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A sensitive and accurate LC-MS/MS method for the identification and quantification of 5 oral anti-diabetics (glipizide, glibenclamide, gliclazide, gliquidone and metformin) in serum and hair was developed using glibornuride as the internal standard. We have developed a rapid and robust extraction procedure by using acetonitrile for serum protein precipitation and methanol for the extraction of anti-diabetics from hair. Anti-diabetics (ADs) were separated by UPLC over a C18 column and detection was performed on a Waters Xevo TQ MS mass spectrometer in positive ionization mode using electrospray ionization. Each AD was identified by three specific ion transitions in multiple reaction monitoring (MRM) mode. The method was validated according to international guidelines. For all compounds the variation coefficient (CV) was

Background: Identification of sulfonylureas in blood may be useful in the evaluation of hypoglycemic crises of unknown origin. The aim of the present study was to develop a highly selective liquid chromatography–electrospray tandem mass spectrometry (MS-MS) method using an ion-trap detector for rapid screening, identification, and quantification of sulfonylureas in human plasma. Methods: After standard liquid–liquid extraction with glisoxepide as an internal standard, 8 sulfonylureas (glibenclamide, glipizide, gliclazide, glibornuride, glimepiride, carbutamide, chlorpropamide, and tolbutamide) were eluted from a C18 column within 10 min with an isocratic mobile phase. Drugs were identified and quantified in full-scan MS-MS mode by use of a homemade MS-MS library. We used the assay in 134 cases of hypoglycemic crises of unknown origin. Results: No ion suppression effect was noted for the analytes at their specific retention-time windows. For all drugs, assay validation showed good linearity (r2 >0.990) and acceptable imprecision and recovery based on commonly used criteria of acceptance. The mean extraction recoveries were 63%–87% for 5 sulfonylureas but Conclusion: The described assay method allows accurate, rapid identification and quantification of 8 sulfonylureas in human plasma and can be used for specific diagnosis of factitious hypoglycemia caused by ingestion of these drugs.

An atmospheric pressure chemical ionization liquid chromatographic-mass spectrometric (APCI-LC-MS) LC-MS assay is presented for fast and reliable screening and identification as well as precise and sensitive quantification of oral antidiabetics of the sulfonylurea-type (OADs) in plasma. It allowed the specific diagnosis of an overdose situation or a Munchausen syndrome caused by ingestion of OADs. After liquid-liquid extraction, the OADs glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, tolazamide and tolbutamide were separated using fast gradient elution. After screening and identification in the scan mode using our new LC-MS library, the OADs were quantified in the selected-ion mode. The quantification assay was validated according to the criteria established by the Journal of Chromatography B. All validation data were inside the required limits. The assay is part of a general LC-MS procedure for fast screening, identification and quantification of different toxicologically relevant compounds in plasma and has proven to be appropriate for OADs.

1. The binding of [3H]-P1075, a potent opener of adenosine-5'-triphosphate-(ATP)-sensitive K+ channels, was studied in a crude heart membrane preparation of the rat, at 37 degrees C. 2. Binding required MgATP. In the presence of an ATP-regenerating system, MgATP supported [3H]-P1075 binding with an EC50 value of 100 microM and a Hill coefficient of 1.4. 3. In saturation experiments [3H]-P1075 binding was homogeneous with a KD value of 6+/-1 nM and a binding capacity (Bmax) of 33+/-3 fmol mg(-1) protein. 4. Upon addition of an excess of unlabelled P1075, the [3H]-P1075-receptor complex dissociated in a mono-exponential manner with a dissociation rate constant of 0.13+/-0.01 min(-1). If a bi-molecular association mechanism was assumed, the dependence of the association kinetics on label concentration gave an association rate constant of 0.030+/-0.003 nM(-1) min(-1). From the kinetic experiments the KD value was calculated as 4.7+/-0.6 nM. 5. Openers of the ATP-sensitive K+ channel belonging to different structural classes inhibited specific [3H]-P1075 binding in a monophasic manner to completion; an exception was minoxidil sulphate where maximum inhibition was 68%. The potencies of the openers in this assay agree with published values obtained in rat cardiocytes and are on average 3.5 times lower than those determined in rat aorta. 6. Sulphonylureas, such as glibenclamide and glibornuride and the sulphonylurea-related carboxylate, AZ-DF 265, inhibited [3H]-P1075 binding with biphasic inhibition curves. The high affinity component comprised about 60% of the curves with the IC50 value of glibenclamide being approximately 90 nM; affinities for the low affinity component were in the microM concentration range. The fluorescein derivative, phloxine B, showed a monophasic inhibition curve with an IC50 value of 6 microM, a maximum inhibition of 94% and a Hill coefficient of 1.5. 7. It is concluded that binding studies with [3H]-P1075 are feasible in rat heart membranes in the presence of MgATP and of an ATP-regenerating system. The pharmacological profile of the [3H]-P1075 binding sites in the cardiac preparation, which probably contains sulphonylurea receptors (SURs) from cardiac myocytes (SUR2A) and vascular smooth muscle cells (SUR2B), differs from that expected for SUR2A and SUR2B.

A method is described for the separation, identification and quantification of six sulfonylureas in serum by liquid chromatography/mass spectrometry with atmospheric-pressure chemical-ionization (APCI LC/MS). The sample pretreatment is based on single-step liquid-liquid extraction, using the 4-methylcyclohexyl analogue of glibenclamide as internal standard. Carbutamide and tolbutamide have been chosen as representative sulfonylureas of the first generation and glipizide, glibornuride, glibenclamide and gliquidone as those of the second generation, widely used in the treatment of diabetes mellitus. This method allows a screening of these sulfonylureas in serum and subsequently the quantification of the serum level in one run of measurement. Accuracy, precision, specificity and sensitivity for each sulfonylurea are presented and discussed.

The oral hypoglycemic sulfonamides carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glymidine, tolazamide, and tolbutamide were investigated for photohemolytic properties in vitro. Irradiation with a solar simulator revealed hemolysis in the presence of chlorpropamide, glipizide, gliquidone, glymidine, and tolbutamide (all at a concentration of 10−3 mol/L). Except for glymidine, which exerted photohemolysis at the concentration 10−4 mol/L, no hemolytic effects were seen in the concentration of 10−4 mol/L or 10−5 mol/L. Irradiation with light sources emitting mainly ultraviolet B (UVB), ultraviolet A (UVA), or visible light did not induce phototoxic hemolysis with any of the test substances. Tolbutamide and chlorpropamide have previously been described as a cause of clinical photosensitivity, whereas the other drugs so far have not shown phototoxic effects in humans.

Parsley (Petroselinum crispum) is one of the medicinal herbs used by diabetics in Turkey. The aim of this study is to investigate the effects of parsley (2g/kg) and glibornuride (5mg/kg) on the liver tissue of streptozotocin-induced diabetic rats. Swiss albino rats were divided into six groups: control; control+parsley; control+glibornuride; diabetic; diabetic+parsley; diabetic+glibornuride. Diabetes was induced by intraperitoneal injection of 65 mg/kg streptozotocin (STZ). Parsley extract and glibornuride were given daily to both diabetic and control rats separately, until the end of the experiment, at day 42. The drugs were administered to one diabetic and one control group from days 14 to 42. On day 42, liver tissues were taken from each rat. In STZ-diabetic group, blood glucose levels, serum alkaline phosphatase activity, uric acid, sialic acid, sodium and potassium levels, liver lipid peroxidation (LPO), and non-enzymatic glycosylation (NEG) levels increased, while liver glutathione (GSH) levels and body weight decreased. In the diabetic group given parsley, blood glucose, serum alkaline phosphatase activity, sialic acid, uric acid, potassium and sodium levels, and liver LPO and NEG levels decreased, but GSH levels increased. The diabetic group, given glibornuride, blood glucose, serum alkaline phosphatase activity, serum sialic acid, uric acid, potassium, and liver NEG levels decreased, but liver LPO, GSH, serum sodium levels, and body weight increased. It was concluded that probably, due to its antioxidant property, parsley extract has a protective effect comparable to glibornuride against hepatotoxicity caused by diabetes.

Glibornuride is a sulphonylurea derivative used as an oral hypoglycaemic drug in diabetics. The aim of this study was to examine the histological, ultrastructural and biochemical effects of glibornuride in streptozotocin (STZ)-treated rats. The animals were rendered diabetic by intraperitoneal injection of 65 mg/kg STZ. Fourteen days later, glibornuride was given at 5 mg/kg by gavage, daily for 28 days, to one STZ-diabetic and one control group. In the STZ-diabetic group, remarkable degenerative changes were observed. On the other hand, in the STZ-diabetic group given glibornuride, the degenerative changes decreased. In the STZ-diabetic group, blood glucose levels, serum aspartate transaminase activity, and total lipid levels increased, whereas the blood glutathione levels decreased. In contrast, in the STZ-diabetic group given glibornuride blood glucose levels, serum aspartate transaminase activity and total lipid levels decreased and blood glutathione levels increased. Significant changes in total protein levels in the serum were not observed in any group. As a conclusion, we can say that glibornuride has a protective effect against the hepatotoxicity produced by STZ-diabetes.

Antidiabetic sulfonylureas completely relaxed isolated rabbit coronary arteries contracted by prostaglandin F2 alpha. The order of potency was glibenclamide (EC50 = 4.75 microM) greater than glipizide = glibornuride = tolbutamide = chlorpropamide. The drugs also relaxed the contractions induced by 30 mM K+ but much less potently. The effectiveness of the drugs as vascular smooth muscle relaxants did not correlate with their ability to antagonize the vasorelaxant action of cromakalim. Sulfonylurea-induced vasorelaxation probably involves mechanisms other than an interaction with ATP-regulated K+ channels.

Summary Aims A comparison of the frequency of severe hypoglycaemia leading to hospital admission in people with Type 2 diabetes mellitus (DM) treated with long vs. short-acting sulphonylureas. Methods A community based study over a 12-year period in the population of the city of Basle, Switzerland. The number of diabetic patients treated with oral hypoglycaemic agents was established on the basis of tablet consumption and a defined daily dose, e.g. 7.5 mg for glibenclamide, and 50 mg for glibornuride. Results Twenty-eight Type 2 diabetic patients were admitted for severe hypo- glycaemia, with a median age of 73 years. There were no deaths. Sixteen of these admissions were patients treated with long-acting sulphonylureas and 12 were patients treated with short-acting forms. Only 23.5% of the population with Type 2 DM in Basle were treated with long-acting sulphonylureas. With 30 345 person-years of observation, the incidence of severe hypoglycaemia was 2.24 per 1000 person-years for long-acting sulphonylureas vs. 0.75 per 1000 person-year for short-acting forms, odds ratio 3.01 (95% confidence interval 1.35–6.77). Decreased food intake (nine patients) was a major contributing factor. Conclusions Severe hypoglycaemia leading to hospital admission is more common in elderly Type 2 diabetic patients treated with long-acting compared to short-acting sulphonylureas. Such long-acting sulphonylureas should be avoided.

The sulphonamide-derived oral antidiabetic drugs carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glymidine, tolazamide and tolbutamide were investigated for photohemolytic properties in vitro. Irradiation with a SOL 3 apparatus (solar simulating irradiation) revealed hemolysis in the presence of chlor-propamide, glipizide, gliquidone, glymidine and tolbutamide (all in the concentration 10 -3 mol/l). Except for glymidine, which exerted photohemolysis in the concentration 10 -4 mol/l, no hemolytic effects were seen in the concentration of 10 -4 mol/l or 10 -5 mol/l. Irradiation with TL 12 light bulbs (UVB), a UVASUN 5000 apparatus (UVA) or an experimental lamp (visible light) did not induce phototoxic hemolysis with either of the test substances. Addition of the antioxidants ascorbic acid, alpha-tocopherol or superoxide dismutase significantly inhibited the phototoxic hemolysis. Investigations carried out in a nitrogen-rich atmosphere reduced the hemolysis as well. These findings indicate an involvement of reactive oxygen species in the mechanism of action of the hemolytic process in the presence of oral antidiabetic drugs.

39 ÖZET Diabetes Mellitusta en önemli morbidite ve mortalite nedenlerinden olan nefropati gelişiminde sorumlu tutulan mekanizmalardan biri hastalığın erken döneminde hastaların %25-40'mda saptanan glömerüler hiperfiltrasyondur. GFH artışının da, yüksek plazma ANF düzeyleri ile paralellik gösterdiği ortaya konmuştur. Bu çalışmadaki amaç, yeni tanı alan Tip II DM lu hastalarda plazma ANF düzeylerini belirlemek ve 2.Kuşak Sülfonilüre grubundan glibornuridin ANF düzeyleri ve natriüreze etkisini incelemekti. Yeni tanı alan 10 DM' lu hasta ve 10 sağlıklı kontrol grubunda, öglisemik insulin klempi altında, bazal ve intravenöz SF yüklemesi (2mmol/kg/sa) ardından plazma ANF düzeyleri ve idrarda saatlik sodyum, potasyum atılımı incelendi. Hasta grupta aynı değerler, oral 50mg glibornurid alımından sonra tekrar bakıldı. İlaç öncesi ortalama bazal plazma ANF düzeyleri hasta ve kontrol grubunda sırasıyla, 15.05±2.32pg/ml ve 11.13±0.85pg/ml iken, SF yükleme sonrası benzer şekilde anlamlı bir artış göstererek 28.89tb4-.72pg/ml ve 20.18±2.48pg/ml değerlerine yükseldî(p0.0S). Çalışmada elde edilen sonuçlar doğrultusunda, glibornuridin, böbrekte Henle kulpu ve toplayıcı tübüllerde bulunan Katp kanallarım bloke edici etkisiyle nonkaliürik natriüreze devam ederken, diabetik hastalarda, ani hacim artışım önleyerek plazma ANF düzey artışını engellediği fikri ortaya atılabilir. Bu çalışma daha geniş bir seride tekrarlanarak desteklenirse, glibornuridle bir yandan DM hastalarında oluşabilecek sodyum retansiyonu engellenirken bir yandan da glömerüler hiperfiltrasyona yol açacak ANF yüksekliği ortadan kaldırılarak ileride gelişebilecek bir nefropati için iyi bir proflaktik tedavi seçeneği sağlanmış olacaktır. 40 SUMMARY Diabetic nephropathy is a common microvascular complication of diabetes mellitus (DM). In the early phase of DM, glomerular filtration rate is found to be elevated on average by 20 to 40% above that of normal subjects. A positive correlation has been described between initial hyperfiltration and subsequent increase in albuminuria and development of clinical nephropathy has been described. Elevated plasma atrial natriuretic factor(ANF) levels have been suggested to be one of the factors that contribute to the risk of developing diabetic nephropathy by increasing the intraglomerular pressure. The aim of this study was to determine the plasma ANF levels in 10 newly diagnosed DM Type II patients compared with 10 control subjects and the effect of glybornuride on the plasma ANF levels and natriuresis in these patients. At base-line, plasma ANF levels(15.05£232pgml, 11.13±0.85pg/ml) and the urinary sodium and potassium excretion rates were similar in patients and control subjects,respectively. As well as that, intravenous saline infusion (2mmol/kg/sa) was associated with marked elevation in plasma ANF levels in patients and in controls, respectively (28.89M.72pgfal, 20.18±2.48pgfal) and with increased urinary sodium and potassium excretion rates in both groups. On the contrary, after 50mg glibornuride p.o. plasma ANF levels did not elevate with saline infusion (15.13±1.00pgml) while natriuresis but not kaliuresis persisted. All the tests were held during euglycemic clamp. It was concluded that glibornuride, with its natriuretic effect through the ATP sensitive potassium channels on the apical membrane of thick ascending limb of loop of Henle and cortical collecting duct cells, might inhibit the elevation of plasma ANF levels in response to extracellular fluid volume expansion. Similarly, with its natriuretic effect, it protects the diabetic patients against a possible sodium retention. This result is noteworthy as the inhibition of plasma ANF elevation in early diabetes with glybornuride may prevent glomerular hypertension and subsequent development of nephropathy. 51

Summary: Glibenclamide, glipizide and glibornuride showed dual effects in guinea-pig isolated trachea. The drugs antagonized the relaxant response to the K+ channel opener cromakalim (order of effectiveness: glibenclamide > glipizide > glibornuride) and at concentrations of 1-1000 μM produced airway smooth muscle relaxation (order of potency: glibenclamide > glipizide = glibornuride). Gliclazide, tolbutamide and chlorpropamide did not antagonize cromakalim nor did the two latter drugs produce tracheal relaxation. The sulphonylureas and cromakalim were compared as airway relaxants against a panel of different spasmogens. The order of tissue responsiveness for the sulphonylureas was: spontaneous tone = LTD4 > PGF2α = histamine = 30 mM K+ > carbachol and for cromakalim: spontaneous tone = LTD4 = PGF2α = histamine > carbachol > 30 mM K+. Glibenclamide, but not cromakalim, relaxed contractions induced by 124 mM K+. Phentolamine and Ba2+, which are reported blockers of ATP-regulated K+ channels, failed to influence sulphonylurea-induced airway smooth muscle relaxation. Glibenclamide reversed tracheal relaxation produced by cromakalim, whereas cromakalim failed to reverse relaxation induced by glibenclamide. The mechanism for the additional property of sulphonylureas to relax airway smooth muscle is unclear, but the results do not support a role for involvement of cromakalim-sensitive K+ channels.

The effect of exogenous acid amyloglucosidase on sulphonylurea-induced insulin release was investigated in mice and rats. 1. Pretreatment of mice with acid amyloglucosidase enhanced insulin release induced by the different sulphonylurea derivatives, carbutamide, tolbutamide, glibenclamide, and glibornuride. 2. A dose-response relationship between glibenclamide-induced insulin response and amyloglucosidase dosage covering a 64-fold concentration range was established in mice. 3. Pretreatment of the animals with other macromolecules of similar physiological or chemical properties to acid amyloglucosidase such asα-amylase,β-glucuronidase and albumin did not influence glibenlamide-induced insulin release. 4. The effect of acid amyloglucosidase pretreatment on insulin release induced by different agents known to affect the islet-cell adenylate cyclase-cyclic AMP system such as secretin, L-isopropylnoradrenaline (L-IPNA), arginine, glibenclamide and 3-isobutyl-1-methylxanthine (IBMX) was tested. It was observed that in animals pretreated with acid amyloglucosidase, insulin release was enhanced when stimulated by glibenclamide, a phosphodiesterase inhibitor, but it was similarly enhanced by arginine, a phosphodiesterase activator. Insulin release induced by secretin, L-IPNA, and IBMX was unaffected. 5. Acid amyloglucosidase pretreatment in rats enhanced plasma immunoreactive insulin levels following glibenclamide injection not only in the peripheral veins but also in the portal vein. 6. Mice fasted for 24 hrs displayed a markedly depressed insulin response to tolbutamide injection. Pretreatment of the fasted animals with acid amyloglucosidase could restore the tolbutamide-induced insulin release to the same level as that recorded in a group of freely fed mice. It is suggested that acid amyloglucosidase plays an important role in insulin secretion induced by sulphonylureas. Most evidence suggests that this effect is exerted within the B-cell although an additional effect on the liver cannot be ruled out.

In this report we review the pharmacology of the hypoglycemic sulfonylurea drugs. The early work with sulfonylureas is briefly described. The pharmacokinetics of first-generation sulfonylureas, such as tolbutamide, chlorpropamide, acetohexamide and tolazamide, are described. The first-generation sulfonylureas are compared with second-generation sulfonylureas such as glyburide, glipizide and glibornuride. These latter drugs have a more nonpolar or lipophilic side chain, which results in a marked increase in their hypoglycemic potency. Because of the low serum concentration required for effective therapy, it is necessary to measure the serum concentration of second-generation sulfonylureas by gas-liquid chromatography or radioimmunoassay. The second-generation sulfonylureas do not produce facial flushing after ethanol ingestion (Antabuse effect) and are not uricosuric. Glyburide (but not glipizide or glibornuride) has been evaluated for its effect on water excretion. Glyburide not only does not increase water retention but in fact also increases free water clearance. The second-generation sulfonylureas bind to human serum albumin by nonionic forces in contrast with tolbutamide and chlorpropamide which bind by ionic forces. Thus, anionic drugs such as phenylbutazone, warfarin and salicylate do not displace glyburide from albumin as they displace tolbutamide and chlorpropamide. Therefore, it may be safer to administer the second-generation sulfonylureas than the more polar sulfonylureas when concurrent administration of other pharmacologic agents is likely. The sulfonylurea drugs lower plasma glucose concentrations in diabetic patients by stimulating insulin secretion and by potentiating the biologic effect of the insulin on such tissues as skeletal muscle, fat and liver. The mechanism of the latter so-called extra-pancreatic effect may be activated by increasing the deficient numbers of insulin receptors on muscle, fat or liver cells.

Bei den Photolysen der Pharmaka 1a-h fielen als Reaktionsprodukte die Verbindungen 2,3,5,6 an. In bestimmten Fallen wurden noch weitere Produkte isoliert. Die Photofragmentierung kann sowohl auf eine α′-, als auch auf eine α-Spaltung zuruckgefuhrt werden. In mechanistischen Untersuchungen konnte gezeigt werden, das die α′- und die α-Spaltung aus einem angeregten 1S-Zustand erfolgen durfte. Die Bedeutung dieser Studien im Zusammenhang mit dem Problem der Lichtdermatosen wird kurz behandelt. Photochemical Model Studies on Photosensitizing Drugs: Sulfonamides and Sulfonylureas Photolysis of the drugs 1a-h affords the products 2, 3, 5 and 6. In some photolyses additional photofragmentation products were obtained. α′- or α-cleavage of 1 explains the nature of the products. Mechanistic studies demonstrate that most probably an excited S1-state is involved. The relevance of this work to “photosensitization” is briefly discussed.

The influence of various antidiabetic treatments on the kinetics and efficacy of a single oral dose of 12 mg phenprocoumon were studied in 71 hospitalized patients, 58 with adult-onset diabetes mellitus and 13 non-diabetic aged patients, and 13 healthy young volunteers. Treatment for one week or longer with insulin or the antidiabetic sulphonylureas tolbutamide, glibenclamide or glibornuride, altered neither the plasma level (1.29 – 1.40 µg/ml at zero time) nor the half-life of phenprocoumon (5.2 – 6.8 d) compared to treatment by diet alone. The mean half-life of phenprocoumon was significantly shorter in non-diabetic aged patients (4.2 d) than in diabetic patients of the same age (5.1 – 6.8 d), or in young healthy volunteers (5.7 d). The efficacy of a single dose of phenprocoumon (maximal reduction of Quick-values by 34 – 47% after 48 to 72 hrs) in diabetic patients treated with diet, or diet and antidiabetic drugs, was the same as in non-diabetic aged patients. In healthy young volunteers phenprocoumon was half as effective as in aged patients.

Sulphonylureas are still prescribed in increasing amounts in the UK (Statistics and Research Division, DHSS, personal communication) despite the suggestion from the Universities Group Diabetic Program trial (1970) that their use may be associated with an increased risk of cardiovascular death. Tolbutamide, the first of the sulphonylureas still in common use, has a half-life of only five hours and is usually taken in two or three daily doses. The half-life of chlorpropamide, which is not metabolized by the liver, is 36 hours and its use may lead to prolonged hypoglycaemia particularly in the elderly and those with renal impairment (Schen & Benaroya 1976). Glibornuride has been widely used on the continent for several years, but only recently became available in the UK. This compound is rapidly absorbed from the gut and inactivated by the liver to give a half-life of eight hours. A trial was set up to examine the clinical acceptability of glibornuride and to confirm that like other sulphonylureas it leads to an increase in insulin secretion (Perkins et al. 1977).

The acute effects of therapeutic doses of intravenous tolbutamide and glibornuride on the systolic time intervals (QS2c, LVETc, PEPc and PEP/LVET) were examined in 5 healthy volunteers. Blood sugar was maintained constant throughout the study. No significant changes of these intervals as well as of heart rate and blood pressure were observed. Therefore, it is concluded that tolbutamide and glibornuride have no acute positive inotropic action.

Six hypoglycaemic sulphonylurea compounds were compared with regard to their ability to bind to β-cell-rich pancreatic islets microdissected from ob/ob mice. Glibenclamide differed from carbutamide, tolbutamide, chlorpropamide, glibornuride and glipizide in not being rapidly bound to an equilibrium, but accumulating progressively in amounts far exceeding the water space. An inhibitor of the anion channels in the β-cell membrane, 4-acetamido-4'-isothiocyanate-stilbene-2,2'-disulphonic acid (SITS), suppressed the islet uptake of glibenclamide and to some extent also that of carbutamide and glibornuride. The unusual uptake characteristics of glibenclamide had their counterpart in a retardation of its maximal action in promoting the entry of Ca2+ into the β-cells.

The pharmacokinetics of glibornuride (25 mg i.v.) and the accompanying insulin and glucose responses were characterized in eight human subjects in the presence and absence of steady-state tenoxicam (20 mg p.o./day for 2 weeks). Tenoxicam affected neither the pharmacokinetic parameters of glibornuride (systemic clearance, volume of distribution and biological half-life) nor the responses of plasma insulin and blood glucose to glibornuride. The single i.v. dose of glibornuride had no detectable effect on the kinetics of tenoxicam.

Pharmacodynamic studies were performed using tolbutamide, glibenclamide, glibornuride (Ro 6-4563) and glisoxepide (BS 4231). The four compounds were administered intravenously, and exact dose-response relations were established, calculating the ED 30 of the decrease in blood glucose in healthy volunteers. Accordingly, the dose corresponding to the ED 30 was given twice with a three hour interval to maturity-onset diabetics. Different dynamics of insulin response were observed after tolbutamide, glibornuride and glisoxepide on the one hand, and glibenclamide on the other. In contrast to other reports in the literature, an obvious uniformly weaker degree of insulin secretion was seen after each of the different sulphonylurea compounds when given repeatedly.

The uptake of 3H-labelled glibomuride wasstudied in microdissected pancreatic islets of ob/ob- mice . The islets rapidly accumulated this insulin-releasi

Glibornuride is an addition to the second-generation sulphonylureas, that has been shown in clinical trials to be effective and non-toxic. Twenty-three diabetics who were poorly controlled on other oral hypoglycaemic agents and seven newly diagnosed diabetics were treated with glibornuride. The efficacy and lack of toxicity of this drug was confirmed, but there was no evidence to suggest that it is significantly more potent than other sulphonylureas. It does not seem to represent a significant therapeutic advance.

In the isolated perfused rat pancreas various sulfonylurea drugs were tested with a basal glucose level of 1 mg/ml in the perfusion buffer and were found to cause a biphasic insulin response. NOVO CS 476, a new and potent sulfonylurea, and glibenclamide qualitatively differed from tolbutamide, glibornuride, glipizide, and glisoxepide, which were all alike in terms of the relationship between first and second phases of insulin release.

To assess whether extrapancreatic effects of sulfonylureas in vivo are detectable in the absence of endogenous insulin secretion, insulin sensitivity was determined in six insulin-deficient type 1-diabetic subjects. Peripheral uptake and hepatic production of glucose and lipolysis were measured during hyperinsulinemia using the euglycemic clamp technique and 3-3H-glucose infusions twice, once during a period with glibornuride treatment (50 mg b.i.d.), and once without. Hepatic glucose production decreased in diabetic subjects during hyperinsulinemia (insulin infusion of 20 mU/m2 X min; plasma free insulin levels of 40 +/- 4 mU/l) from 2.9 +/- 0.6 mg/kg min to 0.2 +/- 0.1 mg/kg X min after 120 min, and plasma free fatty acid (FFA) concentrations decreased from 1.33 +/- 0.29 to 0.38 +/- 0.08 mmol/l. Hepatic production, peripheral uptake of glucose and plasma FFA concentrations before and during hyperinsulinemia were not influenced by pretreatment with glibornuride. Compared to 8 non-diabetic subjects, type 1-diabetics demonstrated a diminished effect of hyperinsulinemia on peripheral glucose clearance (2.4 +/- 0.04 vs 4.2 +/- 0.5 ml/kg X min, P less than 0.01), whereas hepatic glucose production and plasma FFA levels were similarly suppressed by insulin. The data indicate that sulfonylurea treatment did not improve the diminished insulin sensitivity of peripheral glucose clearance in type 1-diabetic subjects; insulin action on hepatic glucose production and lipolysis was unimpaired in diabetics and remained uninfluenced by glibornuride. Thus, extrapancreatic effects of sulfonylureas in vivo are dependent on the presence of functioning beta-cells.

The aim of the study was to investigate the effect of glibornuride (CAS 26944-48-9) and metformin (CAS 657-24-9) on eye lenses and skin of streptozotocin (STZ)-induced diabetic rats. The drugs were administered daily to one diabetic and one control group separately from day 14 to day 42. After 42 days, diabetes caused significant increases in blood glucose levels, non-enzymatic glycosylation (NEG) of skin and lens proteins and skin lipid peroxidation (LPO) levels as well as decreases in body weights and lens glutathione (GSH) levels. Metformin administration to the diabetic rats produced more significant reduction in blood glucose than glibornuride. Metformin produced non-significant increase in NEG levels in lenses and skin. Unlike metformin, glibornuride increased NEG levels significantly in lenses. Both drugs produced non-significant increase in lens GSH levels and decreases in skin LPO levels in diabetic rats. Sodium dodecyl sulphate (SDS) polyacrylamid gel electrophoresis revealed no significant difference in any of the protein bands between any of the groups. These observations suggest that metformin and glibornuride as oral antidiabetics have similar protective effects on tissues in STZ induced diabetic rats.

1. Anhand des Sekretionsverhaltens von Insulin ist Ro 6-4563, ein neues Sulfonylharnstoffderivat, in die Reihe der „tolbutamidartig wirkenden Sulfonylharnstoffderivate“ einzuordnen. 2. Die intravenose Gabe von 25 mg R 6-4563 fuhrt im Vergleich zur intravenosen Gabe von 1000 mg Tolbutamid zu teilweise geringfugig hoheren Seruminsulinspiegeln. Die Glucose- und NFS-Werte im Serum sind unter beiden Praparaten jedoch nahezu identisch, so das 25 mg Ro 6-4563 und 1000 mg Tolbutamid als annahernd gleichwertig zu bezeichnen sind.

Treatment with any of the sulphonylurea group of oral hypoglycaemic agents may cause hypoglycaemia, usually in situations where there may be restriction of carbohydrate intake at times of anorexia and where a potentiating drug such as salicylates, warfarin or co-trimoxazole is given (Ref 1). There is particular risk of this occurring in the elderly and in those with impaired renal function, as many of the commonly used sulphonylureas (tolbutamide, chlorpropamide, acetohexamide, tolazamide, glibenclamide, glipizide and glibornuride) are primarily excreted by the kidney. Gliquidone is a recently introduced sulphonylurea to the UK, with a short plasma half-life of 1.4h and which is excreted in the bile and does not accumulate with renal impairment. We describe a case of gliquidone-induced hypoglycaemia occurring in a female diabetic with chronic renal failure.