Localisation of drug permeability along the rat small intestine, using markers of the paracellular, transcellular and some transporter routes

The small intestine is the major site of drug absorption. Some reports in the literature have evoked the concept of “absorption windows” in the small intestine: are there specific regions where drug absorption is significantly higher than others? To investigate this question, we used an everted gut sac method to study the permeability of drugs and markers every 3–4 cm down the entire small intestine in rat. These markers were chosen to be representative of the mechanisms by which drugs cross the small intestinal mucosa: paracellular and transcellular passive diffusion, via influx transporters, and a drug (digoxin) that is effluxed from cells by P-glycoprotein (P-gp). The passive diffusion and influx transporter markers gave similar profiles with a plateau of permeability along the jejunum, and with the exception of L-Dopa, lower permeability in the ileum. Digoxin showed a linear decrease in the profile from the proximal jejunum to the ileum. Permeability in the duodenum was two to three times lower than the jejunum for all compounds. There were no narrow specific regions of high permeability and so the concept of discrete “absorption windows” along the small intestine as suggested from some pharmacokinetic studies may be related to other effects such as pH and/or solubility.     

Efficacy of sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men in remission from depression

Erectile dysfunction (ED) and depression are highly prevalent and frequently comorbid. Sildenafil effectively treats ED in men with depression and in men taking antidepressants. We evaluated the efficacy of sildenafil in men with depression in remission and ED. Patients with a history of ED when major depressive disorder (MDD) was diagnosed, which persisted after MDD was treated to remission, were randomized to 12 weeks of treatment with sildenafil (50 mg, flexible) or placebo. Efficacy was assessed using intercourse success rates, a global efficacy question (Has treatment improved your erections?), the International Index of Erectile Function (IIEF) and Life Satisfaction Checklist (LSC). By week 12, intercourse success rates were significantly higher among sildenafil- (74%) compared to placebo-treated patients (29%; P=0.0001). About 83% and 34% of sildenafil- and placebo-treated patients, respectively, reported improved erections (odds ratio=9.4, P=0.0001). IIEF scores in the sildenafil group (n=83) were significantly improved compared to those in the placebo group (n=85; P <0.0001). LSC sexual life item improved significantly among sildenafil- versus placebo-treated patients. The most frequently reported adverse events were transient and mild-to-moderate. Sildenafil is an effective and well-tolerated treatment for ED in patients with a history of ED at the time of MDD diagnosis, and which persisted after the MDD was treated to remission.     

Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults

The effects of cannabis extracts on nocturnal sleep, early-morning performance, memory, and sleepiness were studied in 8 healthy volunteers (4 males, 4 females; 21 to 34 years). The study was double-blind and placebo-controlled with a 4-way crossover design. The 4 treatments were placebo, 15 mg Delta-9-tetrahydrocannabinol (THC), 5 mg THC combined with 5 mg cannabidiol (CBD), and 15 mg THC combined with 15 mg CBD. These were formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-minute period from 10 pm. The electroencephalogram was recorded during the sleep period (11 pm to 7 am). Performance, sleep latency, and subjective assessments of sleepiness and mood were measured from 8:30 am (10 hours after drug administration). There were no effects of 15 mg THC on nocturnal sleep. With the concomitant administration of the drugs (5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD), there was a decrease in stage 3 sleep, and with the higher dose combination, wakefulness was increased. The next day, with 15 mg THC, memory was impaired, sleep latency was reduced, and the subjects reported increased sleepiness and changes in mood. With the lower dose combination, reaction time was faster on the digit recall task, and with the higher dose combination, subjects reported increased sleepiness and changes in mood. Fifteen milligrams THC would appear to be sedative, while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counteracted the residual sedative activity of 15 mg THC.     

Role of PDE4 in superoxide anion generation through p44/42MAPK regulation: a cAMP and a PKA-independent mechanism

We investigated the generation of reactive oxygen species (ROS) from bronchoalveolar lavage (BAL) cells of either control or LPS-exposed rats and the effects of PDE4 inhibitors on ROS production. The PDE4 inhibitors, rolipram and Ariflo (cilomilast, SB 207499) dose-dependently (0.1-10 microm) inhibited fMLP-induced superoxide anion (O(2)(*-)) production (IC(50)s: 0.03 and 0.55 microm, respectively) in BAL cells of Wistar rats collected 3 h after an LPS-aerosol (200 micrograms ml(-1), 1 h). These BAL contained 85-95% neutrophils (BAL cells enriched in neutrophils). In contrast, BAL cells collected at the end of the challenge contained only macrophages and in these conditions, rolipram and Ariflo (0.1-10 microm) could only inhibit 25 and 45% of fMLP-induced O(2)(*-) release, respectively. We also observed that the inhibition of p44/42(MAPK) by PD98059 (1-10 microm) increased O(2)(*-) release by BAL cells enriched in neutrophils, but not by macrophages, and prevented the inhibition of O(2)(*-) production induced by PDE4 inhibitors. Western blot analysis showed that PDE4 inhibitors strongly activated p44/42(MAPK) in BAL cells enriched in neutrophils but not in macrophages. And in these cells, PDE4 and p44/42(MAPK) were co-immunoprecipitated by a polyclonal anti-PDE4 antibody. The following cell permeable-cAMP analogues, dbcAMP (10 microm-1 mm), 8-CPT-cAMP (1 mm) and 8-pMeOPT-2'-O-Me-cAMP (0.5 mm), could not reduce fMLP-induced O(2)(*-) production and both PKA inhibitors, PKA inhibitor 14-22 amide myristoylated (50 nm-1 microm) and H-89 (100 nm-1 microm), did not affect the decrease of O(2)(*-) release induced by PDE4 inhibitors in BAL cells enriched in neutrophils. These data suggest that PDE4 inhibitors decreased fMLP-induced O(2)(*-) release in BAL cells enriched in neutrophils but not in macrophages, through p44/42(MAPK) activation by a cAMP- and a PKA-independent mechanism.     

Chronic low-level mercury exposure, BDNF polymorphism, and associations with self-reported symptoms and mood.

Recent reports have described neurobehavioral impairments in human subjects carrying a V66M polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF). Inasmuch as ventral nervous system (CNS) deficits associated with this BDNF polymorphism are similar to those observed among subjects with chronic exposure to elemental mercury (Hg degrees ), we examined the potential effect of this BDNF polymorphism on symptoms and mood in an established cohort of dental practitioners with chronic low-level Hg degrees exposure. Self-reported symptoms and mood were obtained by computerized questionnaire from 193 male dentists (DTs) and 230 female dental assistants (DAs). Spot urine samples were analyzed for mercury concentrations to evaluate recent exposure. Detailed work histories were obtained to calculate chronic indices of Hg degrees exposure. Buccal cell samples were obtained to identify the V66M polymorphism of BDNF. Scores for 11 current and 12 recent and chronic symptom groups, along with six mood factors, were evaluated with respect to recent and chronic Hg degrees exposure and BDNF polymorphism. Multiple regression analysis controlled for age, race, socioeconomic status, tobacco and alcohol use, self-reported health problems, and medications. Separate evaluations were conducted for DTs and DAs. Twenty-three associations between recent or chronic Hg degrees exposure and BDNF status and self-reported symptoms were observed with p < 0.10. All but three were in the expected direction (symptom scores increasing with Hg degrees exposure or BDNF polymorphism), and all but six were among DAs. All eight correlations between chronic exposure indices and recent and chronic symptoms among DAs were in the expected direction. All seven associations between BDNF and symptoms were in the expected direction and split between DTs and DAs. All three associations with mood factors were among DAs and in the expected direction. These results indicate that among DAs very low levels of occupational Hg degrees exposure are associated with increased symptoms. The BDNF polymorphism is also associated with increased symptom and mood scores. Notably, Hg degrees and BDNF polymorphism were additive with respect to their associations with the same symptom group.     

SNS-595, a naphthyridine cell cycle inhibitor and stimulator of apoptosis for the treatment of cancers

Sunesis Pharmaceuticals Inc, under license from Dainippon Sumitomo Pharma Co Ltd, is developing SNS-595, a naphthyridine cell cycle inhibitor and apoptosis stimulator, for the potential treatment of a variety of solid and hematological malignancies. Phase I clinical trials had been completed in several solid tumor types and phase II clinical trials had been completed in patients with small-cell lung cancer and NSCLC. A phase II clinical trial in patients with platinum-resistant ovarian cancer and phase I/II and phase II clinical trials in patients with acute leukemias were ongoing at the time of publication.     

Characterization of a cidofovir-resistant HHV-6 mutant obtained by in vitro selection

Cidofovir (CDV) was used for in vitro selection of a human herpesvirus 6 (HHV-6) mutant with decreased susceptibility to this drug. The resulting mutant was highly resistant to CDV as compared to its sensitive counterpart (inhibitory concentration 50% (IC50): 213 microM versus 1.8 microM). Its replication fitness was not impaired. Genotypic characterization of the resistant virus revealed a mutation in the U38 gene encoding the viral DNA polymerase. The resulting R798I amino acid change was located in the conserved domain VII close to the highly conserved motif KKRY interacting with the DNA primer-template duplex, and is likely responsible for the high-level resistance to CDV, even though a definite virological and/or biochemical confirmation is required. The possible emergence of such changes in HHV-6 DNA polymerase in patients receiving CDV therapy should be taken into account in the treatment of HHV-6 infections.     

“Only Two Months Destroys Everything”: A Case Study of Communication About Nonadherence to Antiretroviral Therapy in a South African HIV Pharmacy Context

Adherence to antiretroviral treatment (ART) is a complex phenomenon and patients do not always adhere for a variety of reasons. The quality of communication and the therapeutic relationship between health professionals and patients have an important influence on adherence, as do contextual and environmental factors. Little qualitative research exists that examines health care interactions in the context of adherence counselling. This article presents a case study of a discussion about nonadherence between a pharmacy assistant and a patient in a South African HIV context. A hybrid analytical approach revealed various themes such as how the topic of nonadherence is addressed, participants' responses to the patient's nonadherence, and the process of negotiating a new commitment to adherence. The case provides insight into the impact of contextual factors on the interaction and challenges involved in discussing nonadherence—in particular, the patient's attempts to save face, the pharmacy assistant's irritation and anger, and the patient's expressed regrets. This case raises questions around issues of patient agency. Health professionals are encouraged to consider the influence of context, lifeworld, and culture on patients' ability to adhere to treatment regimens. By working to improve communication processes and strengthen the therapeutic relationship, patients may be empowered to achieve better adherence levels.     

Gender,migration and perceptions of HIV risk in Mexico

Abstract

This study examines the role that duty plays in men’s and women’s perceptions of HIV-related risk in Mexico, and how gender and migration influence these perceptions. We draw on qualitative data from the 2014 Study of Health and Migration in Mexico (SHMM), which included 24 in-depth interviews with migrant men and non-migrant women living in a medium-sized city in Guanajuato, Mexico. While men report migrating out of responsibility to provide for their families, this sense of duty also had implications for their sexual health behaviours. Duty permeates how residents in this migrant-sending community described their perceptions of HIV risk, with men and women drawing consistently on three aspects of duty: fidelity, gendered sexual expectations, and the burden of HIV prevention. We argue that a strong sense of duty can prompt gender role expansion for migrant men and limit gender role expansion for non-migrant women.