Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies

Method:

The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study.

Results:

In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m⁻² dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37% median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0).

Conclusion:

Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.     

Sustained efficacy and long-term safety of oxcarbazepine: one-year open-label extension of a study in refractory partial epilepsy

PURPOSE: To evaluate the long-term efficacy, tolerability, and safety of oxcarbazepine (OXC) in medically refractory partial epilepsy. METHODS: This study is the open-label extension phase that followed a multicenter, randomized, double-blind, dose-response clinical study of OXC monotherapy in patients with medically refractory partial epilepsy. We analyzed the efficacy, tolerability, and safety of OXC during the first 48 weeks of open-label therapy. To evaluate efficacy, we compared the change in seizure frequency throughout the 48 weeks of treatment with OXC with the baseline seizure frequency that preceded the double-blind phase of the core study by an intent-to-treat and completer analysis. Safety and tolerability were evaluated by using an intent-to-treat analysis. RESULTS: Of the 87 patients enrolled in the double-blind study, 76 patients participated in the open-label extension phase. Fifty-five (72%) patients completed 48 weeks of open-label treatment on a median OXC dose of 2,400 mg/day. Based on an intent-to-treat analysis, the median reduction in seizure frequency was 47%(p = 0.0054); the 50 and 75% responder rates were 46.1 and 25.0%, respectively, with 6.6% of patients remaining seizure free. The completer analysis yielded comparable efficacy results. OXC was well tolerated, with 13% of patients exiting because of adverse events. The six most common adverse events, irrespective of their causal relation to OXC, were dizziness, headache, fatigue, diplopia, nausea, and rash. For the most part, these adverse events tended to be transient. CONCLUSIONS: The efficacy of OXC is sustained with good safety and tolerability profiles during long-term treatment of patients with medically refractory partial epilepsy.     

In Vitro Analysis of CsA-Induced Hepatotoxicity in HepG2 Cell Line: Oxidative Stress and α2 and β1 Integrin Subunits Expression

Background

Cyclosporine A (CsA)-induced hepatotoxicity could be due to a reduction in α2β1 integrin expression that may either be from the direct effect of CsA itself or from reactive oxygen species (ROS) overproduction.

Objectives

In this study we aimed to identify the cellular mechanisms underlying CsA-induced hepatic injury by investigating the activation patterns of the antioxidant enzymes, using HepG2 as an in vitro model.

Materials and Methods

HepG2 cells were cultured with different concentrations of CsA (0, 0.1, 1, 10 μg/ml) for 72 h. Effect of CsA on, 1) cellular integrity, 2) glutathione reductase (GR) and glutathione peroxidase (GPx) activity, 3) cellular levels of glutathione (GSH), 4) intracellular ROS, 5) ALT and AST activities, 6) urea production and 7) α2β1 integrin expression were assayed.

Results

CsA treatment demonstrated a dose dependent increase in intracellular levels of ROS, GPx activity and decrease in GSH levels (P<0.05). GR activity was mildly attenuated in 1 and 10 µg/ml concentrations of CsA. Alanine aminotranferase (ALT) and aspartate aminotransferase (AST) levels increased in CsA treated cells, while urea synthesis was significantly decreased following treatment with higher concentrations of CsA (P<0.05). Significant down-regulation of β1integrin expression was observed in 1 and 10 µg/ml CsA treated cells while α2 integrin mRNA was significantly down-regulated in all CsA treated cells.

Conclusions

The observed reduction of α2β1 integrin expression following CsA treatment could be proposed as a possible pathway of CsA-induced hepatotoxicity. Further studies are required to elucidate whether this attenuated expression is due to the direct effect of CsA or caused by overproduction of ROS.     

Efficient protocol for rapid Aloe vera micropropagation

Context: Aloe vera Linn. (Liliaceae) is a medicinal plant and has a number of curative properties. Vegetative propagation has not enough potential for supplying market demand. However, via in vitro propagation makes possible the mass production of Aloe plants.

Objective: The current study was conducted to investigate growth regulators’ effects on proliferation of A. vera.

Materials and methods: In this study, for comparison of plant growth regulators’ effects on proliferation, the shoot tips and auxiliary buds of A. vera were cultured in the Murashige and Skoog (MS) medium. Rooted plantlets were transferred to garden soil, compost, and sand in the proportion of 1:1:1, respectively, after hardening.

Results: The maximum number of shoots was obtained on the medium supplemented with 1?mg/L IAA?+?4?mg/L BAP and 0.2?mg/L IAA?+?0.8?BAP mg/L. Rooting was also achieved in the same media composition proliferation of shoot. The acclimatized plants showed 100% of survival. The regenerated plants looked healthy, and they were morphologically similar to that of stock plants.

Conclusion: These results suggest that in vitro culture may be used as a technique for rapid propagation of A. vera.     

Overweight and obesity in the eastern province of Saudi Arabia

OBJECTIVE: To describe anthropometric characteristics of participants and the influence of sociodemographic and cardiovascular risk factors involved in the prevalence of obesity in the eastern province of Saudi Arabia. METHODS: In the year 2004, all Saudi residents in the Eastern province aged 30 years and above, were invited to participate in a community screening campaign for early detection of diabetes and hypertension. Demographic data, medical history, life habits, weight, height, blood pressure, and glucose concentration were recorded using a structured questionnaire. Obesity and overweight were defined by body mass index (BMI) >or=30 kg/m2 and 25-29.9 kg/m2, respectively. Logistic regression was used to predict the association of the significant factors with the prevalence of obesity. RESULTS: Out of 195,874 participants, the overall prevalence of obesity was 43.8%, while 35.1% were overweight. The prevalence of underweight was 1.3%. The peak prevalence of obesity was observed in the age group 50-59 years. Obesity was higher among women than men, higher in housewives, and among the less educated than others (p<0.0001). Linear regression analysis showed a strong proportional association of BMI with diabetes, hypertension, triglycerides and cholesterol, and an inverse proportional association with physical activity and smoking CONCLUSION: Obesity and overweight constitute an important health problem affecting a high proportion of Saudi population. Addressing associated factors, and enhancing public health education is an important aim to focus on for weight control.     

Initial description of radiofrequency catheter ablation as treatment for atrial flutter in Marfan’s syndrome: A case report and literature review

Marfan's syndrome is a common connective tissue disease with different musculoskeletal, ophthalmic and cardiac manifestations. Marfan's patients carry increased risk for cardiac arrhythmias. Only three cases of atrial flutter in Marfan's patients are described in the literature. We report a fourth case of a young Marfan's patient who presents with typical atrial flutter after motor vehicle accident. After electrical cardioversion, sinus rhythm was restored but he had recurrent atrial flutter on follow up. The patient then underwent electrophysiological study and successful radiofrequency catheter ablation of the flutter circuit. Since discharge, the patient has had no documented arrhythmias on follow up.     

New Insights into Dose- and Time-Dependent Response of Five Typical PPCPs on Soil Microbial Respiration

Bulletin of Environmental Contamination and Toxicology - The widespread use of pharmaceutical and personal care products (PPCPs) has attracted much attention and the impact of PPCPs on indigenous...     

Xenon-133 retention in hepatic steatosis-correlation with liver biopsy in 45 patients: concise communication

This study presents the results of comparison of hepatic fat content with hepatic xenon retention in 45 patients. The degree of hepatic Xe-133 retention was measured during pulmonary ventilation studies. The amount of hepatic steatosis was graded 0 to 4+ on histologic liver sections obtained by needle or surgical biopsy. There was agreement between the amount of hepatic xenon retention determined scintigraphically and the degree of steatosis determined histologically. These results suggest that Xe-133 retention in the liver provides a simple means of evaluating fatty infiltration of the liver. The potential of this technique as a noninvasive means of investigating hepatic fatty infiltration is discussed.     

Modulation of pyloric motor activity via adrenergic receptors

The influences of adrenergic nerves on pyloric motor function and the locus and types of receptors involved were examined. Using glyoxylic acid fluorescence a dense adrenergic innervation of the inner pyloric muscle ring was demonstrated. Pyloric motor activity was monitored while close i.a. injections of a selective alpha-1 adrenoceptor agonist, phenylephrine, or a selective alpha-2 adrenoceptor agonist, B-HT-920, were given. Neither agonist affected basal pyloric motor activity, but both inhibited pyloric activity when it was stimulated by duodenal field stimulation or by intraduodenal acid infusion. The actions of each of the inhibitory agonists, phenylephrine or B-HT-920, were blocked selectively by prazosin or rauwolscine, respectively. Injection of isoproterenol usually had no effect or excited basal pyloric activity. This excitation could be antagonized selectively by propranolol or by atropine. Injection of isoproterenol after neural blockade by tetrodotoxin inhibited pyloric motor activity. Receptor binding studies carried out with subcellular nerve or muscle enriched membrane fractions of canine pyloric muscle with [3H]prazosin, [3H]rauwolscine and [125I]cyanopindolol revealed a dual location of alpha-1, alpha-2 and beta receptors on both nerve membranes and smooth muscle membranes. These results suggest that adrenergic effects on the pyloric muscle can be exerted by pre- and postsynaptic beta receptors which, respectively, excite by releasing acetylcholine and inhibit by acting on receptors on the pyloric muscle. Also inhibitory alpha-1 and alpha-2 receptors are present on cholinergic nerves. The functions of postsynaptic alpha-1 and alpha-2 adrenoceptor binding sites on smooth muscle are so far unknown.