Search

The study of the high-pressure behavior of molecular crystals helps find limits of their stability, as well as obtain previously unknown new phases. This may result in the creation of new materials and their forms for a variety of applications: pharmaceutics, optoelectronics, etc. Nevertheless, until recently, there was no practical unified scheme for high-pressure studies of organic molecules, paying close attention to various inter- and intramolecular interactions. In this work, we compare different computational methods for the high-pressure research of molecular crystals in terms of the energy of particular interactions. Tolazamide polymorphs are taken as a representative system. It is shown that not only “structure-forming” interactions, e.g. H-bonds and stacking interactions, but also multiple van der Waals interactions should be taken into account. Moreover, we compare two different concepts for studying particular H-bonds in terms of absolute and relative energies, showing their importance in understanding the high-pressure behavior of tolazamide polymorphs. Finally, several important details about the high-pressure research of organic crystals at a molecular level by computational methods are formulated.

The theoretical study of chlorpropamide, tolazamide and glipizide was carried out by the Density Functional Theory (DFT) at B3LYP/6-31G(d) level. This study made it possible to determine the global reactivity parameters in order to better understand the interactions between the molecules studied and the copper surface. Then, the determination of local reactivity indices (Fukui functions and dual descriptor) on these molecules resulted in the precision on the most probable centers of nucleophilic and electrophilic attacks within each molecule. The results obtained, show that chloropropamide, tolazamide and glipizide can be good inhibitors against copper corrosion. Thus, the mechanism of copper corrosion inhibition of these compounds in nitric acid solution has been explained by means of theoretical calculations.

Sulfonylurea drugs are antidiabetic drugs that are utilized in the treatment of type II diabetes and often have significant binding with human serum albumin (HSA). Immobilized samples of normal or glycated HSA in affinity microcolumns were used to investigate interactions of these proteins with the sulfonylurea drug tolazamide. HPLC and frontal analysis were used to first examine the overall binding of this drug with these samples of HSA. It was found that tolazamide had two general classes of binding sites (i.e., high and low affinity) for normal and glycated HSA. The higher affinity sites had binding constants of around 4.3–6.0 × 104 M−1 for these interactions at pH 7.4 and 37 °C, while the lower affinity sites had binding strengths of 4.9–9.1 × 103 M−1. Zonal competition studies between tolazamide and probes for Sudlow sites I and II on HSA were also performed and used to provide site-specific affinities for tolazamide at these sites. A decrease of 22% in affinity was observed for tolazamide at Sudlow site I and an increase up to 58% was seen at Sudlow site II when comparing glycated HSA with normal HSA. These observed changes were compared to those of other first-generation sulfonylurea drugs, providing information on how glycation can alter the total and local binding strength of tolazamide and related compounds with HSA under levels of glycation seen in patients with diabetes.

Diabetes is characterized by elevated levels of blood glucose, which can result in the modification of serum proteins. The modification of a protein by glucose, or glycation, can also lead to the formation of advanced glycated end-products (AGEs). One protein that can be modified through glycation and AGE formation is human serum albumin (HSA). In this study, immunoextraction based on polyclonal anti-HSA antibodies was used with high-performance affinity microcolumns to see how AGE-related modifications produced by glyoxal (Go) and methylglyoxal (MGo) affected the binding of HSA to several first- and second-generation sulfonylureas, a class of drugs used to treat type II diabetes and known to bind to HSA. With this approach, it was possible to use a single platform to examine drug interactions with several preparations of HSA. Each applied protein sample could be used over 20–50 experiments, and global affinity constants for most of the examined drugs could be obtained in less than 7.5 min. The binding constants measured for these drugs with normal HSA gave good agreement with global affinities based on the literature. Both Go- and MGo-related modifications at clinically relevant levels were found by this method to create significant changes in the binding by some sulfonylureas with HSA. The global affinities for many of the drugs increased by 1.4-fold or more; gliclazide and tolazamide had no significant change with some preparations of modified HSA, and a small-to-moderate decrease in binding strength was noted for glibenclamide and gliclazide with Go-modified HSA. This approach can be adapted for the study of other drug-protein interactions and alternative modified proteins by altering the antibodies that are employed for immunoextraction and within the affinity microcolumn.

Two polymorphs of tolazamide, N-[(azepan-1-ylamino)carbonyl]-4-methylbenzenesulfonamide, a sulfonylurea anti-diabetic drug, have different densities and molecular packings. Polymorph II converts into polymorph I in the solid state on heating or via recrystallization if solvent-assisted. The effect of pressure on the two forms and the possibility of a transformation to a denser form on compression have been studied. No phase transitions have been observed in either of the forms in a pentane–isopentane mixture (when no recrystallization is possible). Polymorph II recrystallized partly into a denser polymorph I in methanol at 0.1 GPa, but the transformation stopped at an early stage. Solid state DFT calculations of the two forms as well as conformational landscape investigation in the gas phase were used to rationalize this result. The anisotropic pressure-induced strain of the two polymorphs has been compared in relation to changes in the hydrogen bond geometry and the behavior of stacking interactions.

In the present case study of tolazamide we illustrate how many seemingly contradictory results that have been obtained from experimental observations and theoretical calculations can finally start forming a consistent picture: a "puzzle put together". For many years, tolazamide was considered to have no polymorphs. This made this drug substance unique among the large family of sulfonylureas, which was known to be significantly more prone to polymorphism than many other organic compounds. The present work employs a broad and in-depth analysis that includes the use of optical microscopy, single-crystal and powder X-ray diffraction, IR and Raman spectroscopies, DSC, semiempirical PIXEL calculations and DFT of three polymorphs of tolazamide. This case study shows how the polymorphs of a molecular crystal can be overlooked even if discovered serendipitously on one of numerous crystallizations, and how very different molecular packings can be practically isoenergetic but still crystallize quite selectively and transform one into another irreversibly upon heating.

In this paper, vibrational spectra of tolazamide have been investigated by ab initio techniques in combination with experimental studies. Data on the FT-IR spectra (400–4000 cm−1) and Laser-Raman spectra (100–4000 cm−1) of tolazamide have been obtained in the solid phase. Assignments corresponding to the vibrational frequencies have been found and interpreted by the contribution of the potential energy distributions. The theoretical results are compared X-ray experimental data for this. Structural parameters such as bond lengths and angles, frequencies and intensities regarding Raman and IR spectra of the compound have been computed by density functional theory and Hartree–Fock methods with 6-311G++(d,p) and 6-31G(d) basis sets. They have been observed that the computed vibrational frequencies and optimized structural parameters are consistent with the corresponding experimental results. In addition, the images of frontier molecular orbitals (highest occupied and lowest unoccupied) have been presented and interpreted.

An ultraperformance liquid chromatography–tandem mass spectrometry method was developed for simultaneous determination of seven sulfonylurea-type oral anti-diabetic agents (glipizide, tolbutamide, tolazamide, gliclazide, glibenclamide, glimepiride, and glurenor) in dietary supplements and traditional Chinese medicines. The samples were extracted twice with methanol by ultrasound. The separation was achieved on a C18 column with the mobile phase consisting of acetonitrile and water (0.2% formic acid (v/v) and 5 mM ammonium acetate), at a flow rate of 0.3 mL/min with gradient elution. The analysis time was 8 min per sample. The proposed method was validated for linearity (r > 0.99), precision (relative standard deviation better than 6.0%), recoveries (83–110%), and the limit of detection in the range 0.3–2 µg kg−1. The proposed method is rapid, reliable, sensitive, accurate, and good applicability, and it was successfully applied to analyze 20 real samples of 15 dietary supplements and five traditional Chin...

In an attempt to gain insight in the mode of inclusion of sulfonylurea hypoglycemic drugs into β-cyclodextrin (βCD), the molecular structures of the inclusion complexes of three such drugs, tolbutamide (TBM), tolazamide (TLZ) and glimepiride (GLP), have been determined for the first time by X-ray crystallography. The drugs share a common moiety, a H-bond forming sulfonylurea group in the middle, flanked by a tolyl-group at one end and an additional hydrophobic group (different in the three drugs) at the other end, GLP being further elongated by a 2-pyrrolidinone moiety at the tolyl end. The structures of the inclusion complexes comprise βCD dimers aligned in channels. The hydrophobic groups enter the cavities of two adjacent βCD dimers from the primary sides, whereas the hydrophilic sulfonylurea moiety is located in-between, forming H-bonds with the hosts without disturbing the dimers. In the GLP/βCD complex, the pyrrolidinone extension threads the βCD cavity and emerges from the secondary side. These results are supported by NMR 2D ROESY spectra in aqueous solutions. The extended length of GLP imposes a change in the crystal packing placing the βCD dimers further apart. However, the overall inclusion mode of the three drugs is the same, thus a common inclusion and crystallization process is proposed for sulfonylurea drugs. The structures of the complexes explain the effects of complexation on dissolution, bioavailability and hypoglycemic activity.

The effect of tolazamide (TZ), a sulfonylurea, on 14C-2-deoxyglucose (14C-2DG) tissue distribution and insulin levels of normal and obese mice was investigated using an in vivo physiological method. Acute doses of TZ (50 mg/kg ip) increased 14C-2DG levels in gastrocnemius muscle and retroperitoneal fat and produced a transient elevation of insulin which most likely accounts for the increased 14C-2DG levels in muscle and fat. The results demonstrate that the in vivo 14C-2DG method produced results consistent with known actions of sulfonylureas on in vitro hexose assimilation in muscle and fat. Subchronic treatment (7 days) with TZ 50 mg/kg ip twice daily did not result in increased insulin-stimulated 14C-2DG tissue levels in normal mice when compared to saline treated controls. However, insulin levels were lower in mice treated subchronically with TZ compared to saline controls suggesting an enhancement of insulin action. Viable yellow obese mice represent a model of maturity onset obesity presenting with insulin resistance. The insulin resistance of this obese strain appears to reside in the fat tissue as assessed by comparing 14C-2DG tissue levels of obese mice with lean littermate controls. Subchronic TZ treatment had no effect on 14C-2DG uptake in fat or muscle tissue of viable yellow obese mice and did not alter their plasma insulin levels. It appears that genetically obese viable yellow mice may be resistant to subchronic treatment with TZ.

Concentrations of fibrinogen-fibrin break-down products (b.d.p.), above 10 ug/ml of serum (+EACA), estimated by haemagglutination inhibition immuno assays, were seldom found in healthy people. In 51 patients with coronary sclerosis and in 31 with other atherosclerotic diseases the amounts were in the lower part of normal range. The mean concentration in 16 patients with metastatic carcinoma was 86.7 and in 16 with hepatic cirrhosis 21.1 ug/ml. 93 patients with other diseases were examined. Huge amounts might be found even when fibrinolytic activity in the blood was very low. Several experiments indicate that b.d.p. also are formed extravascularly and presumably also by other proteases than plasmin. Short-term stimulation of fibrinolytic activity with nicotinic acid (41 patients), venous stasis (35 pts.) and physical exertion (21 pts.), and long-term stimulation with male hormones (5 pts.), metformin (4 pts.), clofibrate (3 pts.), tolazamid (4 pts.) and ethyloestranol + diguanides (11 pts.) was not followed by in vivo increase in b.d.p.

Purpose Diabetic retinopathy (DR) is the most common diabetic eye disease and a leading cause of blindness. The role of angiopoietin-2 a tyrosine kinase receptor is well-reported in angiogenesis during the onset of the disease. The purpose of this study is to screen out more potential herbal molecules which can evidently be used as a better, natural and safe herbal drug against this disease. Design In silico virtual screening and molecular interaction studies were performed. Methods The current course of work focused on molecular interactions on angiopoietin-2 protein with selected natural ligands, namely allicin, ajoene, D-pinitol and salacinol, along with synthetic ones like nateglinide, biguanide, tolbutamide and tolazamide. There was an attempt to carry out the virtual comparative study between natural and synthetic ligands. Proceeding toward this approach, docking of all molecules was performed using the Autodock 4.2 program. Results Inference of this interaction study is that D-pinitol, which is the herbal extract of Glycine max, shows a very reliable docking pattern as compared with the synthetic ligand tolazamide. Although the binding energy of a synthetic ligand is lower compared to that of the natural ones, the binding energy of synthetic and natural ligands are at an approximate level. The lower the binding energy, the better the ligand molecular interaction. Conclusions Our findings suggest that D-pinitol, the natural, safe ligand, can be used in the treatment of diabetic retinopathy with few or no side effects after estimating and calculating proper doses using in vitro approaches.

A turbidity measurement-based experimental method for the determination of the crystallization induction period is described. The induction times for crystallization of tolazamide, an oral hypoglycemic agent, were measured over a range of supersaturation in both unseeded and seeded crystallization experiments. The measured induction times were then treated using the expressions developed by van der Leeden et al., which relates the induction time and the supersaturation for various growth mechanisms in unseeded and seeded crystallization. On the basis of these analyses, the growth mechanism of tolazamide was identified as two-dimensional nucleation-mediated growth. The analyses also afforded estimation of the kinetic parameters such as nucleation and growth rate constants. In addition, atomic force microscopy imaging of the major faces of tolazamide crystals corroborated this growth mechanism.

The purpose of this study is to evaluate amphiphilic block copolymers, a new class of additives, for the habit modification of pharmaceuticals. The additive chosen is poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA). The model compound chosen is tolazamide, an oral hypoglycemic pharmaceutical agent. Crystallization was carried out in aqueous media by pH adjustment, with or without additives. PEG-b-PLA was found to be very effective in modifying the crystal habit of tolazamide. The habit changed from a needle shape to a plate shape at a concentration of 12.5 μg/mL. This change in habit required both blocks and could not be achieved in the presence of either block alone. A small amount of copolymer (0.55% weight) was found on/in tolazamide particles crystallized in the presence of 30 μg/mL of copolymer. Washing the crystals with toluene effectively removed the copolymer. It is thus concluded that the block copolymer is mainly adsorbed on the crystal surface(s) rather than being incorporated into the lattice of tolazamide crystals. The recrystallized tolazamide is of the same crystal form as that of the original solid, regardless of the concentration of the copolymer used.

Sulfonylureas are insulin secretagogues used in the management of type 2 diabetes mellitus. The most common side effects are hypoglycemia and weight gain. Less frequent side effects are nausea, vomiting, cholestatic jaundice, agranulocytosis, generalized hypersensitivity reactions which include dermatological reactions. Dermatological reactions of sulfonylurea include photosensitivity. Drug induced photosensitivity is one of the important adverse drug reaction. Hence we would like to present here a case of sulfonylurea induced photosensitivity in an elderly diabetic male. He presented with rashes, itching, and intolerance to light and eruptions with exfoliation of skin over the sun exposed parts of the body. INTRODUCTION: Sulfonylureas are insulin secretagogues used in type 2 diabetes mellitus. They are substituted aryl sulfonylureas. They differ by substitutions at the para position on the benzene ring and at one nitrogen residue of the urea moiety. The sulfonylureas are divided into two generations. The first generation sulfonylureas (tolbutamide, tolazamide and chlorpropamide) are rarely used now. The second generation sulfonylureas are more potent and include glimepiride, glipizide and glyburide. Main side effects of sulfonylureas are hypoglycemia and weight gain. Other less common side effects are nausea, vomiting, cholestatic jaundice, agranulocytosis, generalized hypersensitivity reactions which include dermatological reactions like photosensitivity1. Photosensitivity is one of the neglected side effects of sulfonylureas and here we present a rare case of sulfonylurea induced photosensitivity. CASE REPORT: A 60 year old male patient presented with rashes, itching, and intolerance to light with exfoliation of skin over the sun exposed parts of the body. He had developed phobia for exposure to light and avoided taking pictures with camera flash. He was known diabetic on treatment with tablet glyburide 5mg (sulfonylurea) and metformin 500mg twice daily since 2 years. The patient was treated with sunscreen lotion for his skin lesions, but showed no improvement even after 2 months. Later, upon review of his drug history, it was revealed that glyburide (sulfonylurea) caused phototoxicity, and was withdrawn. The patient was put on an alternate hypoglycemic drug combination of pioglitazone 15mg and metformin 500mg twice daily. He also continued sunscreen application and sun protection. He improved gradually within 15 days and this suggests that it is a case of sulfonylurea induced phototoxicity.

Aim: Anti-diabetics such as sulfonylurea and thiazolidinedione derivatives are hypoglycemic drugs used for the treatment of diabetes. However, they can also be used as a stopper in horseracing. This paper describes a convenient method for the separation and simultaneous detection of 10 anti-diabetic drugs (namely glipizide, glibenclamide, glimepiride, gliclazide, tolazamide, tolbutamide, nateglinide, repaglinide, rosiglitazone and pioglitazone) in equine plasma and urine by LC–MS-MS. Method: The anti-diabetics were isolated from equine plasma and urine by liquid–liquid extraction with 1,2-dichloroethane at acidic pH, and analysed by LC–MS-MS in the positive electrospray ionisation mode. Separation of 10 anti-diabetic drugs was achieved with a reversed phase C8 column using a mixture of aqueous ammonium formate (pH 3.0, 10 mM) and methanol as the mobile phase. Results: Detection and confirmation of the 10 anti-diabetic drugs at 10 ng/mL each in equine plasma and equine urine were achieved by full-scan MS-MS. All of these drugs were detected consistently at this concentration in spiked samples of different plasma and urine ( n = 15 each). No significant matrix interferences were observed at the expected retention times of the targeted ions in blank urine samples ( n = 30). This method has been used successfully in the analysis of drug-administration samples as well as official racing samples. Conclusion: An LC–MS-MS method has been developed for the simultaneous detection of 10 anti-diabetics in equine plasma and urine. This method can be used to detect the abuse of anti-diabetic drugs in racehorses.

BACKGROUND: In subjects with type 2 diabetes mellitus, glycemic control deteroriates while patients use sulfonylurea drugs during the course of the disease. Adjunctive therapy with insulin at this stage requires a lesser daily insulin dose in comparison with insulin monotherapy while restoring desirable glycemic control. However, data regarding direct comparison between various sulfonylureas in this regard are lacking. OBJECTIVE: To examine comparative efficacies of adjunctive therapy with insulin in subjects with type 2 diabetes manifesting lapse of glycemic control while receiving various individual sulfonylurea drugs. METHODS: Four groups of 10 subjects, each presenting with glycosylated hemoglobin (HbA1C) >8.0% while using either tolazamide, glyburide, glipizide Gastrointestinal Therapeutic System (GITS), or glimepiride, were recruited. Two from each group were randomized to receive placebo; the others continued the same drug. Pre-supper subcutaneous 70 NPH/30 regular insulin was initiated at 10 units and gradually increased and adjusted as necessary to attain fasting blood glucose levels between 80 and 120 mg/dL and maintain the same range for 6 months. Fasting plasma glucose, plasma C-peptide, and HbA1C concentrations were determined prior to the addition of insulin and at the end of the study. Daily insulin dose and changes in body weight (BW) were noted at the end of the study, and the number of hypoglycemic events during the last 4 weeks of the study was determined. RESULTS: Daily insulin dose (units/kg BW), weight gain, and number of hypoglycemic events were significantly lower (p < 0.01) in subjects receiving sulfonylureas in comparison with placebo. However, the daily insulin dose alone was significantly lower (p < 0.05) with glimepiride (0.49 ± 0.10; mean ± SE) than with other sulfonylureas (tolazamide 0.58 ± 0.12, glyburide 0.59 ± 0.12, glipizide GITS 0.59 ± 0.14). Finally, a significant correlation (r = 0.68; p < 0.001) was noted between suppression of plasma C-peptide level and the daily insulin dose among all participants. CONCLUSIONS: By lowering the daily insulin dose, sulfonylurea drugs appear to improve the sensitivity of exogenous insulin in subjects with type 2 diabetes mellitus manifesting lapse of glycemic control. Moreover, glimepiride appears to possess a greater insulin-sparing property than other sulfonylureas.

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.

A silicone rubber thin membrane extraction probe was developed and evaluated as a sample preparation device prior to LC-MS/MS analysis. The permeation properties of the membrane were evaluated using the five selected sulphonylureas, tolbutamide, gliclazide, chlorpropamide, tolazamide, and glibenclamide. The effects of pH, temperature, and immersion time were investigated. A method for the determination of gliclazide in plasma was validated over the concentration range of 0.10-9.85 μg/mL covering the anticipated in-vivo concentrations. The applicability of the method was demonstrated by the determination of plasma concentrations of gliclazide in a human volunteer following an 80 mg oral dose of gliclazide with blood sampling out to 48 hours.

Effects of oral antihyperglycemic agents on extracellular matrix synthesis by mesangial cells. Background Increased expression of the glucose transporter GLUT1 in mesangial cells (MCs) markedly stimulates glucose transport and the formation of extracellular matrix (ECM), even when ambient glucose concentrations are low. Certain antihyperglycemic agents cause GLUT1 overexpression and increase glucose transport in various tissues. However, their effects on the kidney are unknown. Because diabetic glomerulosclerosis is characterized by the accumulation of mesangial matrix, we studied the effects of antihyperglycemic agents on matrix metabolism in MCs cultured either in 8 or 20mm glucose. Methods Membrane-associated GLUT1 was measured by immunoblotting. The initial rate of glucose transport was determined according to the 2-deoxy-D[ 14 C(U)]glucose uptake. Collagen metabolism was studied by metabolic radiolabeling with [ 14 C]-proline. Fibronectin in the medium was measured by ELISA. GLUT1 mRNA was estimated by Northern analysis. Results The sulfonylurea tolazamide increased GLUT1 protein expression by 107 and 69% in 8 and 20mm glucose-grown cells, respectively. However, GLUT1 mRNA levels remained unchanged. Transporter-dependent deoxyglucose uptake was increased by tolazamide up to 184% in a dose-dependent fashion and was evident at both glucose concentrations after three or five days of exposure to the drug. Tolazamide significantly stimulated transforming growth factor-β1 (TGF-β1) secretion and the total synthesis of collagen and collagen and fibronectin accumulation in the medium of MCs maintained in high or low glucose concentrations. The biguanide metformin did not alter GLUT1 expression, glucose transport, fibronectin formation, or collagen metabolism, except at high concentrations. Conclusion Tolazamide markedly enhances ECM synthesis and accumulation in MCs probably by stimulating GLUT1 expression, glucose transport and TGF-β1 secretion, irrespective of the ambient glucose concentration. This effect was dose-dependent and minimally inducible by metformin.

In addition to their hypoglycemic influence, sulfonylureas have been reported to inhibit prostanoid-induced vasoconstriction. Using isometric tension measurements we investigated whether this inhibitory influence is exerted by different sulfonylureas in various types of blood vessels from different species and in other types of smooth muscle cells. It was found that in addition to glibenclamide and tolbutamide also gliclazide (1 mM) and tolazamide (1 mM) block contractions induced by prostaglandin F2α and the thromboxane A2 mimetic U-46619 in rat aorta, but not the contractions elicited by norepinephrine, serotonin or high potassium. Glibenclamide (10 μM) inhibits the prostaglandin F2α- and U-46619-induced contractions on rat tail, femoral and renal interlobar arteries and on bovine retinal and ciliary arteries, but not those on aorta and carotid artery from guinea pigs and on human subcutaneous arteries. Glibenclamide (10 μM), tolbutamide (1 mM), tolazamide (1 mM) and gliclazide (1 mM) all block contractions induced by U-46619, but not those induced by carbachol, on rat intrapulmonary bronchioles. However, prostanoid-induced contractions of guinea-pig trachea and main bronchi are not influenced by glibenclamide (10 μM). From these results it is concluded that the ability of sulfonylureas to block prostanoid-induced contractions is shared by all sulfonylureas tested, that this is not limited to vascular smooth muscle cells and that it shows a heterogeneity, that might be linked to interspecies differences. © 1997 Elsevier Science B.V.

The oral antidiabetics glibenclamide, glipizide, glymidine, tolazamide and tolbutamide and the diuretics bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, furosemide, hydrochlorothiazide, hydroflumethiazide and trichlormethiazide were investigated for phototoxic effects in hairless mice. The back of the animals (hr/hr-c3H/TifBom) was covered with Duoderm dressing, and at the site of two punched out holes 0.05 ml of the test substances at 0.25 mol/1 concentration and the solvent alone as control were injected intradermally, respectively. Both test and control sites were irradiated with 6–12 J/cm2 of longwave UVA light from a “Bluelight 2000” apparatus (Honle, Martinsried, Germany). Skin reactions were read at 24 and 48 h. Compared to the solvent alone, all of the test substances induced reactions (necrosis or oedema) - most frequently seen by macroscopic and histologic investigation and by measurements with a thickness gage. Injection of the test substance or solvent alone without or with subsequent UVA irradiation, as well as UVA alone, did not induce measurable skin changes in this model. Three oral antidiabetics and four diuretics, not yet described to induce photosensitivity in vitro nor in vivo, were detected as potential photosensitizers using our animal model.

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.

The objective of this study is to prepare solid dispersions of tolazamide (TLZ) using polyethylene glycol (PEG) and measure the dissolution of TLZ. PEG 8000 was used as carrier to prepare solid dispersions by melt and solvent methods. Dissolution studies indicated a remarkable increase in the rate of dissolution of TLZ when dispersed in PEG as well as with physical mixture of TLZ and PEG. The rate of dissolution of TLZ was faster with solid dispersions containing TLZ:PEG (1:5) and (1:10) compared to physical mixtures and pure TLZ. The effect of buffer on dissolution was studied. In general the dissolution of TLZ was less in phosphate buffered saline (PBS, pH 7.4) compared to Tris buffer. However, there was no significant difference in the extent of dissolution of TLZ from solid dispersions and physical mixture compared to pure TLZ. Solid dispersions prepared by solvent method showed faster dissolution rates compared to melt method. These results suggest that the rate of dissolution can be increase...

A spectrophotometric method for the determination of some pharmaceutical amides, hydrazides and thiols is described. The method is based on the reaction of the studied drugs with 2,2-diphenyl-1-picryl hydrazyl (DPPH). The latter is employed to abstract a hydrogen atom from the drugs thereby promoting a process of radical coupling. This results in a reduction of the violet colour of DPPH with the formation of the yellow coloured 2,2-diphenyl-1-picrylhydrazine (DPPH2). This fading in colour of DPPH reagent depends on the concentration of the drug being determined. Beer's law is obeyed in the ranges of 1–5 μg/ml (for isocarboxazid and gliclazide), 0.25–2.5 μg/ml (for isoniazid), 0.5–5 μg/ml (for iproniazid), 1–7 μg/ml (for tolazamide), 2–15 μg/ml (for captopril) and 1–6 μg/ml (for sulphathiourea). The validity of the method was tested by analysing the studied drugs in pure form as well as in tablets. Results of analyses were compared statistically with the official or reported methods.

OBJECTIVE To assess the efficacy of combination therapy with insulin and sulfonylurea in the treatment of NIDDM. RESEARCH DESIGN AND METHODS Studies published between January 1966 and January 1991 were identified through a computerized Medline search and by hand searching the bibliographies of identified articles. We identified 17 eligible randomized, controlled trials of combination therapy in NIDDM. These trials had a minimum duration of 8 wk and at least one of three outcome measures (fasting glucose, HbA1, or C-peptide) with SD or SE of the mean reported to do metaanalysis. With standardized forms, three independent reviews abstracted measures of study quality and specific descriptive information about population, intervention, and outcome measurements. RESULTS We calculated effect size and weighted mean changes of the three outcome measures for control and treatment groups. In the treatment group, the fasting plasma glucose decreased from a mean of 11.4 mM (206 mg/dl) at baseline to a mean of 9.16 mM (165 mg/dl) posttreatment, whereas the control group decreased from (11.3 to 10.8 mM) (204 to 194 mg/dl) (effect size 0.39, P < 0.0001). For HbA1, the treatment group decreased from a baseline of 11.0 to 10.2% compared to 11.0 and 11.2% in the control group (effect size 0.43, P < 0.0001). For fasting C-peptide, the treatment group increased from 0.49 to 0.58 nM (1.45 to 1.75 ng/ml) compared with 0.47 and 0.43 (1.42 and 1.30) for the control group (effect size 0.26, P < 0.017). CONCLUSION Combined insulin-sulfonylurea therapy leads to modest improvement in glycemic control compared with insulin therapy alone. With combined therapy, lower insulin doses may be used to achieve similar control. Obese patients with higher fasting C-peptides may be more likely to respond than others.

A spectrophotometric method is described for the assay of fenpipramide hydrochloride, isopropamide iodide, trimethobenzamide hydrochloride, morphazinamide hydrochloride and tolazamide. The method is based on the formation of a charge—transfer complex between the drug as n -donor and iodine, a ∂-acceptor. The product exhibits absorption maxima at 295 and 365 nm; measurements are made at 365 nm for fenpipramide and at 295 nm for the other compounds. Beer's law is obeyed in a concentration range of 1–120 μg ml −1 . The method is rapid, simple and sensitive and can be applied to the analysis of some commercial and laboratory prepared tablets without interference. A more detailed investigation of the complex was made with respect to its composition. association constant and free energy change.

The elderly patient with type II diabetes should be treated in much the same fashion as a younger person with the same disease, although emphasis needs to be placed on minimizing side effects, drug interactions, and hypoglycemia. Chlorpropamide should not be used in these patients, unless there is no other choice. The remaining agents--tolbutamide, acetohexamide, tolazamide, glyburide, and glipizide--should be started at low doses and gradually increased until optimal diabetic control is reached. The initial treatment goal is a FPG level of less than 180 mg/dl and a final goal is a 1- to 2-hour PPG concentration between 140 and 180 mg/dl. The glycosylated hemoglobin value should be no greater than 1.5% above the upper limit of normal, and should be lower, if possible. It must be kept in mind, however, that the closer diabetic patients are to achieving euglycemia, the more likely is hypoglycemia. Treatment goals therefore may have to be relaxed in someone at increased risk of hypoglycemia (e.g., patients with irregular eating habits or renal insufficiency) or when hypoglycemia may pose a greater hazard (e.g., patients with coronary artery or cerebral vascular disease). Patients on sulfonylurea agents should have blood glucose values measured once a month and glycosylated hemoglobin levels determined once every 3 months to alert the clinician to the possible need to adjust therapy. In this way, potential hypoglycemia can be avoided if blood glucose levels are drifting too low and chronic hyperglycemia can be identified and treated within a short period of time. When a patient's status changes--e.g., he is placed on new medication, becomes depressed and anorexic, or develops another medical problem--care must be taken to re-evaluate his diabetes management. Drugs such as sulfonamide antibiotics can potentiate the action of the sulfonylureas and cause hypoglycemia, renal insufficiency may necessitate changing the type of sulfonylurea agent or decreasing the dose, and malnutrition may obviate any need for therapy with an oral hypoglycemic agent. If these guidelines are kept in mind, the older diabetic patient can be managed on a sulfonylurea agent in conjunction with the appropriate diet. Should these measures prove to be ineffective, then insulin therapy should be instituted. Controlling chronic hyperglycemia will help improve the quality of life for patients with diabetes and decrease the probability of developing some of the devastating complications associated with this disease.

Recent data suggests that one of the major actions of sulfonylureas is to potentiate the anabolic cellular effects of insulin. This is the first study to examine the use of sulfonylureas as adjunctive therapy in newly-diagnosed type I diabetic children. A random, prospective, double blind study over 15 months, stratified by age at diagnosis, was conducted. The treatment group (n = 13) received daily oral weight-adjusted tolazamide whereas the control group (n = 11) received placebo. Monthly comparison of the HbA1 values between groups revealed no statistical difference; likewise, the fasting serum C-peptide values were not dissimilar. The mean daily insulin dose per kilogram, however, was less in the tolazamide group (P less than 0.001). The data suggests that the addition of tolazamide may not be of therapeutic benefit in newly diagnosed juvenile diabetics, although insulin requirements may be reduced.

Drugs used for lowering the glucose level in the blood are called hypoglycemic agents. Changes in the level of glucose in the blood can be caused by various reasons, the primary cause being diabetes mellitus. Diabetes mellitus is a metabolic disease associated with a high level of blood sugar and as a rule, disturbance of carbohydrate, lipid, and protein metabolism. Insulin and other hypoglycemic agents are used to treat diabetes mellitus. Insulin, a pancreatic hormone, is a specific antidiabetic agent, especially for type I diabetes. In the body, insulin is synthesized by β-cells of Langerhans islets in the pancreas. The rate of formation changes depending on the type of food consumed, gastrointestinal hormones, and neuronal control. The chapter describes the specific uses on insulin, its mechanish and chemical structure. For patients with type II diabetes, in which endogenic secretion of insulin functions to some degree, a number of very effective hypoglycemic drugs are prescribed. The chapter discusses some of the major synthetic drugs hypoglycemic drugs, such as Tolbutamide, Chlorpropamide, Acetohexamide, Tolazamide, Glyburide, and Glipizide.

Sulfonylureas are widely used as an antidiabetic drug. In the present study, the effects of sulfonylurea administered supraspinally on immobilization stress-induced blood glucose level were studied in ICR mice. Mice were once enforced into immobilization stress for 30 min and returned to the cage. The blood glucose level was measured 30, 60, and 120 min after immobilization stress initiation. We found that intracerebroventricular (i.c.v.) injection with 30 µg of glyburide, glipizide, glimepiride or tolazamide attenuated the increased blood glucose level induced by immobilization stress. Immobilization stress causes an elevation of the blood corticosterone and insulin levels. Sulfonylureas pretreated i.c.v. caused a further elevation of the blood corticosterone level when mice were forced into the stress. In addition, sulfonylureas pretreated i.c.v. alone caused an elevation of the plasma insulin level. Furthermore, immobilization stress-induced insulin level was reduced by i.c.v. pretreated sulfonylureas. Our results suggest that lowering effect of sulfonylureas administered supraspinally against immobilization stress-induced increase of the blood glucose level appears to be primarily mediated via elevation of the plasma insulin level.

Orale Antidiabetica vom Sulfonylsemicarbazid-Typ wie Tolazamid (1) und Glisoxepid (2) wurden unter milden nitrosierenden Bedingungen, auch annahernd physiologischen in vitro Bedingungen, nach einem neuartigen Reaktionsverlauf in Sulfonyltriazene 3a, b umgewandelt. Modellverbindungen mit N4-Acyl-semicarbazidstruktur 4 zeigen abweichendes Reaktionsverhalten, wobei Saureamide 5 neben Nitrosaminen 6 gebildet werden. Nitrosations with Hydrazine Derivatives, VI: Novel Reaction of Oral Antidiabetics of the Sulfonylsemicarbazide Type under Nitrosating Conditions Oral antidiabetics of the sulfonylsemicarbazide type like Tolazamide (1) and Glisoxepide (2) were transformed under mild nitrosating conditions, even nearly physiological in vitro conditions, to sulfonyl triazenes 3a, b by a novel reaction pathway. Model compounds with N4-Acyl-semicarbazide structure 4 showed different reaction behaviour yielding carbonamides 5 and nitrosamines 6.

Characterization of the rat mesangial cell type 2 sulfonylurea receptor. Background Sulfonylurea receptors are classified as either high-affinity type 1 (SUR1) or low-affinity type 2 receptors (SUR2), and the gene expression of SURs has recently been demonstrated in kidney. However, functional data regarding a renal SUR are lacking. We previously demonstrated that mesangial cell (MC) gene and protein expression of extracellular matrix components were up-regulated by the sulfonylurea, tolazamide. After noting this biological response, we next sought to investigate the presence of a sulfonylurea receptor in rat MCs. Methods Equilibrium binding studies employing [ 3 H]glibenclamide as a ligand were performed on crude MC membrane preparations. Gene expression for SUR was explored by Northern analysis of cultured MCs and whole kidney tissue. The effect of sulfonylurea on intracellular Ca 2+ in MCs was assayed by spectrofluorometry, and glibenclamide-induced changes in the contractility of MCs were assessed. Results MCs bound [ 3 H]glibenclamide with a K D of 2.6 μm and a B max of 30.4 pmol/mg protein as determined by Scatchard analysis. Three SUR2 transcripts were detected in MCs. A major transcript was detected at 5.5kb and minor transcripts at 7.5 and 8.6kb. Following sulfonylurea treatment of MCs, real-time videomicroscopy revealed intense MC contraction, coinciding with oscillatory increments of intracellular Ca 2+ concentration. Further evidence of sulfonylurea-induced MC contraction was demonstrated by glibenclamide-induced deformation of a silicone rubber substrate. Conclusions These results demonstrate that SUR2 resides on MCs. Functional activation of this receptor by sulfonylurea induces Ca 2+ transients that result in MC contraction.

Sulphonylureas have remained the mainstay of oral therapy for type 2 (non-insulin-dependent) diabetes mellitus (NIDDM). They stimulate insulin release from pancreatic beta cells. Pharmacokinetic differences between the various sulphonylureas are of clinical importance in terms of the time to onset of action, timing of drug administration in relation to food intake, magnitude and duration of the glucose-lowering effect and the risk of serious hypoglycaemia. Recent studies with improved analytical sensitivity have shown that the elimination half-life of glibenclamide is longer than previously thought and that 2 metabolites of glibenclamide have significant hypoglycaemic activity. Furthermore, single dose studies in healthy volunteers using an integrated pharmacokinetic-pharmacodynamic model have identified clear concentration-effect relationships for both glibenclamide and its metabolites after oral and intravenous administration. Under multiple dose conditions, kinetic-dynamic relations have been identified with shorter-acting drugs in dosages that give discontinuous sulphonylurea exposure. However, at continuous exposure, i.e. sustained 24-hour therapeutic concentrations in plasma, there is evidence indicating the development of tolerance, which may be caused by downregulation of beta cell sensitivity. As more sophisticated concentration-effect studies appear, it has become evident that currently recommended maximum daily doses of many sulphonylureas are too high.

Seven oral antidiabetics (chlorpropamide, glibenclamide, glipizide, gliquidone, glymidine, tolazamide, and tolbutamide), and 14 diuretics (bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlortalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, piretanide, polythiazide, trichlormethiazide, and xipamide) were investigated for potential phototoxicity in vitro using a cell culture model and in vivo in hairless mice. After exposure to broad band UVA, the majority of the substances tested in vitro yielded phototoxic action leading to loss of culture forming ability. In vivo, all tested substances induced edema or ulceration, and lead to a significant increase in skin fold thickness of the mouse skin. In all a number of substances not described to induce clinical photosensitivity nor phototoxicity in vitro or in vivo were detected in our testing. In determining potential photosensitizers, it seems important to utilize different test methods, as not all substances will exhibit action in a given assay.© (1997) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

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.

Potassium channels closed by increases in intracellular ATP levels (KATP channels) have been described in vascular smooth muscle cells and other cell types. These channels are responsive to the metabolic state of the cells, and can be opened by a decrease in intracellular ATP levels and intra- or extracellular acidosis. Hemorrhagic shock is associated with early vasomotor paralysis as well as with early derangements in the intracellular metabolic status. Here we have tested whether activation of KATP channels contributes to the vasodilatation and early mortality in a rat model of severe hemorrhagic shock. In anesthetized rats hemorrhaged to a mean arterial blood pressure (MAP) of 35 mmHg, inhibition of KATP channels with glibenclamide or tolazamide (10 mg/kg i.v. bolus injection followed by an infusion of 10 mg/kg/h for 60 min), rapidly increased MAP and improved survival rate. The same dose of the KATP channel inhibitors did not cause a significant increase of MAP in animals not subjected to hemorrhage. The approach of inhibition of KATP channel activation in hemorrhagic shock is worthy of further investigations to determine whether it may represent a novel approach for early resuscitation during hemorrhage.

OBJECTIVE: To review the comparative efficacy of metformin, sulfonylureas, and insulin in the treatment of patients with type II diabetes. DATA SOURCES: Articles were identified by a MEDLINE search of articles from 1966 to 1994, using the terms metformin, sulfonylurea, chlorpropamide, glipizide, glyburide, tolazamide, tolbutamide, and insulin, published in English, French, or German. Articles also were identified from bibliographies of pertinent articles. STUDY SELECTION: With the exception of articles dealing with the pharmacology of metformin, only randomized, active, controlled studies were selected for review. DATA EXTRACTION: Effects of metformin therapy on metabolic and cardiovascular risk factors were abstracted: weight, blood pressure, total and low-density lipoprotein cholesterol, triglycerides, fasting and postprandial glucose, and glycosylated hemoglobin. DATA SYNTHESIS: Metformin is an antihyperglycemic agent with a mean bioavailability of 50–60%. It is eliminated primarily by renal filtration and secretion and has a half-life of approximately 6 hours in patients with type II diabetes. Although the half-life of metformin is prolonged in patients with renal impairment, no specific dosage adjustments have been recommended. This agent has no effect in the absence of insulin. Metformin is as effective as the sulfonylureas in treating patients with type II diabetes and has a more prominent postprandial effect than the sulfonylureas or insulin. When combined with a sulfonylurea, metformin has been shown to exert antihyperglycemic effects in addition to the sulfonylurea with which it is combined. Metformin decreases absorption of vitamin B12 and folic acid, although reported cases of megaloblastic anemia are rare. Cimetidine decreases the elimination of metformin; therefore, the manufacturer reccommends a reduced metformin dosage when these agents are combined. The most frequently reported adverse effects of metformin are gastrointestinal in nature (diarrhea, nausea, abdominal pain, and metallic taste, in decreasing order). Metformin has been used in Canada, Great Britain, and the rest of Europe for more than 30 years and was approved for use in the US in December 1994. CONCLUSIONS: Three trials comprise the Food and Drug Administration approval database (one foreign). Metformin will be most useful in managing patients with poorly controlled postprandial hyperglycemia, as its postprandial effect is much greater than that of the sulfonylureas. In contrast, sulfonylureas or insulin are more effective for managing patients with poorly controlled fasting hyperglycemia. Metformin should be considered a first-line agent, particularly in obese or hyperlipidemic patients. Wayne R Melchior PharmD BCPS, Drug Information Specialist, St Joseph Mercy Hospital, Pontiac, MI; and Adjunct Professor, Drug Information, Department of Pharmacy Practice, Ferris State University, Big Rapids, MI Linda A Jaber PharmD, Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, Wayne State University, 328 Shapero Hall, 1400 Chrysler Dr, Detroit, MI 48201, FAX 313/577-5369

Oral antidiabetic drugs are widely used in the treatment of diabetes mellitus and are effective in controlling blood glucose levels. These drugs are of several distinct types with different modes of action and include sulfonylureas, biguanides and α-glucosidase inhibitors. The sulfonylurea antidiabetic drugs include acetohexamide, acetylcarbutamide, carboxytolbutamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, metahexamide, tolazamide and tolbutamide. The structural formulas of some of the important antidiabetic agents are given in Fig. 1.

Micellar electrokinetic chromatography (MEKC) is evaluated as a potential analytical method for the separation and detection of a series of sulfonylurea drugs used in the treatment of hyperglycemia. These drugs are often surreptitiously abused, producing extremely low blood glucose levels and symptoms indistinguishable from those associated with an insulin-secreting tumor. Separation buffer containing 50 mM sodium dodecyl sulfate (SDS) was found to be adequate for the MEKC separation of the third generation drugs (glipizide and glyburide) but not the second generation drugs (acetohexamide chlorpropamide, tolazamide, and tolbutamide). At a pH of 8.5 in the presence of 20 mM borate/20 mM phosphate and 150 mM SDS, all seven components were adequately resolved with an analysis time of 17 min. Altering the concentration of the buffering components to either 5 mM borate/5 mM phosphate or 40 mM borate alone reduced the analysis time to less than 10 min with no observable loss in resolution. A series of other micelle-forming surfactants were evaluated, and only sodium cholate provided an improvement over the SDS-based system. Optimal separation was obtained with 75 mM sodium cholate and led to complete analysis with baseline resolution of all seven components in less than 8 min. These conditions were shown to be adequate for the detection of the hypoglycemic drugs spiked into normal urine and in patients taking these drugs. The precision associated with nine consecutive injections of six samples (n = 54) was found to be acceptable with percent coefficient of variance for absolute migration times (MTabs) for all peaks averaging 0.89 with peak area and peak height being 8.49 and 8.26, respectively. The between-sample precision was found to average 0.92% for MTabs and 8.56% and 8.45%, respectively, for the relative peak area and peak height. With a detection limit for the drugs in urine (following extraction) in the 50 ng/mL range, the potential exists for an MEKC-based assay for the detection of sulfonylurea drugs in urine.

In a retrospective study we investigated the effects of altering treatment of type II diabetes mellitus from insulin to tolazamide on weight and blood pressure. In 17 patients, weight decreased from 136 +/- 6 to 131 +/- 6% of ideal body weight (P = .01). Even though weight loss occurred, mean systolic blood pressure increased from 133 +/- 3 mm Hg to 142 +/- 4 mm Hg (P = .025). There was no difference in diastolic blood pressure on the two treatments (79 +/- 3 v 78 +/- 4 mm Hg). In an additional 10 patients whose treatment was changed from tolazamide to insulin, mean systolic blood pressure decreased from 136 +/- 1 to 124 +/- 2 mm Hg (P.01). In spite of the potential benefits of reversal of insulin resistance and weight reduction, altering therapy of type II diabetes mellitus from insulin to tolazamide may increase blood pressure, thereby increasing cardiovascular risk.

The article reviews the effect of diabetes on the pharmacokinetics and pharmacodynamics of drugs in humans. For most drugs which cross the gastrointestinal wall by passive diffusion, oral absorption is unlikely to be affected by diabetes, although a delay in the absorption of tolazamide and a decrease in the extent of absorption of ampicillin have been reported. Subcutaneous absorption of insulin is more rapid in diabetic patients, whereas the intramuscular absorption of several drugs is slower. The binding of a number of drugs in the blood is reduced in diabetes, which may be due to glycosylation of plasma proteins or displacement by plasma free fatty acids, the level of which is increased in diabetic patients. Plasma concentrations of albumin and alpha 1-acid glycoprotein do not appear to be changed by the disease. The distribution of drugs with little or no binding in the blood is generally not altered, although the volume of distribution of phenazone (antipyrine) is reduced by 20% in insulin-dependent diabetes mellitus (IDDM). In contrast to animal studies, the metabolic clearance of most drugs in humans appears to be unaffected or slightly reduced by the disease. The presence of fatty liver in non-insulin-dependent diabetes mellitus (NIDDM) may contribute to a reduced hepatic clearance, whereas decreased binding in the blood may cause an increase in clearance. The effect of diabetes on hepatic blood flow in humans appears to be unknown. Diabetes affects kidney function in a significant number of diabetic patients. During the first 10 years after the onset of the disease, glomerular filtration is elevated in these patients. Thus, the renal clearance of a number of antibiotics has been shown to be increased in diabetic children. As the disease progresses, renal function is impaired and glomerular function declines from the initial elevated state. In diabetic adults the renal clearance of drugs either is comparable with that found in nondiabetic individuals or is reduced. A limited number of studies have been conducted comparing the dose-response of cardiovascular drugs in diabetic patients with that in nondiabetic controls. Decreased, increased and unchanged responses have been reported. It is apparent that in some cases an altered response may be observed for a drug when administered to a diabetic patient compared with a similar nondiabetic individual. At the present time, it is not possible to ascertain whether these studies reflect true pharmacodynamic changes or merely alterations in pharmacokinetics.(ABSTRACT TRUNCATED AT 400 WORDS)

We report a case of persistent, raised, annular, erythematous plaques in a patient taking chlorpropamide. A diagnosis of lichenoid drug eruption was made

We evaluated therapeutic usefulness of the second-generation sulfonylurea agents glyburide and glipizide in non-insulin-dependent diabetic patients who were secondary failures on chlorpropamide or tolazamide. Twenty patients were treated with glyburide, and 10 of them were subsequently treated with glipizide. Fasting and postprandial serum glucose, insulin, C-peptide, glycosylated hemoglobin, urinary C-peptide, and glucose levels all failed to show significant improvement. We conclude that both glyburide and glipizide proved ineffective in the treatment of secondary failures to first-generation sulfonylureas.

The adsorption of acetohexamide, tolazamide and tolbutamide at pH 7.4 on kaolin and activated charcoal was studied at 37°C. Langmuir adsorption isotherms were established and the maximum adsorption capacities of activated charcoal and kaolin were estimated. The results of desorption experiments suggested that desorption was incomplete, but to a relatively greater extent from activated charcoal than from kaolin. The hypoglycaemic activity of the 3 drugs was suppressed in the presence of both activated charcoal or kaolin.

To assess the effects of sulfonylurea therapy on plasma lipids and high-density lipoprotein composition, 11 obese diabetic Pima Indians with type II, or non-insulin-dependent, diabetes mellitus were studied before and after tolazamide therapy for one month. Diet composition and weight were kept constant, and the data were compared with a control group of 18 age-, sex-, and weight-matched non-diabetic subjects. Improvement of glycemic control was accompanied by significant decreases in total and very-low-density lipoprotein triglycerides. Total and low-density lipoprotein cholesterol also declined significantly, and there was an increase in the ratio of high-density lipoprotein to low-density lipoprotein cholesterol. Concentrations of total high-density lipoprotein cholesterol, phospholipid, and apolipoprotein A 1 were unchanged. An increase in the proportion of the high-density lipoprotein 2 subfraction, however, was suggested by significant increases in the ratios of high-density lipoportein 2 to high-density lipoprotein 3 cholesterol and apolipoprotein A 1 . There was also a change in the composition of the high-density lipoprotein 2 particle, as indicated by changes in the molar ratio of cholesterol to apolipoprotein A 1 . The data suggest that improvement of glycemic control after sulfonylurea therapy, when weight and diet composition remain constant, reverses several of the lipoprotein abnormalities observed in type II diabetic patients. There was no evidence of changes in lipoproteins in directions associated with an increased risk for atherosclerosis.

The metabolic fate of tolazamide, 1-(hexahydroazepin-1-yl)-3-p-tolylsulfonylurea (1), was studied in man and in the rat using tritium-labeled 1. The metabolites were isolated in crystalline form from urine for structure determination. The crystal structure and final molecular structure of one of these, 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5), were determined using single-crystal X-ray techniques. Following oral administration of tritiated tolazamide to male humans, 85% of the radioactivity was excreted in urine during a 5-day period. In addition to being excreted in urine unchanged, tolazamide was metabolized to 1-(hexahydroazepin-1-yl)-3-p-(carboxyphenyl)sulfonylurea (2), p-toluenesulfonamide (3), 1-(hexahydroazepin-1-yl)-3-p-(hydroxymethylphenyl)sulfonylurea (4), 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5) and a labile, unidentified metabolite 6 by man. The relative amounts of these materials excreted in 0-24-h urine collections from eight subjects averaged 7, 17, 26, 10, 25, and 15% for 1-6, respectively. In the female rat, 79% of an orally administered dose of tritiated tolazamide was excreted in urine during a 5-day period as 1-4. The relative amounts of these materials excreted during the 24-h period following administration of tolazamide were 10, 5, 5, and 80% for 1-4, respectively.

Polypeptide hormones such as insulin must cross the vascular barrier to mediate their biologic actions. A substantial vascular barrier may be encountered in muscle and fat tissues, which are supplied by continuous capillaries lined with tightly joined endothelial cells. Endothelial cells have previously been shown to bind and release insulin with minimal degradation. Because 125 I-labeled insulin transport was demonstrated to be receptor-mediated, factors regulating insulin-receptor binding may also affect the insulin transport rate across the vascular barrier. Since sulfonylureas may have a glucose-lowering action by altering insulin receptors, the effects of tolazamide and glyburide on vascular endothelial cell insulin receptors were evaluated. Exposure of aortic endothelial cells in culture to insulin at 37°C resulted in a 75 percent loss of receptors. Five to seven days of tolazamide exposure led to a 35 percent time-dependent increase in insulin binding. More strikingly, tolazamide altered the dose-receptor to insulin-induced down-regulation. Cells down-regulated with insulin (10 ng/ml) showed a 100 percent increase in binding in the presence of tolazamide; a dose-dependent effect occurred at the 75 to 200 μg/ml dosage level. Scatchard analysis indicated that the increase in 125 I-labeled insulin binding was due to an increase in receptor number. When insulin receptors were identified with 125 I-labeled insulin, tolazamide-treated cells clearly showed an increase of a band at M r =145 K, the alpha subunit of the receptor. Tolazamide may thus help normalize glucose in diabetes by preventing receptor down-regulation in endothelial cells.

Adsorption of carbutamide, chlorpropamide, tolazamide, tolbutamide, glibenclamide (glyburide), and glipizide onto activated charcoal was compared in vitro using different charcoal-to-drug ratios. Maximal binding capacities of different sulfonylureas were 0.45-0.52 g/g of charcoal at pH 7.5. The affinity of the second generation derivatives, glibenclamide and glipizide, was considerably higher than that of the first generation derivatives. The affinity of sulfonylureas to charcoal was higher at pH 4.9 than at pH 7.5. Poor water solubility of sulfonylureas at pH 1 prevents the adequate testing in these conditions. Contrary to what has appeared previously, activated charcoal effectively adsorbs different sulfonylureas and can be used to possibly prevent their gastrointestinal absorption.

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.