Current Drug Therapy - Volume 2, Issue 3, 2007

Tardive dyskinesia (TD) manifests as abnormal involuntary movements that develop gradually in patients receiving antipsychotic medication. The clinical characteristics are a) the movements disappear from the group of muscles engaged in a voluntary activity, b) they can be voluntarily suppressed for a few seconds c) during sleep they disappear and d) the most frequent site is the bucco-oral area. Movements indistinguishable from those of TD can also occur in several neurological disorders as well as in patients receiving phenytoin and metoclopramide. If the offending agents are removed, drug-induced TD improves over time in most of the patients. Its incidence in patients receiving typical antipsychotic drugs is 5% per year and with atypical antipsychotic drugs 0.5-1% per year indicating that atypical antipsychotics (AAP) drugs produce TD five to ten times less often than typical antipsychotic drugs. While the pathophysiology of TD is not known, D2 blocking and subsequent dopaminergic supersensitivity, GABA deficiency and structural changes in the brain have all been implicated. The condition is not innocuous and can produce jerky breathing, dental problems and even premature death. Quetiapine and clozapine have very low affinity to D2 receptors and yet they also are known to produce TD. Recent studies have found a high prevalence of TD; the mild TD rate was found to be increased but severe rates were decreased. An efficient monitoring system is needed during atypical anti-psychotic drug treatment. Such a monitoring system should not only focus on metabolic disturbances, but also on the occurrence of TD.

The Metabolic Syndrome is commonly associated with an atherogenic dyslipidemia which accounts for a high risk of atherothrombosis and cardiovascular events. The fundamental defect of patients with the Metabolic Syndrome is the resistance to insulin action which is involved in the appearance of a combined dyslipidemia -i.e. hypertriglyceridemia, low HDL cholesterol, preponderance of small dense LDL particles and post-prandial lipidemia- owing to a reduced suppression of lipolysis in adipose tissue which leads to higher flux of free fatty acids to liver and increased synthesis and secretion of VLDL particles. Beyond the primary management which involves lifestyle intervention, patients with the Metabolic Syndrome could be treated with different therapeutic strategies to reduce cardiovascular risk. The main therapeutic option is statin therapy which provides effective decrease of LDL cholesterol levels and is shown effective in the prevention of coronary artery events, even though controlled studies are available only for few molecules. In turn, controlled trials -such as BIP, VA-HIT and FIELD- have proposed a possible benefit from fibrate administration in normalizing lipid profile and decrease insulin resistance in patients with the Metabolic Syndrome which exhibit low HDL cholesterol and hypertriglyceridemia. Other lipid modifying strategies based on nicotinic acid or ezetimibe have recently proposed as effective in the Metabolic Syndrome on the basis of preliminary results and could be future options. Finally, the simultaneous use of different drugs could provide benefits, avoiding inappropriate combinations due to the potential hazard of adverse drug interaction. The present review extensively examines the most recent results in the field of treatment of dyslipidemia in patients with the Metabolic Syndrome, starting from the trials with statin therapy. We consider also the role of drugs which regulate serum lipids by different mechanisms, such as fibrates, ezetimibe, nicotinic acid and omega3 fatty acids, on the basis of the evidences of effectiveness and safety. Finally, we take into account the therapeutic efficacy of new drugs, such as glitazones and rimonabant, whose main target is to improve the insulin sensitivity.

With the alarming increase in the incidence of diabetes mellitus worldwide, there is a growing need to develop new strategies to control hyperglycemia. Currently available treatments cause various adverse effects and do not necessarily achieve optimal glycemic control. Recently, peptides that may ameliorate the symptoms of diabetes mellitus have been investigated extensively and show great promise. Synthetic analogs of amylin and incretin mimetics may be ideal adjuncts to diabetes therapy. Amylin analogs significantly improve postprandial control in patients with either type 1 or type 2 diabetes without an increased risk of hypoglycemia or weight gain. Incretin mimetics are a new option for patients suffering from type 2 diabetes and are being considered as a stand-alone therapy. The present paper reviews novel peptides as potential agents for glucose control and prevention of the complications associated with diabetes.

Ion exchange resins have been used to formulate pharmaceuticals for many years. The use of ion exchange resins as drug carrier system has been an attractive area of research because of its many extraordinary benefits. They have not only proved to be safe and effective excipient but they are successfully used for their therapeutic potential as well and are now used in many commercial formulations throughout the world. The present review focuses on some of the common problems faced by the formulator and how using ion exchange resins help to solve them.

Artemisinin and its derivatives were discovered to be highly effective antimalarial drugs, which combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance. Artemisinins as a group are poorly efficacious at curing malaria as monotherapy. However, this shortfall is being overcome by using oral artemisinin-based combination therapy (ACT) and intravenous artesunate (AS) in sequential administration with slower acting antimalarial drugs. Pharmacokinetic and pharmacodynamic (PK/PD) evaluations demonstrate that the rapid efficacy of artemisinins is principally due to the drug peak concentration (Cmax), and other pharmacokinetic parameters, such as drug exposure level (AUC) and drug exposure time (half-life) tend to be of minor significance. The evaluation also demonstrated that AS is a superior in PK/PD achievements either following oral or intravenous administration when compared to other four artemisinin drugs. Most recently, a decrease in mortality (34.7%) has been demonstrated in a large study using intravenous AS, as opposed to the standard of care quinine injection. The fast efficacy and less mortality show that current artemisinins have great advantage over other antimalarials in ACTs for uncomplicated malaria and in sequential therapy of AS injection for severe and complicated malaria.

Diabetic retinopathy and glaucoma are major diseases that cause blindness in a high percentage of the population. However, the precise mechanisms involved in the onset and the progression of these diseases are still not completely known. Recent studies have shown that there appears to be an association between these two disease processes because the incidence of glaucoma is higher in diabetic patients than in non-diabetic patients. To reduce the number of patients with vision loss from these diseases, new therapeutic strategies must be established to prevent the development and the progression of these diseases. In this report, we focus on the biochemical links between diabetic retinopathy and glaucoma, viz., an overexpression of extracellular matrix and death of retinal ganglion cells. To establish new therapeutic strategies for both diseases, the biochemical links between diabetic retinopathy and glaucoma and an identification of the factors that are common to the pathogenesis of both diseases, must be determined. In addition, the potential use of gene therapies including antisense oligonucleotides and small interference RNAs should be considered for both diseases. We expect that with the advent of new therapies, a larger number of patients with diabetic retinopathy and/or glaucoma will be cured.

Apoptosis, induced in tumors by anticancer agents, is characterized by caspase activation, impaired cellular respiration and decreased cellular ATP. Respiration in Jurkat and HL-60 cells treated with doxorubicin, dactinomycin or platinum drugs is measured using a Pd(II) phosphor that monitors [O2] in cell suspensions as a function of time. Cellular ATP is determined using the luciferin-luciferase bioluminescence system. Intracellular caspase activation is measured by allowing caspases to cleave Ac-DEVD-AFC to the fluorescent AFC, which is detected on HPLC. Comparing the ways in which respiration, ATP level, and caspase activity vary with time points up differences between the mechanisms of actions of doxorubicin, dactinomycin and the platinum compounds. These methods accurately determine the sensitivity of tumors to anticancer drugs.

Hypertension is one of the major causes of cardiovascular morbidity. Most patients who are on treatment for hypertension fail to achieve adequate control with the existing therapy and rates of cardiovascular morbidity remain high. As the renin-angiotensin-aldosterone system is strongly implicated in the development of hypertension-related target organ damage, intensive efforts have been devoted towards the development of drugs targeting this system. In addition to angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), inhibition of renin has also become a clinical reality. Aliskiren, a novel renin inhibitor, has overcome a number of shortcomings of existing drugs and is now available to address angiotensin production directly at its rate-limiting step.