appear to be dependent on reduction in mean resting anal pressure. Our description of the process of CAF healing is based on understanding the balance between nitric oxide (NO) concentration and a level of oxidative and nitroxidative stress in wounds, which is responsible for contraction of smooth muscles (also anal sphincters), endothelial/skeletal muscle cell remodelling and proliferation. Pharmacological sphincterotomy with botulinum toxin (BTX) has an effect on motor endplate but it also has an influence on nitric oxide synthase (NOS) and other agents. Hypoxia in contracted anal sphincters induces vasoconstriction, in part, by decreasing endothelial NOS expression. Clostridium botulinum C3 exoenzyme - Rho-kinase inhibitor reverses this vasoconstriction. CAF is a site where the haemostatic mechanisms are activated. Rho inactivator C3-transferase from Clostridium botulinum abolished thrombin - stimulated endothelial cell contraction. Attenuated biotransformation of Glyceryl trinitrate (GTN) by mitochondrial aldehyde dehydrogenase and suppression of cGMP-dependent protein kinase expression may play a key role in understanding the problem of synergistic action of BTX and GTN. BTX and GTN are different forms of pharmacological sphincterectomies. This mechanism could explain the potentiate effect of BTX action after NO donors application for CAF. The application of BTX releases the blockage in GTN bioactivation in smooth muscle cells and suppresses basal continuous sympathetic activity, causing modulation of anal sphincters. It is responsible for CAF healing.
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Recent Advances in Obesity Pharmacotherapy
Authors: Marcos A. Mayer, Christian Hocht, Ana Puyo and Carlos A. TairaObesity is considered a worldwide epidemic. Weight reduction by means of lifestyle changes is difficult to achieve, and pharmacotherapy is frequently needed. Although all currently approved anti-obesity agents have proven to be effective to achieve some degree of weight reduction and improve cardiometabolic risk factors, different compounds differ in their mechanism of action and safety profile. However, it is still difficult to achieve and maintain therapeutic objectives along time. The aim of the present article is to summarize the main characteristics of available anti-obesity agents and to explore novel agents that may provide significant clinical benefits in the future.
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Evaluation of Efficacy and Safety of Fixed Dose Combination of Ceftazidime-Tobramycin in Comparison with Ceftazidime in Lower Respiratory Tract Infections
Authors: Manu Chaudhary, Sanjay M. Shrivastava and Rajesh SehgalLower respiratory tract infections are major cause of morbidity and mortality. Objectives were to evaluate efficacy and safety of fixed dose combination (FDC) of Ceftazidime and Tobramycin in comparison with Ceftazidime alone in patients with lower respiratory tract infections. Patients (n=240) were randomly distributed in two arms: one arm was treated with Ceftazidime(1g)-Tobramycin(120mg) and other arm was treated with Ceftazidime (1g) alone. Patients were clinically, radiologically and bacteriologically evaluated. Clinically successful outcome was seen in 88.4% of the patients in Ceftazidime-Tobramycin treated group as compared to 61.2% in Ceftazidime alone treated group. In Ceftazidime- Tobramycin treated group, majority of pathogen isolated were H.inflenzae (35%), P. aeruginosa (24.16%), K. pneumoniae (16.66%) and M. catarrhalis (24.16%), whereas in Ceftazidime alone treated group majority of pathogen isolated were H.inflenzae (33.33%), P. aeruginosa (20%), K. pneumoniae (18.33%) and M. catarrhalis (28.33%). In Ceftazidime- Tobramycin treated group (98%), a significantly higher bacterial eradication was observed than Ceftazidime alone treated group (79%). Radiological improvement was also superior in Ceftazidime-Tobramycin treated group. No major adverse events were observed. Results showed that fixed dose combination of Ceftazidime Tobramycin is superior than Ceftazidime alone in the treatment of lower respiratory tract infections.
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Structurally Modified ‘Dietary Flavonoids’: Are these Viable Drug Candidates for Chemoprevention?
More LessThe field of chemoprevention continues to be a heavily researched area since a few decades now. Whereas, the dietary intake of flavonoids occur via daily intakes of fruits, vegetables, herbal preparations, beverages etc, it appears that the active ingredients(s) contained in these dietary sources may not reach the required plasma and/or tissue concentrations in vivo to produce the desired pharmacological response expected of these agents. Akin to the common problems of druggability encountered often times in drug discovery/development scenario, low bioavailability of flavonoids have been attributed to: lack of stability, excessive metabolism, permeability problems, lack of site specificity in distribution, rapid elimination etc. The scope of the review is to assess and put into perspectives salient features of some of the recently reported work on dietary flavonoids including the methylated compounds that showed improved drug-like properties in context with the required features for the lead optimization program rendering a clinical candidate. In addition, it aims to provide some perspectives into the present day considerations for early drug development such as healthy subjects versus cancer patients, single agent versus combination potential with other cancer therapeutics, selection of a cancer indication, potential for drug-drug interaction etc. Although there has been an unabated use of ‘dietary flavonoids’ with tall order claims for chemoprevention, it may be extremely challenging to confirm it in a clinical setting. Overall, it appears prudent to develop a comprehensive prospective strategy for clinical development and regulatory approval.
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Intensive Insulin Therapy in Critical Care Settings
Authors: Darla K. Eastman, Michelle M. Bottenberg, Karly A. Hegge, Heather Ourth and Udaya KabadiHyperglycemia in hospitalized patients has been shown to increase both morbidity and mortality, regardless of the presence of preexisting diabetes. In order to achieve recommended glycemic goals, many patients require the use of intravenous insulin therapy in the critical care setting. Following the publication of a landmark trial evaluating the benefits of intensive insulin therapy in critically ill patients, a worldwide increased effort to achieve strict glycemic control has ensued. Maintaining blood glucose levels between 80 and 110 mg/dL has been shown to improve outcomes such as mortality and infectious complications in critically ill patients, while also decreasing length of hospital stay and healthcare expenditures. However, achieving strict glycemic control has proven to be a challenge for many institutions, partly due to the prevalence of hypoglycemia. As demonstrated by studies which have been terminated prematurely due to increased risk for hypoglycemic episodes, the benefits versus risks of intensive insulin therapy must be weighed carefully. Patients receiving continuous infusions of insulin require close monitoring, which may increase workload for intensive care unit staff. In an effort to balance the risks and benefits of intensive insulin therapy, many hospitals are incorporating standardized protocols and using an interdisciplinary approach toward patient care.
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Pharmacological Profile of SSRIs and SNRIs in the Treatment of Eating Disorders
Authors: Anna Capasso, Claudio Petrella and Walter MilanoBulimia Nervosa (BN) and Binge Eating Disorder (BED) are some of the most common eating disorders (ED) in industrialized societies, characterized by uncontrolled binge eating and self-induced purging or other compensatory behaviours aiming to prevent body weight gain. It has been suggested that reduced serotonergic and noradrenergig tone triggers some of the cognitive and mood disturbances associated with ED. In fact in the active phase of ED the concentration of serotonin and noradrenaline in cerebral fluid is reduced. For these reasons, the pharmacologic treatment of ED consists mainly of selective serotonin reuptake inhibitors (SSRIs) or selective noradrenaline reuptake inhibitors (SNRIs) . At present, the physiologic basis of this disorder are not yet completely understood. In this review we evaluate several randomized controlled trials to compare the efficacy of several SSRIs and SNRIs in patients with a diagnosis of ED as defined by the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders [DSM IV]) These findings indicate that both SSRIs and SNRIs are well tolerated and reduce effectively the bulimic crisis and purging episodes in patients with ED.
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