Drug-free Period Research Articles

The orexin receptors in the ventral tegmental area are involved in the development of sensitization to expression of morphine-induced preference in rats.

Recent studies have shown that orexin neurons in the lateral hypothalamus send a compelling project to the ventral tegmental area (VTA). Besides, orexin-1 (OX1) and orexin-2 (OX2) in the VTA are necessary for the development of morphine-induced place preference. Also, sensitivity to morphine can reinforce the rewarding effects of morphine. The current study aims to determine the role of VTAs orexin receptors in morphine sensitization in rats. In 84 adult male albino Wistar rats, two separate cannulae bilaterally implanted into the VTA. They received intra-VTA infusions of SB334867 (0.1, 1 and 10 nM) and TCS OX2 29 (1, 7 and 20 nM) as OX1 and OX2 receptor antagonists, respectively, 10 min before subcutaneous administration of morphine (5 mg/kg) during 3-day sensitization period. After a 5-day drug-free period, the conditioned place preference (CPP) paradigm induced by subthreshold doses of morphine (0.5 mg/kg), and CPP scores were measured by EthoVision software. The results revealed that the blockade of both OX1 and OX2 receptors within the VTA reduced the expression of morphine-induced CPP in the sensitized rats. It is plausible that VTAs orexin receptors are involved in the development/acquisition of sensitization to morphine-induced CPP in the rats.

Effect of 4-Fluoro-N-(4-Sulfamoylbenzyl) Benzene Sulfonamide on Acquisition and Expression of Nicotine-Induced Behavioral Sensitization and Striatal Adenosine Levels.

IntroductionBehavioral sensitization is a phenomenon that develops from intermittent exposure to nicotine and other psychostimulants, which often leads to heightened locomotor activity and then relapse. Sulfonamides that act as carbonic anhydrase inhibitors have a documented role in enhancing dopaminergic tone and normalizing neuroplasticity by stabilizing glutamate release.ObjectiveThe aim of the current study was to explore synthetic sulfonamides derivative 4-fluoro-N-(4-sulfamoylbenzyl) benzene-sulfonamide (4-FBS) (with documented carbonic anhydrase inhibitory activity) on acquisition and expression of nicotine-induced behavioral sensitization.MethodsIn the acquisition phase, selected 5 groups of mice were exposed to saline or nicotine 0.5mg/kg intraperitoneal (i.p) for 7 consecutive days. Selected 3 groups were administered with 4-FBS 20, 40, and 60 mg/kg p.o. along with nicotine. After 3 days of the drug-free period, ie, day 11, a challenge dose of nicotine was injected to all groups except saline and locomotor activity was recorded for 30 minutes. In the expression phase, mice were exposed to saline and nicotine only 0.5 mg/kg i.p for 7 consecutive days. After 3 days of the drug-free period, ie, day 11, 4-FBS at 20, 40, and 60 mg/kg were administered to the selected groups, one hour after drug a nicotine challenge dose was administered, and locomotion was recorded. At the end of behavioral experiments, all animals were decapitated and the striatum was excised and screened for changes in adenosine levels, using HPLC-UV.ResultsTaken together, our findings showed that 4-FBS in all 3 doses, in both sets of experiments significantly attenuated nicotine-induced behavioral sensitization in mice. Additionally, 4-FBS at 60mg/kg significantly lowered the adenosine level in the striatum.ConclusionThe behavioral and adenosine modulation is promising, and more receptors level studies are warranted to explore the exact mechanism of action of 4-FBS.

Sex chromosome complement influences vulnerability to cocaine in mice

Women acquire cocaine habits faster and are more motivated to obtain drug than men. In general, female rodents acquire intravenous cocaine self-administration (SA) faster and show greater locomotor responses to cocaine than males. Sex differences are attributed to differences in circulating estradiol. We used the four core genotype (FCG) mouse to ask whether sex chromosome complement influences vulnerability to cocaine's reinforcing and/or locomotor-activating effects. The FCG cross produces ovary-bearing mice with XX or XY genotypes (XXF, XYF) and testes-bearing mice with XX or XY genotypes (XXM, XYM). A greater percentage of gonadal females acquired cocaine SA via infusions into jugular catheters as compared with XYM mice, but XXM mice were not significantly different than any other group. Discrimination of the active versus inactive nose poke holes and cocaine intake were in general greater in gonadal females than in gonadal males. Progressive ratio tests for motivation revealed an interaction between sex chromosomes and gonads: XYM mice were more motivated to self-administer cocaine taking more infusions than mice in any other group. Locomotor responses to cocaine exposure revealed effects of sex chromosomes. After acute exposure, activity was greater in XX than in XY mice and the reverse was true for behavioral sensitization. Mice with XY genotypes displayed more activity than XX mice when given cocaine after a 10-day drug-free period. Our data demonstrate that sex chromosome complement alone and/or interacting with gonadal status can modify cocaine's reinforcing and locomotor-activating effects. These data should inform current studies of sex differences in drug use.

Intermittent β-adrenergic blockade downregulates the gene expression of β-myosin heavy chain in the mouse heart

Expression of the β-myosin heavy chain (β-MHC), a major component of the cardiac contractile apparatus, is tightly regulated as even modest increases can be detrimental to heart under stress. In healthy hearts, continuous inhibition of β-adrenergic tone upregulates β-MHC expression. However, it is unknown whether the duration of the β-adrenergic inhibition and β-MHC expression are related. Here, we evaluated the effects of intermittent β-blockade on cardiac β-MHC expression. To this end, the β-blocker propranolol, at the dose of 15mg/kg, was administered once a day in mice for 14 days. This dosing schedule caused daily drug-free periods of at least 6 h as evidenced by propranolol plasma concentrations and cardiac β-adrenergic responsiveness. Under these conditions, β-MHC expression decreased by about 75% compared to controls. This effect was abolished in mice lacking β1- but not β2-adrenergic receptors (β-AR) indicating that β-MHC expression is regulated in a β1-AR-dependent manner. In β1-AR knockout mice, the baseline β-MHC expression was fourfold higher than in wild-type mice. Also, we evaluated the impact of intermittent β-blockade on β-MHC expression in mice with systolic dysfunction, in which an increased β-MHC expression occurs. At 3 weeks after myocardial infarction, mice showed systolic dysfunction and upregulation of β-MHC expression. Intermittent β-blockade decreased β-MHC expression while attenuating cardiac dysfunction. In vitro studies showed that propranolol does not affect β-MHC expression on its own but antagonizes catecholamine effects on β-MHC expression. In conclusion, a direct relationship occurs between the duration of the β-adrenergic inhibition and β-MHC expression through the β1-AR.

Disruption of the Keap1/Nrf2-Antioxidant Response System After Chronic Doxorubicin Exposure In Vivo.

Doxorubicin (DOX) is a widely prescribed anthracycline antineoplastic drug for treating human solid tumors and leukemias. However, DOX therapy is limited by a cumulative, dose-dependent, and irreversible cardiomyopathy that occurs with repeated administration. Presumably, a pivotal initiating event of DOX-induced cardiotoxicity is the production of reactive oxygen species (ROS) and oxidation of lipids, DNA, and proteins. We recently identified activation of the Keap1/Nrf2-antioxidant response system-a major cellular defense mechanism against such oxidative stress-as an important response to acute DOX exposure in vitro. In the present study, we address the hypothesis that dysregulation of this pathway in cardiac tissue is also manifested in vivo following chronic DOX administration. Male, Sprague-Dawley rats received 6 weekly injections of 2mg/kg (s.c.) DOX or saline followed by a 5-week drug-free period prior to analysis of cardiac tissue transcripts and proteins. In contrast to in vitro findings, the Keap1/Nrf2-antioxidant response system was suppressed in hearts of DOX-treated animals and consistent with the observed decrease in protein abundance for Nrf2 and PGAM5, both of which are substrates for Keap1. Although this shift in Keap1/Nrf2 suppresses the antioxidant pathway, the concurrent loss of PGAM5 could function as a signal for disposal of damaged mitochondria from the cell, thus removing the source of ROS. These findings identify the Keap1/Nrf2 and Keap1/PGAM5 pathways as important responses to DOX-induced cardiac injury in vivo; disruption of this system for mitochondrial hormesis may be an important contributing factor to cardiotoxicity after chronic drug administration.

Effects of chronic nicotine exposure on Δ9-tetrahydrocannabinol-induced locomotor activity and neural activation in male and female adolescent and adult rats

RationaleHigh rates of comorbid tobacco and cannabis use in adolescents and young adults may be related to functional interactions between the nicotinic cholinergic and cannabinoid systems in the brain during development. This study examined the effects of chronic exposure to nicotine (the psychoactive component in tobacco) on acute exposure to delta-9-tetrahydrocannabinol (THC) (the psychoactive component of cannabis). MethodsMale and female adolescent and adult Sprague-Dawley rats (N = 112) were injected daily with nicotine (1 mg/kg, i.p.) or vehicle for 14 days, followed by a 14-day drug-free period. On test day, rats were injected with THC (5 mg/kg, i.p.) or vehicle, locomotor activity was recorded for 2 h, and brains harvested for c-Fos immunoreactivity (IR). ResultsLocomotor activity and c-Fos IR changes induced by THC challenge were altered by nicotine pre-exposure and modified by age and sex. THC-induced suppression of locomotor activity was attenuated by nicotine pre-exposure in adult but not adolescent males. THC-induced suppression of locomotor activity was potentiated by nicotine pre-exposure in female adolescents, with no effects of THC or nicotine observed in female adults. THC increased c-Fos IR in the caudate, nucleus accumbens, stria terminalis, septum, amygdala, hypothalamus, and thalamus. Nicotine pre-exposure potentiated this effect in all regions. Several brain regions showed age and sex differences in c-Fos IR such that expression was greater in adults than adolescents and in females than males. ConclusionsChronic nicotine pre-exposure produces lasting effects on cannabinoid-mediated signalling in the brain and on behaviour that are mediated by age and sex. Funding supportNSERC.

A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression.

Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. A 7-chlorokynurenic acid is a potent and specific glycine site N-methyl-d-aspartate receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN), exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression. After a 2-week drug-free period, 19 participants with treatment-resistant depression were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1080 mg/d for 7 days, then 1440 mg/d for 7 days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was the Hamilton Depression Rating Scale score, assessed at several time points over a 2-week period; secondary outcome measures included additional rating scale scores. Pharmacokinetic measures of 7-chlorokynurenic acid and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy brain glutamate levels, resting-state functional magnetic resonance imaging, and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors. Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. A 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events. In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied.ClinicalTrials.gov identifier: NCT02484456.

Toxicity and postwithdrawal effects of ketamine on the reproductive function of male albino rats: Hormonal, histological, and immunohistochemical study

Ketamine is increasingly used in clinical practice, and ketamine addiction is common in young individuals. There are limited reviews on the chronic effects of ketamine on the testes. Three groups of rats received saline or ketamine 50 mg/kg/day intraperitoneally for 6 weeks with or without a subsequent 4-week drug-free period. Serum follicle-stimulating hormone, luteinizing hormone, prolactin, and testosterone levels, as well as testicular malondialdehyde concentrations, were measured. Epididymal sperm parameters were assessed. Testicular tissues were examined by hematoxylin and eosin staining and immunohistochemical staining using caspase-3 and vimentin antibodies. Chronic ketamine injection significantly decreased the levels of the examined hormones and adversely affected sperm parameters. Testicular tissue showed a significant increase in caspase-3 expression. In addition, Sertoli cell shape and position were disrupted. These effects disappeared 4 weeks after drug withdrawal. Chronic ketamine treatment has revisable hazardous effects on the rat reproductive function. There is a need to increase the knowledge of physicians and the public regarding these harmful effects of ketamine.

Tailoring Biologic or Immunomodulator Treatment Withdrawal in Inflammatory Bowel Disease.

There is currently no cure for inflammatory bowel disease. Most recent treatments and treatment strategies allow for healing intestinal lesions and maintaining steroid-free remission in a subset of patients. These patients and their doctors often ask themselves whether the treatment could be withdrawn. Several studies in both Crohn's disease and ulcerative colitis have demonstrated a risk of relapse, which varies between 20 and 50% at 1 year and between 50 and 80% beyond 5 years. These numbers clearly highlight that stopping therapy should not be a systematically proposed strategy in those remitting patients. Nevertheless, they also indicate that a minority of patients may not relapse over mid-term and that those who have relapsed may have benefited from a drug-free period before being treated again for a new cycle of treatment. In this context, it would be good to optimally select patients who can be candidates for a successful treatment withdrawal. The criteria impacting this decision are as follows: the risk of relapse (linked to factors like mucosal healing and biomarkers), the consequence of a potential relapse, the tolerance and potential side effects of therapy, patients' priorities and preferences, and the costs. Integration of these parameters allows for the proposal of a decisional algorithm that may help the patients and doctors to make an appropriate decision for their individual case.

Quantifying the impact of treatment history on plasmid-mediated resistance evolution in human gut microbiota

To understand how antibiotic use affects the risk of a resistant infection, we present a computational model of the population dynamics of gut microbiota including antibiotic resistance-conferring plasmids. We then describe how this model is parameterized based on published microbiota data. Finally, we investigate how treatment history affects the prevalence of resistance among opportunistic enterobacterial pathogens. We simulate treatment histories and identify which properties of prior antibiotic exposure are most influential in determining the prevalence of resistance. We find that resistance prevalence can be predicted by 3 properties, namely the total days of drug exposure, the duration of the drug-free period after last treatment, and the center of mass of the treatment pattern. Overall this work provides a framework for capturing the role of the microbiome in the selection of antibiotic resistance and highlights the role of treatment history for the prevalence of resistance.

Locomotor sensitization in male Sprague-Dawley rats following repeated concurrent treatment with 4-methylmethcathinone and 3,4-methylenedioxymethamphetamine.

Recreational abuse of illicit synthetic cathinones is an ongoing public health concern. Recent studies indicate that the methcathinone derivative 4-methylmethcathinone (4-MMC) produces behavioral and neurochemical effects similar to the entactogen 3,4-methylenedioxymethamphetamine (MDMA). Whereas polysubstance abuse is common, most preclinical studies of drug abuse liability only evaluate the effects of single drugs. Utilizing the locomotor sensitization paradigm, the present study assessed the combined locomotor stimulant effects of 4-MMC and MDMA for induction of sensitization following repeated administration and for expression of sensitization to a challenge dose of either substance alone after a 10-day period of drug abstinence. Male Sprague-Dawley rats received once daily intraperitoneal injections of saline, 4-MMC (1.0 mg/kg or 5.0 mg/kg), MDMA (3.0 mg/kg), or a mixture containing 4-MMC (1.0 mg/kg or 5.0 mg/kg) + MDMA (3.0 mg/kg) for 7 consecutive days. Following a 10-day drug-free period, rats were given a single intraperitoneal injection of either saline, 4-MMC (1.0 or 5.0 mg/kg), or 3.0 mg/kg MDMA. Activity was recorded for 1 h immediately before and 1 h immediately after injections on days 1, 7, and 17. 4-MMC treatment failed to induce locomotor sensitization, but, when combined with MDMA, sensitization was induced to a greater extent than with MDMA alone. Furthermore, the expression of sensitization to a subsequent challenge dose of MDMA was observed only in animals previously exposed to MDMA or a 5.0 mg/kg 4-MMC + MDMA mixture. In consideration of these findings along with the fact that 4-MMC has similar neurochemical actions to MDMA, further research may be warranted to determine the abuse liability of drug mixtures including 4-MMC and MDMA.

Adolescent exposure to fluoxetine impairs serial pattern learning in the serial multiple choice (SMC) task in adult rats.

The effects of chronic adolescent fluoxetine (FLX, Prozac®) exposure on adult cognition are largely unknown. We used a serial multiple choice (SMC) task to characterize the effects of adolescent FLX exposure on rat serial pattern learning in adulthood. Male rats were exposed to either 1.0, 2.0, or 4.0 mg/kg/day FLX for five consecutive days each week for five weeks during adolescence, followed by a 35-day drug-free period. As adults, the rats were trained in a task that required them to learn a highly structured sequential pattern of responses in an octagonal chamber for water reinforcement. In a transfer phase, the terminal element of the pattern was replaced by a violation element that was inconsistent with previously learned pattern structure. Results indicated that adolescent FLX exposure caused differential learning deficits for different types of elements in the serial pattern. Adolescent exposure to 1.0 or 4.0 mg/kg/day FLX, but not 2.0 mg/kg/day FLX, impaired chunk-boundary element learning, which is known to be mediated by stimulus-response (S-R) learning. All three doses of FLX impaired violation element learning, which is known to be mediated by multiple-cue learning. FLX did not impair within-chunk element learning, which is known to be mediated by rule-learning mechanisms. The results indicate that adolescent FLX exposure produced multiple cognitive impairments that were detectable in adulthood long after drug exposure ended.

Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy.

Metronomic chemotherapy (MCT) is defined as the frequent administration of low-dose chemotherapeutics, without long drug-free periods, with the exertion of antitumor activity exclusively through anti-angiogenic mechanisms. In this study, we have developed an orally available formulation of pemetrexed (PMX) for MCT. PMX was first complexed ionically with Nα-deoxycholyl-l-lysyl-methylester (DCK) as the permeation enhancer. This was followed by dispersion with poloxamer 188 and Labrasol to form the solid oral formulation of PMX (PMX/DCK-OP). PMX/DCK-OP exhibited a 10.6-fold increase in permeability across a Caco-2 cell monolayer compared to PMX alone. This resulted in a 70-fold increase in the oral bioavailability of PMX/DCK-OP in mice over oral PMX alone. In the A549 xenograft model, tumor volume was reduced by 51.1% in the PMX/DCK-OP treated group compared to only 32.8% in the maximum tolerated dose (MTD)-treated group. Furthermore, PMX/DCK-OP exhibited a significant anti-angiogenic effect on the A549 xenograft mice when compared to the MTD-treated group, as indicated by microvessel density quantification for CD-31. In addition, PMX/DCK-OP enhanced the release of an endogenous angiogenesis inhibitor, thrombospondin-1 (TSP-1), into both the blood circulation and the tumor microenvironment. Therefore, due to its oral route of administration, PMX/DCK-OP appears to be a better alternative to the conventional treatment of PMX.

Eliminated patient fee and changes in dispensing patterns of asthma medication in children-An interrupted time series analysis.

In 2016, all prescription drugs included in the reimbursement system in Sweden were made available for children (age 0-17years) without any patient fees. Our aim was to estimate the association between this intervention and the dispensing patterns of asthma medications among children. Dispensing data on asthma medications for all children living in Stockholm County during 2014-2017 were selected to include two years before (January 2014-December 2015) and after (January 2016-December 2017) the intervention. In an uncontrolled before and after study, the measures of utilization were as follows: the proportion of children with at least one dispensed asthma medication (prevalence); the number of children initiated on treatment after an 18-month drug-free period (incidence); the number of defined daily doses (DDDs) dispensed per child; and the number of children with at least two prescriptions with controller medication (inhaled corticosteroid or leukotriene receptor antagonist) dispensed during 18months (persistence). In an interrupted time series (ITS) analysis, all measures were included except for persistence. Socio-economic status was defined using Mosaic data. The prevalence increased after the intervention (from 11.9% to 13.0%). However, the ITS analysis showed a positive trend already before the intervention, and consequently, the increase was not attributable to the intervention. For incidence, similar patterns were observed. There was an increase in dispensed volumes related to the intervention, 46.3 DDDs/child/month before and 51.1 after the intervention (P-value 0.01). The proportion of children with persistent asthma medication increased from 46.0% to 51.9% in children with low socio-economic status. In conclusion, the intervention was only modestly associated with changes in the dispensing patterns of asthma medication, with the volume dispensed per child increasing slightly, particularly in children with low socio-economic status.

A preliminary results of integrated chemotherapy with EGFR receptor tyrosine kinase inhibitors in patients with non-small-cell-lung cancer harboring EGFR mutation

In the open prospective non-randomized single-center study we recruited patients with advanced NSCLC harboring EGFR mutations. Initially there were two months of treatment by gefitinib 250 mg daily. Then, after a 2-week drug-free period, 3 cycles of paclitaxel 175 mg / m2 and carboplatin AUC5 were administrated at days 71-113. Thereafter, gefitinib was re-started on day 135 and continued until disease progression. The primary endpoint was progressive free survival (PFS) time. One-year PFS in all patients group included in the study at the time of the preliminary analysis was 79.8%, median PFS was 17 months (13.5–23, CI 95%). In the group of integrated chemotherapy one-year PFS was 89.3%, median PFS was 19 months (14–23.5, CI 95%).

Effect of Aslagh Capsule, a Traditional Compound Herbal Product on Oligomenorrhea in Patients with Polycystic Ovary Syndrome: A Three-Arm, Open-label, Randomized, Controlled Trial

Background: Oligomenorrhea is a common complaint in patients with polycystic ovary syndrome (PCOS). There are some useful medicinal recommendations such as Aslagh product (include fennel fruits, carrot seeds, chaste tree fruits) in Iranian traditional medicine for the treatment of oligomenorrhea in PCOS. Hence, the present investigation was designed to compare Aslagh capsule with metformin on the oligomenorrhea. Materials and Methods: One hundred fifty women aged between 18-43 years with oligomenorrhea due to PCOS were randomly divided into Aslagh, metformin, and Aslagh + metformin groups. The occurrence of menstrual bleeding was considered as the primary outcome. Menstrual cyclicity, duration, and volume of the bleeding were also evaluated. Results: Occurrence of menstrual bleeding was 87.2% in all patients, with no significant difference between the three groups (P> 0.05). Menstrual cyclicity significantly improved from baseline in Aslagh and Aslagh+ metformin groups (P=0.02). Duration of menstrual bleeding was significantly higher in Aslagh group in the first and the second menstrual bleeding cycle compared to the other two groups (P<0.05). No significant change was observed in the volume of the bleeding after the intervention in any of the three groups. The occurrence of menstrual bleeding in Aslagh group was significantly (P=0.03) higher than the other two groups in the fourth month (drug-free period). Conclusion: Aslagh capsule showed beneficial effects similar to metformin in the treatment of oligomenorrhea in PCOS women and could be suggested for use as an alternative treatment in these patients. [GMJ.2019;8:e1261]

Effect of Aslagh Capsule, a Traditional Compound Herbal Product on Oligomenorrhea in Patients with Polycystic Ovary Syndrome: A Three-Arm, Open-label, Randomized, Controlled Trial

Background: Oligomenorrhea is a common complaint in patients with polycystic ovary syndrome (PCOS). There are some useful medicinal recommendations such as Aslagh product (include fennel fruits, carrot seeds, chaste tree fruits) in Iranian traditional medicine for the treatment of oligomenorrhea in PCOS. Hence, the present investigation was designed to compare Aslagh capsule with metformin on the oligomenorrhea. Materials and Methods: One hundred fifty women aged between 18-43 years with oligomenorrhea due to PCOS were randomly divided into Aslagh, metformin, and Aslagh + metformin groups. The occurrence of menstrual bleeding was considered as the primary outcome. Menstrual cyclicity, duration, and volume of the bleeding were also evaluated. Results: Occurrence of menstrual bleeding was 87.2% in all patients, with no significant difference between the three groups (P> 0.05). Menstrual cyclicity significantly improved from baseline in Aslagh and Aslagh + metformin groups (P=0.02). Duration of menstrual bleeding was significantly higher in Aslagh group in the first and the second menstrual bleeding cycle compared to the other two groups (P<0.05). No significant change was observed in the volume of the bleeding after the intervention in any of the three groups. The occurrence of menstrual bleeding in Aslagh group was significantly (P=0.03) higher than the other two groups in the fourth month (drug-free period). Conclusion:Aslagh capsule showed beneficial effects similar to metformin in the treatment of oligomenorrhea in PCOS women and could be suggested for use as an alternative treatment in these patients.

Increased Cocaine Motivation Is Associated with Degraded Spatial and Temporal Representations in IL-NAc Neurons

Craving for cocaine progressively increases in cocaine users during drug-free periods, contributing to relapse. The projection from the infralimbic cortex to the nucleus accumbens shell (IL-NAc) is thought to inhibit cocaine seeking. However, it is not known whether and how IL-NAc neurons contribute to the increased motivation associated with a drug-free period. We first performed cellular resolution imaging of IL-NAc neurons in rats during a drug-seeking test. This revealed neurons with spatial selectivity within the cocaine-associated context, a decrease in activity around the time of cocaine seeking, and an inverse relationship between cocaine-seeking activity and subsequent cocaine motivation. All these properties were reduced by a drug-free period. Next, we transiently activated this projection, which resulted in reduced drug seeking, regardless of thedrug-free period. Taken together, this suggests thataltered IL-NAc activity after a drug-free period may enhance cocaine motivation without fundamentally altering the projection's ability to inhibit drug seeking.

Clinical outcome and laboratory markers for predicting disease activity in patients with disseminated opportunistic infections associated with anti-interferon-γ autoantibodies.

BackgroundClinical courses and treatment outcomes are largely unknown in patients with adult-onset immunodeficiency associated with anti-interferon-gamma autoantibodies due to the fact that it was recently recognized and anti-IFN-γ auto-Abs detection is not widely available.Methods and findingsNon-HIV-infected adult patients with detectable anti-IFN-γ auto-Abs diagnosed and followed at Siriraj Hospital, Bangkok, Thailand during January 2013 to November 2016 were prospectively studied. At each follow-up visit, patients were classified as stable or active disease according to symptoms and signs, and all proven OIs were recorded. Laboratory parameters, including erythrocyte sedimentation rate, C-reactive protein, and anti-IFN-γ auto-Abs level, were compared between active and stable disease episodes. We identified 80 patients with this clinical syndrome and followed them up during study period. Seventy-nine patients developed overall 194 proven opportunistic infections. Mycobacterium abscessus (34.5%) and Salmonella spp. (23.2%) were the two most common pathogens identified among these patients. Sixty-three patients were followed for a median of 2.7 years (range 0.6–4.8 years). Eleven (17.5%) patients achieved the drug-free remission period for at least 9 months. Four patients died. Anti-IFN-γ auto-Abs concentration was significantly lower at baseline and decreased over time in the drug-free remission group compared to another group (p = 0.001). C-reactive protein, erythrocyte sedimentation rate and white cell count were found to be useful biomarkers for determining disease activity during follow-up.ConclusionsReinfection or relapse of OIs is common despite long-term antimicrobial treatment in patients with anti-IFN-γ auto-Abs. Treatment to modify anti-IFN-γ auto-Abs production may improve long-term outcomes in this patient population.

Drug properties of fosravuconazole L-lysine ethanolate (NAILIN&lt;sup&gt;®&lt;/sup&gt; Capsules 100 mg), a new oral azole therapeutic for onychomycosis: an analysis based on non-clinical and clinical trial data

Ravuconazole is a fourth generation azole exerting strong antifungal activity, with low drug-drug interaction and hepatic dysfunction risks. Fosravuconazole l-lysine ethanolate (fosravuconazole; NAILIN® Capsules 100 mg) was developed as a ravuconazole prodrug. Ravuconazole exerts strong antifungal activity against various pathogenic fungi including dermatophytes and Candida. Through prodrug formation, pharmacokinetic improvement was achieved, and bioavailability after oral administration reached 100%. The plasma ravuconazole concentration became 10-35 times higher than with current oral anti-onychomycosis drugs, and showed good skin and nail tissue transition plus tissue retention. This improvement obtained with fosravuconazole reflects its superior pharmacokinetic properties. We conducted a clinical trial with fosravuconazole orally administered once a day (100 mg ravuconazole) for 12 weeks in Japanese onychomycosis patients. The ravuconazole concentration in nail tissues exceeded the MIC90 against dermatophytes, even after treatment completion. Furthermore, the placebo-controlled, double-blind, comparative trial showed significantly superior effects (at 48 weeks after starting treatment, with a complete cure rate of 59.4%, a marked clinical improvement rate of 83.1%, and a mycological cure rate by direct microscopy of 82.0%). The major adverse reactions were laboratory abnormalities and gastrointestinal disorders with no severe symptoms, suggesting good tolerability. Fosravuconazole has fewer drug-drug interactions, is not affected by food, and is also expected to improve medication adherence since the administration period is only 12 weeks and there is no drug-free period as required with pulse therapy. Thus, fosravuconazole has many favorable pharmacological properties and can reasonably be expected to become a new oral treatment option for onychomycosis.