Decoding Clozapine-Induced Agranulocytosis: Unraveling Interactions and Mitigation Strategies.

Agranulocytosis represents a severe complication associated with the administration of clozapine. Clozapine is an antipsychotic medication that has demonstrated substantial efficacy in remediating refractory schizophrenia and various other psychiatric disorders. Nonetheless, it is crucial to monitor patients for neutropenia regularly during clozapine therapy. Therefore, this article aimed to delve into the prevalence of agranulocytosis during clozapine treatment by scrutinizing the extant literature to discern trends and correlations. This review endeavored to explore factors such as drug interactions, dose-related factors, duration of treatment, and genetic predispositions that could potentially influence the likelihood of patients developing agranulocytosis while undergoing clozapine therapy. Moreover, this review enunciates the ramifications of agranulocytosis on both patients and healthcare providers and meticulously evaluates the strategies to mitigate this risk and ensure optimal patient outcomes.

Sitagliptin ameliorates L-arginine-induced acute pancreatitis via modulating inflammatory cytokines expression and combating oxidative stress.

Background: Acute pancreatitis (AP) is an inflammatory condition that resolves spontaneously, but occasionally, develops into systemic inflammation, organ failure and mortality. Oxidative stress and activation of inflammatory pathways represent major players in AP pathogenesis. Current management of AP relies on attenuating injuries to the pancreas and putting the inflammatory process under control. In this study, we investigated the role of sitagliptin in modulating L-arginine-induced AP in rats. Methods: Swiss rats were subdivided into a healthy control group, AP group (a single dose of L-arginine 250 mg/100 g, intraperitoneal), and sitagliptin + L-arginine-treated group (10 mg sitagliptin/kg body weight/day, orally). Sitagliptin treatment started 1 hour after L-arginine injection and continued for 3days. Biochemical and histopathological investigations were performed on serum and tissue samples collected from test animals. Results: L-arginine increased pancreatic meyloperoxidase and serum amylase- and lipase activities and serum levels of TNF-α, LT-α, IFN-γ, IL-1α/ß, IL-6, IL-10, IL-12, and IL-15. AP animals showed elevated MDA and NO and decreased GSH and serum calcium levels. Histopathological changes were observed by H&E staining. Sitagliptin treatment significantly ameliorated these biochemical and histological changes diminishing the signs of AP. Conclusion: Sitagliptin treatment was effective in ameliorating L-arginine-induced AP which can be regarded to its anti-inflammatory and antioxidant effect.

Postoperative Pain Following Transoral Thyroidectomy via Vestibular Approach and Cervical Thyroidectomy: A Systematic Review and Meta-Analysis.

Transoral endoscopic thyroidectomy via the vestibular approach (TOETVA) represents a minimally invasive alternative to traditional open thyroidectomy (OT). The objective of this systematic review and meta-analysis was to comprehensively analyze and compare postoperative pain outcomes between conventional open thyroidectomy (COT) and TOETVA. We conducted a systematic search across multiple databases, including PubMed, Medline, Elton B. Stephens Company (EBSCO), and Google Scholar, to identify cohorts and randomized trials comparing postoperative pain outcomes between patients undergoing transoral endoscopic thyroidectomy via the vestibular approach (TOETVA) and those undergoing conventional thyroidectomy. The search period spanned from the earliest available article up to January 15, 2022. Keywords such as "scarless thyroidectomy," "endoscopic transoral via vestibular thyroidectomy," "conventional thyroidectomy," "transcervical thyroidectomy," "postoperative pain," and "visual analog pain score" were utilized to retrieve relevant studies. A total of 1,291 patients from 11 studies were included in our analysis, with 10 studies originating from Asia and one from Europe. Among these studies, seven were prospective, while four were retrospective. The primary outcome measure was postoperative pain. Various statistical tests were also performed for data analysis, including the Chi-square and random effects model. The Newcastle Ottawa Scale was used to assess the quality of studies. There was no significant statistical difference observed between the endoscopic transoral vestibular route and the conventional cervical approach in terms of visual analog scale (VAS) score, with an odds ratio of -0.37 and a 95% confidence interval ranging from -0.9 to 0.17. The overall effect had a P-value of 0.18. However, substantial heterogeneity was noted, with an I2 value for heterogeneity of 98% and a P-value for heterogeneity of less than 0.001. The Chi-square value was calculated as 364.02, and the main difference was 9. In comparison, TOETVA exhibited lower pain levels on the first day post-operation compared to conventional thyroidectomy, with an odds ratio of -1.36 and a 95% confidence interval ranging from -2.65 to -0.06. Transoral endoscopic thyroidectomy via the vestibular approach demonstrated superior outcomes compared to conventional thyroidectomy in terms of postoperative pain management on the first day following surgery. However, when considering overall pain management throughout the recovery period, no significant difference was observed between the two approaches. More extensive studies evaluating pain levels on the day of surgery and controlling for analgesic interventions are warranted.

Assessment of Public Knowledge about Chronic Kidney Disease and Factors Influencing Knowledge Levels: A Cross-Sectional Study.

Background and Objectives: Chronic kidney disease (CKD) poses a significant risk for end-stage renal disease (ESRD), cardiovascular diseases, and premature death. The study aims to assess CKD knowledge and predictive variables among the general public. Materials and Methods: A cross-sectional study was conducted among the general public in Al Medina Al-Munawara, Saudi Arabia, utilizing a 21-item questionnaire-based approach over a 4-month period from January 2023 to April 2023. The developed questionnaire was validated for readability by experts and refined in light of the feedback received from the experts and the final version was prepared. The reliability of the questionnaire was 0.71, which shows an acceptable level of internal consistency. The data analysis was performed using IBM SPSS software (version 25). Results: A total of 777 complete surveys were received after applying the exclusion criteria. The study results revealed that the majority of the respondents had poor knowledge 505 (65%), 203 (26.1) had moderate knowledge, and 69 (8.9%) had good knowledge. Gender (p = 0.004), age (<0.001), education level (p = 0.039), marital status (p = 0.003), and occupation (p = 0.002) play significant roles in shaping participants' knowledge levels regarding CKD. Lower odds of good knowledge were associated with females with an OR (95% CI) of 0.448 (0.263-0.764) and intermediate or higher secondary school level of education displayed an OR (95% CI) of 0.39 (0.18-0.89). Higher odds of good knowledge levels were associated with the age group of 18-27 with an OR (95% CI) of 5.077 (1.21-21.38) and being employed with an OR of 3.555 (1.04-12.21). Conclusions: A significant proportion of respondents had poor knowledge about CKD. Several demographic factors were associated with CKD knowledge. Further research is needed to explore these knowledge disparities and develop targeted interventions to improve CKD knowledge among the general public.

Uptake, Safety and Attitudes Towards COVID-19 Vaccination: A Cross-Sectional Study on First and Second Doses Among the General Public.

Objective: To investigate public uptake, attitudes and the safety of the first and second doses of COVID-19 vaccination. Methods: This was a cross-sectional web-based survey study. A self-administered questionnaire was prepared from a literature search and information about COVID-19 available at various resources. The developed questionnaire was validated for readability by experts and refined in light of the feedback received from the experts and the final version was prepared. The reliability of the questionnaire was 0.7 which shows an acceptable level of scale internal consistency. The data analysis was performed using IBM SPSS software (version 25). Results: A total of 513 participants completed the survey, including 311 (60.6%) women and 202 (39.4%) men. The mean age was (31.5±12.8) years. It was found that 493 (96.1%) took the first and second doses of COVID-19 and 376 (73.3%) suffered from side effects, of these 14% (56/376) reported the side effects to the health authorities. The most common side effects were fatigue (51.5%), fever (42.3%), headache (39.5%), and injection site pain (37.6%). Half of the participants (50.5%) had a positive attitude towards COVID-19 preventive measures. Females had higher odds of experiencing side effects than males OR (95% CI); 2.002 (1.312-3.056). Individuals living in urban areas had lower odds of experiencing side effects than those living in rural areas OR (95% CI); 0.364 (0.142-0.933). Conclusion: Vaccine uptake was massive and side effects due to the COVID-19 vaccine were common but minor. The majority of the participants had positive attitudes towards recommended COVID-19 preventive measures. Being female and living in rural areas were associated with experiencing side effects.

Alpha-Mangostin ameliorates acute kidney injury via modifying levels of circulating TNF-α and IL-6 in glycerol-induced rhabdomyolysis animal model.

Alpha mangostin (AM), isolated from G. mangostana, showed beneficial effects in several disorders due to its antioxidant and anti-inflammatory properties. Acute kidney injury (AKI) due to different etiologies can develop into severe complications, resulting in high mortality rates. In this work, AM is tested for its ability to alleviate AKI in glycerol-induced AKI rat model, where 30 Male Sprague-Dawley rats were assigned to a healthy group, glycerol-treated group and AM-treated group. Glycerol- and AM groups received a single dose of glycerol (per IM, 50% glycerol in saline, 8 ml/kg), whereas control group was injected with saline. AM treatment (a single daily dose, per IP, 175mg/kg) was accomplished for three days. Animals were executed to collect blood samples and kidney tissue for biochemical and histological examination. It was found that glycerol induced increase in serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, serum magnesium, TNF-α and IL-6. It also induced renal edema and hypocalcemia along with histopathological renal damage. AM treatment improved renal histological features and alleviated increase in serum creatinine, BUN, serum magnesium, TNF-α and IL-6 levels, as well as renal edema and lipid peroxidation but did not affect serum calcium levels. This suggests AM as a potential therapeutic agent for treating AKI mainly via its antioxidant and anti-inflammatory properties.

Acute paracetamol toxicity-induced inflammatory and oxidative effects are relieved by Aleppo galls: a novel experimental study.

BACKGROUND: Paracetamol (acetaminophen) is an over-the-counter non-steroidal anti-inflammatory drug that may cause acute toxic overdosage particularly in neuropsychiatric patients. Paracetamol is also very commonly prescribed as an analgesic and antipyretic agent. Paracetamol toxicity causes decreased reduced glutathione and oxidative tissue damage. Aleppo galls is a promising natural remedy exerting antioxidant and tissue-protective effects that may combat acetaminophen-induced oxidative tissue damage. METHODOLOGY: Biochemical and toxicological effects of a toxic dose of paracetamol (250 mg/kg) were investigated for three consecutive days versus the tissue-protective effects of Aleppo galls. Eighteen white albino mice were randomly allocated in this study and divided into three experimental groups (six mice per group): negative control (received intraperitoneal sterile water injection), paracetamol toxicity group (received intraperitoneal paracetamol injection) and the third group (received paracetamol injection at 250 mg/kg/day together with oral Aleppo galls treatment at 250 mg/kg/day for 3 consecutive days). All mice were sacrificed by the end of the study. RESULTS: Our data revealed that paracetamol toxicity exerted significant oxidative stress damaging effects (high serum malondialdehyde, decreased serum catalase and decreased total antioxidant capacity), and significant inflammatory effects (high serum IL-6) and significant tissue-damaging effects (high serum LDH). Aleppo galls treatment significantly protected against acetaminophen toxicity-induced oxidative stress effects (P<0.001), inflammatory effects (P<0.001) and tissue-damaging effects (P<0.001). CONCLUSION: Aleppo galls are promising for future drug therapeutics and for the synthesis of natural remedies for treating paracetamol toxicity. We recommend formulating Aleppo galls extract as a pharmaceutical nutrition and to be given to those who need to take large doses of paracetamol.

Aleppo galls alleviate paracetamol-induced hepatotoxicity and tissue damage: an experimental study.

BACKGROUND: Acute paracetamol toxicity is a common and potentially life-threatening emergency causing liver failure that may necessitate liver transplantation. Unfortunately, current therapies are still defective. OBJECTIVES: To investigate the protective effects exerted by Aleppo galls (Quercus infectoria Olivier) extract against acute paracetamol toxicity in mice. METHODOLOGY: Eighteen mice were divided into three experimental groups, each included six mice in each group. The groups included: negative control group, paracetamol toxicity group that received an acute toxic intraperitoneal dose of paracetamol (250 mg/kg) for four consecutive days, and treatment group (received 250 mg/kg paracetamol followed few hours later by Aleppo galls extract for the same duration). Animals were anaesthetized using ether anaesthesia. Animals were sacrificed by decapitation and blood samples were drawn. Paracetamol toxicity effects versus Aleppo galls protection were evaluated on liver function tests, liver histology, serum cholesterol and serum triglycerides. RESULTS: Acute paracetamol toxicity caused significantly elevated serum transaminases (ALT and AST), decreased serum albumin, and increased serum cholesterol and triglycerides. Aleppo galls extract exerted significant protective effects and restored near normal serum levels of the previously-mentioned parameters. Upon histopathological evaluation, mice in the control group showed normal hepatic architecture with preserved hepatic cords and sinuses. Acute paracetamol toxicity induced peripheral zonal degeneration with focal necrosis of the hepatic tissue. The hepatocytes showed cytoplasmic vacuolation with indistinct cell borders. Central hepatic venules were congested. Administration of Aleppo galls extract reduced the tissue damaging effects induced by paracetamol toxicity with only minimal residual degenerative changes that were observed with absent necrosis. CONCLUSION: Quercus infectoria Olivier (Aleppo galls) is a promising source of phytochemicals and future therapeutics.

Developmental treatments with Δ9- tetrahydrocannabinol and the MAGL inhibitor JZL184 persistently alter adult cocaine conditioning in contrasting ways.

Using a songbird, zebra finches, as a developmental drug abuse model we found previously that cannabinoid agonists administered during the sensorimotor period of vocal learning (50-75 days of age) persistently alter song patterns and cocaine responsiveness in adulthood. However, these effects were not produced in adults exposed to similar treatment regimens. Currently, we have used the MAGL inhibitor, JZL184, to test whether enhanced endocannabinoid signaling may similarly alter cocaine responsiveness. We found that, as expected and consistent with prior results, repeated developmental (but not adult) treatments with Δ9-tetrahydrocannabinol (THC, 3 mg/kg QD IM) resulted in increased time spent in cocaine-paired chambers. Unexpectedly and in contrast, repeated developmental JZL184 (4 mg/kg QD IM) treatments decreased time spent in cocaine-conditioned chambers. That is, young finches repeatedly treated with JZL184 avoided cocaine-paired chambers later in adulthood, while similar development treatments with THC had the opposite effect. To begin to identify brain regions that may underly this differential responsiveness we used c-Fos expression as a marker of neuronal activity. Differences in c-Fos expression patterns following placement of cocaine-conditioned finches into vehicle- vs. cocaine-paired chambers suggest distinct involvement of circuits through striatal and amygdaloid regions in respective effects of THC and JZL184. Results demonstrate that, like exogenous cannabinoid exposure, inhibition of MAGL activity during late post-natal development persistently alters behavior in adulthood. Contrasting effects of THC vs. MAGL inhibition with JZL184 suggests the latter alters development of brain regions to favor promotion of aversive rather than appetitive cocaine responsiveness later in adulthood.

Boosting Tadalafil Bioavailability via Sono-Assisted Nano-Emulsion-Based Oral Jellies: Box-Behnken Optimization and Assessment.

Tadalafil (TAD) is a poorly soluble, phosphodiesterase inhibitor used to treat erectile dysfunction. The primary goal of this project was to prepare nano-emulsions using ultrasonic technology to address TAD bioavailability concerns. The Box−Behnken design was employed to find prominent correlations between factors impacting the sono-emulsification process. The emulsifier concentration, amplitude level, and ultrasonication time were the independent factors, whereas the average droplet size (ADS) and polydispersity index (PDI) were designated as the response variables. TAD-loaded nano-emulsions (93−289 nm) were generated and the emulsifier concentration showed a crucial role in directing emulsion droplet size. The model desirability function was utilized to optimize a nano-emulsion with a small ADS (99.67 ± 7.55 nm) and PDI (0.45 ± 0.04) by adjusting the emulsifiers concentration, amplitude level, and ultrasonication time at 9.85%, 33%, 49 s, respectively. The optimized nano-emulsions did not demonstrate any precipitation or phase separation after stability stress tests. TAD jellies were formulated based on the optimized nano-emulsion and subjected to in vitro evaluation for physical characteristics; TAD content, pH, spreadability, viscosity, syneresis, and taste-masking ability. An optimized nano-emulsion-based jelly (NEJ) formulation showed more than 96% drug dissolution in 30 min relative to 14% for the unprocessed TAD. In vivo assessment of NEJ in experimental rats demonstrated a significant enhancement (p < 0.05) of TAD bioavailability with an AUC0−24h of 2045 ± 70.2 vs. 259.9 ± 17.7 ng·h·mL−1 for the unprocessed TAD. Storage stability results revealed that NEJ remained stable with unremarkable changes in properties for 3 months. Overall, NEJ can be regarded as a successful therapeutic option for TAD administration with immediate-release properties and improved bioavailability.

Fabric phase sorptive extraction coupled with UPLC-ESI-MS/MS method for fast and sensitive quantitation of tadalafil in a bioequivalence study.

The current study coupled fabric phase sorptive extraction (FPSE) with ultraperformance liquid chromatography method with electrospray ionization and tandem mass detection (UPLC-ESI-MS/MS) for fast and sensitive determination of tadalafil (TAD) in a bioequivalence study. Fabric phase sorptive extraction allowed direct extraction of TAD from the sample matrix with improved selectivity, repeatability, and recoveries. A sol-gel Carbowax 20 M (CX-20 M) coated FPSE membrane revealed the best extraction efficiency for TAD because of its strong affinity for analytes via intermolecular interactions, high mass transfer rate to FPSE membrane, and high permeability. An automated multiple reaction monitoring (MRM) optimizer was employed for the best selection of the precursor and product ions, ion breakdown profile, the fine adjustment of the fragmentor voltages for each precursor ions, and the collision energies for the product ions. The chromatographic separation was conducted using a mobile phase A: 5.0 mM ammonium acetate with 0.1 % formic acid in water and mobile phase B: formic acid (0.1%) in acetonitrile in ratio (55:45, v/v) through isocratic elution mode on an Agilent EclipsePlus C18 (50 × 2.1 mm, 1.8 µm) column and the flow rate was adjusted at 0.4 mL min-1. The total run time per sample was 1.0 min. The method was validated by FDA standards for bioanalytical method validation over a concentration range of 0.1-100 ng mL-1 with a correlation coefficient of 0.9993 and the lower limit of quantitation (LLOQ) was 0.1 ng mL-1 in rat plasma. Intra- and inter-assay precision (%RSD) were lower than 4.1% and accuracy (%RE) was within 2.4%. The developed FPSE-UPLC-ESI-MS/MS method was effectively used in a randomized, two-way, single-dose, crossover study to compare the bioequivalence of two TAD formulations from different companies in male rats and verified to be bioequivalent.

Ramadan fasting outcome among high-risk patients.

BACKGROUND: There is a growing literature on guidelines regarding Ramadan fasting for chronic kidney disease (CKD) patients. However, most studies only consider the impact of fasting on renal function. This study additionally aims to assess factors influencing Ramadan fasting in patients with CKD. METHOD: This is a prospective before and after cohort study. CKD patients were counseled regarding fasting and followed-up post-Ramadan for renal function status, actual fasting behavior, and other relevant outcomes. RESULTS: Of the 360 patients who attended the pre-Ramadan consultation, 306 were reachable after Ramadan of whom 55.3% were female. Of these 306 67.1% reported that they had fasted, 4.9% had attempted to fast but stopped, and 28% did not fast at all. Of these 74 has a post-fasting kidney test. Of the patients, 68.1% had stage 3A CKD, 21.7% had stage 3B, 7.9% stage 4, and only 2% stage 5. Of those who fasted, 11.1% had a drop in Glomerular Filtration Rate (eGFR) of 20% or more. Those who did not fast (16.7%) presented a similar drop. Conversely, among the few who attempted to fast and had to stop, half showed a drop in eGFR of more than 20%. In linear regression, fasting was not associated with post-Ramadan eGFR, when controlling for age and baseline eGRF. There were 17 (5.6%) significant events, including one death. More significant events occurred among the group who fasted some of Ramadan days, 26.7% of the subjects experienced an adverse event-while 4.7% of the group who did not fast had a significant adverse event compared to 4.4% among those who fasted all Ramadan. CONCLUSION: Fasting was not a significant determining factor in renal function deterioration in the study's population, nor did it have any significant association with adverse events.

Tadalafil-Loaded Self-Nanoemulsifying Chewable Tablets for Improved Bioavailability: Design, In Vitro, and In Vivo Testing.

This research aimed to develop innovative self-nanoemulsifying chewable tablets (SNECT) to increase oral bioavailability of tadalafil (TDL), a nearly insoluble phosphodiesterase-5 inhibitor. Cinnamon essential oil, PEG 40 hydrogenated castor oil (Cremophor® RH 40), and polyethylene glycol 400 served as the oil, surfactant, and cosurfactant in the nanoemulsifying system, respectively. Primary liquid self-nanoemulsifying delivery systems (L-SNEDDS) were designed using phase diagrams and tested for dispersibility, droplet size, self-emulsifying capability, and thermodynamic stability. Adsorption on a carrier mix of silicon dioxide and microcrystalline cellulose was exploited to solidify the optimum L-SNEDDS formulation as self-nanoemulsifying granules (SNEG). Lack of crystalline TDL within the granules was verified by DSC and XRPD. SNEG were able to create a nanoemulsion instantaneously (165 nm), a little larger than the original nanoemulsion (159 nm). SNECT were fabricated by compressing SNEG with appropriate excipients. The obtained SNECT retained their quick dispersibility dissolving 84% of TDL within 30 min compared to only 18% dissolution from tablets of unprocessed TDL. A pharmacokinetic study in Sprague−Dawley rats showed a significant increase in Cmax (2.3-fold) and AUC0−24 h (5.33-fold) of SNECT relative to the unprocessed TDL-tablet (p < 0.05). The stability of TDL-SNECT was checked against dilutions with simulated GI fluids. In addition, accelerated stability tests were performed for three months at 40 ± 2 °C and 75% relative humidity. Results revealed the absence of obvious changes in size, PDI, or other tablet parameters before and after testing. In conclusion, current findings illustrated effectiveness of SNECT to enhance TDL dissolution and bioavailability in addition to facilitating dose administration.

The detection of SARS-CoV-2 in outpatient clinics and public facilities during the COVID-19 pandemic.

The transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can occur through an airborne route, in addition to contaminated surfaces and objects. In hospitals, it has been confirmed by several studies that SARS-CoV-2 can contaminate surfaces and medical equipment especially in hospitals dedicated to coronavirus disease 2019 (COVID-19) patients. The aim of this study was to detect the contamination of hands, objects, and surfaces in isolation rooms and also in outpatients' clinics in hospitals and polyclinics. Environmental contamination of public high-touch surfaces in public facilities was also investigated during an active COVID-19 pandemic. Random swabs were also taken from public shops, pharmacies, bakeries, groceries, banknotes, and automated teller machines (ATMs). Samples were analyzed for SARS-CoV-2 positivity using real-time polymerase chain reaction. In the COVID-19 regional reference hospital, only 3 out of 20 samples were positive for SARS-CoV-2 RNA. Hand swabs from SARS-CoV-2-positive patients in isolation rooms were occasionally positive for viral RNA. In outpatients' clinics, door handles were the most contaminated surfaces. Dental chairs, sinks, keyboards, ophthalmoscopes, and laboratory equipment were also contaminated. Although no positive swabs were found in shops and public facilities, random ATM swabs returned a positive result for SARS-CoV-2. Although there is no longer a focus on COVID-19 wards and isolation hospitals, more attention is required to decontaminate frequently touched surfaces in health-care facilities used by patients not diagnosed with COVID-19. Additionally, high-touch public surfaces such as ATMs require further disinfection procedures to limit the transmission of the infection.

Delta-9-THC exposure during zebra finch sensorimotor vocal learning increases cocaine reinforcement in adulthood.

Zebra finches are songbirds that learn vocal patterns during a sensitive period of development that approximates adolescence. Exposure of these animals to a cannabinoid agonist during their period of sensorimotor vocal learning alters song patterns produced in adulthood. Thus, songbirds have unique value in studying developmental effects of drug exposure on a naturally learned behavior. A missing feature of this animal model has been a method to study drug reinforcement of behavior. To address this gap we have adapted place conditioning methods, used previously to determine that singing behavior is rewarding, to study cocaine reinforcement of behavior. We have found that cocaine dose-dependently reinforces both place conditioning and aversion at potencies consistent with those observed in mammalian species. Use of this place conditioning method has allowed us to determine that, when administered during periods of sensorimotor vocal learning, delta-9-THC, but not nicotine persistently increases sensitivity to cocaine through adulthood. Establishment of this method significantly expands the songbird drug exposure model, and holds promise for better appreciation of mechanisms important to sensorimotor learning that is dependent upon successful progress through sensitive periods of CNS development.

Cannabidiol improves vocal learning-dependent recovery from, and reduces magnitude of deficits following, damage to a cortical-like brain region in a songbird pre-clinical animal model.

Cannabidiol (CBD), a non-euphorigenic compound derived from Cannabis, shows promise for improving recovery following cerebral ischemia and has recently been shown effective for the treatment of childhood seizures caused by Dravet and Lennox-Gastaut syndromes. Given evidence for activity to mitigate effects of CNS insult and dysfunction, we considered the possibility that CBD may also protect and improve functional recovery of a complex learned behavior. To test this hypothesis, we have applied a songbird, the adult male zebra finch, as a novel pre-clinical animal model. Their learned vocalizations were temporarily disrupted with bilateral microlesions of HVC (used as a proper name) a pre-vocal motor cortical-like brain region that drives song. These microlesions destroy about 10% of HVC, and temporarily impair song production, syntax and phonology for about seven days. Recovery requires sensorimotor learning as it depends upon auditory feedback. Four CBD doses (0, 1, 10 and 100 mg/kg) within three surgery conditions (microlesion, no-microlesion, sham-microlesion) were evaluated (n = 5-6). Birds were recorded over 20 days: three baseline; six pre-microlesion drug treatment days and; 11 post-microlesion treatment and recovery days. Results indicate 10 and 100 mg/kg CBD effectively reduced the time required to recover vocal phonology and syntax. In the case of phonology, the magnitude of microlesion-related disruptions were also reduced. These results suggest CBD holds promise to improve functional recovery of complex learned behaviors following brain injury, and represent establishment of an important new animal model to screen drugs for efficacy to improve vocal recovery.

Pharmacological activities of some new polycyclic triazolopyrazolopyridazine derivatives.

In continuation of our previous work, a novel series of polycyclic derivatives were synthesized and their anti-inflammatory, analgesic and antimicrobial activities were evaluated. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). Some of the newly compounds exhibited better biological and pharmacological activities than the reference controls with low toxicity (LD(50)). The structure of the new compounds has been established on the bases of chemical and spectroscopic evidences. The detailed synthesis, spectroscopic data, LD(50) and pharmacological activities of the synthesized compounds were reported.