Absence of clinically relevant pharmacokinetic interaction between ribavirin and tenofovir in healthy subjects

This was a 36-day, open-label, fixed-sequence, multiple-dose drug interaction study in 23 healthy subjects to evaluate the effects of multiple doses of tenofovir disoproxil fumarate on the single-dose pharmacokinetics of ribavirin. Subjects received a 600-mg once-daily oral dose of ribavirin on days 1 and 22 and 300-mg once-daily oral doses of tenofovir disoproxil fumarate on days 17 through 24. Pharmacokinetic sampling was performed on days 1 through 4 and 22 through 25. Pharmacokinetics of ribavirin was not altered by its coadministration with tenofovir disoproxil fumarate as the point estimates (day 22 [test treatment]/day 1 [reference treatment]), and the 90% confidence interval for maximum observed concentration (0.95; 88.7-101) and area under the plasma concentration-time curve up to time of last measurable concentration (1.12; 106-117) were within the equivalence bounds of 80% to 125%. Tenofovir pharmacokinetics after ribavirin coadministration was similar to that observed in previous studies. These results indicate that coadministration of tenofovir disoproxil fumarate and ribavirin does not result in substantial changes to their individual pharmacokinetic profiles.     

Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma.

PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha). PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.     

Introduction of macromolecules into synaptosomes using electroporation

Synaptic terminals are sites of high metabolic activity and thus are particularly vulnerable to oxidative stress. Oxidative damage to proteins can be toxic to neurons and may cause irreversible cell damage and neurodegeneration. A neuroprotective mechanism used by cells to combat oxidative damage is to selectively degrade damaged proteins. Therefore, it is of interest to study the mechanism of degradation of oxidatively damaged proteins in synaptosomes. One way of oxidizing synaptosomal proteins in vitro is by incubating intact synaptosomes in the presence of an oxidizing agent. A problem with this approach is that it may also cause oxidative damage to the machinery required to recognize and degrade oxidized proteins. We have, therefore, introduced a fluorescent macromolecule into synaptosomes to assess the feasibility of using this technique to study how oxidized proteins are degraded and removed from synaptic terminals. Synaptosomes were subjected to electroporation in the presence of FITC labelled-dextran with an average molecular weight of 70000 (FD-70) and non-specific binding was determined by running parallel experiments in lysed synaptosomes. Following extensive washing, synaptosomes were assayed for the presence of intra-synaptosomal FD-70 by measuring fluorescence in a microplate fluorescence reader. Significant differences in fluorescence were found between intact and lysed synaptosomes with maximal uptake at 100 V/ 1500 microF (approx. 36 pmol/mg protein). To determine if membrane transport was compromised by electroporation, uptake of 3H-arginine was compared in control and electroporated synaptosomes. While untreated electroporated synaptosomes showed a loss of 22% in the ability to transport arginine, preincubation in the presence of 1 mM ATP resulted in a complete restoration of arginine transport. These results show that electroporation is a potentially useful technique for introducing a specific oxidized protein, into synaptic terminals so its metabolic fate can be examined.     

Protein-free diets do not protect high-incidence diabetes-prone BioBreeding rats from diabetes

Dietary factors have been reported to affect the development of spontaneous diabetes in various colonies of inbred and outbred diabetes-prone (DP) BioBreeding (BB) rats. Several studies have attributed a protective effect to a diet omitting crude protein mixtures in favor of purified casein, hydrolyzed casein, or free amino acids. We have used inbred BB rats, all of which become diabetic in specific pathogen-free (SPF) conditions when fed ordinary rat chow, to test the capacity of 2 different protein-free diets to modulate BB rat diabetes in 2 distinct pathogen-free environments. BB rats known to all develop diabetes by 100 days of age were fed from birth with 1 of 3 diets. By 120 days of age, 100% of the animals on a standard diabetogenic chow diet, 83% of animals on an amino acid-based protein-free diet, and 100% of animals on a hydrolyzed casein-based diet had developed diabetes (P >.05). A slight delay in the age of onset was observed among rats fed the amino acid-based diet, but this delay coincided with a reduction in weight gain among these animals compared with the rats on a standard diet. Histology showed insulitis in all rats at either diabetes onset or 120 days of age. We conclude that our unique strain of specific pathogen-free BB rats are not protected from diabetes when fed an amino acid-based diet and suggest that their insensitivity to dietary manipulation may be due to an as yet unknown factor present in the diabetes-resistant (DR), but not the DP BB rat genetic background.     

Multiple paragangliomas in a pregnant patient with a succinate dehydrogenase B mutation

In this case report, we document the clinical course, laboratory findings, and imaging findings of a 21-year-old pregnant woman with multiple paragangliomas due to a succinate dehydrogenase B (SDHB) mutation. We also review the literature on previously reported cases. The patient presented with nausea, palpitations, angina, and amenorrhea. Her blood pressure was 170/100 mm Hg and her beta-human chorionic gonadotropin was positive. Her blood pressure remained high despite phenoxybenzamine titration. A 24-hour urine analysis revealed elevated plasma metanephrines. Imaging was initially deferred due to early gestational age. After the patient terminated the pregnancy, magnetic resonance imaging revealed a left suprarenal mass, a mass at the aortic bifurcation, and a left periaortic mass. Her blood pressure was controlled on phenoxybenzamine and labetalol. The masses were excised. Pathology revealed paragangliomas. Genetic testing revealed mutation in the SDHB gene. One month later, her blood pressure was 122/86 mm Hg off of medication. Paraganglioma/pheochromocytoma should be suspected when hypertension occurs early in pregnancy. Genetic testing is important, as this may impact future offspring.     

Precursors of cardiorespiratory events in infants detected by home memory monitor

In 1,079 infants monitored for >700,000 hr at home for apnea or bradycardia, we found an association between infants having multiple events exceeding conventional or a priori defined more extreme thresholds and less favorable developmental outcome at 1 year of age than infants with few or no events. If it is necessary to prevent such events to minimize risk for developmental morbidity, there is reason to determine whether there are disturbances in advance of the apnea or bradycardia that herald their onset. In the 85 infants with at least 1 extreme event and 1 conventional event, we hypothesized that apnea and bradycardia do not occur de novo but rather are preceded by cardiorespiratory and hemoglobin O2 saturation changes. We compared recorded time intervals preceding these events, and we analyzed three preceding time intervals for each conventional and extreme event, and each non-event recording: Time-2 hr: up to 2 hr before; Time-1 hr: up to 1 hr before; and Time-75 sec: the 75 sec immediately preceding each event. O2 saturation progressively decreased preceding both conventional and extreme events, and progressive increases occurred in heart and breathing rate variability. Duration of respiratory pauses and of periodic breathing progressively increased preceding conventional events, respiratory rate variability increased immediately preceding conventional events and at 1 hr preceding extreme events, and O2 saturation decreased immediately preceding both conventional and extreme events. Thus, conventional and extreme events do not occur de novo but rather are preceded by autonomic instability of the cardiorespiratory system.     

Imaging of the adult male urethra,penile prostheses and artificial urinary sphincters

Abdominal Radiology - To discuss the imaging appearances of various pathologies affecting adult male urethra and to review the role of imaging in the assessment of artificial urinary sphincters and...     

Antiplasmodial activity of two marine polyherbal preparations from <Emphasis Type="Italic">Chaetomorpha antennina</Emphasis> and <Emphasis Type="Italic">Aegiceras corniculatum</Emphasis> against <Emphasis Type="Italic">Plasmodium falciparum</Emphasis>

The ocean covers more than 70% of earth surface and hosts most 300,000 described species of plants and animals to use, which have been virtually unexploited for the development of medicines. Marine plants are the good source of biologically active entities which exhibit therapeutic properties, when applied single or in combination of different plant extracts (polyherbal). Polyherbal preparations are always a complex mixture of different forms and thus different compounds, which might act as agonistic, synergistic, complementary, antagonistic or toxic way. The present study was initially carried out to test the antiplasmodial activity of 13 mangrove plants and eight seaweeds species distributed along the coast of south India. Of these, mangrove species Aegiceras corniculatum and the seaweed species Chaetomorpha antennina have shown maximum antiplasmodial activity. Hence, the present study was mooted out to increase the percentage of antiplasmodial activity when applied as polyherbal preparations. The effect of marine polyherbal preparations from the methanolic extracts of two marine plants A. corniculatum and C. antennina for their antiplasmodial activity was tested. It shows that the polyherbal extract showed 63.50 ± 0.408% suppression of parasitaemia against Plasmodium falciparum at 1.5 mg ml⁻¹ concentration. In vivo test was carried out with rat animal model to find out the effectiveness of the polyherbal extracts in the live system, which reveals that polyherbal extracts have exhibited remarkable antiplasmodial activity (50.57 ± 0.465%) against Plasmodium berghei at 120 mg kg⁻¹ bw. This study shows that combinations of mangrove plants and seaweeds extracts had a source of lead compounds for the development of new drugs for the treatment of malaria.