Research Records and Possibilities of the Department of Pharmacology Physiology in Kerman University of Medical Sciences, Iran

Background: The publication of information and possibilities of a university department and the experiences of its faculty members make others aware of these issues and can be regarded as one of the methods of publishing and teaching science. It seems that the report of research experiences, capabilities, and achievements in Department of Pharmacology Physiology, Kerman University of Medical Sciences, Iran, make it easier for further researches of other researchers. Methods: Data were obtained via observing, searching in valuable scientific databases and group archives, and asking the department manager, faculty members, and experts in Department of Pharmacology Physiology, as well as gathering the information in research centers of the university. Results: Department of Physiology and Pharmacology was the first group that initiated postgraduate and doctoral degrees’ courses at Kerman University of Medical Sciences. The annual per capita of paper production in this group was close to 7 with 10 faculty members. Three faculty members were among the first 15 of the university in terms of the H-index. The country, provincial, university, and faculty rankings achieved by the department, variety in research projects, and the collaborative studies in the university were the features of this department. The first and second research centers of the university in terms of history and rank were managed by faculty members of this department. Conclusion: Department of Pharmacology Physiology is one of the successful and high history departments in Kerman University of Medical Sciences. Other researchers can use the experience of these faculty members, and department facilities for their advancement. Keywords Physiology; research; Equipment; Department; Pharmacy facult

The effect of opium addiction on serum adiponectin and leptin levels in male subjects

Serum adiponectin and leptin levels have been shown to be related to obesity, insulin resistance and cardiovascular diseases (CVD). Opium addiction has a positive association with endocrine system disorders. The relationship between adipokines and opium addiction is unclear. In the present study, we aimed to determine serum adiponectin and leptin levels in opium addicted subjects. Methods: 176 men, 88 opium addicts and 88 non-addicts were randomly selected from subjects who participated in Kerman Coronary Artery Disease Risk factors Study (KERCADRS); a population-based study. Serum adiponectin and leptin levels were measured using ELISA and compared between two groups. We adjusted the effect of some confounding factors such as the patients’ demographic, clinical and medical history in multivariate analysis model. Results: The serum level of adiponectin in opium addicts was significantly lower than control group (6.5±3.6 vs. 9.8±8.1 μg/ml, P<0.001). There was no significant difference in serum leptin level between two groups (11.8±10.3 ng/ml in control group vs. 11.5±10.8 ng/ml in opium addicts, p = 0.80). In the multivariate analysis, after adjusting for age, cigarette smoking, body mass index, type 2 diabetes, hypertension, cholesterol, triglyceride and high and low density lipoproteins, the negative association between opium addiction and decreased adiponectin level was still present (β = -0.144, P value = 0.005). Conclusions: The results showed that opium addiction reduces serum adiponectin level. Since adiponectin has been shown to have anti-diabetic and anti-atherogenic effects, its reduction may account for increase in the risk of metabolic disorders such as insulin resistance and CVD amongst opium addicted patients

Potential Effect of Opium Consumption on Controlling Diabetes and Some Cardiovascular Risk Factors in Diabetic Patients

Background: Due to this belief that opium may have beneficial effects on diabetes or cardiovascular risk factors, the present study aimed to assess the potential and possible effects of opium consumption on diabetes control and some cardiovascular risk factors in diabetic patients. Methods: This study enrolled 374 diabetic subjects from diabetes care centers in Kerman, Iran including opium user group (n = 179) and a non opium user group (n = 195). The data were collected through a questionnaire completed by interviewing, physical examination and laboratory assessment. Findings: Opium did not show any statistically significant effect on blood glucose, glycated hemoglobin (HbA1C), fasting blood sugar (FBS), low-density lipoprotein (LDL) and diastolic blood pressure. However, systolic blood pressure and prevalence of high systolic blood pressure were significantly higher in opium user group (P < 0.050). In addition, lower serum high-density lipoprotein (HDL) and frequency of lower HDL was significantly higher in opium user group (P < 0.001). Conclusion: According to this study, opium does not seem to have beneficial effects on diabetes control or cardiovascular risk factors. Therefore, it would not be advisable to consume opium as an anti-diabetes or cardioprotective agent

B12 and Folate Concentrations in Opium Addicts Compared to Healthy Subjects: A Case Control Study from Kerman Coronary Artery Disease Risk Study

Background: Opium addiction is a global problem which has implicated many societies. Opium addiction and drug abuse is related to harmful consequences which affect life style, biochemical factors, and vitamins values, and also is considered as a risk for heart diseases. Folate and B12 levels are related to homocysteine and studies about their levels in opium addicts are controversial; therefore, we designed this study to evaluate B12 and folate values in opium addicts. Methods: From the Kerman Coronary Artery Disease Risk Study (KERCADRS) which is a population-based study, we randomly selected 340 men and entered them into two groups: case (n = 170) and control group (n = 170). Then vitamin B12 and folate levels were measured. Findings: Opium addiction did not change B12 and folate levels significantly in opium addicts compared to non-addict control subjects. However, only some variables including blood pressure (BP) and diabetes positively and cigarette smoking, triglyceride (TG), alcohol, and cardiovascular disease (CVD) history negatively affected folate, and none of clinical and demographic variables influenced the B12 levels (P > 0.050). TG had significant effects on B12 and folate levels although opium addiction did not show any impact. Conclusion: High TG levels were accompanied by low levels of B12 and folate. Reduced B12 and folate values are accompanied by serum homocysteine elevation. As TG elevates in opium addicts, it can be considered as an important factor which affects vitamins levels and reduces their absorption. Opium addiction elevates homocysteine level, since we can conclude that homocysteine elevation in opium addicts is independent of B12 and folate level

Prevalence of Active and Passive Smoking among Adult Population: Findings ‎of a Population-Based Survey in Kerman (KERCADR), Iran

Background: Smoking is one of the major modifiable non-communicable disease risk factors. Our aim was to report the pattern of active and passive smoking using the data collected through a population base household survey in Kerman, Iran. Methods: Given a cluster random sampling design, we recruited 5900 adult populations (15-75 years old) into a survey. After consenting, every participant was interviewed by a trained interviewer. The section for smoking had questions about daily (smoking at least one cigarette/day), non-daily, past and passive cigarette smoking as well as the time of exposure to cigarette’s smoke. We used Kerman population distribution (as the target population) to adjust our estimates using direct standardization method. Findings: Overall, 8.3% of study participants (15.5% in men vs. 0.8% in women, P = 0.010) reported themselves as daily smokers and 1.7% (2.9% in men vs. 0.4% in women, P = 0.010) as non-daily smokers. The passive smoking was common in total (27.5%), while women experienced more exposure than men (30.1% vs. 25.0%, P = 0.010). 3.2% of daily smokers smoked more than 20 cigarettes/day. Among passive smokers, 62.6% were exposed to cigarette smoke more than 6 days/week. Conclusion: Smoking is pretty common among adult populations, particularly men. A majority of tobacco-free young adult women are exposed to passive smoking. Age and gender oriented interventions are required to change this risk pattern in our community to prevent from further smoking related morbidities and mortalities

سوابق پژوهشی و امکانات گروه فیزیولوژی و فارماکولوژی دانشگاه علوم پزشکی کرمان

مقدمه: از آن‌جا که انتشار اطلاعات و امکانات یک گروه آموزشی و تجربیات اعضای هیأت علمی آن، موجب آگاهی دیگران از این موارد می‌گردد و می‌تواند از مصادیق نشر و آموزش علوم به دیگران به شمار رود، به نظر می‌رسد که گزارش تجربیات، توانمندی‌ها و دستاوردهای پژوهشی گروه فیزیولوژی و فارماکولوژی دانشگاه علوم پزشکی کرمان، زمینه را برای پیشرفت تحقیقات سایر پژوهشگران فراهم نماید. شیوه مطالعه: داده‌های مطالعه حاضر با مشاهده، جستجو در پایگاه‌های معتبر علمی و بایگانی گروه، اطلاعات مدیر، اعضای هیأت علمی و کارشناسان گروه و همچنین، اطلاعات موجود در معاونت و مراکز پژوهشی دانشگاه به دست آمد. یافته‌ها: گروه فیزیولوژی و فارماکولوژی، اولین گروه تأسیس کننده مقطع کارشناسی ارشد و دکتری تخصصی دانشگاه بوده است. اکنون سرانه سالیانه تولید مقاله در این گروه با 10 عضو هیأت علمی، نزدیک به 7 می‌باشد. 3 نفر از اعضای گروه، در میان 15 نفر اول دانشگاه از نظر شاخص H-Index قرار دارند. تنوع دریافت رتبه‌های کشوری، استانی، دانشگاهی و دانشکده‌ای، پروژه‌های در دست اجرا و همکاری بین‌بخشی در مطالعات تحقیقاتی دانشگاه، از جمله ویژگی‌های گروه فیزیولوژی و فارماکولوژی به شمار می‌رود. اولین و دومین مرکز تحقیقاتی دانشگاه از نظر سابقه و رتبه، توسط اعضای این گروه مدیریت می‌شوند. نتیجه‌گیری: گروه فیزیولوژی و فارماکولوژی از جمله گروه‌های موفق و با سابقه دانشگاه می‌باشد و محققان دیگر می‌توانند از تجربیات اعضای هیأت علمی و امکانات این گروه برای پیشرفت خود بهره ببرند. کلیدواژه‌ها فیزیولوژی؛ تحقیقات؛ تجهیزات؛ گروه؛ هیأت علمی داروساز

Opium Induces Apoptosis in Jurkat Cells

Background: The direct effect of some opioids on immune cells has been demonstrated. The aim of this study was to assess the apoptotic effect of opium on Jurkat T lymphocyte cells. Methods: Different concentrations of opium (2.86 × 10-3 to 2.86 × 10-11 g/ml) were added to 24-well plates containing 5 × 105 Jurkat cells. Apoptotic events were assessed after 6, 24, and 72 hours by flow-cytometric detection of surface phosphatidylserine. Findings: Significant differences in apoptosis of Jurkat cells were seen at 24 and 72 hours in different concentrations of opium (P < 0.05). After 72 hours, significant increase in necrosis of Jurkat cells was seen in opium concentration of 2.85 × 10-3 g/ml compared to cells without opium (control) (P < 0.05). Conclusion: These results showed that opium directly increases apoptosis and necrosis of T lymphocytes. This effect may play a role in immune dysfunction in opium addicts.Keywords: Opium, Apoptosis, Necrosis, Jurkat cell

Early and late preventive effect of Nigella sativa on the bleomycin-induced pulmonary fibrosis in rats: An experimental study

Objective: Pulmonary fibhrosis is a disease of the connective tissues in the respiratory system. Nigella sativa has been used for the treatment of pulmonary diseases like asthma. This study investigated the early and late preventive effect of methanolic extract of N. sativa on a bleomycin- induced pulmonary fibrosis model. Materials and Methods: This study was carried out using 52 rats. Pulmonary fibrosis was induced by a single endotracheal injection of bleomycin (5 mg/kg). Extract of N. sativa (500 mg/kg per day) or methylprednisolone succinate (4 mg/kg per day) was injected intraperitoneally in two periods (i.e. days 1-14 as early preventive group and days 15-28 days as late preventive group). The lung tissues were histologically examined at the end of each period and inspected for the amount of hydroxyproline and biomarkers of oxidative stress. Results: The pulmonary inflammation and fibrosis were significantly decreased in groups treated with methylprednisolone and N. sativa extract compared to bleomycin group in both early and late prevention groups (

DISCOVERY OF NOVEL PHARMACOTHERAPEUTICS FOR SUBSTANCE USE DISORDERS

Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding pathway commonly activated by opioids and cocaine. With respect to METH, it induces release of dopamine (DA) in neuronal terminals by interacting with the vesicular monoamine transporter-2 (VMAT2) and DA transporter (DAT). VMAT2 inhibitors have been found by our research group to decrease METH-evoked DA release, METH-induced hyperlocomotion, and METH self-administration in rats. However, these VMAT2 inhibitors lacked selectivity and tolerance developed to these pharmacologic effects after repeated administration, thereby limiting their potential as pharmacotherapeutics for METH use disorders. In the current study, analogs from a novel scaffold were found to selectively inhibit VMAT2 and were evaluated using neurochemical and behavioral pharmacological approaches. R- and S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610 and GZ-11608, respectively) exhibited 94- to 3450-fold selectivity for VMAT2 over human-ether-a-go-go (hERG) channel, DAT, serotonin transporter, and nicotinic acetylcholine receptors. GZ-11608 competitively and concentration-dependently inhibited METH-evoked DA release via VMAT2. Also, GZ-11610 (56-300 mg/kg, oral) and GZ-11608 (300 mg/kg, oral; 10-30 mg/kg, s.c.) reduced METH-induced hyperlocomotor activity in METH-sensitized rats. Furthermore, GZ-11608 (1-30 mg/kg, s.c.) inhibited METH self-administration, cue- and METH-induced reinstatement in a dose-dependent manner, and 30 mg/kg (s.c.), 10 mg/kg (s.c.), and 17 mg/kg (s.c.) produced significant effect, respectively. Importantly, the GZ-11608-induced decrease in METH self-administration was not surmounted by increasing the amount of METH available. GZ-11608 did not substitute for METH and did not serve as a reinforcer in rats self-administering METH and drug naïve rats, respectively. Thus, these VMAT2 inhibitors incorporating a new scaffold are novel leads for new pharmacotherapeutics to treat METH use disorders. Substances with high abuse potential including opioids and cocaine elevate extracellular DA concentration in the nucleus accumbens, and this mechanism has long been considered to underly substance-induced reward. DA in the nucleus accumbens originates from DA neuron cell bodies located in the ventral tegmental area in the midbrain. Interestingly, M5 muscarinic acetylcholine receptors (mAChRs) are proteins that are highly expressed on ventral tegmental area DA neurons. Also, studies investigating M5 mAChRs knockout mice showed reduced responding for cocaine in cocaine self-administration and decreased time spent in cocaine-paired and morphine-paired place preference studies. Pharmacological inhibition of M5 mAChRs function via microinfusing mAChR antagonists exhibiting no selectivity among M1-M5 mAChRs subtypes into the ventral tegmental area where expression of M5 mAChRs are dominant, reduced morphine-induced hyperlocomotion and cocaine seeking behaviors in rats. These studies support therapeutic potential of M5 mAChRs selectivity antagonists in opioids and cocaine use disorders. Thus, in the current study, affinity of a series of pethidine and quinuclidinyl N-phenylcarbamate analogs for M5 mAChRs was evaluated using in vitro and ex vivo neuropharmacological assays. Among the pethidine analogs, compound 6a showed the highest binding affinity at M5 (Ki = 0.38 µM), but also high affinity at M1 and M3 mAChRs (0.67 and 0.37 µM, respectively). Among the quinuclidinyl N-phenylcarbamate analogs, compound 13c exhibited the highest affinity at M5 (Ki = 1.8 nM), but also high affinity at M1, M2, M3 and M4 mAChRs (Ki = 1.6, 13, 2.6, 2.2 nM, respectively). Also, 13c acted as an agonist of mAChRs on oxotremorine-induced DA release from rat striatal slices. In addition, compound 13b was found exhibiting the highest selectivity (17-fold) at M3 over M2 mAChRs, suggesting potential of 13b as a chronic obstructive pulmonary disease therapeutics. Taken together, these novel analogs serve as leads for further discovery of subtype-selective M5 mAChR antagonists that may have potential as therapeutics for substance use disorders, as well as for chronic obstructive pulmonary disease

The effects of herbal extracts and compounds on the glucose metabolism in HepG2 cells

The aim of this study is to investigate the effects of herbal substances on glucose metabolism in HepG2 cellular models, this project's main objective was to evaluate and compare the metabolic activities of HepG2 cells following treatment with herbal compounds and botanical extracts like phloretin, ouabain, berberine, metformin, rebaudioside-A, and Stevia extracts, goldenseal extracts, goat's rue extracts, and Gymnema extracts. In the screening tests, changes in glucose uptake in response to treatment with extracts and individual compounds were recorded. Extracts of goldenseal (Hydrastis candensis L.) and the alkaloid berberine induced remarkable glucose uptake, and consumption, compared with the other compounds and extracts. And demonstrated significant glucose uptake (p<0.05, p<0.01) and consumption activity (p<0.05, p<0.001) when compared to the biguanide drug metformin (p<0.01). As a result, goldenseal ethanolic extracts (10µL/mL) and berberine (10µM) were identified as the key candidates of the research to investigate glucose uptake using flowcytometry, Glucose transporter-1, estimation of glycogen content and glucose release, and seahorse metabolic analysis. In glucose uptake studies using flowcytometry, berberine augmented 3.4 times more glucose uptake, goldenseal stimulated 2 times, and metformin upsurges 1.8 times compared to the control (p<0.001). In the glucose transporter-1 expression assays, goldenseal, and berberine were augmented the expression 1.7 times and 1.4 times compared to the control (p<0.05). Berberine was upregulated 2.4 times, metformin twice, and goldenseal twice in glycogen synthesis studies after long-term treatment (p<0.05). In glucose release assays, berberine, metformin, and goldenseal releasing 50%, 30%, and 23% less glucose compared to the control (p<0.05). The Seahorse XF analysis, which is more in line with the literature, shows that the three treatments increase the rate of lactate production (p<0.01) while also improving glucose metabolism. When compared to the pure compound alkaloid berberine, goldenseal extract was found to be less effective in improving glucose metabolism. Nonetheless, both appear promising for the development of new oral anti-diabetic medications