Developmental delay, Epilepsy and Neonatal Diabetes (DEND) syndrome is the most severe form of Permanent Neonatal Diabetes with KCNJ11 gene mutation which accounts for most of the cases. We report the first DEND syndrome in Malaysia with heterozygous missense mutation Q52R at KCNJ11 (Kir6.2) gene with delayed presentation beyond 6 months of age and failure to transition to glibenclamide. This report signifies the phenotypical variability among patients with the same genetic mutation and the different response to treatment.
Glyburide

Background and Objective: Type 2 (T2DM) and gestational diabetes mellitus (GDM) among pregnant Filipinos have been increasing over the years because of lifestyle westernization. While insulin has been the safe mainstay when dietary measures fail to maintain normoglycemia during pregnancy, recent studies have suggested oral hypoglycemic agents (OHAs) such as metformin and glibenclamide, may offer cheaper and efficacious alternatives. The problem however, is the passage of these drugs through the placenta which may pose possible danger towards the development of the growing embryo. The proposed study aims to evaluate and compare the embryotoxic and teratogenic potentials of the varying concentrations of the two PhilHealth covered oral hypoglycemic agents in the Philippines, namely metformin (biguanide) and glibenclamide (sulfonylureas). Methodology: In this study, a comparison on embryotoxic potentials of metformin and glibenclamide was conducted using zebrafish embryotoxicity test (ZFET) across concentrations found in fetal (10, 20, 100, 500, 1000, 2000 μg/L) and maternal serum (10, 20, 100, 500, 1000, 2000 mg/L). Results and Conclusions Results revealed that metformin showed no significant (p>0.05) lethal effects, but revealed significant risk for teratogenicity, specifically decreased head and tail lengths and advanced hatching. Conversely, glibenclamide revealed significant potential for lethal (e.g., coagulation) and teratogenic effects including pericardial and yolk sac edema, spinal deformity and increased tail length. Comparative evaluation between the two OHAs reveal that glibenclamide has significantly (p<0.05) higher lethal and teratogenic effects. Together, our results suggest that the use of metformin over glibenclamide is favorable for safety testing in pregnant women suffering T2DM and GDM for the benefit of expanding treatment options for these diseases.
Glyburide ; Metformin ; Teratogenesis ; Zebrafish

PURPOSE: To determine the relationship of illnesses and medical drug consumption with the occurrence of traffic accidents among truck and bus drivers. METHODS: This is a cross-sectional study on truck and bus drivers in Tehran, Iran. The criteria for participating in this study were: married males over 30 years old, driving license in grade one, five years of job experience, mental health and non-addiction license. The criterion for not participating in this study was the lack of cooperation in responding to the questions. Six months was spent to collect the latest five years data of driving accidents from 2011 to 2016. A total of 323 truck and bus drivers in Tehran city and the suburbs, Iran were chosen. Among them, 112 were responsible for accidents (accident group) while 211 were not responsible for any accidents or involved in an accident in the last five years (non-accident group). A specially designed questionnaire was used to investigate the demographic information, medical drug consumption, medical backgrounds and history of accidents. RESULTS: The results revealed that compared with healthy subjects, the occurrence of accidents among people with diabetes (OR = 2.3, p = 0.001) and vision weakness (OR = 1.7, p = 0.020) was significantly higher, while that among people with cardiac (OR = 0.5, p = 0.002) and hypertension (OR = 0.9, p = 0.048) problems was remarkably lower. Moreover, consumption of Gemfibrozil (OR = 1.8, p = 0.010) and Glibenclamide (OR = 2.2, p = 0.002) drugs resulted in significantly higher incidence of accidents than those without. CONCLUSION Frequencies of illnesses like cardiovascular and hypertension were not higher in accident drivers than in non-accident drivers; but diabetes, vision weakness and consumption of Gemfibrozil and Glibenclamide lead to more traffic accidents.
Accidents, Traffic ; statistics & numerical data ; Adult ; Automobile Driving ; statistics & numerical data ; Cross-Sectional Studies ; Diabetes Mellitus ; epidemiology ; Drug Utilization ; statistics & numerical data ; Gemfibrozil ; administration & dosage ; Glyburide ; administration & dosage ; Humans ; Hypolipidemic Agents ; administration & dosage ; Incidence ; Iran ; epidemiology ; Male ; Middle Aged ; Surveys and Questionnaires ; Vision Disorders ; epidemiology

BACKGROUND: The use of aroma oils dates back to at least 3000 B.C., where it was applied to mummify corpses and treat the wounds of soldiers. Since the 1920s, the term “aromatherapy” has been used for fragrance therapy with essential oils. The purpose of this study was to determine whether the essential oil of Eucalyptus (EOE) affects pain pathways in various pain conditions and motor coordination. METHODS: Mice were subjected to inhalation or intraperitoneal injection of EOE, and its analgesic effects were assessed by conducting formalin, thermal plantar, and acetic acid tests; the effects of EOE on motor coordination were evaluated using a rotarod test. To determine the analgesic mechanism, 5′-guanidinonaltrindole (κ-opioid antagonist, 0.3 mg/kg), naltrindole (δ-opioid antagonist, 5 mg/kg), glibenclamide (δ-opioid antagonist, 2 mg/kg), and naloxone (μ-opioid antagonist, 4, 8, 12 mg/kg) were injected intraperitoneally. RESULTS: EOE showed an analgesic effect against visceral pain caused by acetic acid (EOE, 45 mg/kg); however, no analgesic effect was observed against thermal nociceptive pain. Moreover, it was demonstrated that EOE did not have an effect on motor coordination. In addition, an anti-inflammatory effect was observed during the formalin test. CONCLUSIONS: EOE, which is associated with the μ-opioid pain pathway, showed potential effects against somatic, inflammatory, and visceral pain and could be a potential therapeutic agent for pain.
Acetic Acid ; Analgesics ; Animals ; Aromatherapy ; Cadaver ; Eucalyptus ; Formaldehyde ; Glyburide ; Humans ; Inhalation ; Injections, Intraperitoneal ; Mice ; Military Personnel ; Naloxone ; Narcotic Antagonists ; Nociceptive Pain ; Oils ; Oils, Volatile ; Pain Measurement ; Rotarod Performance Test ; Visceral Pain ; Wounds and Injuries

BACKGROUND: Previous studies have noted that the simultaneous use of sulfonylureas and antimicrobials, which is common, could increase the risk of hypoglycemia. In particular, an age of 65 years or older is a known risk factor for sulfonylurea-related hypoglycemia in hospitalized patients. Therefore, we performed this study to determine the potential risk of hypoglycemia from the concurrent use of antimicrobials and sulfonylureas. METHODS: We performed a cross-sectional study on the National Health Insurance Service-National Sample Cohort from 2013. The eligibility criteria included patients of 65 years of age or older taking a sulfonylurea with 25 different antimicrobials. Different risk ratings of severity in drug-drug interactions (potential DDIs), level X, D, or C in Lexi-Interact™online, and contraindicated, major, or moderate severity level in Micromedex® were included. SAS version 9.4 was used for data analysis. RESULTS: A total of 6,006 elderly patients with 25,613 prescriptions were included. The largest age group was 70 to 74 (32.7%), and 39.7% of patients were men. The mean number of prescriptions was 4.3 per patient. The most frequently used antimicrobials were levofloxacin (6,583, 25.7%), ofloxacin (6,549, 25.6%), fluconazole (4,678, 18.0%), and ciprofloxacin (2,551, 9.8%). Among sulfonylureas, glimepiride was prescribed most frequently, followed by gliclazide, glibenclamide, and glipizide. CONCLUSION: Of the antimicrobials with a high potential of hypoglycemia, levofloxacin, ofloxacin, fluconazole, and ciprofloxacin were used frequently. Thus, the monitoring of clinically relevant interactions is required for patients concurrently administered sulfonylureas and antimicrobials.
Aged* ; Anti-Infective Agents ; Ciprofloxacin ; Cohort Studies ; Cross-Sectional Studies ; Drug Interactions ; Fluconazole ; Gliclazide ; Glipizide ; Glyburide ; Humans ; Hypoglycemia* ; Korea* ; Levofloxacin ; Male ; National Health Programs ; Ofloxacin ; Prescriptions ; Risk Factors ; Statistics as Topic ; Sulfonylurea Compounds

PURPOSE: We studied the effects of alcohol administration on the corpus cavernosum (CC) using an animal model. MATERIALS AND METHODS: CC sections and the aortic ring of rabbits were used in an organ bath study. After acute alcohol administration, changes in blood alcohol concentration and electrical stimulation induced intracavernosal pressure/mean arterial pressure (ICP/MAP) percentage were compared in rats. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in the CC were measured using immunoassays. After chronic alcohol administration, ICP/MAP percentage, cAMP and cGMP were compared in rats. Histological changes were examined using the Masson trichrome stain and the Sircol collagen assay. Endothelial nitric oxide synthase (eNOS) expression was examined using immunohistochemistry and Western blotting. RESULTS: Alcohol relaxed the CC in a dose-dependent manner, and the relaxation response was suppressed when pretreated with propranolol, indomethacin, glibenclamide, and 4-aminopyridine. In rats with acute alcohol exposure, the cAMP level in the CC was significantly greater than was observed in the control group (p<0.05). In rats with chronic alcohol exposure, however, changes in cAMP and cGMP levels were insignificant, and the CC showed markedly smaller areas of smooth muscle, greater amounts of dense collagen (p<0.05). Immunohistochemical analysis of eNOS showed a less intense response, and western blotting showed that eNOS expression was significantly lower in this group (p<0.05). CONCLUSIONS: Acute alcohol administration activated the cAMP pathway with positive effects on erectile function. In contrast, chronic alcohol administration changed the ultrastructures of the CC and suppressed eNOS expression, thereby leading to erectile dysfunction.
4-Aminopyridine ; Adenosine Monophosphate ; Animals ; Arterial Pressure ; Baths ; Blood Alcohol Content ; Blotting, Western ; Collagen ; Cyclic AMP ; Electric Stimulation ; Erectile Dysfunction ; Glyburide ; Guanosine Monophosphate ; Immunoassay ; Immunohistochemistry ; Indomethacin ; Male ; Models, Animal ; Muscle, Smooth ; Nitric Oxide Synthase Type III ; Penile Erection ; Propranolol ; Rabbits ; Rats ; Relaxation

The vascular actions and mechanisms of taurine were investigated in the isolated human radial artery (RA). RA rings were suspended in isolated organ baths and tension was recorded isometrically. First, a precontraction was achieved by adding potassium chloride (KCl, 45 mM) or serotonin (5-hydroxytryptamine, 5-HT, 30 µM) to organ baths. When the precontractions were stable, taurine (20, 40, 80 mM) was added cumulatively. Antagonistic effect of taurine on calcium chloride (10 µM to 10 mM)-induced contractions was investigated. Taurine-induced relaxations were also tested in the presence of the K⁺ channel inhibitors tetraethylammonium (1 mM), glibenclamide (10 µM) and 4-aminopyridine (1 mM). Taurine did not affect the basal tone but inhibited the contraction induced by 5-HT and KCl. Calcium chloride-induced contractions were significantly inhibited in the presence of taurine (20, 40, 80 mM) (p<0.05). The relaxation to taurine was inhibited by tetraethylammonium (p<0.05). However, glibenclamide and 4-aminopyridine did not affect taurine-induced relaxations. Present experiments show that taurine inhibits 5-HT and KCl-induced contractions in RA, and suggest that large conductance Ca²⁺-activated K⁺ channels may be involved in taurine-induced relaxation of RA.
4-Aminopyridine ; Baths ; Calcium ; Calcium Chloride ; Glyburide ; Humans* ; Potassium Channels* ; Potassium Chloride ; Potassium* ; Radial Artery* ; Relaxation ; Serotonin ; Taurine* ; Tetraethylammonium ; Vasodilation

Use of oral hypoglycemic agents during pregnant women with type 2 diabetes is controversial due to safety issues. Recently, randomized controlled trials support short-term safety of glyburide and metformin for the treatment of gestational diabetes mellitus. However, long-term safety data are not available. Moreover, use of oral hypoglycemic agents, except for metformin and glyburide, during pregnancy were limited to a few case reports. We report the case of a pregnant woman with type 2 diabetes unintentionally exposed to metformin and voglibose in addition to lercanidipine and bisoprolol during fetal organogenesis. The patient was continuously exposed to oral agents because we were not aware of her pregnancy until 22 weeks of gestation. After pregnancy was confirmed, we replaced oral hypoglycemic agents with insulin and discontinue betablockers. Delivery occurred without maternal or fetal complications.
Bisoprolol ; Diabetes, Gestational ; Female ; Glyburide ; Humans ; Hypoglycemic Agents ; Insulin ; Metformin* ; Organogenesis ; Pregnancy ; Pregnancy Trimester, Second* ; Pregnancy* ; Pregnant Women*

Allergic reaction to insulin is uncommon since the introduction of human recombinant insulin preparations and is more rare in pregnant than non-pregnant females due to altered immune reaction during pregnancy. Herein, we report two cases of allergic reaction to insulin in gestational diabetes that were successfully managed. One case was a 33-year-old female using isophane-neutral protamine Hagedorn human insulin and insulin lispro. She experienced dyspnea, cough, urticaria and itching sensation at the sites of insulin injection immediately after insulin administration. We discontinued insulin therapy and started oral hypoglycemic agents with metformin and glibenclamide. The other case was a 32-year-old female using insulin lispro and insulin detemer. She experienced pruritus and burning sensation and multiple nodules at the sites of insulin injection. We changed the insulin from insulin lispro to insulin aspart. Assessments including immunoglobulin E (IgE), IgG, eosinophil, insulin antibody level and skin biopsy were performed. In the two cases, the symptoms were resolved after changing the insulin to oral agents or other insulin preparations. We report two cases of allergic reaction to human insulin in gestational diabetes due to its rarity.
Adult ; Biopsy ; Burns ; Cough ; Diabetes, Gestational* ; Dyspnea ; Eosinophils ; Female ; Glyburide ; Humans ; Hypersensitivity* ; Hypersensitivity, Immediate ; Hypoglycemic Agents ; Immunoglobulin E ; Immunoglobulin G ; Immunoglobulins ; Insulin Aspart ; Insulin Lispro ; Insulin* ; Metformin ; Pregnancy ; Pruritus ; Sensation ; Skin ; Urticaria

This study aimed to investigate the effect of pituitary adenylate cyclase-activating peptide (PACAP) on the pacemaker activity of interstitial cells of Cajal (ICC) in mouse colon and to identify the underlying mechanisms of PACAP action. Spontaneous pacemaker activity of colonic ICC and the effects of PACAP were studied using electrophysiological recordings. Exogenously applied PACAP induced hyperpolarization of the cell membrane and inhibited pacemaker frequency in a dose-dependent manner (from 0.1 nM to 100 nM). To investigate cyclic AMP (cAMP) involvement in the effects of PACAP on ICC, SQ-22536 (an inhibitor of adenylate cyclase) and cell-permeable 8-bromo-cAMP were used. SQ-22536 decreased the frequency of pacemaker potentials, and cell-permeable 8-bromo-cAMP increased the frequency of pacemaker potentials. The effects of SQ-22536 on pacemaker potential frequency and membrane hyperpolarization were rescued by co-treatment with glibenclamide (an ATP-sensitive K+ channel blocker). However, neither N(G)-nitro-L-arginine methyl ester (L-NAME, a competitive inhibitor of NO synthase) nor 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, an inhibitor of guanylate cyclase) had any effect on PACAP-induced activity. In conclusion, this study describes the effects of PACAP on ICC in the mouse colon. PACAP inhibited the pacemaker activity of ICC by acting through ATP-sensitive K+ channels. These results provide evidence of a physiological role for PACAP in regulating gastrointestinal (GI) motility through the modulation of ICC activity.
8-Bromo Cyclic Adenosine Monophosphate ; Animals ; Cell Membrane ; Colon* ; Cyclic AMP ; Glyburide ; Interstitial Cells of Cajal* ; Membranes ; Mice ; NG-Nitroarginine Methyl Ester ; Pituitary Adenylate Cyclase-Activating Polypeptide*