Current Drug Safety - Volume 6, Issue 5, 2011

A-955840, a selective CB2 agonist, has been shown to elicit concentration-dependent decreases in cardiac contractility in the anesthetized dog (decreased maximal velocity of left ventricular pressure development [LV dP/dt max]). However, it is unknown whether this represents a direct effect or a response dependent on other factors (such as autonomic tone and neurohumoral factors) present in vivo. This study examined if A-955840 had a direct effect on contractility of isolated cardiac myocytes, and if so to determine the potential mechanisms. Contractility was assessed in vitro using percent changes in maximal shortening velocity of sarcomeres (dL/dt max) and fractional shortening of sarcomere length (FS) in rabbit left ventricular myocytes. L-type calcium current in myocytes was recorded using wholecell voltage-clamp techniques. A-955840 reduced dL/dt max and FS in a reversible and concentration-dependent manner with an IC50 of 11.4 μg/mL (based on dL/dt max) which is similar to the estimated IC50 value of 9.8 μg/mL based on the effects of A-955840 on LV dP/dt max in anesthetized dogs. A-955840 (4.1 μg/mL) reduced myocyte contractility (%FS) to a similar extent in the absence and presence of a CB2 antagonist, SR-2 (24.0 ± 3.4 vs 23.1 ± 3.0 %, n=5) or a CB1 antagonist, Rimonabant (18.8 ± 2.3 vs 19.8 ± 2.7 %, n=5). A-955840 (4.1 μg/mL) also reduced L-type calcium current of rabbit ventricular myocytes (1.05 ± 0.11 vs 0.70 ± 0.12 nA, n=5, P<0.01). These results suggest that A-955840 exerts direct negative inotropic effects on isolated rabbit ventricular myocytes, which is mediated by neither CB2 nor CB1 receptors, and consistent with off-target negative inotropy mediated by inhibition of the cardiac L-type calcium current.

Objective: To investigate differences in medication adherence, treatment satisfaction and clinical symptoms in schizophrenic outpatients taking different antipsychotic treatment regimens. Methodology: Medication adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS-8) while treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4). Psychiatric symptoms were measured using the 24-item expanded Brief Psychiatric Rating Scale (BPRS-E). Data were entered and analyzed using SPSS 16 for windows. Results: A convenience sample of 131 schizophrenic patients was studied. Patients belonged to 7 groups based on their antipsychotic treatment regimens. There was no significant difference in the means of adherence (P=0.6) and BPRS domains: positive (P=0.6), negative (P=0.8), manic (P=0.2) and depression (P=0.9) scores among the studied groups. Satisfaction with side effect domain was significantly different among studied groups (P=0.006, F=3). However, no significant difference was found in other satisfaction domains: effectiveness (P=0.8), convenience (P=0.3), and global satisfaction (P=0.8). Conclusions: Medications adherence, most treatment satisfaction domains and clinical symptom scores were not significantly different among patients taking different antipsychotic regimens.

Lithium, an old and invaluable psychiatric therapy, is still the best treatment option in several clinical circumstances, including acute mania, bipolar and unipolar recurrent mood disorders, suicidal ideation and behavior, recurrent or chronic unipolar depression that has not responded to other treatments, aggressive or impulsive behavior and alcoholism, especially when an affective component is manifest. However, lithium has a narrow therapeutic index and is associated with many serious acute and long-term side effects. Furthermore, monitoring requirements, i.e., frequent blood draws and frequent visits, discourage lithium use. Therefore, the drug is underused. Full awareness of lithium side effects and competence to minimize them is the only contrast to this ominous trend. Renal side effects are frequent in the course of lithium treatment. Although not serious in the large majority of cases, they may seldom become severe and result in chronic renal failure and end stage renal disease. The aim of the paper is reviewing the renal safety profile of lithium and the suggested strategies in the management of the lithium associated renal side effects.

Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new class of drugs introduced in 2006 for treatment of type 2 diabetes. In clinical trials lasting up to 2 years, these agents are well tolerated. Incidence of hypoglycemia associated with the use of DPP-4 inhibitors is similar to placebo, but is markedly increased when used in conjunction with sulfonylureas (SUs). DPP-4 inhibitors have neutral effect on body weight but their combination with a thiazolidinedione (TZD) results in slight weight gain averaging 0.5 to 1.3 kg compared with placebo. Other adverse effects recorded more commonly with DPP-4 inhibitors versus placebo are mild, and include nasopharyngitis, headache, and possibly urinary tract infections (UTIs). In the postmarketing period, new adverse effects are reported such as angioedema, increased rates of infection, and skin toxicity. Pancreatitis is inconsistently reported in relationship to sitagliptin, and one analysis links this agent to elevated risk of pancreatic cancer. Pancreatitis is also a rare adverse effect observed in linagliptin clinical studies. There is no evidence that DPP-4 inhibitors increase cardiovascular events or death. Overall, although short-term safety of DPP-4 inhibitors is reassuring, their safety needs to be established by long-term clinical trials and close surveillance during the postmarketing period.

NSAIDs are the most frequently used drugs for treatment, in Europe and the United States, accounting for approximately 5% of all prescriptions. Moreover, the use of NSAIDs is increasing because these constitute the first-line drug therapy for a wide range of rheumatic conditions. This increase is in part the result of the increasing population of elderly patients, who constitute the group of patients with greatest demand for these agents. There are many types of NSAIDs that vary in potency, action and potential side effects. Thus various efforts have been made to determine the safety considerations including adverse drug effects, duration of drug therapy, drug interactions, precautions and other drugs applied to reduce side effects. Researchers have introduced some novel techniques to diagnose NSAIDs related adverse effects on the gastrointestinal mucosa. The researchers dealing with the development of drug delivery system for these drugs should aim at designing a therapeutically efficacious dosage form with reduced side/adverse effects. Thus an effort has been made in this review to deal with the safety parameters of various NSAIDs with a special emphasis on preclinical and clinical safety analysis and various attempts to minimize the side effects by structural modification or by drug delivery system.

There are conflicting data on the course of bipolar disorder during pregnancy but childbirth is generally considered a time of high risk for the onset or exacerbation of mood and psychotic episodes in women with bipolar disorder. Despite the increasing use of psychotropic drugs in women with psychiatric disorders, there is a paucity of information in the pharmacological treatment of bipolar disorder during and after pregnancy. Optimal drug treatment requires an understanding of the illness course prior to, during, and after pregnancy; bipolar disorder type and dominant polarity, psychiatric comorbidity, physical health status, prior response to psychotropic drugs, effectiveness of medications in the acute and preventative treatment of mood episodes, side effect profile including teratogenicity, and finally family history of psychiatric illness. For women who discontinue psychotropic drugs abruptly upon finding out about the pregnancy, the withdrawal symptoms of medications should be distinguished from the symptoms of the disorder. Compatibility of drugs with breastfeeding is another important consideration. Antidepressants should be avoided as much as possible due to their association with manic switches, rapid cycling, and suicidality. An important aspect of pharmacotherapy in women with a personal or family history of bipolar I disorder or postpartum psychosis should be the management of insomnia that can either be an early symptom of, or a trigger for postpartum manic/mixed or psychotic episodes. Whereas polypharmacy may be unavoidable, every effort should be made to keep the overall number of medications and dosages to a minimum.

Relaxin (RLX), formerly known for its effects on reproduction and pregnancy, has been later shown to be a pleiotropic hormone, capable of also targeting numerous non-reproductive organs of the cardiovascular, nervous, respiratory, tegumental, excretory and digestive systems. Most of these effects have been studied in animal models, but there is compelling evidence that RLX also acts in humans. In more recent years, human luteal-type (H2) RLX synthesised by recombinant DNA technology has been investigated in clinical trials, mostly oriented to assess its therapeutic potential in cardiovascular disease. This indication was based on the accumulating pre-clinical evidence that RLX possesses prominent biological effects on systemic and coronary blood vessels, cardiomyocyte growth and differentiation, and cardiac/vascular connective tissue remodelling. This mini-review was intended as an update of our previous article that appeared in this journal in 2009, as the last 2 years have been characterised by fundamental achievements on the clinical profile of RLX. Eventually, after many years of inconclusive studies, RLX appears to be about to reach a recognised dignity as a cardiovascular drug.

Purpose: In the present study, Cremophor EL free paclitaxel elastic liposomal formulation consisting of soya phosphatidylcholine and biosurfactant sodium deoxycholate was developed and optimized. The toxicological profile, antitumor efficacy and hemolytic toxicity of paclitaxel elastic liposomal formulation in comparison to Cremophor EL based marketed formulation were evaluated. Methods: Paclitaxel elastic liposomal formulations were prepared and characterized in vitro, ex-vivo and in vivo. Single dose toxicity study of paclitaxel elastic liposomal and marketed formulation was carried out in dose range of 10, 20, 40, 80, 120, 160 and 200 mg/kg. Cytotoxicity of developed formulation was evaluated using small cell lung cancer cell line (A549). Antitumor activity of developed formulation was compared with the marketed formulation using Cytoselect™ 96-well cell transformation assay. Results: In vivo administration of paclitaxel elastic liposomal formulation into mice showed 6 fold increase in Maximum Tolerated Dose (MTD) in comparison to the marketed formulation. Similarly, LD50 (141.6 mg/kg) was also found to increase significantly than the marketed formulation (16.7 mg/kg). Result of antitumor assay revealed a high reduction of tumor density with paclitaxel elastic liposomal formulation. Reduction in hemolytic toxicity was also observed with paclitaxel elastic liposomal formulation in comparison to the marketed formulation. Conclusion: The carrier based approach for paclitaxel delivery demonstrated significant reduction in toxicity as compared to the Cremophor EL based marketed formulation following intra-peritoneal administration in mice model. The reduced toxicity and enhanced anti-cancer activity of elastic liposomal formulation strongly indicate its potential for safe and effective delivery of paclitaxel.

Background: Omalizumab is prescribed as a step-up therapy for patients with moderate to severe allergic asthma uncontrolled on high-dose inhaled corticosteroids and long acting beta agonists. However, hypersensitivity reactions may lead to its discontinuation and subsequent worsening or loss of asthma control. No successful desensitization protocols to omalizumab have been previously reported. Objective: We aimed to determine the efficacy and safety of a novel one-day outpatient omalizumab desensitization protocol for patients with hypersensitivity reactions to omalizumab. Methods: We retrospectively assessed the efficacy of omalizumab desensitization protocol performed in a university allergy-immunology clinic from July 2009 to July 2010. Results: We successfully desensitized 3 patients with moderate-severe asthma to omalizumab. After desensitization all patients had improvement in asthma control and were able to discontinue or decrease chronic systemic steroid therapy. Conclusions: This novel outpatient omalizumab desensitization protocol was a safe and effective approach for the treatment of omalizumab hypersensitivity in patients with moderate to severe allergic asthma who required omalizumab therapy.

Intravenous thrombolytic treatment represents the gold standard for acute ischemic stroke treatment. However there is some concern to perform this treatment in patients with known cardiac myxomas for the risk of haemorragic complications. Here we described a 63-year-old patient with ischemic stroke due to embolization of atrial myxoma and treated with intravenous recombinant tissue plasminogen activator alteplase. The patient did not show improvement after treatment; 25 days later a brain CT showed an asymptomatic small hemorrhagic infarction, probably due to the large size of ischemic lesion. The lack of response might be explained by the embolization of a large tumor fragment. One-year after cardiac surgery clinical follow-up did not reveal new neurological signs nor symptoms. This case report suggests that systemic thrombolysis is a safe procedure also in patient with atrial myxoma. The efficacy of therapy seems to be related to embolus composition.

Metformin and glyburide are antihyperglycemic agents that are widely used in the United States. There have been several cases of overdose of these medications reported in the world literature. Glyburide overdose is associated with hypoglycemia that can be severe, while metformin overdoses have been associated with lactic acidosis. In many cases of metformin overdose, lactic acidosis has led to profound hypotension and respiratory failure. In this article we will present the case of a 49-year-old man who ingested 52 grams of metformin and 350 mg of glyburide in a suicide attempt. The patient developed hypoglycemia, lactic acidosis, hypotension, respiratory failure and a profound sudden sensorineural hearing loss. We discuss prior cases of overdose with these agents, and the connection between overdose and the development of sudden sensorineural hearing loss.

Bentham Science Publishers would like to thank and appreciate the co-operation from all our reviewers for their constructive comments and feedback on the manuscripts submitted to “Current Drug Safety”. Their efforts have contributed greatly to the high quality and continuous growth of the journal. Given below is the list of reviewers who reviewed articles for the journal during 2010-2011.