Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new glucotrol research articles will be listed here shortly after becoming available to us.
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Medical research on glucotrol
Clin Ther. 2008 Jul; 30(7): 1330-5
Hsieh CY, Chen CH
Background: Danazol is a steroid analogue with anabolic and androgenic effects and is indicated for the treatment of endometriosis, fibrocystic diseases of the breast, and hereditary angioedema. Lovastatin has been prescribed to lower total cholesterol and low-density lipoprotein cholesterol, reducing cardiovascular-related morbidity and mortality in patients with hypercholesterolemia. As monotherapies, both danazol and lovastatin have been reported to induce myopathy and pancreatitis. Case summary: A 59-year-old Asian woman (height, 155 cm; weight, 54 kg; and body mass index, 22.5 kg/m2) presented to the outpatient neurology clinic with acute progressive quadriparesis and generalized myalgia (without focal sensory loss, numbness, dizziness, diplopia, dysarthria, dysphagia, or sphincter incontinence), lasting for 5 days. She was admitted to the National Cheng Kung University Hospital, Tainan, Taiwan. The patient's medical history revealed multiple comorbidities (eg, end-stage renal disease, hypertension, diabetes mellitus) for which she was receiving concomitant medication. Her medication history revealed that at the time the patient presented, she was also receiving calcium bicarbonate 1500 mg/d, labetalol 100 mg/d, and glipizide 10 mg/d in the treatment of her other comorbid illnesses. The patient was also receiving alprazolam 0.5 mg/d for insomnia. Her medical records also revealed that lovastatin 40 mg/d (a particularly high dose and not recommended) had been administered for 7 weeks, and danazol 600 mg/d was added ( approximately 15 days later) to treat thrombocytopenia due to hypoplastic bone marrow. Laboratory findings revealed elevated creatine kinase (68,193 U/L), elevated pancreatic enzymes (amylase/lipase, 361/2788 U/L), and elevated liver enzymes (aspartate/alanine aminotransferase, 1496/1493 U/L), consistent with rhabdomyolysis and pancreatitis. After discontinuation of both drugs, the symptoms improved 5 days after admission and completely disappeared 1 month after admission. In addition, laboratory abnormalities completely normalized approximately 2 months after admission.Danazol was resumed to treat persistent thrombocytopenia, while lovastatin was replaced with ezetimibe 10 mg QD to treat high cholesterol (dyslipidemia). Conclusion: The coadministration of high-dose lovastatin and danazol was probably associated with rhabdomyolysis and pancreatitis in this patient with multiple underlying comorbidities for which concomitant medications were being administered.
J Chromatogr Sci. 2008 Jul; 46(6): 510-7
Bansal G, Singh M, Jindal KC, Singh S
Forced degradation studies on glipizide are conducted under the conditions of hydrolysis, oxidation, photolysis, and dry heat. The solutions are subjected to liquid chromatographic (LC) investigations to establish the number of products formed in each condition. The degradation products are characterized through isolation and subsequent NMR, IR, and MS spectral analyses, or through LC-mass spectrometry (MS) fragmentation pattern study. The drug is shown to degrade in 0.1M HCl at 85 degrees C to two products: 5-methyl-N-[2-(4-sulphamoylphenyl)ethyl]pyrazine-2-carboxamide (II) and methyl N-[4-[2-{(5-methyl-2-pyrazinoyl)amino}ethyl] phenyl]sulfonyl carbamate (III). The latter, a methyl ester, is formed only in the presence of methanol (used as a solubilizer), and does not appear on use of acetonitrile. III is shown to convert to II on continued heating in acid. The drug degrades slowly in water at the same temperature, and both II and III could be seen in the chromatograms until the end of the study. The heating of the drug in alkali (0.1M NaOH) at 85 degrees C yields 5-methyl-2-pyrazinecarboxylic acid (IV), along with a small quantity of 4-(2-aminoethyl) benzenesulfonamide (I). On extended heating in the same condition, a new product, 4-(2-aminoethyl)-N,N-bis[(cyclohexylamino)carbonyl] benzenesulfonamide (VI) is formed in small quantities. At the lower temperature of 40 degrees C, the drug converts under each hydrolytic condition and in both the absence and presence of light to products II, III, or IV, along with a new product, 1-cyclohexyl-3-[[4-(2aminoethyl)phenyl] sulfonyl]urea (V). The light catalyzes formation of V, and it is formed until one or two weeks, after which its level decreases. The drug remains stable in 30% H2O2, except that products II and III appear as small peaks due to acidic character of the peroxide solution. Also, the drug remains unaffected in solid state under thermal and photolytic stress conditions. Based on the results, a more complete picture on degradation pathway of the drug is obtained, highlighting a clear advantage of the approach suggested by International Conference on Harmonization.
Acta Pharmacol Sin. 2008 Jul; 29(7): 789-99
Li L, Ma KT, Zhao L, Si JQ, Zhang ZS, Zhu H, Li J
AIM: The influence of niflumic acid (NFA), a Cl(-)channel antagonist, on the membrane potentials in smooth muscle cells (SMC) of the cochlear spiral modiolar artery (SMA) in guinea pigs was examined. METHODS: The intracellular recording and whole-cell recording technique were used to record the NFA-induced response on the acutely-isolated SMA preparation. RESULTS: The SMC had 2 stable but mutually convertible levels of resting potentials (RP), that is, one was near -45 mV and the other was approximately -75 mV, termed as low and high RP, respectively. The bath application of NFA could cause a hyperpolarization in all the low RP cells, but had little effect on high RP cells. The induced responses were concentration-dependent. Large concentrations of NFA (>or=100 micromol/L) often induced a shift of a low RP to high RP in cells with an initial RP at low level, and NFA (up to 100 micromol/L) had little effect on the membrane potentials of the high RP cells. However, when the high RP cells were depolarized to a level beyond -45 mV by barium and ouabain, NFA hyperpolarized these cells with the similar effect on those cells initially being the low RP. The NFA-induced response was almost completely blocked by charybdotoxin, iberiotoxin, tetraethylammonium, 1,2-bis(2- aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetrakis acetoxymethyl ester, but not by 4-aminopyridine, barium, glipizide, apamin, ouabain, and CdCl2. CONCLUSION: NFA induces a concentration-dependent reversible hyperpolarization in SMC in the cochlear SMA via activation of the Ca2+-activated potassium channels.
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Jul 1; 870(1): 135-9
Niu Z, Chen F, Sun J, Liu X, Wang Y, Chen D, He Z
A rapid, sensitive and specific high performance liquid chromatography-electrospray ionization tandem quadrupole mass spectrometry (HPLC-MS/MS) method was developed and validated for the determination of 3-n-butylphthalide in rat plasma. Following protein precipitation with acetonitrile, 3-n-butylphthalide and glipizide (internal standard, I.S.) were separated using a gradient elution program on a C(18) column and detected by mass spectrometry in positive ion mode with the multiple reaction monitoring (MRM) mode using the respective precursor to product ion combinations of m/z 191/145 for 3-n-butylphthalide and m/z 446/321 for glipizide, respectively. The total chromatographic running time was 2.5min. The method was linear over the concentration range of 11.14-3480.00ng/mL, using as little as 100muL plasma. The lower limit of quantification (LLOQ) was 5.57ng/mL. Finally, the method was successfully used to support a preclinical pharmacokinetic study of 3-n-butylphthalide in rats following intravenous administration.
Guang Pu Xue Yu Guang Pu Fen Xi. 2008 Mar; 28(3): 711-4
Zhang YM, Li X, Sun CS, Chen CF
The interaction of glipizide and hydroxypropyl-pcyclodextrin was investigated in the present paper. The stability constant and molar ratio of glipizide and hydroxypropyl-beta-cyclodextrin was calculated from the phase soluility diagram. The solid state inclusion complex of hydroxypropyl-beta-cyclodextrin/glipizide prepared by neutralization method was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). It was found that the phase solubility diagram of the HP-beta-CD solution showed a typical AL-type, suggesting the formation of a soluble complex of 1 : 1 molar ratio, and the stability constant was 359 L x mol(-1) at 25 degrees C. The spectra of IR, thermograph of DSC and XRD pattern of the inclusion complex were remarkably different from the glipizide and hydroxypropyl-beta-cyclodextrin/glipizide physical mixture, and indicated that hydroxypropyl-beta-cyclodextrin/glipizide inclusion complex displayed amorphous characteristic. The experiment of solubility of inclusion complex indicated that the solubility of inclusion complex increased 25-fold.
Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency.
Diabetes Obes Metab. 2008 Jul; 10(7): 545-55
Chan JC, Scott R, Arjona Ferreira JC, Sheng D, Gonzalez E, Davies MJ, Stein PP, Kaufman KD, Amatruda JM, Williams-Herman D
OBJECTIVE: To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) > or =30 to
New treatments for type 2 diabetes mellitus: combined therapy with sitagliptin.
Expert Opin Pharmacother. 2008 Jun; 9(9): 1495-507
Gagliardino JJ, Santoro S, Arellano S, Di Girolamo G
BACKGROUND: Sitagliptin is a highly selective oral dipeptidyl peptidase-4 inhibitor. This drug increases the plasma concentration of active glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide. These two hormones then simulate the secretion of insulin in a glucose-dependent manner and inhibit glucagon secretion, thus reducing circulating glucose levels. In animal models, GLP-1 increases beta-cell mass. OBJECTIVE: To review the efficacy and safety of sitagliptin in combined therapies (as add on or initial combination treatment) in type 2 diabetes. METHODS: A Medline search on published clinical trials involving sitagliptin in combined therapies was performed; additional information from published papers and abstracts to congresses on preclinical and basic science issues was also included to support the mechanistic rationale of combinations. RESULTS/CONCLUSION: In humans sitagliptin administration reduces fasting and postprandial glucose and A1c levels. Sitagliptin is as effective as glipizide (close to 0.7% mean A1c reduction), but has fewer hypoglycemic events than other oral insulin secretagogues. Since metformin reduces hepatic glucose production and increases GLP-1 release, combined therapy with sitagliptin becomes complementary and has been shown to have important additive effects. Sitagliptin combined with pioglitazone resulted in improved metabolic control when compared with pioglitazone plus placebo. Combined administration with insulin requires further studies. The weight neutral effect of sitagliptin, its glucose-dependent action (lower risk of hypoglycemia), the beneficial effects on beta-cell function and its eventual protective action on beta-cell mass makes it an excellent option for monotherapy or combined with metformin, glitazones or even sulfonylurea.
J Control Release. 2008 Jul 2; 129(1): 49-58
Sankalia JM, Sankalia MG, Mashru RC
The purpose of this study was to examine a level A in vitro-in vivo correlation (IVIVC) for glipizide hydrophilic sustained-release matrices, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. The effect of polymeric blends of ethylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, xanthan gum, guar gum, Starch 1500, and lactose on in vitro release profiles was studied and fitted to various release kinetics models. Water uptake kinetics with scanning electron microscopy (SEM) was carried out to support the drug release mechanism. An IVIVC was established by comparing the pharmacokinetic parameters of optimized (M-24) and marketed (Glytop-2.5 SR) formulations after single oral dose studies on white albino rabbits. The matrix M-19 (xanthan:MCC PH301 at 70:40) and M-24 (xanthan:HPMC K4M:Starch 1500 at 70:25:15) showed the glipizide release within the predetermined constraints at all time points with Korsmeyer-Peppas' and zero-order release mechanism, respectively. Kopcha model revealed that the xanthan gum is the major excipient responsible for the diffusional release profile and was further supported by SEM and swelling studies. A significant level A IVIVC with acceptable limits of prediction errors (below 15%) enables the prediction of in vivo performance from their in vitro release profile. It was concluded that proper selection of rate-controlling polymers with release rate modifier excipients will determine overall release profile, duration and mechanism from directly compressed matrices.
Mutations at arginine 352 alter the pore architecture of CFTR.
J Membr Biol. 2008 Mar; 222(2): 91-106
Cui G, Zhang ZR, O'Brien AR, Song B, McCarty NA
Arginine 352 (R352) in the sixth transmembrane domain of the cystic fibrosis transmembrane conductance regulator (CFTR) previously was reported to form an anion/cation selectivity filter and to provide positive charge in the intracellular vestibule. However, mutations at this site have nonspecific effects, such as inducing susceptibility of endogenous cysteines to chemical modification. We hypothesized that R352 stabilizes channel structure and that charge-destroying mutations at this site disrupt pore architecture, with multiple consequences. We tested the effects of mutations at R352 on conductance, anion selectivity and block by the sulfonylurea drug glipizide, using recordings of wild-type and mutant channels. Charge-altering mutations at R352 destabilized the open state and altered both selectivity and block. In contrast, R352K-CFTR was similar to wild-type. Full conductance state amplitude was similar to that of wild-type CFTR in all mutants except R352E, suggesting that R352 does not itself form an anion coordination site. In an attempt to identify an acidic residue that may interact with R352, we found that permeation properties were similarly affected by charge-reversing mutations at D993. Wild-type-like properties were rescued in R352E/D993R-CFTR, suggesting that R352 and D993 in the wild-type channel may interact to stabilize pore architecture. Finally, R352A-CFTR was sensitive to modification by externally applied MTSEA+, while wild-type and R352E/D993R-CFTR were not. These data suggest that R352 plays an important structural role in CFTR, perhaps reflecting its involvement in forming a salt bridge with residue D993.
PDA J Pharm Sci Technol. 2007 Nov-Dec; 61(6): 472-91
Shivakumar HN, Desai BG, Pandya S, Karki SS
Glipizide was complexed with beta-cyclodextrin in an attempt to enhance the drug solubility. The phase solubility diagram was classified as A(L) type, which was characterized by an apparent 1:1 stability constant that had a value of 413.82 M(-1). Fourier transform infrared spectrophotometry, differential scanning calorimetry, powder x-ray diffractometry and proton nuclear magnetic resonance spectral analysis indicated considerable interaction between the drug and beta-cyclodextrin. A 2(3) factorial design was employed to prepare hydroxypropyl methylcellulose (HPMC) matrix tablets containing the drug or its complex. The effect of the total polymer loads (X1), levels of HPMC K100LV (X9), and complexation (X3) on release at first hour (Y1), 24 h (Y2), time taken for 50% release (Y3), and diffusion exponent (Y4) was systematically analyzed using the F test. Mathematical models containing only the significant terms (P < 0.05) were generated for each parameter by multiple linear regression analysis and analysis of variance. Complexation was found to exert a significant effect on Y1, Y2, and Y3, whereas total polymer loads significantly influenced all the responses. The models generated were validated by developing two new formulations with a combination of factors within the experimental domain. The experimental values of the response parameters were in close agreement with the predicted values, thereby proving-the validity of the generated mathematical models.