Current Clinical Pharmacology - Volume 6, Issue 4, 2011

Effective pain management remains an important indicator of the quality of care provided to neonates, not only from an ethical, but also from a clinical outcome perspective. Significant progresses in non-pharmacological therapies have been made. However - in the meanwhile - neonatal practice also evolved. These shifts in clinical care also induced in a shift in pharmacodynamic end points, and consequently, new pharmacological observations are needed with emphasis on short acting procedural analgo-sedatives. Analgo-sedation in neonates remains a balanced decision based on systematic assessment (pharmacodynamics, PD), followed by titrated administration of the most appropriate analgesic(s) (PK) with subsequent re-assessment (PD) to adapt and further titrate exposure and effects. In this review, we will focus on aspects of the clinical pharmacology (pharmacokinetics (PK) and -dynamics) of newly emerging, short acting analgo-sedatives (midazolam, propofol, remifentanil, inhalational agents, ketamine) in neonates. Based on the currently available information on predictability of disposition and the limited pharmacodynamic side effects (hemodynamics, neuro-apoptosis), it seems that remifentanil is the most promising compound for further evaluation.

Anacetrapib is a cholesteryl-ester-transfer-protein (CETP) inhibitor, a new class of experimental drugs in the treatment of primary hypercholesterolemia and dyslipidaemia associated with the metabolic syndrome. One of the major advantages of this agent is, apart from the significant decrease in LDL-C it produces a substantial increase in HDL-C. Phase I, II, and III clinical trials have shown that anacetrapib is safe alone or in combination with statins. However, longterm clinical trials are required in order to assess whether it reduces mortality in individuals at high-risk of cardiovascular disease.

A decrease in olfactory function with age has been attributed to a variety of factors including normal anatomical and physiological changes in aging, surgery, trauma, environmental factors, medications and disease. Olfactory impairment has also been associated with neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease. Deficits in these chemical senses cannot only reduce the pleasure and comfort from food, but represent risk factors for nutritional and immune deficiencies as well as adherence to specific dietary regimens. Therapy is limited, but one should be aware of the existing medical and surgical treatment modalities. Reactive oxygen and nitrogen species, copper and zinc ions, glycating agents and reactive aldehydes, protein cross-linking and proteolytic dysfunction may all contribute to neurodegeneration, olfactory dysfunction, AD. Carnosine (beta-alanyl- L-histidine) is a naturally-occurring, pluripotent, homeostatic transglycating agent. The olfactory lobe is normally enriched in carnosine and zinc. Loss of olfactory function and oxidative damage to olfactory tissue are early symptoms of AD. Protein and lipid oxidation and glycation are integral components of the AD pathophysiology. Carnosine can suppress amyloidbeta peptide toxicity, inhibit production of oxygen free-radicals, scavenge hydroxyl radicals and reactive aldehydes, and suppresses protein glycation. The observations suggest that patented non-hydrolyzed carnosine lubricant drug delivery or perfume toilet water formulations combined with related moiety amino acid structures, such as beta-alanine, should be explored for therapeutic potential towards olfactory dysfunction, AD and other neurodegenerative disorders. “The olfactory system, anatomically, is right in the middle of the part of the brain that's very important for memory. There are strong neural connections between the two.” ~ Donald Wilson

Current Clinical Management Guidelines of Diabetic Peripheral Neuropathy (DPN) are based on adequate glucose control and symptomatic pain relief. However, meticulous glycemic control could delay the onset or slow the progression of diabetic neuropathy in patients with DM type 2, but it does not completely prevent the progression of the disease. Complications of DPN as it continues its natural course, produce increasing pain and discomfort, loss of sensation, ulcers, infections, amputations and even death. In addition to the increased suffering, disability and loss of productivity, there is a very significant economic impact related to the treatment of DPN and its complications. In USA alone, it has been estimated that there are more than 5,000,000 patients suffering from DPN and the total annual cost of treating the disease and its complications is over $10,000 million dollars. In order to be able to reduce complications of DPN, it is crucial to improve or correct the metabolic conditions that lead to the pathology present in this condition. Pathophysiologic mechanisms implicated in diabetic neuropathy include: increased polyol pathway with accumulation of sorbitol and reduced Na+/K+-ATPase activity, microvascular damage and hypoxia due to nitric oxide deficit and increased oxygen free radical activity. Moreover, there is a decrease in glutathione and increase in homocysteine. Clinical trials in the last two decades have demonstrated that the use of specific nutrients can correct some of these metabolic derangements, improving symptom control and providing further benefits such as improved sensorium, blood flow and nerve regeneration. We will discuss the evidence on lipoic acid, acetyl-L-carnitine, benfotiamine and the combination of active B vitamins L-methylfolate, methylcobalamin and piridoxal-6-phosphate. In addition, we discuss the role of metformin, an important drug in the management of diabetes, and the presence of specific polymorphic genes, in the risk of developing DPN and how metabolic correction can reduce these risks.

Background: This study was a multi-centre, dose-escalation trial in patients with advanced cancers. Primary objective was to determine maximum tolerated dose (MTD) of vorinostat, a competitive inhibitor of histone deacetylase (HDAC), in combination with vinorelbine. Secondary aims were to determine (1) corresponding pharmacokinetics, (2) safety of this regimen, and (3) impact of UGT1A1 and 2B17 polymorphisms on vorinostat pharmacokinetics. Methods: Starting dose of once daily oral vorinostat was 200 mg for 7 days every 21 days in combination with a 20-min intraveinous weekly infusion of vinorelbine 25 mg/m2, starting 4 hours after the first vorinostat dose. During cycle 1, blood samples were collected at day 1 for vorinostat and at days 1 and 8 for vinorelbine for pharmacokinetic evaluation. Results: Seven patients were included. Most of adverse events observed were mild (grades 0-2) and reversible after treatment discontinuation (hemotological toxicity, asthenia, diarrhea, dyspnea, fever, hyperglycemia and nausea). Two patients had a dose limiting toxicity at the first dose level that consisted of grade 3 hyperglycemia and vinorelbine administration was delayed. The first dose-level was considered as the MDT and therefore dose escalation was stopped. Mean vorinostat plasma AUC was higher than reported previously at a similar dose when used as single agent or in combination with other cytotoxics. There was no obvious vinorelbine-vorinostat interaction nor any correlation with UGT1A1 or 2B17 polymorphisms. Conclusion: MDT of the combination was 200 mg oral vorinostat for 7 days in combination with 25 mg/m2 weekly vinorelbine. Severity of hyperglycemia was most likely related to unexpected high vorinostat exposures.

Pain is an unpleasant sensory perception warning of actual or impending tissue damage. Pain serves a vital physiological role, however, severe and uncontrolled pain in the peri-operative setting can adversely affect outcome from surgery and lead to chronic pain. Multiple neurochemical and receptor processes are involved in pain perception but the role of pro-inflammatory cytokines and adrenergic pathways has only recently been recognised. Clonidine is an agonist at the alpha2-adrenergic receptor that has been in clinical use for over 40 years. Clonidine was recognised at an early stage as having analgesic properties however its systemic use was frequently limited by side-effects. Recent advances in anaesthetic practice, allowing more targeted drug delivery and a better understanding of the basic physiology of pain have led to a re-evaluation of the role of clonidine in pain management. Experimental and clinical studies have identified a diverse action of clonidine in modifying not only the adrenergic component to pain perception but also an important effect on modifying the neurohumoral response to tissue injury. This has implications for the management of a diverse range of pain problems and potentially offers a method of preventing the transition from acute to chronic pain. Clonidine is likely to play an increasing role in clinical practice in anaesthetics and pain management.

With its increasing prevalence throughout the world, heart failure continues to be associated with high morbidity and mortality. Patients with heart failure develop progressive metabolic abnormalities, inflammation, and atrophy in the myocardium and skeletal muscle. Improvement in functional capacity as defined by exercise tolerance is essential for better quality of life and potentially survival of these patients. Therapeutic management options aimed at improving peripheral organ function are limited. Nutritional approaches with dietary supplementation in addition to current therapies are particularly appealing as they are novel and mechanistically different. In this article, we review the role of glutamine and omega-3 polyunsaturated fatty acids on metabolism and functional capacity in heart failure. These two compounds are of particular interest due to their synergistic role on oxidative metabolism, lipolysis and inflammation.

Several medications have been linked to red blood cell (RBC) disorders. The frequency of these side effects varies, depending on the condition, but they can be associated with significant morbidity and mortality. The problem is likely to exacerbate in aging populations with frequent comorbidities, proportional to the growing number of medications used. Notable drug-related RBC disorders include hemolytic anemia, megaloblastic anemia, sideroblastic anemia, polycythemia, methemoglobinemia, anemia of irritation/inflammation, and anemia caused by suppression of RBC production. The list of medications that are associated with these disorders is long and includes many commonly-used drugs. This could pose a challenge in timely diagnosis and management of these disorders. Prior knowledge of the potential for drug-related RBC disorders and monitoring the patients who are being treated with medications known to cause RBC disorders are critical to ensure timely and effective response, should such adverse reactions occur.

Background and Objectives: No studies about resistance of bacteria isolated from patients with communityacquired urinary tract infections (CA-UTI) or local guidelines for antibiotic use in these infections have been published or established in the West Bank, Palestine. The objectives of this study were to determine the (1) type and frequency of isolated bacteria and (2) their resistance to commonly used antibiotics. Methods: A cross sectional study on community urinary isolates was carried out in Nablus, Palestine between November 2009 and April 2010. A convenience sampling method was used for collection of specimens. Results: A total of 375 specimens were collected from 306 (81.6%) females and 69 (18.4%) males. Three hundred and thirty nine (90.4%) of isolated uropathogens were Gram-negative bacteria, of which 243 (71.7%) were Escherichia coli. Thirty six (9.6 %) of the total isolates were Gram-positive bacteria, of which 21 (58.3%) were Staphylococcus saprophyticus. High resistance rates were recorded for E. coli against trimethoprim/sulfamethoxazole (37%), nitrofurantoin (29%), ampicillin (65%), and nalidixic acid (37%). E. coli showed low resistance to amoxicillin/clavulanic acid, ciprofloxacin, cefotaxime and ceftriaxone with rates of 12.2, 17.2, 11.1, and 11.1% respectively. Conclusion: E. coli was the most frequent bacterium in the studied sample and showed high resistance to first-line antibiotics. Our results highlight the need for developing local guidelines where elevated resistance to antibiotics should influence prescribing decisions.