Search results for: anticonvulsant%20activity
Commenced in January 2007
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Edition: International
Paper Count: 18

Search results for: anticonvulsant%20activity

18 Synthesis, Electrochemical and Fluorimetric Analysis of Caffeic Cinnamic and Acid-Conjugated Hemorphine Derivatives Designed as Potential Anticonvulsant Agents

Authors: Jana Tchekalarova, Stela Georgieva, Petia Peneva, Petar Todorov

Abstract:

In the present study, a series of bioconjugates of N-modified hemorphine analogs containing second pharmacophore cinnamic acids (CA) or caffeic acid (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorometric analysis and in vivo anticonvulsant activity in mice were conducted on the compounds. The three CA (H4-CA, H5-CA, and H7-CA) and three KA (H4-KA, H5-KA, and H7-KA)-conjugated hemorphine derivatives showed dose-dependent anticonvulsant activity in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate was the only compound that suppressed clonic seizures at the lowest dose of 0.5 µg/mouse in the scPTZ test. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. The peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA hemorphine peptides can be used as a background for developing hemorphin-related analogs with anticonvulsant activity. Acknowledgments: This study is funded by the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0002, "BiOrgaMCT".

Keywords: hemorphins, SPSS, caffeic/cinnamic acid, anticonvulsant activity, electrochemistry, fluorimetry

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17 Synthesis, Electrochemical and Fluorimetric Analysis of Caffeic Cinnamic and Acid-Conjugated Hemorphin Derivatives Designed as Potential Anticonvulsant Agents

Authors: Jana Tchekalarova, Stela Georgieva, Petia Peneva, Petar Todorov

Abstract:

In the present study, a series of bioconjugates of N-modified hemorphine analogs containing second pharmacophore cinnamic acids (CA) or caffeic (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorimetrical analysis and in vivo anticonvulsant activity in mice were conducted on the compounds. The three CA acids (H4-CA, H5-CA, and H7-CA) and three KA acids (H4-KA, H5-KA, and H7-KA)-conjugated hemorphine derivatives showed dose-dependent anticonvulsant activity in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate was the only compound that suppressed clonic seizures at the lowest dose of 0.5 µg/mouse in the scPTZ test. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. The peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA hemorphine peptides can be used as a background for developing hemorphin-related analogs with anticonvulsant activity. Acknowledgements: This study is funded by the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0002, "BiOrgaMCT".

Keywords: hemorphins, caffeic/cinnamic acid, anticonvulsant activity, electrochemistry, fluorimetry

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16 Evaluation of Anticonvulsant and Sedative-Hypnotic Activities of Novel 2-Fluorobenzyloxy 4,6- Diphenylpyrimidin-2-Ol Derivatives in Mice

Authors: Golnar Hasheminasab, Mehrdad Faizi, Mona Khoramjouy

Abstract:

Introduction: Benzodiazepines (BZDs) have pharmacological effects, including anxiolytic, sedative-hypnotic, anticonvulsant, and muscle relaxant properties. However, they have adverse effects such as interaction with alcohol, ataxia, impaired learning, and psychological and physical dependence. According to the structure of zolpidem and on the basis of the structure-activity relationship of BZD receptor ligands, six novel derivatives of 2-fluorobenzyloxy 4,6- diphenylpyramidin-2-ol have been synthesized. We studied the hypnotic, sedative, and anticonvulsant effects of the novel compounds. Method: In this study, we used male mice (18 to 25 g). All the substances were injected intraperitoneally. The hypnotic effect of the compounds was examined by pentobarbital induced sleeping test. The locomotor activities and sedative effects of the novel compounds were evaluated by open field and loss of righting reflex test, respectively. The anticonvulsant effects of the novel compounds were assessed by PTZ and MES tests. Results: In the pentobarbital induced sleeping and open field tests, compound 4-(2-((2-fluorobenzyl)oxy)phenyl)-6-(p-tolyl) pyrimidine-2-ol with ED50=14.20 mg/kg and ED50=47.88 mg/kg, respectively, was the most effective compound. None of the novel compounds showed a significant anticonvulsant effect in the PTZ test. In MES test, compound 4-(2-((2-fluorobenzyl)oxy)phenyl)-6-(p-tolyl)pyrimidine-2-ol with ED50=12.92 mg/kg was the most effective compound. Flumazenil blocked the sedation and hypnosis of all the compounds. Conclusion: All of the novel derivatives showed significant sedative-hypnotic activities and caused the reduction of locomotor activities. The results show that the methyl lipophilic substitutes on the phenyl ring of 4,6-diphenylpyramidin-2-ol derivatives can increase the sedative and hypnotic effects of the derivatives. Flumazenil antagonized the sedative, and the hypnotic effects of the compounds indicate that BZD receptors are involved in the effects.

Keywords: BZD, sedative, hyptonic, anticonvulsant, zolpidem, MES, PTZ, benzodiazepine, locomotor activities, pentobarbital induced sleeping tests

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15 Effect of Amlodipine on Dichlorvos-Induced Seizure in Mice

Authors: Omid Ghollipoor Bashiri, Farzam Hatefi

Abstract:

Dichlorvos a synthetic organophosphate poisons are used as insecticide. These toxins can be used insecticides in agriculture and medicine for destruction and/or eradication of ectoparasites of animals. Studies have shown that Dichlorvos creation seizure effects in different animals. Amlodipine, dihydropyridine calcium channel blockers, widely used for treatment of cardiovascular diseases. Studies have shown that the calcium channel blockers are anticonvulsant effects in different animal models. The aim of this study was to determine the effect of Amlodipine on Dichlorvos-induced seizures in mice. In this experiment, the animals were received different doses of Amlodipine (2.5, 5, 10, 20 and 40 mg/ kg b.wt.) intraperitoneally 30 min before intraperitoneal injection of Dichlorvos (50 mg/kg b.wt). After Dichlorvos injection, clonic and tonic seizures, and finally was the fate was investigated. Results showed that Amlodipine dose-dependently reduced the severity of Dichlorvos-induced seizures, so that Amlodipine at a dose of 5mg (The lowest, p<0.05) and 40 mg/kg b.wt. (The highest, p<0.001) which had anticonvulsant effects. The anticonvulsant activity of Amlodipine suggests that possibly due to the antagonistic effect on voltage-dependent calcium channel.

Keywords: dichlorvos, amlodipine, seizures, mice

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14 Novel Pyrimidine Based Semicarbazones: Confirmation of Four Binding Site Pharmacophoric Model Hypothesis for Antiepileptic Activity

Authors: Harish Rajak, Swati Singh

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A series of novel pyrimidine based semicarbazone were designed and synthesized on the basis of semicarbazone based pharmacophoric model to satisfy the structural prerequisite crucial for antiepileptic activity. The semicarbazones based pharmacophoric model consists of following four essential binding sites: (i) An aryl hydrophobic binding site with halo substituent; (ii) A hydrogen bonding domain; (iii) An electron donor group and (iv) Another hydrophobic-hydrophilic site controlling the pharmacokinetic features of the anticonvulsant. The aryl semicarbazones has been recognized as a structurally novel class of compounds with remarkable anticonvulsant activity. In the present study, all the test semicarbazones were subjected to molecular docking using Glide v5.8. Some of the compounds were found to interact with ARG192, GLU270 and THR353 residues of 1OHV protein, present in GABA-AT receptor. The chemical structures of the synthesized molecules were characterized by elemental and spectral (IR, 1H NMR, 13C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models. The neurotoxicity was evaluated in mice by the rotorod test. The attempts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study confirmed that the pharmacophore model with four binding sites is essential for antiepileptic activity.

Keywords: pyrimidine, semicarbazones, anticonvulsant activity, neurotoxicity

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13 Schiff Bases of Isatin and Admantane-1-Carbohydrazide: Synthesis, Characterization, and Anticonvulsant Activity

Authors: Hind O. Osman, Tilal Elsaman, Bashir A. Yousef, Esraa Elhadi, Aimun A. E. Ahmed, Eyman Mohamed Eltayib, Malik Suliman Mohamed, Magdi Awadalla Mohamed

Abstract:

Epilepsy is the most common neurological condition and cause of substantial morbidity and mortality. In the present study, the molecular hybridization tool was adopted to obtain six Schiff bases of isatin and adamantane-1-carbohydrazide (18–23). Then, their anticonvulsant activity was evaluated using a pentylenetetrazole- (PTZ-) induced seizure model using phenobarbitone as a positive control. Our findings showed that compounds 18–23 provided significant protection against PTZ-induced seizure, and maximum activities were associated with compound 23. Moreover, all investigated compounds increased the latency of induced convulsion and reduced the duration of epilepsy, with compound 23 being the best. Interestingly, most of the synthesized molecules showed a reduction in neurological symptoms and severity of the seizure. Molecular docking studies suggest GABA-A receptor as a potential target, and in silico ADME screening revealed that the pharmaceutical properties of compound 23 are within the specified limit. Thus, compound 23 was identified as a promising candidate that warrants further drug discovery processes.

Keywords: isatin and adamantane, anticonvulsant activity, PTZ-induced seizure, molecular docking

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12 Protective Effect of Levetiracetam on Aggravation of Memory Impairment in Temporal Lobe Epilepsy by Phenytoin

Authors: Asher John Mohan, Krishna K. L.

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Objectives: (1) To assess the extent of memory impairment induced by Phenytoin (PHT) at normal and reduced dose on temporal lobe epileptic mice. (2) To evaluate the protective effect of Levetiracetam (LEV) on aggravation of memory impairment in temporal lobe epileptic mice by PHT. Materials and Methods: Albino mice of either sex (n=36) were used for the study for a period of 64 days. Convulsions were induced by intraperitoneal administration of pilocarpine 280 mg/kg on every 6th day. Radial arm maze (RAM) was employed to evaluate the memory impairment activity on every 7th day. The anticonvulsant and memory impairment activity were assessed in PHT normal and reduced doses both alone and in combination with LEV. RAM error scores and convulsive scores were the parameters considered for this study. Brain acetylcholine esterase and glutamate were determined along with histopathological studies of frontal cortex. Results: Administration of PHT for 64 days on mice has shown aggravation of memory impairment activity on temporal lobe epileptic mice. Although the reduction in PHT dose was found to decrease the degree of memory impairment the same decreased the anticonvulsant potency. The combination with LEV not only brought about the correction of impaired memory but also replaced the loss of potency due to the reduction of the dose of the antiepileptic drug employed. These findings were confirmed with enzyme and neurotransmitter levels in addition to histopathological studies. Conclusion: This study thus builds a foundation in combining a nootropic anticonvulsant with an antiepileptic drug to curb the adverse effect of memory impairment associated with temporal lobe epilepsy. However further extensive research is a must for the practical incorporation of this approach into disease therapy.

Keywords: anti-epileptic drug, Phenytoin, memory impairment, Pilocarpine

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11 Synthesis and Pharmacological Activity of Some Oxyindole Derivatives

Authors: Vivek Singh Bhadauria, Abhishek Pandey

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Indole-2,3-diones are known for their various biological activities. By suitable control of a substituent, different novel indole-2,3-diones were synthesized. In this present study, various Schiff and Mannich bases were synthesized and characterized, and evaluated their for different pharmacological activities. The compounds were prepared by reacting indole-2,3-dione with benzyl chloride and 4-substituted thiosemicarbazides. All the synthesized compounds were characterized by the TLC, MP, Elemental analysis, FTIR, 1H-NMR and Mass spectroscopy. The compounds have been evaluated for their anticancer, antituberculosis, anticonvulsant, antiinflammatory as well as anti-SARS activity and the results are presented. Some of compounds possessed different pharmacological activity at a concentration of 200 mg/kg body weight and even at lower concentration.

Keywords: indoles, isatin, NMR, biological activities

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10 Acupuncture and Topiramat in Treatment of Migraine

Authors: Lazgeen Mohammed

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The greatest advantage of acupuncture over western medicine is that it is safe . Unlike synthetic drugs, acupuncture has virtually no side effects, and the procedures for treating headaches are much less invasive. Migraine headaches are usually one-sided, pulsating or throbbing, and moderate or severe in intensity.. Some patients also experience auras, a neurological symptom that develops gradually over 5-20 minutes. The patient may see brief flashes or waves of light, or changes in their vision. Other common features of auras include vertigo, imbalance, confusion and numbness.Acupuncture had been used to treat 50 patients suffering from migraine ,topiramat (topamax) given to prevent the attacks, duration of treatment is 10 weeks , the patients were fallowed up for one year .Topiramat is called an anticonvulsant.Topiramat is also used to prevent migraine headaches in adults and teenagers who are at least 12 years old. This medicine will only prevent migraine headaches or reduce the number of attacks. It will not treat a headache that has already begun.

Keywords: acpuncture, migraine, topiramat, headache

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9 Multiclass Analysis of Pharmaceuticals in Fish and Shrimp Tissues by High-Performance Liquid Chromatography-Tandem Mass Spectrometry

Authors: Reza Pashaei, Reda Dzingelevičienė

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An efficient, reliable, and sensitive multiclass analytical method has been expanded to simultaneously determine 15 human pharmaceutical residues in fish and shrimp tissue samples by ultra-high-performance liquid chromatography-tandem mass spectrometry. The investigated compounds comprise ten classes, namely analgesic, antibacterial, anticonvulsant, cardiovascular, fluoroquinolones, macrolides, nonsteroidal anti-inflammatory, penicillins, stimulant, and sulfonamide. A simple liquid extraction procedure based on 0.1% formic acid in methanol was developed. Chromatographic conditions were optimized, and mobile phase namely 0.1 % ammonium acetate (A), and acetonitrile (B): 0 – 2 min, 15% B; 2 – 5 min, linear to 95% B; 5 – 10 min, 95% B; and 10 – 12 min was obtained. Limits of detection and quantification ranged from 0.017 to 1.371 μg/kg and 0.051 to 4.113 μg/kg, respectively. Finally, amoxicillin, azithromycin, caffeine, carbamazepine, ciprofloxacin, clarithromycin, diclofenac, erythromycin, furosemide, ibuprofen, ketoprofen, naproxen, sulfamethoxazole, tetracycline, and triclosan were quantifiable in fish and shrimp samples.

Keywords: fish, liquid chromatography, mass spectrometry, pharmaceuticals, shrimp, solid-phase extraction

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8 Naltrexone and Borderline Personality Disorder: A Brief Review

Authors: Azadeh Moghaddas, Mehrnoush Dianatkhah, Padideh Ghaeli

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The main characteristics of borderline personality disorder (BPD) are instable regulation of affect and self-image, impulsive behavior, and lack of interpersonal relationships. Clinically, emotional dysregulation, impulsive aggression, repeated self-injury, and suicidal thought are noted with this disorder. Proper management of patients with BPD is a difficult challenge due to the complex features of this disorder. Pharmacotherapy of BPD in order to control impulsive behavior and to stabilize affect in patients with BPD has been receiving a lot of attention. Anticonvulsant agents such as topiramate, valproate, or lamotrigine, atypical antipsychotics such as aripiprazole and olanzapine and antidepressants such as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors like fluvoxamine have been implicated in the treatment of BPD. Unfortunately, none of these medications can be used alone or even in combination as sole treatment of BPD. Medications may be used mostly to resolve or reduce impulsivity and aggression in these patients. Naltrexone (NTX), a nonspecific competitive opiate antagonist has been suggested, in the literature, to control self-injurious behavior (SIB) and dissociative symptoms in patients with BPD. This brief review has been intended to look at all documented evidence on the use of NTX in the management of BPD and to reach a comprehensive conclusion.

Keywords: borderline personality disorder, naltrexone, self-injurious behavior, dissociative symptoms

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7 Synthesis, Crystallography and Anti-TB Activity of Substituted Benzothiazole Analogues

Authors: Katharigatta N. Venugopala, Melendhran Pillay, Bander E. Al-Dhubiab

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Tuberculosis (TB) infection is caused mainly by Mycobacterium tuberculosis (MTB) and it is one of the most threatening and wide spread infectious diseases in the world. Benzothiazole derivatives are found to have diverse chemical reactivity and broad spectrum of pharmacological activity. Some of the important pharmacological activities shown by the benzothiazole analogues are antitumor, anti-inflammatory, antimicrobial, anti-tubercular, anti-leishmanial, anticonvulsant and anti-HIV properties. Keeping all these facts in mind in the present investigation it was envisaged to synthesize a series of novel {2-(benzo[d]-thiazol-2-yl-methoxy)-substitutedaryl}-(substitutedaryl)-methanones (4a-f) and characterize by IR, NMR (1H and 13C), HRMS and single crystal x-ray studies. The title compounds are investigated for in vitro anti-tubercular activity against two TB strains such as H37Rv (ATCC 25177) and MDR-MTB (multi drug resistant MTB resistant to Isoniazid, Rifampicin and Ethambutol) by agar diffusion method. Among the synthesized compounds in the series, test compound {2-(benzo[d]thiazol-2-yl-methoxy)-5-fluorophenyl}-(4-chlorophenyl)-methanone (2c) was found to exhibit significant activity with MICs of 1 µg/mL and 2 µg/mL against H37Rv and MDR-MTB, respectively when compared to standard drugs. Single crystal x-ray studies was used to study intra and intermolecular interactions, including polymorphism behavior of the test compounds, but none of the compounds exhibited polymorphism behavior.

Keywords: benzothiazole analogues, characterization, crystallography, anti-TB activity

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6 The Effect of Pregabalin on Postoperative Pain after Anterior Cruciate Ligament Reconstruction: A Systematic Review of Randomized Clinical Trials

Authors: Emad Kouhestani

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Background: Despite the enormous success of anterior cruciate ligament (ACL) reconstruction, acute neuropathic pain can develop postoperatively and is both distressing and difficult to treat once established. Pregabalin, as an anticonvulsant agent that selectively affects the nociceptive process, has been used as a pain relief agent. The purpose of this systematic review of randomized controlled trials (RCTs) was to evaluate the pain control effect of pregabalin versus placebo after ACL reconstruction. Method: A search of the literature was performed from inception to June 2022, using PubMed, Scopus, Google Scholar, Web of Science, Cochrane, and EBSCO. Studies considered for inclusion were RCTs that reported relevant outcomes (postoperative pain scores, or cumulative opioid consumption, adverse events) following the administration of pregabalin in patients undergoing ACL reconstruction. Result: Five placebo-controlled RCTs involving 272 participants met the inclusion criteria. 75 mg and 150 mg of oral pregabalin were used in included trials. Two studies used a single dose of pregabalin one hour before anesthesia induction. Two studies used pregabalin 1 hour before anesthesia induction and 12 hours after. One study used daily pregabalin 7 days before and 7 days after surgery. Out of five papers, three papers found significantly lower pain intensity and cumulative opioid consumption in the pregabalin group compared with the placebo group. However, a decrease in pain scores was found in all trials. Pregabalin administration was associated with dizziness and nausea. Conclusion: The use of pregabalin may be a valuable asset in pain management after ACL reconstruction. However, future studies with larger sample sizes and longer follow-up periods are required.

Keywords: pregabalin, anterior cruciate ligament, postoperative pain, clinical trial

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5 Occurrence of Pharmaceutical Compounds in an Urban Lake

Authors: J. D. Villanueva, N. Peyraube, I. Allan, G. D. Salvosa, M. Reid, C. Harman, K. D. Salvosa, J. M. V. Castro, M. V. O. Espaldon, J. B. Sevilla-Nastor, P. Le Coustumer

Abstract:

The main objectives of this research are to (1) assess the occurrence of the pharmaceutical compounds and (2) present the environmental challenges posed by the existence of these pharmaceutical compounds in the surface water. These pharmaceuticals were measured in Napindan Lake, Philippines. This lake is not only a major tributary of the Pasig River (an estuary) and Laguna Lake (freshwater). It also joins these two important surface waters of the National Capital Region. Pharmaceutical compounds such as Atenolol, Carbamazepine, and two other over the counter medicines: Cetirizine, and Ibuprofen were measured in Napindan Lake. Atenolol is a beta blocker that helps in lowering hypertensions. Carbamazepine is an anticonvulsant used as treatment for epilepsy and neuropathic pain. Cetirizine is an antihistamine that can relieve allergies. Ibuprofen is a non-steroidal anti-inflammatory drug normally used to relieve pains. Three different climatological conditions with corresponding hydro physico chemical characteristics were considered. First, was during a dry season with a simultaneous dredging. Second was during a transition period from dry to wet season. Finally, the third was during a continuous wet event. Based from the results of the study, most of these pharmaceuticals can be found in Napindan Lake. This is a proof that these pharmaceutical compounds are being released to a natural surface water. Even though climatological conditions were different, concentrations of these pharmaceuticals can still be detected. This implies that there is an incessant supply of these pharmaceutical compounds in Napindan Lake. Chronic exposure to these compounds even at low concentrations can lead to possible environmental and health risks. Given this information and since consistent occurrence of these compounds can be expected, the main challenge, at present, is on how to control the sources of these pharmaceutical compounds. Primarily, there is a need to manage the disposal of the pharmaceutical compounds. Yet, the main question is how to? This study would like to present the challenges and institutional roles in helping manage the pharmaceutical disposals in a developing country like the Philippines.

Keywords: atenolol, carbamazepine, cetirizine, ibuprofen, institutional roles, Napindan lake, pharmaceutical compound disposal management, surface water, urban lake

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4 Exploring Polypnenolics Content and Antioxidant Activity of R. damascena Dry Extract by Spectroscopic and Chromatographic Techniques

Authors: Daniela Nedeltcheva-Antonova, Kamelia Getchovska, Vera Deneva, Stanislav Bozhanov, Liudmil Antonov

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Rosa damascena Mill. (Damask rose) is one of the most important plants belonging to the Rosaceae family, with a long historical use in traditional medicine and as a valuable oil-bearing plant. Many pharmacological effects have been reported from this plant, including anti-inflammatory, hypnotic, analgesic, anticonvulsant, anti-depressant, antianxiety, antitussive, antidiabetic, relaxant effects on tracheal chains, laxative, prokinetic and hepatoprotective activities. Pharmacological studies have shown that the various health effects of R. damascena flowers can mainly be attributed to its large amount of polyphenolic components. Phenolics possess a wide range of pharmacological activities, such as antioxidants, free-radical scavengers, anticancer, anti-inflammatory, antimutagenic, and antidepressant, with flavonoids being the most numerous group of natural polyphenolic compounds. According to the technological process in the production of rose concrete (solvent extraction with non-polar solvents of fresh rose flowers), it can be assumed that the resulting plant residue would be as rich of polyphenolics, as the plant itself, and could be used for the development of novel products with promising health-promoting effect. Therefore, an optimisation of the extraction procedure of the by-product from the rose concrete production was carried out. An assay of the extracts in respect of their total polyphenols and total flavonoids content was performed. HPLC analysis of quercetin and kaempferol, the two main flavonoids found in R. damascena, was also carried out. The preliminary results have shown that the flavonoid content in the rose extracts is comparable to that of the green tea or Gingko biloba, and they could be used for the development of various products (food supplements, natural cosmetics and phyto-pharmaceutical formulation, etc.). The fact that they are derived from the by-product of industrial plant processing could add the marketing value of the final products in addition to the well-known reputation of the products obtained from Bulgarian roses (R. damascena Mill.).

Keywords: gas chromatography-mass-spectromrtry, dry extract, flavonoids, Rosa damascena Mill

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3 Exploring Valproic Acid (VPA) Analogues Interactions with HDAC8 Involved in VPA Mediated Teratogenicity: A Toxicoinformatics Analysis

Authors: Sakshi Piplani, Ajit Kumar

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Valproic acid (VPA) is the first synthetic therapeutic agent used to treat epileptic disorders, which account for affecting nearly 1% world population. Teratogenicity caused by VPA has prompted the search for next generation drug with better efficacy and lower side effects. Recent studies have posed HDAC8 as direct target of VPA that causes the teratogenic effect in foetus. We have employed molecular dynamics (MD) and docking simulations to understand the binding mode of VPA and their analogues onto HDAC8. A total of twenty 3D-structures of human HDAC8 isoforms were selected using BLAST-P search against PDB. Multiple sequence alignment was carried out using ClustalW and PDB-3F07 having least missing and mutated regions was selected for study. The missing residues of loop region were constructed using MODELLER and energy was minimized. A set of 216 structural analogues (>90% identity) of VPA were obtained from Pubchem and ZINC database and their energy was optimized with Chemsketch software using 3-D CHARMM-type force field. Four major neurotransmitters (GABAt, SSADH, α-KGDH, GAD) involved in anticonvulsant activity were docked with VPA and its analogues. Out of 216 analogues, 75 were selected on the basis of lower binding energy and inhibition constant as compared to VPA, thus predicted to have anti-convulsant activity. Selected hHDAC8 structure was then subjected to MD Simulation using licenced version YASARA with AMBER99SB force field. The structure was solvated in rectangular box of TIP3P. The simulation was carried out with periodic boundary conditions and electrostatic interactions and treated with Particle mesh Ewald algorithm. pH of system was set to 7.4, temperature 323K and pressure 1atm respectively. Simulation snapshots were stored every 25ps. The MD simulation was carried out for 20ns and pdb file of HDAC8 structure was saved every 2ns. The structures were analysed using castP and UCSF Chimera and most stabilized structure (20ns) was used for docking study. Molecular docking of 75 selected VPA-analogues with PDB-3F07 was performed using AUTODOCK4.2.6. Lamarckian Genetic Algorithm was used to generate conformations of docked ligand and structure. The docking study revealed that VPA and its analogues have more affinity towards ‘hydrophobic active site channel’, due to its hydrophobic properties and allows VPA and their analogues to take part in van der Waal interactions with TYR24, HIS42, VAL41, TYR20, SER138, TRP137 while TRP137 and SER138 showed hydrogen bonding interaction with VPA-analogues. 14 analogues showed better binding affinity than VPA. ADMET SAR server was used to predict the ADMET properties of selected VPA analogues for predicting their druggability. On the basis of ADMET screening, 09 molecules were selected and are being used for in-vivo evaluation using Danio rerio model.

Keywords: HDAC8, docking, molecular dynamics simulation, valproic acid

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2 Competence of the Health Workers in Diagnosing and Managing Complicated Pregnancies: A Clinical Vignette Based Assessment in District and Sub-District Hospitals in Bangladesh

Authors: Abdullah Nurus Salam Khan, Farhana Karim, Mohiuddin Ahsanul Kabir Chowdhury, S. Masum Billah, Nabila Zaka, Alexander Manu, Shams El Arifeen

Abstract:

Globally, pre-eclampsia (PE) and ante-partum haemorrhage (APH) are two major causes of maternal mortality. Prompt identification and management of these conditions depend on competency of the birth attendants. Since these conditions are infrequent to be observed, clinical vignette based assessment could identify the extent of health worker’s competence in managing emergency obstetric care (EmOC). During June-August 2016, competence of 39 medical officers (MO) and 95 nurses working in obstetric ward of 15 government health facilities (3 district hospital, 12 sub-district hospital) was measured using clinical vignettes on PE and APH. The vignettes resulted in three outcome measures: total vignette scores, scores for diagnosis component, and scores for management component. T-test was conducted to compare mean vignette scores and linear regression was conducted to measure the strength and association of vignette scores with different cadres of health workers, facility’s readiness for EmOC and average annual utilization of normal deliveries after adjusting for type of health facility, health workers’ work experience, training status on managing maternal complication. For each of the seven component of EmOC items (administration of injectable antibiotics, oxytocic and anticonvulsant; manual removal of retained placenta, retained products of conception; blood transfusion and caesarean delivery), if any was practised in the facility within last 6 months, a point was added and cumulative EmOC readiness score (range: 0-7) was generated for each facility. The yearly utilization of delivery cases were identified by taking the average of all normal deliveries conducted during three years (2013-2015) preceding the survey. About 31% of MO and all nurses were female. Mean ( ± sd) age of the nurses were higher than the MO (40.0 ± 6.9 vs. 32.2 ± 6.1 years) and also longer mean( ± sd) working experience (8.9 ± 7.9 vs. 1.9 ± 3.9 years). About 80% health workers received any training on managing maternal complication, however, only 7% received any refresher’s training within last 12 months. The overall vignette score was 8.8 (range: 0-19), which was significantly higher among MO than nurses (10.7 vs. 8.1, p < 0.001) and the score was not associated with health facility types, training status and years of experience of the providers. Vignette score for management component (range: 0-9) increased with higher annual average number of deliveries in their respective working facility (adjusted β-coefficient 0.16, CI 0.03-0.28, p=0.01) and increased with each unit increase in EmOC readiness score (adjusted β-coefficient 0.44, CI 0.04-0.8, p=0.03). The diagnosis component of vignette score was not associated with any of the factors except it was higher among the MO than the nurses (adjusted β-coefficient 1.2, CI 0.13-2.18, p=0.03). Lack of competence in diagnosing and managing obstetric complication by the nurses than the MO is of concern especially when majority of normal deliveries are conducted by the nurses. Better EmOC preparedness of the facility and higher utilization of normal deliveries resulted in higher vignette score for the management component; implying the impact of experiential learning through higher case management. Focus should be given on improving the facility readiness for EmOC and providing the health workers periodic refresher’s training to make them more competent in managing obstetric cases.

Keywords: Bangladesh, emergency obstetric care, clinical vignette, competence of health workers

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1 [Keynote Talk]: Bioactive Cyclic Dipeptides of Microbial Origin in Discovery of Cytokine Inhibitors

Authors: Sajeli A. Begum, Ameer Basha, Kirti Hira, Rukaiyya Khan

Abstract:

Cyclic dipeptides are simple diketopiperazine derivatives being investigated by several scientists for their biological effects which include anticancer, antimicrobial, haematological, anticonvulsant, immunomodulatory effect, etc. They are potentially active microbial metabolites having been synthesized too, for developing into drug candidates. Cultures of Pseudomonas species have earlier been reported to produce cyclic dipeptides, helping in quorum sensing signals and bacterial–host colonization phenomena during infections, causing cell anti-proliferation and immunosuppression. Fluorescing Pseudomonas species have been identified to secrete lipid derivatives, peptides, pyrroles, phenazines, indoles, aminoacids, pterines, pseudomonic acids and some antibiotics. In the present work, results of investigation on the cyclic dipeptide metabolites secreted by the culture broth of Pseudomonas species as potent pro-inflammatory cytokine inhibitors are discussed. The bacterial strain was isolated from the rhizospheric soil of groundnut crop and identified as Pseudomonas aeruginosa by 16S rDNA sequence (GenBank Accession No. KT625586). Culture broth of this strain was prepared by inoculating into King’s B broth and incubating at 30 ºC for 7 days. The ethyl acetate extract of culture broth was prepared and lyophilized to get a dry residue (EEPA). Lipopolysaccharide (LPS)-induced ELISA assay proved the inhibition of tumor necrosis factor-alpha (TNF-α) secretion in culture supernatant of RAW 264.7 cells by EEPA (IC50 38.8 μg/mL). The effect of oral administration of EEPA on plasma TNF-α level in rats was tested by ELISA kit. The LPS mediated plasma TNF-α level was reduced to 45% with 125 mg/kg dose of EEPA. Isolation of the chemical constituents of EEPA through column chromatography yielded ten cyclic dipeptides, which were characterized using nuclear magnetic resonance and mass spectroscopic techniques. These cyclic dipeptides are biosynthesized in microorganisms by multifunctional assembly of non-ribosomal peptide synthases and cyclic dipeptide synthase. Cyclo (Gly-L-Pro) was found to be more potentially (IC50 value 4.5 μg/mL) inhibiting TNF-α production followed by cyclo (trans-4-hydroxy-L-Pro-L-Phe) (IC50 value 14.2 μg/mL) and the effect was equal to that of standard immunosuppressant drug, prednisolone. Further, the effect was analyzed by determining mRNA expression of TNF-α in LPS-stimulated RAW 264.7 macrophages using quantitative real-time reverse transcription polymerase chain reaction. EEPA and isolated cyclic dipeptides demonstrated diminution of TNF-α mRNA expression levels in a dose-dependent manner under the tested conditions. Also, they were found to control the expression of other pro-inflammatory cytokines like IL-1β and IL-6, when tested through their mRNA expression levels in LPS-stimulated RAW 264.7 macrophages under LPS-stimulated conditions. In addition, significant inhibition effect was found on Nitric oxide production. Further all the compounds exhibited weak toxicity to LPS-induced RAW 264.7 cells. Thus the outcome of the study disclosed the effectiveness of EEPA and the isolated cyclic dipeptides in down-regulating key cytokines involved in pathophysiology of autoimmune diseases.In another study led by the investigators, microbial cyclic dipeptides were found to exhibit excellent antimicrobial effect against Fusarium moniliforme which is an important causative agent of Sorghum grain mold disease. Thus, cyclic dipeptides are emerging small molecular drug candidates for various autoimmune diseases.

Keywords: cyclic dipeptides, cytokines, Fusarium moniliforme, Pseudomonas, TNF-alpha

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