Association between oral antidiabetic use, adverse events and outcomes in patients with type 2 diabetes.

OBJECTIVE: To quantify adverse events (AEs) associated with the use of metformin (MET), sulphonylureas (SUs) and thiazolidinediones (TZDs) in a usual care setting, and to assess the relationship of AEs to treatment patterns and glycaemic response in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: An electronic medical record database was used to identify patients with type 2 diabetes age >or=18 years from 1996 to 2005. Patients naïve to oral antidiabetic therapy were followed for 395 days postinitiation of MET, SU or TZD treatment. AEs related to study drugs were evaluated during the follow-up period. Baseline and follow-up A1C levels were compared by drug regimen. Associations between the change in A1C, drug regimen changes and AEs were evaluated. RESULTS: A total of 14,512 patients (mean age 60.8 years, 52.9% female) were identified. During the follow-up period, 12.7% of patients experienced an AE (8.6% MET, 15.9% SU and 19.8% TZD patients). SU and TZD patients were more likely to experience an AE than MET (p < 0.001) patients. AEs did not significantly influence A1C outcomes, although MET and SU patients experiencing an AE were more likely to add-on therapy (odds ratio (OR) = 1.34 and OR = 1.37, respectively; p < 0.05) than those without an AE. MET patients with AEs were more likely to switch therapy (OR = 1.91; p < 0.05) than those without an AE. CONCLUSIONS: The occurrence of AEs did not significantly impact glycaemic response to therapy. However, AEs may lead to greater treatment switches for patients receiving MET and add-on therapy for MET-treated and SU-treated patients.

Prevalence and patterns of alternative medication use in a university hospital outpatient clinic serving rheumatology and geriatric patients.

A random sample of 176 patients seen at least once during 1997 in a University hospital outpatient clinic serving rheumatology and geriatric patients were surveyed in a telephone interview to determine the prevalence of, and reasons for taking, alternative medications. Interviews were conducted from November 1997-March 1998. The survey elicited information about patients' ability to provide self-care, demographics, work status, satisfaction with current disease management, types of alternative medications taken, sources of information about the products, where they obtained the products, and reasons for taking the products. Patients also were questioned as to their knowledge of safety of these products. Statistical comparisons were determined between patients who used alternative agents and those who did not. Prevalence of use was 66%. Most patients thought that the agents were safe and took them because they believed they have "added benefits."

Physician prescribing of anorexigenics for weight loss in Salt Lake County, Utah.

The objective of this survey of primary care physicians in Salt Lake County, Utah, was to determine how many of these providers were prescribing anorexigenics (antiobesity drugs) and to evaluate their knowledge of side effects and drug interactions. A confidential survey was sent to 377 family practice, internal medicine, and obstetrics-gynecology physicians, of whom 236 (62.5%) responded. Of those who answered the survey completely, 146 (65.2%) prescribed anorexigenics to 5,107 patients. Family practice physicians, male physicians less than 40 years old, and internal medicine physicians less than 40 years old prescribed anorexigenics more frequently than their counterparts. Female physicians (vs male) and female family practice physicians (vs male family practice physicians) reported a higher proportion of psychiatric comorbidity among patients for whom they prescribed the drugs. Respondents had limited knowledge of side effects and drug interactions of anorexigenics. Better understanding of physicians' prescribing patterns of these agents is relevant for current and future optimal treatment of obesity.

Use of fenofibrate in the management of protease inhibitor-associated lipid abnormalities.

Human immunodeficiency virus (HIV) protease inhibitors are associated with several metabolic abnormalities including hypercholesterolemia and hypertriglyceridemia. Fenofibrate is a new lipid-lowering agent for adults with very high triglyceride levels that was administered to two HIV-positive patients who were taking protease inhibitors and developed hypertriglyceridemia. Starting dosages were 134 and 201 mg/day, and were increased to 268 mg/day in both patients. Triglyceride levels decreased from 1450 to 337 mg/dl (76.8%) and from 1985 to 322 mg/dl (83.8%), respectively, after 10 months of therapy. High-density lipoprotein levels increased in both patients.

Electron ionization mass fragmentometric detection of urinary ecgonidine, a hydrolytic product of methylecgonidine, as an indicator of smoking cocaine.

When cocaine is smoked, methylecgonidine (anhydroecgonine methyl ester) is also consumed as a pyrolytic product. Methylecgonidine, on incubation with human liver homogenate, was metabolized to a stable compound, ecgonidine. The compound was also formed when methylecgonidine was exposed to a urine pH > or = 8.0. Ecgonidine is a zwitterion and highly water soluble. A method was developed to identify ecgonidine quantitatively in urine. After removal of cocaine, benzoylecgonine and methylecgonidine from urine at pH 5.5 +/- 0.5 using a solid-phase extraction (SPE) technique, the pH of the solution was readjusted to 2.0-3.0. The acidic solution reduced the dissociation of the carboxylic acid and improved the lipophilic and cationic character of ecgonidine. The compound was extracted from the solution with the SPE technique with an 89-99% yield. Ecgonidine was then detected as a tert-butyldimethylsilyl derivative by a gas chromatographic/electron ionization mass spectrometric method. Quantitation was linear over the concentration range 7-2000 ng ml-1. Concentrations as low as 7 ng ml-1 can be detected by this procedure. Ecgonidine was detected in > 95% of benzoylecgonine-positive urine specimens from a random drug testing program, indicating smoking as the major route of cocaine administration.

The role of dehydroepiandrosterone in diabetes mellitus.

Much has been written in the lay literature regarding potential benefits of dehydroepiandrosterone (DHEA). Although it was removed from the over-the-counter market in 1985, the Dietary Supplement Health Education Act of 1994 allowed the drug to be marketed as a food supplement. Because DHEA no longer falls under the scrutiny of the Food and Drug Administration, many unverified claims have been put forth in the press espousing its therapeutic value. This barrage of "infomercials" has left the average American consumer (and health care professional) curious about DHEA and its possible therapeutic utility. One focus of recent research is to define the role of DHEA in diabetes mellitus. Although it has been claimed that decreased levels of endogenous DHEA are associated with diabetes, impaired glucose tolerance, hyperglycemia, and insulin resistance, much of the information is based on cross-sectional studies. Other claims correlate decreased endogenous DHEA levels with adverse cardiovascular effects. Some information is contradictory and indicates high doses of exogenous DHEA may produce adverse cardiovascular effects, an undesirable outcome in patients with diabetes mellitus. At this time, its administration in patients with diabetes is not warranted. Long-term trials evaluating the role of exogenous DHEA and its effect on patients with diabetes should be conducted.

Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems: in vitro permeability and in vivo oral absorption of salmon calcitonin (sCT).

PURPOSE: To evaluate a biopharmaceutical approach for selecting formulation additives and establishing the performance specifications of an oral peptide delivery system using sCT as a model peptide. METHODS: The effect of formulation additives on sCT effective permeability and transepithelial electrical resistance (TEER) was evaluated in side-by-side diffusion chambers using rat intestinal segments. Baseline regional oral absorption of sCT was evaluated in an Intestinal and Vascular Access Port (IVAP) dog model by administration directly into the duodenum, ileum, and colon by means of surgically implanted, chronic catheters. The effect of varying the input rate and volume of the administered solution on the extent of sCT absorption was also evaluated. Citric acid (CA) was utilized in all studies to cause a transient reduction in local pH. In vitro samples and plasma samples were analyzed by radioimmunoassay (RIA). Two oral delivery systems were prepared based on the results of the in vitro and IVAP studies, and evaluated in normal dogs. RESULTS: Maximal permeability enhancement of sCT was observed using taurodeoxycholate (TDC) or lauroyl carnitine (LC) in vitro. Ileal absorption of sCT was higher than in other regions of the intestine. Low volume and bolus input of solution formulations was selected as the optimal condition for the IVAP studies since larger volumes or slower input rates resulted in significantly lower sCT bioavailability (BA). Much lower BA of sCT was observed when CA was not used in the formulation. The absolute oral bioavailability (mean+/-SD) in dogs for the control (sCT + CA) and two proprietary sCT delivery systems was 0.30%+/-0.05%, 1.10+/-0.18%, and 1.31+/-0.56%, respectively. CONCLUSIONS: These studies demonstrate the utility of in vitro evaluation and controlled in vivo studies for developing oral peptide delivery strategies. Formulation additives were selected, the optimal intestinal region for delivery identified, and the optimal release kinetics of additives and actives from the delivery system were characterized. These methods were successfully used for devising delivery strategies and fabricating and evaluating oral sCT delivery systems in animals. Based on these studies, sCT delivery systems have been fabricated and tested in humans with favorable results.

Detection of metabolites of lysergic acid diethylamide (LSD) in human urine specimens: 2-oxo-3-hydroxy-LSD, a prevalent metabolite of LSD.

Seventy-four urine specimens previously found to contain lysergic acid diethylamide (LSD) by gas chromatography-mass spectrometry (GC-MS) were analyzed by a new procedure for the LSD metabolite 2-oxo-3-hydroxy-LSD (O-H-LSD) using a Finnigan LC-MS-MS system. This procedure proved to be less complex, shorter to perform and provides cleaner chromatographic characteristics than the method currently utilized by the Navy Drug Screening Laboratories for the extraction of LSD from urine by GC-MS. All of the specimens used in the study screened positive for LSD by radioimmunoassay (Roche Abuscreen). Analysis by GC-MS revealed detectable amounts of LSD in all of the specimens. In addition, isolysergic diethylamide (iso-LSD), a byproduct of LSD synthesis, was quantitated in 64 of the specimens. Utilizing the new LC-MS-MS method, low levels of N-desmethyl-LSD (nor-LSD), another identified LSD metabolite, were detected in some of the specimens. However, all 74 specimens contained O-H-LSD at significantly higher concentrations than LSD, iso-LSD, or nor-LSD alone. The O-H-LSD concentration ranged from 732 to 112 831 pg/ml (mean, 16340 pg/ml) by quantification with an internal standard. The ratio of O-H-LSD to LSD ranged from 1.1 to 778.1 (mean, 42.9). The presence of O-H-LSD at substantially higher concentrations than LSD suggests that the analysis for O-H-LSD as the target analyte by employing LC-MS-MS will provide a much longer window of detection for the use of LSD than the analysis of the parent compound, LSD.

Enhanced metabolism of levonorgestrel during phenobarbital treatment and resultant pregnancy.

Levonorgestrel implants (Norplant) are an alternative to oral contraceptives and medroxyprogesterone acetate intramuscular injections. An interaction may exist between levonorgestrel and agents that induce the hepatic microsomal enzyme system. A 21-year-old woman with a history of a seizure disorder, treated with phenobarbital, who received levonorgestrel implants became pregnant. After a normal delivery, she took oral contraceptives concomitantly with phenobarbital. Although she was educated about the importance of a backup method of contraception, the woman again became pregnant and delivered twins. A recent national survey of neurologists and obstetricians was conducted evaluating prescriber knowledge of interactions between oral contraceptives and anticonvulsants. Only 4% of neurologists and zero percent of obstetricians knew all the interactions between the six most commonly prescribed anticonvulsants and oral contraceptives. This case supports the importance of continued patient and prescriber education regarding the possibility of drug-drug interactions in women taking anticonvulsants and hormonal contraceptives.

Utility of pharmacodynamic measures for assessing the oral bioavailability of peptides. 1. Administration of recombinant salmon calcitonin in rats.

Salmon calcitonin (sCT) is a therapeutic peptide used in the treatment of Paget's Disease, postmenopausal osteoporosis, and hypercalcemia due to malignancy. In this study, recombinant sCT (rsCT) was administered intravenously (iv), subcutaneously (sc), and intraduodenally (id.) in rats to evaluate pharmacodynamic (PD) response as a measure of rsCT bioavailability (F) and to test the feasibility of delivering rsCT orally. rsCT pharmacokinetics were linear throughout the range of iv and sc doses studied. Following sc administration, F ranged from 11.2% to 23.1% and was linear. The absorption of rsCT after id. administration was low (0.022%); however, a significant lowering of serum calcium concentrations was observed. Serum calcium lowering was nonlinear and saturable after sc administration with the minimum dose required for maximum calcium lowering (Dmin/max) equal to 10.2 ng and a maximal response of 426.8 mg min/dL. Using Dmin/max as the reference dose, absolute Fs were recalculated using PD response after id. administration of 1 and 2 mg of rsCT and were 0.040% and 0.029%, respectively. Substantial overestimates of F were obtained when the reference dose was not properly selected. While the absorption of rsCT was low, the significant lowering of serum calcium levels suggests that oral delivery of sCT is feasible. The results of these studies also suggest that PD response is useful in assessing the oral bioavailability of peptides; however, when PD response is saturable, as is the case for rsCT, the reference dose should be carefully selected in order to avoid overestimates of F.

Amphetamine as an artifact of methamphetamine during periodate degradation of interfering ephedrine, pseudoephedrine, and phenylpropanolamine: an improved procedure for accurate quantitation of amphetamines in urine.

During periodate degradation of interfering ephedrine, pseudoephedrine, and phenylpropanolamine in the extraction of methamphetamine from urine, it was observed that a small amount of methamphetamine was demethylated to amphetamine. although all three interfering phenylpropanolamines could be degraded by periodate at pH 5.2 and above, this periodate-mediated transformation of methamphetamine to amphetamine was observed only at pH 9.1 and above. Therefore, to avoid this transformation, a pH of 6.2 was used for the oxidative degradation of phenylpropanolamines. The excess periodate was then reduced with thiosulfate or ascorbic acid prior to the extraction of methamphetamine using a basic pH.

Determination of gallium concentration in "blood-free" tissues using a radiolabeled blood marker.

Radioiodinated serum albumin has been used as a blood marker to define and quantitate physiological volumes for 12 organs and tissue types. The concentration of gallium-67 in "blood-free" tissues of rats was also determined at various times after intravenous administration. Tissues were divided into two kinetically distinguishable types based on reported nonuniform distribution of the blood marker and the gallium distribution observed in the present study. Gallium distribution into the liver and spleen was observed to be slow, with a discernable accumulation phase followed by monoexponential elimination. In contrast, gallium accumulation into the stomach, small and large intestines, heart, lung, skin/adipose tissue, and muscle was rapid and elimination was monophasic.

Alteration of gallium distribution in the rat using periodically related elements: enhanced early imaging.

Complexes of carrier-gallium and indium were administered to normal rats and rats with tumors 2 to 6 hours after an injection of carrier-free 67Ga citrate in order to determine their effect on the distribution of 67Ga. Both Ga and In rapidly and significantly decreased the blood activity. Imaging with the same dosage schedule showed decreased activity in soft tissue and viscera, and increased activity in bone, kidney, and bladder. In animals with tumor high doses of carrier-Ga were shown to deplete tumor activity as well as activity in viscera and soft tissues. Moderate doses of carrier-Ga allowed blood and soft tissue clearing with no significant loss of tumor activity. When In citrate was administered to animals with tumors 2 hours after administration of 67Ga, tumor activity continued to increase while soft tissue and visceral activity decreased. Simultaneous injection of In citrate and 67Ga drastically altered the distribution of 67Ga. Two hours after the injection activity was present only in the tumor, kidney, bladder, and bone. This rapid clearance of non-productive Ga brings forth the potential for use of short lived, positron emitting 68Ga coupled with emission tomography.