Glucagon-like peptide-1 analogues and thyroid cancer: An analysis of cases reported in the European pharmacovigilance database.

WHAT IS KNOWN AND OBJECTIVE: The use of glucagon-like peptide-1 (GLP-1) analogues has been linked to the risk of thyroid cancer. Spontaneous reports can provide information about rare adverse events occurring after the time of marketing. Our objective was to detect, from the European pharmacovigilance database (EudraVigilance), a signal of thyroid cancer during GLP-1 analogues treatment in patients with diabetes. METHODS: Herein, we analysed all reports of thyroid cancer reported with GLP-1 analogues in EudraVigilance database from their first marketing authorization till 30 January 2020. A case/non-case method was used to assess the association between thyroid cancer and GLP-1 analogues, calculating proportional reporting ratios (PRRs) and their 95% confidence interval (CI) as a measure of disproportionality. The cases were identified with Medical Dictionary for Regulatory Activities (MedDRA) version 22.1. RESULTS AND DISCUSSION: There were 11 243 cases of thyroid cancer and related preferred terms (PTs) in the 6 665 794 reports recorded in EudraVigilance during the study period. GLP-1 analogues were involved in 236 cases. Exenatide, liraglutide and dulaglutide met the criteria to generate a safety signal, suggesting that thyroid cancer is reported relatively more frequently in association with these drugs than with other medicinal products. The association was strongest for liraglutide followed by exenatide with PRR of 27.5 (95% CI, 22.7-33.3) and 22.5 (95% CI, 17.9-28.3), respectively. Disproportionality was also observed for GLP-1 analogues and individual identified preferred term, that is thyroid cancer (N = 111), medullary thyroid cancer (N = 64) and thyroid neoplasm (N = 46) with PRR of 14.4 (95% CI, 11.8-17.4), 221.5 (95% CI, 155.7-315.1) and 35.5 (95% CI, 25.9-48.5), respectively. WHAT IS NEW AND CONCLUSIONS: Our findings showed disproportionality for thyroid cancer, medullary thyroid cancer and thyroid neoplasm in patients treated with GLP-1 analogues. We have found evidence from spontaneous reports that GLP-1 analogues are associated with thyroid cancer in patients with diabetes.

Using focused pharmacovigilance for ensuring patient safety against antileishmanial drugs in Bangladesh's National Kala-azar Elimination Programme.

BACKGROUND: Adverse effects of antileishmanial drugs can affect patients' quality of life and adherence to therapy for visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). In Bangladesh, there are 26 treatment centers that manage leishmaniasis cases coming from 100 endemic upazilas (subdistricts) of 26 districts (these include VL, PKDL, treatment failure, and relapse VL and cutaneous leishmaniasis cases). This study aimed to investigate the feasibility of using focused pharmacovigilance for VL (VLPV) in Bangladesh's National Kala-azar Elimination Programme for the early detection and prevention of expected and unexpected adverse drug reactions (ADRs). METHODS: This activity has been going on since December 2014. Activity area includes secondary public hospital or Upazila health complex (UHC) in hundred sub districts and Surya Kanta Kala-azar Research Center (SKKRC) in Mymensingh District, a specialized center for management of complicated VL and PKDL cases. Communicable Disease Control (CDC) of the Directorate General of Health Services (DGHS) assigned twenty five of hundred UHCs and SKKRC (total 26) as treatment centers depending on their suitable geographical location. This was implemented for better management of VL cases with Liposomal Amphotericin B (AmBisome®) to ensure patient convenience and proper utilization of this expensive donated drug. A VLPV expert committee and a UHC VLPV team were established, an operational manual and pharmacovigilance report forms were developed, training and refresher training of health personnel took place at UHCs and at the central level, collected information such as patient data including demographics, treatment history and response, adverse events were analyzed. This report includes information for the period from December 2014 to December 2016. RESULTS: From December 2014 to December 2016, 1327 leishmaniasis patients were treated and 1066 (80%) were available for VLPV. Out of these, 57, 33, 9, and 1% were new VL, PKDL, VL relapse, and other cases, respectively. Liposomal amphotericin B was mostly used (82%) for case management, followed by miltefosine (20%) and paromomycin (3%). Out of the 1066 patients, 26% experienced ADRs. The most frequent ADR was fever (17%, 176/1066), followed by vomiting (5%, 51/1066). Thirteen serious adverse events (SAEs) (eight deaths and five unexpected SAEs) were observed. The expert committee assessed that three of the deaths and all unexpected SAEs were possibly related to treatment. Out of the five unexpected SAEs, four were miltefosine-induced ophthalmic complications and the other was an AmBisome®-induced avascular necrosis of the nasal alae. The Directorate General of the Drug Administration entered the ADRs into the World Health Organization Uppsala Monitoring Centre (WHO-UMC) VigiFlow database. CONCLUSIONS: This study found that VLPV through NKEP is feasible and should be continued as a routine activity into the public health system of Bangladesh to ensure patient safety against anti-leishmanial drugs.

Changing Epidemiology: A New Focus of Kala-azar at High-Altitude Garhwal Region of North India.

Adult cases of visceral leishmaniasis (VL), predominantly males, have been reported in the past decade from natives of high altitude areas of North Indian state of Uttarakhand. We report 14 pediatric cases of VL, who were diagnosed and treated successfully over the past 7 years. All these children were born and brought up in this area and had never visited any of the endemic areas. High prevalence of pallor, splenohepatomegaly, thrombocytopenia and poor association with HIV are cardinal features of VL in this region. Although newer drugs have become available, the protozoan continues to be sensitive to sodium stibogluconate. We conclude that the transmission cycle of VL has been established in this region and VL should be considered in the differential diagnosis of any child presenting with fever and hepatosplenomegaly. However, molecular and epidemiological studies are needed to identify the ancestry, vector and animal reservoir if any in this region.

Seroprevalence and risk factors of hepatitis B and hepatitis C virus infections in uttarakhand, India.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are a serious global public health problem affecting billions of people. A population based serological survey was conducted in Uttarakhand, India to determine the prevalence and risk factors of HBV and HCV infections. METHODS: A cross-sectional study was conducted to achieve the primary objective of estimating the prevalence of HBsAg and anti-HCV seropositivity and to estimate the potential risk factors. RESULTS: A total of 495 volunteers completed the study questionnaire and underwent blood tests for HBsAg and anti-HCV serology. Of these, 339 (68.5%) were males and 156 (31.5%) were females. The mean age of the volunteers was 31 ± 4 years. The overall infection rate was 4.4% (n = 22) in the studied population. The seroprevalence of HBsAg was found to be 2.8% (n = 14) and of anti-HCV antibodies 1.8% (n = 9), whereas dual infection i.e. HBV and HCV infection was seen in 0.2% (n = 1). The overall analysis of risk factors of our data showed that persons who have received multiple blood transfusions, history of hepatitis among family members, visits to unregistered medical practitioners and uneducated people are at more risk for acquiring hepatitis B and hepatitis C infection. CONCLUSIONS: The results indicate an intermediate level of endemicity of HBV and HCV infection in this geographical area of Uttarakhand. Some independent risk factors like blood transfusion, intra familial transmission, and visit to unregistered practitioners were identified.

Training in Post-authorization Pharmacovigilance.

Post-authorization pharmacovigilance refers to all the activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems, from the time a product gets the authorization to be marketed in a territory. The ultimate objective of pharmacovigilance is patient safety. To ensure this, any responsible pharmaceutical company will readily vouch for the importance of all these activities, each requiring specific training for efficient and effective execution. Having a well planned job specific training curriculum can help the organization realize its goals and objectives by covering the gaps between current and desired job performance levels and existing competencies of its employees. Apart from this, trainings can help in problem solving, increasing productivity and prepare for and respond to future changes in the organization or job duties. As the pharmaceutical business continues to grow, increasing numbers of skilled people are required to manage resultant increase in pharmacovigilance activities to remain compliant. Thus, the need for training qualified resources to develop into highly skilled pharmacovigilance professionals is the need of the hour. Currently, the supply-demand situation for skilled manpower is highly skewed in favor of the demand, as this field is relatively new in India and elsewhere. It is interesting to note that not many resources, be it internet, literature or books, are available specifically addressing the need of the industry to guide them on training requirements to set up and maintain a competent pharmacovigilance department. This article aims to present a comprehensive perspective on the trainings required in the post authorization scenario pertaining to pharmacovigilance activities and suggest ways to manage these in an efficient way so as to be compliant with the global norms and best practices.

Retained forceps: an unusual cause of intestinal obstruction.

Medical errors during surgery are usually under-reported and not well studied. During the past decade, increased interest in medical malpractice has been shown by both the public and the authorities. A particularly high risk of medical errors is seen in emergency settings, unexpected change in procedure, or in patients with a high body mass index. Visually or acoustically controlled monitoring before wound closure are recommended to eliminate human error as thoroughly as possible. Prevention remains the key to solving the problem.

The impact of HIV/AIDS on the quality of life: a cross sectional study in north India.

OBJECTIVE: To determine the impact of Human Deficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) on the quality of life (QOL) on such patients in North India. DESIGN: A cross sectional study. SETTING: Outpatient setting and wards, Department of Medicine at a premier tertiary health care center, North India. PARTICIPANTS: Sixty-eight consecutive HIV/AIDS patients attending Medicine out patient department and/or admitted to the wards of All India Institute of Medical Sciences were administered a structured questionnaire by the HIV nurse coordinator. QOL was evaluated using the WHOQOL-Bref (Hindi) instrument. ANALYSIS: One way Analysis of Variance (ANOVA) was performed to find out significant difference between the clinical categories and socio-demographic variables on QOL domains. RESULTS: The overall QOL mean score on a scale of 0-100 was found to be 25.8. Similarly, on the scale of 0-100 the mean scores in the four domains of QOL in descending order were social (80.9); psychological (27.5); physical (17.7) and environmental domain (11.65). There was a significant difference of quality of life in the physical domain between asymptomatic patients (14.6) and patients with AIDS (10.43) defining illnesses (p< 0.001) and asymptomatic and early symptomatic (12) patients (p=0.014). QOL in the psychological domain was significantly poorer in early symptomatic (12.1) (p< 0.05) and AIDS patients (12.4) (p< 0.006) as compared to asymptomatic individuals (14.2). A significant difference in QOL scores in the psychological domain was observed with respect to the educational status (p< 0.037) and income of patients (p< 0.048). Significantly better QOL scores in the physical (p< 0.040) and environmental domain (p< 0.017) were present with respect to the occupation of the patients. Patients with family support had better QOL scores in environmental domain. CONCLUSIONS: In our study, QOL is associated with education, income, occupation, family support and clinical categories of the patients.

Structure-based design of a novel peptide inhibitor of HIV-1 integrase: a computer modeling approach.

The insertion of viral DNA into the host chromosome is an essential step in the replication of HIV-1, and is carried out by an enzyme, HIV-1 integrase (IN). Since the latter has no human cellular counterpart, it is an attractive target for antiviral drug design. Several IN inhibitors having activities in the micromolar range have been reported to date. However, no clinically useful inhibitors have yet been developed. Recently reported diketo acids represent a novel and selective class of IN inhibitors. These are the only class which appear to selectively target integrase and two of the inhibitors, L-708,906 and L-731,988, are the most potent inhibitors of preintegration complexes described to date. The X-ray crystal structure of the IN catalytic domain complexed with a diketo acid derivative inhibitor, 5CITEP, has recently been determined. Although the structure is of great value as a platform for drug design, experimental data suggest that crystal packing effects influence the observed inhibitor position. This has been confirmed by computational docking studies using the latest version (3.0) of the AutoDock program, which has been shown to give results largely consistent with available experimental data. Using AutoDock 3.0 and SYBYL6.6 we have modeled the complexes of IN with the diketo acid inhibitors so as to identify the enzyme binding site. In the quest for novel, potent and selective small molecule inhibitors, we present here a new approach to peptide inhibitor design using a, b- unsaturated (dehydro) residues, which confer a unique conformation on a peptide sequence. Based on the above models, we selected a tetrapeptide sequence containing a dehydro-Phe residue, which was found to have an open conformation as ascertained from its X-ray crystal structure. Docking results on this peptide led us to propose a modification at the C-terminal end. The modified peptide was found to dock in a similar position as the diketo acid inhibitors and was predicted to have a comparable potency.