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   Table of Contents - Current issue
Coverpage
January-March 2019
Volume 10 | Issue 1
Page Nos. 1-44

Online since Tuesday, May 14, 2019

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REVIEW ARTICLE  

Structural genomics in drug discovery: An overview Highly accessed article p. 1
Karri Sowjanya, Chandrashekaran Girish
DOI:10.4103/jpp.JPP_117_18  
Structural genomics, technology and methodology driven field has emerged in the past 20–25 years and mainly aims at coming up with as many three-dimensional structures of proteins as possible by combining experimental (X-ray crystallography and nuclear magnetic resonance) and comparative modeling methods at a minimal cost in comparison to the traditional approaches. Structure aided drug discovery which is used since long mainly focuses on a single target protein whereas structural genomics targets and investigates multiple proteins simultaneously, thus cutting down time and cost. These activities are done at specialized structural genomic centers available worldwide that help to interpret the biology of humans and pathogenic organisms in a better way leading to an increased productivity and saving time. Virtual screening methods like docking have also brought a great impact to quicken the drug discovery process. In diseases of public health concern (like tuberculosis), structural genomics helped greatly by giving important insights toward a better comprehension of the pathways associated in its pathogenesis and in guiding drug discovery. Several newer targets such as Scaff10-8, MS2734 (6), and GSK-J4 were developed showcasing their beneficial effects in a wide variety of disorders including diabetes insipidus, Parkinson's disease, and autoimmune diseases, respectively. Furthermore, these programs guide to understand the root cause and the mechanism associated with various human diseases and their pathogens. This review tries to look into the high throughput methods of structure determination, the newer targets developed in the past few years and the benefits offered that can pave a way for faster and efficient drug discovery.
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RESEARCH PAPERS Top

Genotype and allele frequency of p450 oxidoreductase *28 gene polymorphism in South Indian population p. 7
R Mirunalini, G Pavithra, D Benet Bosco Dhas, C Adithan
DOI:10.4103/jpp.JPP_95_18  
Objective: To establish the normative frequency of POR *28 genetic variant in South Indian population. Methods: This study is a genetic epidemiological study conducted on healthy volunteers belonging to south India. A total of 108 healthy volunteers who satisfied the eligibility criteria were included in the study. The DNA isolation was done using the QIAGEN Blood DNA isolation kit (Qiagen). The genotyping for POR *28 polymorphism was done using TaqMan genotyping master mix kits (Applied Biosystems) in real-time polymerase chain reaction platform. The data were analyzed using Fisher's exact test. P < 0.05 was considered statistically significant. Hardy–Weinberg principle was tested using the Chi-square test. Results: The genotyping of the POR *28 showed that the wild-type (homozygous) in the south Indian population was 41.7% and heterozygous and mutant type as 47.2% and 11.1%, respectively. The allele frequency showed that the minor allele frequency (MAF) was 34.7% in the south Indian population. This distribution of allele frequency was found to be significantly different from that of African–Americans 0.191 (95% confidence interval 0.157, 0.231). It was not statistically significant when compared to Caucasians 0.264 (0.228, 0.304); Chinese 0.367 (0.319, 0.419); Mexicans 0.310 (0.265, 0.360); and Japanese 0.40 (0.339, 0.464). Conclusion: The frequency distribution of POR *28 genetic variant was established in the south Indian population. The MAF was found to be 34.7% which was significantly different from other major ethnic groups.
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Comparison of safety and efficacy of dexmedetomidine versus propofol sedation for elective awake fiber-optic intubation p. 11
Samarjit Dey, Tridip Jyoti Borah, Jaideep Sonowal, Debasis Pradhan, Md. Yunus, Priyanka Dev
DOI:10.4103/jpp.JPP_71_18  
Objective: To evaluate the safety and efficacy of dexmedetomidine versus propofol as a sedative modality for awake fiber-optic intubation (AFOI) in elective patients with anticipated difficult intubation. Materials and Methods: This randomized prospective study was conducted on 90 patients (Group D and Group P; n = 45) who had undergone AFOI for anticipated difficult airway. Group D received intravenous (IV) dexmedetomidine and Group P patients received IV propofol, until they were adequately sedated. Sedation was measured by Bispectral index© and Ramsay Sedation Scale. Airway blocks were given to all patients undergoing awake fiber-optic intubation. Intubation comfort scores, airway obstruction scores, and hemodynamics were recorded in all patients. Results: Sedation level was comparable in both the groups. Intubation time was less in Group D than Group P (119.06 ± 16.51 s vs. 126.67 ± 18.19 s; P < 0.05). The intubation score for both cough and vocal cord opening was better in the dexmedetomidine group than the propofol group (P = 0.6). There were significant incidences of airway obstruction and hypoxia in Group P compared to Group D (P < 0.05). Significant fall in mean arterial pressure (MAP) was seen in Group P during drug infusion which continued till fiber-optic bronchoscopy (P < 0.05). MAP changes during intubation were similar during intubation in both the groups (P = 0.18). Conclusion: Dexmedetomidine is a better alternative for achieving optimal sedation during AFOI.
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Antidepressants modulate behavioral, biochemical, and histological alterations induced by chronic aluminum chloride administration in wistar rats p. 16
Arshad Basha Shaik, Smita Shenoy, V Anupama, K G Mohandas Rao, Arul Amuthan
DOI:10.4103/jpp.JPP_135_18  
Objective: To assess the effect of duloxetine and escitalopram on aluminum chloride (AlCl3)-induced memory impairment in rats. Materials and Methods: Thirty rats were used. Group-I (control) and Group-II (toxic control) received 2% gum acacia, 10 mL/kg and AlCl3, 175 mg/kg, respectively. Group-III (standard), Group-IV, and Group-V (test drug groups) received rivastigmine (1 mg/kg), duloxetine (10 mg/kg), and escitalopram (10 mg/kg), respectively, along with AlCl3, 175 mg/kg. All drugs and AlCl3 were administered orally daily for 2 months. The effect on cognition was assessed by Morris water maze (MWM). Brain acetylcholinesterase levels, oxidative stress parameters, and histology of the hippocampus were also evaluated. Results: Rats treated with only AlCl3 showed significant (P < 0.001) increase in latency during acquisition trials of day-3 and day-4 and decrease in percentage of both time spent and distance traveled in target zone during probe trial in MWM. Malondialdehyde was increased and glutathione decreased in the brain. Histopathology of the hippocampus showed unhealthy cellular architecture with a large number of degenerated cells. All these changes were significantly reversed in rivastigmine and test drug groups. Chronic administration of AlCl3 resulted in lowering of brain cholinesterase levels (P < 0.001) versus control. Cholinesterase levels were further significantly (P < 0.05) lowered in rats who received AlCl3 along with either rivastigmine or escitalopram. Conclusion: Escitalopram and duloxetine exerted a protective effect against AlCl3-induced memory impairment in rats.
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Pharmacokinetic modeling of propofol in Indian children p. 22
B Naveen Naik, Preethy J Mathew, Smita Pattanaik, Venkateswari Muthukrishnan, Goverdhan Dutt Puri
DOI:10.4103/jpp.JPP_5_19  
Objective: To analyse the PK (pharmacokinetics) of propofol after single bolus dose in children undergoing elective general surgery and to establish a PK model of propofol after single bolus dose in children undergoing elective general surgery and to establish a PK model of propofol. Materials and Methods: Twelve healthy Indian children aged 5–12 years who underwent elective general surgery under general anesthesia received propofol at an intravenous bolus dose of 2.5 mg/kg. The plasma propofol concentration over the next 12 h was estimated using high-performance liquid chromatography. A total of 144 samples were analyzed, and PK parameters were evaluated using nonlinear mixed-effects modeling. Results were validated using bootstrap analysis, and visual predictive check was done to evaluate the final model. Results: Propofol PK in Indian children was characterized by a three-compartment model similar to adults. The model derived estimates of PK parameters are as follows: volume of the central compartment (V1) = 598.73 ml/kg, volume of the second compartment (V2) = 821.12 ml/kg, volume of the third compartment (V3) = 1097 ml/kg, systemic clearance (CL1) = 22.1 ml/kg/min, and intercompartmental clearances CL2 and CL3 which were 42.5 ml/kg/min and 10.4 ml/kg/min, respectively. Conclusion: The final PK model imparted a robust characterization of propofol PK. Inclusion of body weight as a covariate to the model exhibited a significant impact on propofol PK. The execution of this patient derived PK model should support future population PK studies that include diverse population with sparse sampling to support the dosing of propofol in Indian children undergoing surgery under total intravenous anesthesia.
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CORRESPONDENCE Top

Targeted spontaneous reporting on drug safety alerts issued by pharmacovigilance programme of India: A new origin of pharmacovigilance in India p. 33
Prasad Thota, Shabir Sidhu, Bikash Medhi, Phulen Sarma, Ajay Prakash, Kalaiselvan Vivekanandan, Anusha Thota
DOI:10.4103/jpp.JPP_129_18  
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CASE REPORTS Top

Persistent cryptococcal meningitis treated with antiretroviral therapy and alternative antifungals p. 35
Katie E Barber, Svenja Albrecht, Kayla R Stover
DOI:10.4103/jpp.JPP_103_18  
Because of the relative lack of information surrounding persistent cryptococcal meningitis, treatment presents a clinical dilemma. We report two patients who developed persistent cryptococcal meningitis that was nonresponsive to induction therapy over the course of several weeks. In the first patient, induction therapy with amphotericin and flucytosine was extended. Because of persistently high opening pressures (OPs) and cryptococcal antigen titers at 10 weeks, antiretroviral therapy with the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was initiated, and the patient's OP and cryptococcal titers normalized within a week. This patient was well at his 2-week visit but was lost to follow-up after that. In the second patient, induction therapy with amphotericin and flucytosine was continued for 6 weeks due to persistently elevated OPs and cryptococcal antigen titers. At that time, high-dose fluconazole was added. This patient steadily improved and was discharged on fluconazole consolidation therapy. After hospital discharge, this patient was lost to follow-up. Published risk factors for persistent infection that these patients shared were positive human immunodeficiency virus status, elevated cryptococcal antigen titers, and persistently high OP. After initiation of unique, nonstandard therapy of antiretrovirals and high-dose fluconazole, both patients improved. Other potential treatment options for persistent cryptococcal meningitis include voriconazole, posaconazole, interleukin 2, acetazolamide, and the placement of cerebrospinal fluid shunts, but these were not selected because of a variety of relative contraindications or limitations of these agents. With limited data to favor one agent over another, it is important to evaluate case-by-case for treatment decisions.
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Valproic acid induced pancreatitis in an Arab Male p. 38
Ethar Abdelmageed Imam, Abdulrhman Idrees, Mohamed Izham Mohamed Ibrahim, Subish Palaian
DOI:10.4103/jpp.JPP_107_18  
Valproate, a commonly used antiepileptic, is known to cause pancreatitis, which may present days to years after initiation of therapy. A 20-year-old Arab male patient with electroencephalogram (EEG) confirmed epileptiform activity over the left posterior head region was initiated with tablet carbamazepine 400 mg twice daily in the year 2015 and based on subsequent EEG findings (suggestive of more of generalized myoclonic seizure) carbamazepine was withdrawn gradually and started with sodium valproate 500 mg twice daily and levetiracetam 1 g twice daily. During treatment, the patient had status epileptics, treated with diazepam and lamotrigine 50 mg was added. Laboratory data indicated low valproate level, 47 μg/mL (normal range: 50–125 μg/mL) resulting in two episodes of myoclonic jerks necessitating lamotrigine dose escalation (100 mg twice daily). A month later, the patient developed nystagmus and tremors, and lamotrigine dose was deescalated to 75 mg twice daily. Patient was brought to the emergency with severe abdominal pain and vomiting since the day before and valproate level was 179 μg/mL (>150 μg/mL μg/mL is considered toxic), a diagnosis of acute pancreatitis due to valproate was made and the patient was treated in the intensive care unit. The causality assessment of the adverse drug reaction was “probable” (Naranjo score 8), and severity was “Severe” (Level 5; Modified Hartwig and Siegel scale), and the adverse reaction was “Not preventable” (Modified Schumock and Thornton scale). This report suggests the need for constant clinical monitoring and the need for therapeutic drug monitoring for patients undergoing valproate therapy.
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Subconjunctival bevacizumab for recurrent conjunctival pyogenic granuloma p. 42
Nirupama Kasturi, Tharini Senthamizh, Hanuman Srinivas Bheemanathi, K Ramesh Babu
DOI:10.4103/jpp.JPP_123_18  
A 45-year-old male presented with a pyogenic granuloma of the bulbar conjunctiva of the left eye following a stick injury. It was a benign friable, hyperplastic, vascular lesion comprised of inflammatory cells and lobular capillary proliferation. The differential diagnosis includes squamous papillomas, hemangiomas, suture granulomas, and ocular surface tumors, such as squamous cell carcinoma and amelanotic melanoma. Conventional treatment includes topical corticosteroids and surgical excision. Treatment of recurrent lesions with cryotherapy, electrocautery, topical antimetabolites, and plaque irradiation has been described. We present a case of recurrent pyogenic granuloma successfully treated with two subconjunctival bevacizumab injections. The patient developed three recurrences after excision at a peripheral hospital after which he was successfully treated with excision and adjuvant subconjunctival bevacizumab 2.5 mg/0.1 ml injection. This case highlights the novel use of bevacizumab for recurrent pyogenic granuloma.
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