Background GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). Scope of review To summarize current knowledge about GLP-1 receptor agonist. Major conclusions At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art.

Eosinophil cationic protein: Is it useful in asthma? A systematic review☆

Public Health Impact of Pesticides Used in Agriculture.

Eosinophils. A Comprehensive Review and Guide to the Scientific and Medical Literature

Background Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. Objectives To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). Search methods We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. Selection criteria We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms. We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. Data collection and analysis We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. Main results We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias. Ivermectin doses and treatment duration varied among included studies. We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. Authors' conclusions Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.

Ivermectin for preventing and treating COVID-19

Background and objective Increased neutrophil lymphocyte ratio (NLR) is a marker as well as predictor of various cardiac and non cardiac disorders. Our aim was to assess the relationship between NLR and different level of glycemic control in type 2 diabetic patients. Methods An observational study was conducted at diabetic clinic of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan from September 2016 to February 2017 in which 330 type 2 diabetic patients were randomly divided in to three groups based upon diabetes control according to ADA criteria. Patients in group A with HbA1c ≤ 7% (excellent control), group B HbA1c 7.0-9.0 % (poor control) and group C HbA1c ≥ 9 %(worst control). Patients were assessed in terms of complete blood count and C - reactive protein. Results As compared to excellent control (Group A) patients with worst control (Group C)showed a high leukocyte count (p.001), high neutrophil count (P.003) and lower lymphocyte count (P 0.44) while patients in poor control (Group B)did not differ significantly. Similarly value of NLR was also significantly higher in worst control (Group C) as compared to poor control(Group B) and excellent control (Group A) diabetes (4.3±2.8, 2.7±1.0 and2.0±0.5(p.001). NLR were found independent predictor of worst diabetes control (OR: 1.809, 95% CI: 1.459-2.401) along with fasting blood sugar (OR: 0.938, 95% CI: 0.995-0.982) and CRP (OR: 1.020, 95% CI: 1.003-1.028). Conclusion Increased NLR level is associated with elevated HbA1c and poor glycemic control in patients of type 2 diabetes mellitus. It can be used as a disease monitoring tool during the follow up of diabetic patients.

Neutrophil lymphocyte ratio (NLR): A well assessment tool of glycemic control in type 2 diabetic patients.

Background and objective NAFLD affecting up to 30% of the population globally. Drug treatment options are limited with disappointing results. The dietary supplementation in the form of green tea is another option. Our objective was toinvestigate the effect of Green tea extract (GTE) supplementation on various parameters innon-alcoholicfatty liver disease (NAFLD) patients. Methods This study was conducted Dept. of Medicineof Sheikh Zayed Medical College/Hospital, Rahim Yar Khan from 15 April 2016 to 15 July 2016. Eighty overweight, non diabeticand dyslipidemic patients of NAFLD, diagnosed on the basis of ultrasound and aminotransferases level were randomized for treatmentwith capsule GTE500mg (n=40)and capsule placebo (n=40) twice a day for twelve weeks. Anthropometric parameters, liver enzymes, inflammatory markers and liver ultrasound imaging were estimated by SPSS-16 pre and post treatment. Results As compared to placebo, GTE caused a significant improvement in body weight (29.5±3.8 to 27.2±3.2 kg/m2 p=0.03), BMI (86±10.5 to 80±12.4 kg p=0.026), HOMA-IR(4.32±2.25 to 3.16± 1.6 p=0.0081) lipid profile (i.e. TC: L242.5±20.5 to 215.4±18.6 mg/dl p=0.005; TG: 175±22.6 to145±18 mg/dlp=0.003; LDL-C:155±12.5 to 140±16.7 mg/dl p=0.011; HDL-C: 36.8±6.7 to46.4±5.8 mg/dl p =0.001, Aminotransferases (i.e. ALT: 70.4±15.8to52.8±12.2 IU/L p=0.04; AST: 65.8±12.4 to 44.3± 8.5U/L p =0.002) and Inflammatory markers (hs-CRP: 3.14±0.58 to 2.18±0.32 p =0.023 Adiponectin: 8.46±1.02 to 10.55±3.42μg/ml p =0.003)GTE also caused a 67.5% regression of fatty liver changes on ultrasound as compared to placebo which is 25%only. Conclusion GTEtherapy resulted in significant improvement in metabolic, chemical, inflammatory and radiological parameters of non-alcoholic fatty liver disease patients who were non-diabetic anddyslipidemic.

Therapeutic benefits of green tea extract on various parameters in non-alcoholic fatty liver disease patients.

Background: Non-alcoholic Fatty Liver disease (NAFLD) is the most common cause of progressive liver disorders worldwide. Drug options are limited with varying results. Nigella sativa in the form of herbal medicine could be another option because of its strong historical background. The objective of the study was to evaluate the effect Nigella sativa on various parameters in patients of NAFLD. Methods: A randomized controlled trial was conducted at outpatient clinic of medical unit-1 of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan, in which seventy patients of NAFLD were divided in to interventional and non-interventional groups. The interventional group was given cap Nigella sativa 1g twice a day while non-interventional group was given cap placebo in a same way for three months. Body weight, BMI, liver enzymes and ultrasound finding of fatty liver were assayed before and after treatment. Results: After 12 weeks treatment with Nigella sativa body weight decreased significantly from 86±13.8 to76±12.6 kg vs placebo ( p =0.041). BMI also reduced significantly from 29.06±4.6 to 26.25±6.2kg/m 2 vs placebo( p =0.012). There is remarkable reduction in aminotransferases level after treatment with Nigella sativa vs placebo (ALT: 78.05±5.52 to 52.6±5.65 IU/L vs 76.48±4.95–74.32±5.58 IU/L ( p =0.036). AST: 65.54±4.56–44.56±5.52 IU/L vs 63.25±5.43–59.43±3.39 IU/L ( p =0.021). There was overall 57.14 % patient had normal fatty liver grading on ultrasound after 12 weeks treatment with Nigella sativa as compared to placebo ( p =0.002). Conclusion: Nigella sativa improves bio chemical and fatty liver changes in NAFLD patients. Its use in early stages of NAFLD is recommended in order to prevent its life-threatening complication. Keywords: NAFLD; Nigella sativa ; Body weight; ALT; AST; Fatty liver grading

Effects of nigella sativa on various parameters in Patients of non-alcoholic fatty liver disease.

Background: Peripheral neuropathic pain is a devastating complication intype 2 diabetic patients with significant morbidity and mortality. Objectives: To investigate theeffect of oral vitamin D supplementation on symptoms of peripheral neuropathic pain in type 2diabetic patients. Study Design: Prospective randomized placebo controlled trial. Setting:Diabetic Clinic of Sheikh Zayed Medical College/Hospital Rahim Yar Khan. Period: Overa period of 6 months from Jan-July 2017. Methods: 116 vitamin D deficient type 2 diabeticpatients with symptoms of peripheral neuropathic pain were divided in to two groups toprescribed either oral vitamin D3 capsule 50000IU weekly or Placebo capsule for a periodof 12 weeks. Symptoms of diabetic neuropathic pain were assessed by neuropathysymptoms score (NSS) and neuropathy disability score (NDS) while Vitamin D status wasestimated by measuring the serum total 25(OH) D concentration. The primary end pointwas changes in NSS and NDS while secondary end point was changes in HbA1C and 25(OH) D concentrations from baseline. Results: After 12 weeks of vitamin D therapy, vitaminD improved its own level in interventional group (28.5±12.5 to 48.2±15.6) vs placebo group(30.6±16.2 to31.5±12.6) with p-value (0.001). This rise was accompanied by improvementin HbAIc (8.2±1.8 to 7.5±2.2) vs Placebo (7.8±1.5 to 8.0±1.8) with p-value (0.004) and NSSscore (6.02±1.5 to 4.52±0.8) vs placebo (5.82 ±1.8 to 5.65±1.5) with p-value (0.002). Howeverno significant changes were seen in NDS in both study groups. Conclusion: Oral vitamin D3therapy has positive impact on its own status as well as symptoms of peripheral neuropathicpain in type 2 diabetic patients.

Type 2 diabetic patients

OBJECTIVE To determine the effect of Vildagliptin in non-alcoholic, fatty liver disease patients with dyslipidemia. METHODS A randomized placebo controlled trial was conducted at outpatient clinic of Medical Unit-I of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan, in which fifty eight patients of NAFLD with dyslipidemia were divided in to two, case and control groups. The case group was given tablet Vildagliptin 50mg twice a day for twelve weeks and control group was given placebo in same way. Body weight, body mass index (BMI), lipid profile, liver enzymes and ultrasound finding of fatty liver were assayed before and after treatment. RESULTS After 12 weeks treatment of vildagliptin there was significant improvement in following parameters. Body weight and BMI decreased significantly from 88 ± 11 to79 ± 12 kg (p0.036) and 30±4to 27±5 kg/m2 (p 0.005) respectively. Notable reduction in the value of TC, TG and LDL-C (TC:252±24 to 220±20mg/dl (p 0.031); TG: 190±24 to115±22 mg/dl (p 0.005); LDL-C 160±15 to 145±13mg/dl (p 0.004). HDL-C level increased significantly from 29±5to45±4 mg/dl (p 0.001). There was remarkable reduction in aminotransferases level (ALT: 78± 17 to 48±14IU/L (p 0.036). AST: 63.3±13 to41±11IU/L (p 0.002). There was overall 65.5% improvement in fatty liver grading on ultrasound with vildagliptin while non significant effects were seen in placebo group in all of the above parameters. CONCLUSION Vildagliptin exhibited beneficial effects in non-alcoholic fatty liver disease, Non-diabetic patients with dyslipidemia.

Mazhar Hussain

Papers

Neutrophil lymphocyte ratio (NLR): A well assessment tool of glycemic control in type 2 diabetic patients.

Therapeutic benefits of green tea extract on various parameters in non-alcoholic fatty liver disease patients.

Effects of nigella sativa on various parameters in Patients of non-alcoholic fatty liver disease.

Type 2 diabetic patients

Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease.