Siva Reddy Challa

Surgical animal models of neuropathic pain: Pros and Cons.

One of the biggest challenges for discovering more efficacious drugs for the control of neuropathic pain has been the diversity of chronic pain states in humans. It is now acceptable that different mechanisms contribute to normal physiologic pain, pain arising from tissue damage and pain arising from injury to the nervous system. To study pain transmission, spot novel pain targets and characterize the potential analgesic profile of new chemical entities, numerous experimental animal pain models have been developed that attempt to simulate the many human pain conditions. Among the neuropathic pain models, surgical models have paramount importance in the induction of pain states. Many surgical animal models exist, like the chronic constriction injury (CCI) to the sciatic nerve, partial sciatic nerve ligation (pSNL), spinal nerve ligation (SNL), spared nerve injury (SNI), brachial plexus avulsion (BPA), sciatic nerve transaction (SNT) and sciatic nerve trisection. Most of these models induce responses similar to those found in causalgia, a syndrome of sustained burning pain often seen in the distal extremity after partial peripheral nerve injury in humans. Researchers most commonly use these surgical models in both rats and mice during drug discovery to screen new chemical entities for efficacy in the area of neuropathic pain. However, there is scant literature that provides a comparative discussion of all these surgical models. Each surgical model has its own benefits and limitations. It is very difficult for a researcher to choose a suitable surgical animal model to suit their experimental set-up. Therefore, particular attention has been given in this review to comparatively provide the pros and cons of each model of surgically induced neuropathic pain.

Systemic exposure of Paracetamol (acetaminophen) was enhanced by quercetin and chrysin co-administration in Wistar rats and in vitro model: risk of liver toxicity

Abstract Intestinal P-glycoprotein (P-gp) and drug-metabolizing enzymes (DMEs) play an important role in the first-pass-metabolism (FPM) and pharmacokinetics (PK) of majority of drugs. Paracetamol is primarily metabolized by conjugation reactions and a little amount (∼15%) undergoes cytochrome P450 (CYP2E1)-mediated oxidative metabolism produces a hepatotoxic metabolite, N-acetyl-p-benzoquinonimine (NAPQI). Quercetin and chrysin are naturally occurring flavonoids, reported as modulators of P-gp and DMEs. Therefore, the objective of this study was to evaluate the effects of quercetin and chrysin on the pharmacokinetics of paracetamol using rats and non-everted gut sacs in vitro. Paracetamol was given orally (100 mg/kg) to rats alone and in combination with quercetin (5, 10 and 20 mg/kg) and chrysin (50, 100 and 200 mg/kg) once daily for 21 consecutive days. Blood samples were collected on the 1st day in single dose pharmacokinetic study (SDS) and on the 21st day in multiple pharmacokinetic studies (MDS). The plasma concentrations of paracetamol were determined by HPLC and PK parameters were calculated by using Kinetica (Version 5.1). The maximum plasma concentration (Cmax) and area under the curve (AUC0–12) of paracetamol was significantly increased by quercetin and chrysin co-administration in SDS and MDS. In non-everted rat gut sac method, the absorption of paracetamol was increased by presence of P-gp inhibitors (verapamil, quinidine and ketoconazole), quercetin and chrysin (50 μg/mL). Our findings suggested that the quercetin and chrysin might be inhibited the P-gp and metabolism of paracetamol; thereby increased the systemic exposure of paracetamol. Further studies are needed to evaluate whether the quercetin or chrysin are involved in the formation of NAPQI by CYP2E1 or not on isolated rat hepatocytes or using cell lines.

Proteomic Analysis in Diabetic Cardiomyopathy using Bioinformatics Approach

Diabetic cardiomyopathy is a distinct clinical entity that produces asymptomatic heart failure in diabetic patients without evidence of coronary artery disease and hypertension. Abnormalities in diabetic cardiomyopathy include: myocardial hypertrophy, impairment of contractile proteins, accumulation of extracellular matrix proteins, formation of advanced glycation end products, and decreased left ventricular compliance. These abnormalities lead to the most common clinical presentation of diabetic cardiomyopathy in the form of diastolic dysfunction. We evaluated the role of various proteins that are likely to be involved in diabetic cardiomyopathy by employing multiple sequence alignment using ClustalW tool and constructed a Phylogenetic tree using functional protein sequences extracted from NCBI. Phylogenetic tree was constructed using Neighbour—Joining Algorithm in bioinformatics approach. These results suggest a causal relationship between altered calcium homeostasis and diabetic cardiomyopathy that implies that efforts directed to normalize calcium homeostasis could form a novel therapeutic approach.

A prospective study of incidence of medication-related problems in general medicine ward of a tertiary care hospital.

The study is aimed to assess the incidence of drug-related problems (DRPs) and provide pharmacist interventions for identified DRPs. A prospective, observational study was conducted among 189 patients with cardiovascular disease who were aged 18 years or older and admitted to the general medicine in-patient ward. During the 6 months study period, the incidence of DRPs was identified using Pharmaceutical Care Network Europe Foundation classification system version 6.2. A total of 189 patients were screened for DRPs. Among them, 130 patients have at least one DRP. A total of 416 DRPs were identified (on average, 2.2 DRPs per each patient). Of the 416 DRPs, 125 (30.04%) interventions were accepted, 7 (1.68%) interventions were not accepted, while remaining (68.26%) accepted but no action taken. The results of the study indicate that incidence of DRPs is substantial and pharmacist-led interventions resulted in resolution of DRPs. This represents the need for the active role of the clinical pharmacist in the developing countries like India.

Biochanin-A attenuates neuropathic pain in diabetic rats

Background Soya supplements are used in the treatment of neuropathic pain. Previous reports reveal that consumption of soy diet before nerve injury prevents the development of neuropathic pain in rats. Biochanin-A, a soy isoflavone, has a naturally occurring inhibitor of fatty acid amide hydrolase (FAAH) that metabolized endocannabinoids. Objective The objective was to evaluate efficacy of biochanin-A in streptozotocin (STZ) induced neuropathic pain in rat model. Materials and methods Diabetes mellitus was induced by an injection of STZ at a dose of 45 mg/kg, i.v. into tail vein of male albino Wistar rats. Biochanin-A was dosed at 0.1, 1 and 5 mg/kg by intraperitoneal (i.p.) administration in diabetic neuropathic rats. Mechanical hyperalgesia and allodynia was measured using Randall–Selitto analgesymeter and manual von Frey filaments of increasing weights respectively. Paw withdrawal threshold (PWT) and percent PWT was determined with respect to both hyperalgesia and allodynia. Results Treatment of biochanin-A at three different levels of 0.1, 1 and 5 mg/kg had not significantly altered serum glucose levels throughout the treatment period. In hyperalgesia study, acute treatment with higher dose exhibited 51.1% reversal of paw withdrawal threshold (PWT) while with chronic treatment, efficacy declined to 22.5% reversal of PWT. In allodynia study, acute treatment reversed PWT by 79.4% while with chronic treatment, efficacy was raised to 88.2% reversal of PWT. Conclusion Biochanin-A demonstrated better efficacy in reversing mechanical allodynia than mechanical hyperalgesia. Biochanin-A could be a good drug candidate for further studies to establish the mechanism of attenuation of neuropathic pain.

Quercetin declines plasma exposure of metoprolol tartrate in the rat model.

The study was undertaken to evaluate the effect of quercetin on the pharmacokinetics of Metoprolol tartrate. A single dose in vivo pharmacokinetic study was carried out in rat models. In this study, rats were treated with quercetin (10 mg/kg) and metoprolol tartrate (20 mg/kg) orally and blood samples were collected 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 h post treatment. Plasma concentration of metoprolol tartrate was estimated using reverse phase-high-performance liquid chromatography method. Area under the plasma concentration-time curve (AUC0-12) of metoprolol has significantly (P < 0.001) decreased by 9.8 times in the metoprolol and quercetin combination group (9434.65 ± 3525.02) when compared with AUC0-12 metoprolol of metoprolol-alone treated group (962.17 ± 242.81). AUC0-∞ of metoprolol has significantly (P < 0.001) decreased by 14.9 times in the combination group (16670.79 ± 12129.06) in comparison to AUC0-∞ of metoprolol of metoprolol-alone treated group (1113.68 ± 441.83). the results obtained herein indicate that quercetin remarkably declines the plasma exposure of metoprolol when concomitantly administered by oral route.

Pingili et al. Rejoinder to: Basu’s “Letter to the Editor”

Dear Sir, As Dr. Saurav commented, a prospective or repeated crosssectional study design would have been more desirable to assess glycemic control (HbA1c) in diabetic patients. We agree to that, but here we have conducted a cross-sectional study on risk factors and prescription adherence. Even though we have taken HbA1c values at the time of interview, all the patients are diabetic for the last few years. We have mentioned the same thing in the section of participant selection (i. e., patients of either sex diagnosed with T2DM of any duration (as per AACE guidelines) and willing to participate were included in the study) and we have excluded newly diagnosed diabetic patients and diabetic patients on anti-diabetic therapy for < 1 year. That indicates they are diabetic for the last several years and their HbA1c levels were checked by the physicians at stipulated time periods. So we requested the physicians to give the data not exceeding 6 months and we observed that most of the prescriptions (80–85%) are adhering to AACE guidelines. In this study, the observed non adherence was 15–20%. As Dr. Saurav commented, glycemic controls in a majority of diabetics are subject to variability with time and religious festivities which may be of considerable duration extending for several days or even weeks which would render older HbA1c reports as non-representative of the current glycemic control. We also agree to that, if we conduct a repeated crosssectional study or a prospective study or a case control study with sufficient number of participants, the non-adherence may reduce further. Our study focused mainly on risk factors and little on prescription adherence. Currently, we focused and working only on prescription adherence to several other standard guidelines in a prospective study along with quality of life and also working on diabetic complications. The study is not completed yet, and we are extending further. Soon we will complete the study. Other researchers also can conduct similar kind of study in other regions of India, and then we can improve the quality of life of our beloved people.

Trigger Tool Based Detection of Adverse Drug Reactions in a Tertiary Care Teaching Hospital: A Prospective Observational Study

Background: The use of “triggers” to identify Adverse Drug reactions (ADRs) is a novel emerging method for measuring the overall level of harm from medications in a health care organization. Our main objective is to determine the incidence of adverse drug reactions in the hospitalized patients and to compare Global Trigger Tool (GTT) with conventional method to identify ADRs. Methodology: A Prospective observational study was conducted over a period of six months during November 2016-April 2017. Modified Global Trigger Tool was used to identify triggers. 16 triggers were used to identify ADRs. Causality assessment of ADRs was done using Naranjo scale and severity and harm categorization of ADRs were assessed using NCC MERP. Results: A total of 244 patient profiles were analyzed. The results reveal that 193 triggers were identified in 125 patients and 93 ADRs were found in 81 patients. Out of which, 64 (68.81%) ADRs were found by triggers and 29(31.18%) ADRs were found spontaneously without the presence of a trigger. There is a remarkable improvement in the identification of ADRs using trigger tool in comparison to traditional approach. Of 93 ADRs identified, 69 (74.19%) were probable and 24 (25.81%) were possible. Similarly, 65 (69.89%) were determined to be NCC-MERP harm category E and 28 (30.11%) were category F. Conclusion: The study results suggest that IHI global trigger tool could be useful to identify ADRs in hospitals twice as more efficiently when compared to traditional ADR identification methods. It is an effective method to enable clinical pharmacists to identify ADRs and management of the same.

Bioinformatics Analysis of Functional Protein Sequences Reveals a Role for Tumor Necrosis Factor-α and Nitric Oxide in Insulin Resistance Syndrome

Using bioinformatics techniques and sequence analyses algorithms, we identified that tumor necrosis factor-α (TNF-α) and nitric oxide (NO) have a significant role in the pathobiology of insulin resistance syndrome, a condition that is common in subjects with abdominal obesity, hypertension, dyslipidemia, atherosclerosis, and coronary heart disease and are accompanied by endothelial dysfunction due to reduced endothelial nitric oxide generation. TNF-α has neurotoxic actions, stimulates inducible NO synthase activity, and modulates the expression of neurotransmitters involved in the control of feeding and thermogenesis. NO is a neurotransmitter and influences secretion and actions of various hypothalamic peptides and neuropeptides. Insulin suppresses the production of TNF-α but stimulates that of endothelial NO. This close interaction between TNF-α, NO, hypothalamic peptides, and insulin suggests that regulation of TNF-α and NO production and action could be critical in the management of insulin resistance syndrome and its associated conditions.