Research Title: Pn-1, AN ANTINOCICEPTIVE PEPTIDE DERIVED FROM SPIDER TOXIN ACTING THROUGH CB1 CANNABINOID RECEPTORS

Author: Wafa Moh'd Khair Hourani, Published Year: 2018

GPCR Pharmacology - The Next Generation, University of Copenhagen, Denmark

Faculty: Pharmacy

Abstract: Cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) are G-protein-coupled receptors (GPCRs). The stimulation of cannabinoid receptors in the brain may produce dysphoria, euphoria, hypothermia, appetite stimulation, memory impairment and analgesia [1]. The existence of an endogenous cannabinergic pain-modulatory system makes an attractive target in the search for new drugs, in particular when opiates are ineffective for pain treatment. Peptide toxins produced by a variety of organisms have evolved with different targets, including GPCR, enzymes and ion channels. Our group has previously reported synthetic peptides designed from the Brazilian wandering spider toxins. The synthetic nontoxic peptide PnPP-19 (BR 10 2012 020800-8 A2) induced antinociception involving cannabinoid and opioid systems [2]. The present study, antinociceptive synthetic peptide, Pn1 (11 amino acid residues, MW= 1.35 kDa) [3] was undertaken to investigate the interaction of Pn-1 with the CB1R and its pharmacological role on induced analgesia. Nociceptive thresholds were measured by the in vivo paw pressure test on male Wistar rats (180-200 g). Pn1 induced a dose-dependent response. Blocking opioid receptors failed to alter the antinociceptive activity. However, the blocked of CB1R at the highest dose of AM251 inhibited the antinociceptive effect. Also, inhibition of MAGL or the anandamide transporter potentiated the activity of the Pn-1. We evaluated in vitro the selectivity of Pn-1 using CHO-hCB1 and CHO-hCB2 receptors. At low concentrations, Pn-1 appeared to increase [35S]GTPγS binding and at concentrations of 10 μM and above, reduced it. In the presence of CP55940, it acted as an antagonist at high concentrations. Monitoring cAMP levels confirmed selective activity on CB1R. Pn-1 acts complexly at CB1 receptors.

Keywords: cannabinoids, opioid,Pn1,G-protein-coupled receptors (GPCRs)

Research Title: Bioequivalence and Pharmacokinetic Evaluation of Two Batches of Cephalexin Capsules in Healthy Volunteers

Author: Yazan Batineh, Published Year: 2020

Journal of Pharmaceutical Sciences and Researches, 12

Faculty: Pharmacy

Abstract: The aim of this study is to evaluate the difference in pharmacokinetic parameters between the same brand drugs containing Cephalexin as the active ingredient distributed to both the private sector and the governmental sector in Jordan. Method: Plasma samples of two healthy volunteer groups have been examined at different time intervals after oral administration of Cephalexin 500 mg obtained from both private and governmental health sectors, and the pharmacokinetic parameters such as area under plasma concentration time curve (AUC), maximum plasma concentration (Cmax), and time to reach maximum plasma concentration (Tmax), have been measured after conducting high performance liquid chromatography (HPLC) experiment. Results: Measurements have shown a significant difference in almost all parameters between Cephalexin from the private sector and that from the governmental sector that support the call for more control and regulations on drugs supplied to governmental health sectors. Conclusion: More control on drugs supply for governmental hospitals and health centers and almost all drug companies must provide a proof for bioequivalence for their drugs going to that sector and not rely only on that bioequivalence comparison done for registration and FDA requirements.

Keywords: bioequivalence, cephalexin, pharmacokinetic, HPLC.

Research Title: Perinatal depression. Prevalence, suicidal idea, and associated factors

Author: Yazan Batineh, Published Year: 2020

Journal of Pharmaceutical Sciences and Researches, 12

Faculty: Pharmacy

Abstract: This study was aimed to investigate the prevalence of perinatal depression compared to non-pregnant women. Associating factors, suicidal idea and their association with pregnancy. Material: This cross-sectional study included 684 Jordanian women attended pregnancy care department in Jordanian hospitals and the community women from April 2018 to September 2018. Edinburgh Postnatal Depression Scale (EPDS) is used to described depression symptoms. Results: In pregnant women, the prevalence of depression was significantly higher than in single women (p= 0.00812), and a significant number of symptoms of depression experienced by pregnant women compared to post-partum women (p= 0.037). Higher depression symptoms were observed in male — bearing women (p= 0.0436), caesarean birth (p = 0.0068), and women with maternal complications (p = 0.0072). Furthermore, higher symptoms of depression (p= 0.0097, 0076) were associated with Gestational diabetic and anaemic women. The prevalence of depression is significantly higher for pregnant women with family problems (p= 0.0097). There was no significant variability between study groups in suicidal idea, although there was a higher percentage of self—harm in post-partum women (1.67 percent). Conclusions: In pregnant women, there is a higher prevalence of depression compared to post-partum women. Perinatal depression is associated with male infants, cesarean birth, anemia, gestational diabetes, and social issues.

Keywords: Postnatal depression, Perinatal depression, Suicidal idea, Normal delivery, Cesarean delivery, EPDS score.

Research Title: Therapeutic drug monitoring of cytotoxic drugs

Author: Yazan Batineh, Published Year: 2019

Annals of Tropical Medicine & Public Health, 22

Faculty: Pharmacy

Abstract: The majority of anticancer drugs are recognized with narrow therapeutic index, the area under the plasma levels versus time curve (AUC) is the common pharmacokinetic (PK) parameter which utilizes specifically for cytotoxic drugs. TDM approach in these drugs has never been completely applied due to different reasons, for example, the use of combination chemotherapies for different malignant tumors, and the behavior of intracellularcompounds; it’s possible to eliminate these limitations by using specific concentrations of cytotoxic drugs and measure AUC after certain conditions. In this review article, we discussed the common TDM parameters, methods of analysis, and some of drug interactions for a group of cytotoxic drugs.

Keywords: Cytosine arabinoside, Fluorouracil, Methotrexate, Mercaptopurine, Cytotoxic drugs, TDM.

Research Title: Efficacy of Follitropin-A (Gonal-F) Versus Follitropin-B (Puregon) for Controlled Ovarian Stimulation in Women Undergoing in vitro fertilization (IVF)

Author: Yazan Batineh, Published Year: 2019

International Journal of Pharmaceutical Quality Assurance, 10

Faculty: Pharmacy

Abstract: The purpose of this study was to compare the efficacy of two recombinant follicle-stimulating hormone (FSH) on pregnancy rates in infertile patients. Material and Methods: between 2015-2017, 387 females intended to have in vitro fertilization (IVF) for infertility treatment (226 patients use Gonal-F and 161 using Puregon. Results: Serum E2 concentration at hCG time was higher with follitropin-a treated patients, and a larger number of retrieved oocyte result in a large number of the transferred embryo, and high pregnancy rate than Follitropin-b treated patients. Conclusions: Gonal-F (Follitropin-a) is associated with a potential stimulatory effect on ovaries. Puregon (Follitropin-b) was associated with a lower clinical pregnancy rate (PR). E2 level 5-7 days after stimulation can be used as an indicator of the success of IVF.

Keywords: COS, Fertilization, Follitropin-a, Follitropin-b, Gonal-F, IVF, Puregon.

Research Title: Efficacy and Safety of Canagliflozin Compared to Sitagliptin and Glimepride as Add- on Therapy in T2DM

Author: Yazan Batineh, Published Year: 2019

Journal of Global Pharma Technology, 11

Faculty: Pharmacy

Abstract: Diabetes type II is a progressive disease and associated with many complications. Metformin is the firstline pharmacological therapy for type II. However, there is a second anti-diabetic drug can be added for patients who do not achieve sufficient glycemic control with metformin. In this study, we assess the efficacy and safety of newly approved anti-diabetic drugs Canagliflozin compared to Sitagliptin and Glimepiride patient with type II diabetes. Basically, 210 diabetic patients have received Canagliflozin 300 mg or Sitagliptin 100 mg or Glimepiride 4 mg for at least 16 weeks. Previously, the patient's glycemic state was uncontrolled by Metformin monotherapy. Glycated hemoglobin and Fasting blood glucose changes were used as an efficacy assessment from the baseline after metformin discontinuation. The safety profile was determined by comparing patient’s lipid profile, renal function, BUN, renal function and uric acid. Our results had shown a significant reduction in HBA1c and FBS in the three groups after 4 months of treatment (p <0.05). However, there was no significant change in the reducing effect between the three drugs (p= 0.704, 0.521). Canagliflozin and Glimepiride produce more reduction in triglycerides than Sitagliptin through the treatment period, although it is not significant, the change in the effect was significantly higher in Canagliflozin and Glimepiride comparing to Sitagliptin. Unlike Canagliflozin, Glimepiride and Sitagliptin produce a significant reduction in LDL after 4 months of treatment (p = 0.0318, 0.047) and significant difference in the effect (p = 0.042). Canagliflozin cause a significant elevation in LDL after the initiation of therapy (p= 0.034). The effect of Canagliflozin was significantly higher on HDL comparing to Glimepiride and Sitagliptin throughout the treatment (p = 0.048) and as a difference in the effect (p =0.043). Canagliflozin and Glimepiride produce a significant elevation in BUN comparing to Sitagliptin (p = 0. 004, 003), whereas, Canagliflozin and Sitagliptin produce a higher reduction in GFR than Glimepiride. Glimepiride is significantly elevates serum uric acid comparing to Canagliflozin and Sitagliptin with p= 0.0406. Conclusion: Canagliflozin, Sitagliptin, and Glimepiride are effective add-on therapy with metformin for proper control of blood glucose in T2DM. Canagliflozin and Glimepiride improve TGs and LDL greater than Sitagliptin. Sitagliptin produces less elevation in BUN than Canagliflozin and Glimepiride. Canagliflozin and Sitagliptin required renal monitoring throughout treatment

Keywords: T2DM, Canagliflozin, Glimepiride, Sitagliptin

Research Title: Hypolipidemic Efficacy of Artemisia absinthium Extracts in Rabbits

Author: Yazan Batineh, Published Year: 2014

World Applied Sciences Journal, 31

Faculty: Pharmacy

Abstract: The hypolipidemic effects of 70% ethanol extract of Artemisia absinthium in hypercholesterolemic -fed rabbits. Hypercholesterolemia was induced in male rabbits by high cholesterol diet (HCD) (350 mg/kg) for 8 weeks. Hypercholesterolemic rabbits were allocated into groups, treated with simvastatin (SIM 5 mg/kg), different extracts of Artemisia absinthium at two doses of 500, 1000 mg/kg. A normal control group and an HCD control one were used for comparison. During the hall period of the experiment blood samples were collected and serum was analyzed for lipid profile. At the end of the experiment the animals were sacrificed; the heart and the liver were collected and stored at -20°C until assayed. Biochemical analysis of blood serum and tissue (liver and heart muscle) were performed for total cholesterol, total triglycerides, Phospholipid, LDL-C, HDL-C, VLDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatine kinase (CK) and total protein. The extract induces a significant decrease in serum cholesterol, triglycerides and CK levels. Blood levels of AST, ALT, triglycerides and total protein unchanged. The tissues lipids profiles of liver and heart muscle showed similar changes in those noticed in serum lipids. The results concluded that Artemisia absinthium ethanolic extract (500, 1000 mg/kg) have potent antihyperlipidemic activity in high cholesterol diet induced hyperlipidemia model and which is equipotent activity when compared with control group.

Keywords: Artemisia absinthium Anti-Hyperlipidemic Activity Triglyceride Cholesterol High Cholesterol Diet Induced Hyperlipidemia

Research Title: Effect of Stevia Consumption on Blood Pressure, Stress Hormone Levels and Anthropometrical Parameters in Healthy Persons

Author: Yazan Batineh, Published Year: 2017

American Journal of Pharmacology and Toxicology, 12

Faculty: Pharmacy

Abstract: Stevia is a natural sweetener containing steviol glycosides known to be several times sweeter than sucrose. It is thought to have several beneficial properties though some evidence state it may have detrimental effects. The aim of this study was to investigate the potential beneficial or harmful effects of stevia consumption by exploring its effects on blood pressure, stress hormone levels and anthropometrical markers in A crossover placebo controlled study was conducted on 16 volunteers randomly assigned to consume either stevia or a placebo (sugar) for one week. The measurements were attained on three different occasions and each volunteer was allowed a 3-day initiation period before baseline and in between interventions. The systolic BP increased following stevia intake from 114.5±12.7 to 119.9±12.9mmHg (p<0.001) and diastolic BP from 70.8±9.4 to 75.7±9.6mmHg (p<0.01). Systolic BP increased slightly after the sugar placebo to 115.3±13.6 mmHg (not significant). The mean free cortisol excreted in urine has increased from 91.8±49.1 to 125.7±60.5nmole/day (p<0.01) after the stevia and to 109.1±42.6nmole/day after the placebo (p = 0.210). The ratio of urinary free cortisol/cortisone showed a statistically significant increase from 1.73±0.78 to 2.65±1.03 after stevia (p<0.0001). Salivary cortisol levels have also increased (p<0.01 at AM) after stevia. Placebo intake did not produce a significant change in salivary cortisol. The ratio of salivary cortisol/cortisone during the stevia has increased only in the morning (from 1.22±0.65 to 1.75±0.72, p = 0.05) and a modest increase in the daily average of salivary cortisol/cortisone. There was small insignificant reduction in weight and BMI after stevia intervention (p = 0.246 and p = 0.249 respectively). In conclusion, we have shown that short term stevia intake produced a small but significant increase in BP and effect on body weight and BMI were not significant. The rise in BP might be due to the increase in cortisol levels and cortisol/cortisone ratio indicating that stevia may possibly inhibit 11β-HSD2 enzyme by reducing the conversion of cortisol into cortisone. Therefore caution should be taken by the public who want to consume stevia for longer period of time as a weight reducing sweetener.

Keywords: Stevia, Sweeteners, Blood Pressure, BMI, Glucocorticoids, 11β-HSD

Research Title: Formulation and evaluation of diclofenac controlled release matrix tablets made of HPMC and Poloxamer 188 polymer: An assessment on mechanism of drug release.

Author: Yazan Batineh, Published Year: 2018

Pak J Pharm Sci., 31

Faculty: Pharmacy

Abstract: In this study, hydrophilic hydroxypropyl methylcellulose matrices with various concentrations of Poloxamer 188 were used in the development of oral controlled release tablets containing diclofenac sodium. Four formulations of hydrophilic matrix tablets containing 16.7% w/w HPMC and 0, 6.7, 16.7 and 25.0% w/w Poloxamer 188, respectively, were developed. Tablets were prepared by direct compression and characterized for diameter, hardness, thickness, weight and uniformity of content. The influence of various blends of hydroxypropyl methylcellulose and Poloxamer 188 on the in vitro dissolution profile and mechanism of drug release of was investigated. In the four formulations, the rate of drug release decreased with increasing the concentration of Poloxamer 188 at the initial dissolution stages due to the increase in the apparent viscosity of the gel diffusion layer. However, in the late dissolution stages, the rate of drug release increased with increasing Poloxamer 188 concentration due to the increase in wettability and dissolution of the matrix. The kinetic of drug release from the tablets followed non-Fickian mechanism, as predicted by Korsmeyer-Peppas model, which involves diffusion through the gel layer and erosion of the matrix system.

Keywords: Poloxamer 188, iclofenac sodium, hydroxypropyl methylcellulose, dissolution rate, controlled release.

Research Title: A NOVEL BRAZILIAN SPIDER TOXIN ANALOGUE IS ANTINOCICEPTIVE ACTING VIA THE CANNABINOID SYSTEM

Author: Wafa Moh'd Khair Hourani, Published Year: 2018

The 28th Annual International Cannabinoid Research Society Symposium on the Cannabinoids, Leiden university, the Netherlands

Faculty: Pharmacy

Abstract: Peptide toxins produced by a variety of organisms have evolved with different targets, including GPCR, enzymes and ion channels, where there are many examples of ligands with high potency and selectivity. The Brazilian scientific team developed peptide analogues of an active component of the venom of the Brazilian wandering spider (Phoneutria nigriventer). The synthetic nontoxic peptide PnPP-19 (BR 10 2012 020800-8 A2) induced antinociception involving the inhibition of neutral endopeptidase and activation of CB1 cannabinoid receptors as well as µ and δ opioid receptors (Freitas, Br J Pharmacol PMID: 26947933). In this work, a novel synthetic nontoxic peptide, Pn1 (11 amino acid residues, MW= 1.35 kDa, in patent application) modeled from δCtenitoxin-Pn1a toxin was examined. Nociceptive thresholds were measured by the in vivo paw pressure test on male Wistar rats (180- 200 g). First, to investigate the role of Pn1 in nociception, the peptide was injected (1.5, 2.5, 5 and 10 µg per paw) or vehicle (50 µl) into rat paws-that were hyperalgesic following the administration of carrageenan (250 µg). Pn1 induced a dose-dependent antinociceptive response, with the maximal effects at 10 µg per paw, which peaked at 30 min post-administration. The role of the CB1 cannabinoid receptor in these effects was investigated with intraplantar co-administration of AM251 (40, 80 and 160 µg per paw). The highest dose totally inhibited the antinociceptive effect of Pn1 (10 µg per paw). Moreover, we investigated whether enzymatic degradation by FAAH, MAGL and anandamide endocannabinoid transporter pathways could be contributing to the antinociceptive activity using intraplantar administration of JZL184 (14 µg per paw); MAFP, (4 µg per paw); or VDM11 (40 µg per paw). The results showed that inhibition of MAGL or the transporter potentiated the antinociceptive activity of the Pn-1. In in vitro studies, we evaluated the selectivity of Pn1 using CHO-CB1 and CHO-CB2 human receptors and [35S]-GTPγS binding assays. The preliminary results indicated that Pn1 (10 µM) appears to exhibit selectivity and affinity for the CB1 receptor. Further studies of the downstream signalling pathways for the CB1 receptor (calcium elevation and ERK1/2 phosphorylation), however, failed to show significant effects of Pn1 (10 µM). Antinociception induced by Pn1 appears to involve the inhibition of MAGL and anandamide endocannabinoid transporter and the selective activation of CB1 receptors. This novel peptide could be useful as a new antinociceptive drug candidate

Keywords: cannabinoid receptors,Peptide toxins, Antinociception