To report three cases of bullous pemphigoid in patients treated with vildagliptin. Case 1: An 86‐year‐old woman presented with bullous pemphigoid after 1 month of treatment with vildagliptin and ...metformin. After introduction of clobetasol, the symptoms resolved although vildagliptin was continued. However, the skin lesions reappeared 3 months later. Sustained remission was achieved only after definitive withdrawal of vildagliptin. Case 2: A 79‐year‐old man presented with bullous pemphigoid after 37‐month treatment with gliclazide, vildagliptin and metformin. The disease at first responded to clobetasol but 3 months later the lesions reappeared. They finally regressed when the gliptin was discontinued. Case 3: A 77‐year‐old woman, treated with gliclazide and vildagliptin for 26 months, presented with bullous pemphigoid, which responded well to discontinuation of the gliptin and topical clobetasol. Gliptins are new molecules for treatment of type 2 diabetes mellitus, which have been suspected of implication in bullous pemphigoid. Such cases have been described in the literature (seven with vildagliptin and three with sitagliptin). In nine of these cases, the gliptin was associated with metformin, but the latter had never been considered responsible. The mechanism implicated in the development of bullous pemphigoid has not yet been clearly identified, but may involve a modified immune response or alteration of the antigenic properties of the epidermal basement membrane. These reports support the risk of bullous pemphigoid in patients exposed to gliptins.
SGLT‐2 inhibitors, also called gliflozins, are a new class of drugs used in type 2 diabetes. Since their marketing, several cases of ketoacidosis, including life‐threatening conditions, were reported ...with their use. The objective of this study was to investigate the disproportionality of pharmacovigilance reports of ketoacidosis between gliflozins and other drugs used for type 2 diabetes. We performed a case–noncase study within the World Health Organization's pharmacovigilance database, VigiBase. We selected all reports of serious adverse drug reaction associated with a glucose‐lowering drug in patients aged 40 years and older, from January 2013 to March 2016. Cases were the reports of ketoacidosis and noncases were all other serious adverse drug reactions reported. We studied the disproportionality of reports of ketoacidosis for gliflozins by calculating reporting odds ratios (ROR) with their 95% confidence interval (95% CI). We also measured the disproportionality before the warnings issued by the US and European medicines agencies. A total of 68 555 notifications were selected. We identified 487 cases of ketoacidosis exposed to gliflozins. Ketoacidosis was significantly more frequently reported with gliflozins than with other glucose‐lowering drugs (adjusted ROR 15.5; 95% CI: 12.8–18.7). The disproportionality of gliflozin reports was also found before the alerts of the medicines agencies. Our study shows a significant and early pharmacovigilance signal which suggests an increased risk of ketoacidosis associated with the use of gliflozins in patients with diabetes. Further studies are needed to confirm this potential risk.
Carbamazepine (CBZ) and oxcarbazepine (OXCBZ) are both antiepileptic drugs, which are prescribed as first-line drugs for the treatment of partial and generalized tonic–clonic epileptic seizures. In ...this paper, a specific and sensitive liquid chromatography–electrospray ionization mass spectrometry method was described for the simultaneous determination of carbamazepine (CBZ), oxcarbazepine (OXCBZ) and eight of their metabolites CBZ-10,11-epoxide (CBZ-EP), 10,11-dihydro-10,11-
trans-dihydroxy-carbamazepine (DiOH-CBZ), 10-hydroxy-10,11-dihydroCBZ (10-OH-CBZ), 2-hydroxycarbamazepine (2-OH-CBZ), 3-hydroxycarbamazepine (3-OH-CBZ), iminostilbene (IM), acridone (AO) and acridine (AI) in human plasma. The work-up procedure involved a simple precipitation with acetone. Separation of the analytes was achieved within 50
min using a Zorbax eclipse XD8 C8 analytical column. The mobile phase consisted of a mixture of acetonitrile–formate buffer (2
mM, pH 3). Detection was performed using a quadrupole mass spectrometer fitted with an electrospray ion source. Mass spectrometric data were acquired in single ion recording mode at
m/
z 237 for CBZ,
m/
z 180 for CBZ-EP and AI,
m/
z 236 for OXCBZ,
m/
z 237 for 10-OH-CBZ,
m/
z 253 for 2-OH-CBZ, 3-OH-CBZ and DiOH-CBZ,
m/
z 196 for AO and
m/
z 194 for IM. For all analytes, the drug/internal standard peak height ratios were linked via a quadratic relationship to plasma concentrations. The extraction recovery averaged 90% for CBZ, 80% for OXCBZ and was 80–105% for the metabolites. The lower limit of quantitation was 0.5
mg/l for CBZ, 0.4
mg/l for OXCBZ and ranged from 0.02 to 0.3
mg/l for the metabolites. Precision ranged from 2 to 13% and accuracy was between 86 and 112%. This method was found suitable for the analysis of plasma samples collected during therapeutic drug monitoring of patients treated with CBZ or OXCBZ.
To determine whether use of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) is associated with increased risk of thyroid cancer.
A nested case-control analysis was performed with use of the ...French national health care insurance system (SNDS) database. Individuals with type 2 diabetes treated with second-line antidiabetes drugs between 2006 and 2018 were included in the cohort. All thyroid cancers were identified through hospital discharge diagnoses and medical procedures between 2014 and 2018. Exposure to GLP-1 RA was measured within the 6 years preceding a 6-month lag-time period and considered as current use and cumulative duration of use based on defined daily dose (≤1, 1 to 3, >3 years). Case subjects were matched with up to 20 control subjects on age, sex, and length of diabetes with the risk-set sampling procedure. Risk of thyroid cancer related to use of GLP-1 RA was estimated with a conditional logistic regression with adjustment for goiter, hypothyroidism, hyperthyroidism, other antidiabetes drugs, and social deprivation index.
A total of 2,562 case subjects with thyroid cancers were included in the study and matched with 45,184 control subjects. Use of GLP-1 RA for 1-3 years was associated with increased risk of all thyroid cancer (adjusted hazard ratio HR 1.58, 95% CI 1.27-1.95) and medullary thyroid cancer (adjusted HR 1.78, 95% CI 1.04-3.05).
In the current study we found increased risk of all thyroid cancer and medullary thyroid cancer with use of GLP-1 RA, in particular after 1-3 years of treatment.
Ulipristal has recently been suspected to be hepatotoxic by the European Medicines Agency but the evidence base for hepatotoxicity is sparse. This is a brief formal report of a patient administered ...ulipristal for 6–8 weeks and who developed acute liver failure leading to liver transplantation. The explanted liver showed extensive hepatocyte necrosis and inflammation compatible with drug-induced liver injury and cirrhosis. The usual causes of acute hepatitis and cirrhosis were eliminated. There were no other potential causative drugs. This case suggests that ulipristal may cause acute hepatitis, with pre-existing cirrhosis probably contributing to the severity of liver injury observed in this case. Ulipristal prescribers must remain vigilant and monitor liver function in their patients.
We took advantage of the partial protection exerted by suitable dosages of nicotinamide against the beta-cytotoxic effect of streptozotocin (STZ) to create a new experimental diabetic syndrome in ...adult rats that appears closer to NIDDM than other available animal models with regard to insulin responsiveness to glucose and sulfonylureas. Among the various dosages of nicotinamide tested in 3-month-old Wistar rats (100-350 mg/kg body wt), the dosage of 230 mg/kg, given intraperitoneally 15 min before STZ administration (65 mg/kg i.v.) yielded a maximum of animals with moderate and stable nonfasting hyperglycemia (155 +/- 3 vs. 121 +/- 3 mg/dl in controls; P < 0.05) and 40% preservation of pancreatic insulin stores. We also evaluated beta-cell function both in vitro and in vivo 4-9 weeks after inducing diabetes. In the isolated perfused pancreas, insulin response to glucose elevation (5-11 mmol/l) was clearly present, although significantly reduced with respect to controls (P < 0.01). Moreover, the insulin response to tolbutamide (0.19 mmol/l) was similar to that observed in normal pancreases. Perfused pancreases from diabetic animals also exhibited a striking hypersensitivity to arginine infusion (7 mmol/l). In rats administered STZ plus nicotinamide, intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness, which were interestingly reversed by tolbutamide administration (40 mg/kg i.v.). In conclusion, this novel NIDDM syndrome with reduced pancreatic insulin stores, which is similar to human NIDDM in that it has a significant response to glucose (although abnormal in kinetics) and preserved sensitivity to tolbutamide, may provide a particularly advantageous tool for pharmacological investigations of new insulinotropic agents.
The use of dipeptidyl-peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues-a group of drugs used in the management of type 2 diabetes mellitus-may be associated with an ...increased risk of bile duct and gallbladder disease. To date, no observational study has assessed this possible association.
To determine whether the use of DPP-4 inhibitors and GLP-1 analogues is associated with an increased risk of incident bile duct and gallbladder disease in patients with type 2 diabetes.
A population-based cohort study linked the United Kingdom Clinical Practice Research Datalink with the Hospital Episodes Statistics database, yielding a cohort of 71 369 patients, 18 years or older, initiating an antidiabetic drug (including oral and injectable agents) between January 1, 2007, and March 31, 2014.
Current use of DPP-4 inhibitors and GLP-1 analogues (alone or in combination therapy) compared with current use of at least 2 oral antidiabetic drugs.
Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of incident bile duct or gallbladder events (cholelithiasis, cholecystitis, cholangitis) causing hospitalization, comparing current use of DPP-4 inhibitors and GLP-1 analogues with current use of at least 2 oral antidiabetic drugs.
During 227 994 person-years of follow-up, 853 of the 71 369 patients were hospitalized for bile duct and gallbladder disease (incidence rate per 1000 person-years, 3.7; 95% CI, 3.5-4.0). Current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (3.6 vs 3.3 per 1000 person-years; adjusted HR, 0.99; 95% CI, 0.75-1.32). In contrast, the use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (6.1 vs 3.3 per 1000 person-years; adjusted HR, 1.79; 95% CI, 1.21-2.67). In a secondary analysis, GLP-1 analogues were also associated with an increased risk of cholecystectomy (adjusted HR, 2.08; 95% CI, 1.08-4.02).
The use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease. Physicians should be aware of this potential adverse event when prescribing these drugs.
Summary
Objective To improve the definition of the various clinical patterns of patients with drug‐induced cutaneous side‐effects with systemic symptoms, and their possible relationships with the ...triggering medication, with the ultimate goal of helping in the identification of the causal drug in difficult situations when the patient is taking several drugs.
Methods Cases of drug‐induced cutaneous side‐effects associated with various systemic syndromes related to anticonvulsants (carbamazepine, phenytoin and phenobarbitone), minocycline, allopurinol, abacavir and nevirapine were collected retrospectively from the French Pharmacovigilance database (FPD) over a period of 15 years (1985–2000). The clinical patterns typical of the causative drugs were described and compared with data from the literature.
Results Two hundred and sixteen patients with symptoms and signs consistent with cutaneous drug reactions with systemic symptoms were reported to the FPD during this period of time. Their pattern was similar to published data for these drugs, with fever, cutaneous eruption, hepatic abnormalities and eosinophilia being the most prominent but inconstant symptoms. There are clues suggesting that some particular lesional patterns may exist for some drugs.
Conclusions Although some trends emerge from these retrospective data, they suggest that no clear, unified outline can currently be defined for these multi‐organ drug‐induced reactions. Instead, a constellation of various symptoms and signs were recorded, that might be sorted in different patterns according to the causal drug, a finding that might indeed improve accurate identification of the causative drug in patients receiving several principal medications at a time. A national prospective study systematically collecting standardized data is required better to define the outlines of these severe adverse drug reactions and to evaluate prognostic data.
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