PubMed Health⌕ Search

Biomedical subjects

R J Straka

Publications and source records attributed to R J Straka.

At least 19 recordsLinked to original sources
PubMed2001

Assessment of hypercholesterolemia control in a managed care organization.

To determine the extent of achievement of goal low-density lipoprotein cholesterol (LDL) as defined by National Cholesterol Education Program-Adult Treatment Panel II (NCEP-ATP 11) and American Diabetes Association (ADA) 2000 guidelines, we conducted a retrospective study by integrating data from medical, laboratory, and pharmacy claims databases. Subjects were selected from a 232,000-member staff-model managed care organization consisting of 19 clinics in the Minneapolis-St. Paul, Minnesota, metropolitan area. A total of 124,971 members aged 18 years and older, who had been continuously enrolled from July 1, 1996-June 6, 1998, were included. Outcome measures were the extent of achievement of goal LDL as defined by NCEP-ATP II and the use of antihyperlipidemic drugs for patients with and without diabetes at various levels of risk for coronary heart disease (CHD). Of 124,971 subjects, 6538 had a history of CHD, 1523 of whom met their LDL goal. Of the population with CHD who did not achieve goal, 1141 (43%) missed by over 30 mg/dl; 621 (54%) of these patients were not receiving drug therapy A total of 17,267 had no history of CHD but had two or more risk factors; 3,298 of these achieved their LDL goal. Of those who did not achieve goal, 1,136 (35%) missed by over 30 mg/dl; 897 (79%) of these were not receiving drug therapy A total of 6,586 had a history of diabetes; 1,004 and 2,340 reached an LDL of 100 mg/dl or lower and less than 130 mg/dl, respectively Of those with diabetes who had an LDL greater than 100 mg/dl, 1,276 (49%) missed their goal by over 30 mg/dl; 898 (70%) of these were not receiving drug therapy. Inadequate use of pharmacologic agents plays a significant role in failure to achieve goal LDL for patients with CHD, without CHD, and with diabetes. Analysis of the data based on the new ADA guidelines for LDL demonstrates the need for continued vigilance. Finally, the successful merging of medical, laboratory, and pharmacy claims databases provides a benchmark for other institutions.

Adult↗
PubMed2000

Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity.

STUDY OBJECTIVE: To evaluate the metabolism of antipyrine, a general metabolic probe, caffeine, a probe for cytochrome P450 (CYP) 1A2 and N-acetyltransferase activity, and dextromethorphan, a specific probe for CYP2D6 activity in patients with type 1 or 2 diabetes mellitus. DESIGN: Prospective, controlled study. SETTING: Research facility. Patients. Fifteen patients with type 1 and 16 with type 2 diabetes, and 16 healthy controls. INTERVENTION: Each subject simultaneously received antipyrine 10 mg/kg, caffeine 100 mg, and dextromethorphan 30 mg. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of antipyrine and its primary metabolites were determined from saliva and urine samples. Type 1 diabetes had marked effects on antipyrine metabolism whereas type 2 disease did not alter the metabolism of any of the probe drugs. The apparent oral clearance of antipyrine was increased 72% in patients with type 1 disease compared with controls (p=0.0001). In addition, formation clearances of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine were increased by 74% and 137% in those patients relative to controls. The caffeine metabolic index (paraxanthine/caffeine) was increased 34% (p=0.11), and N-acetylation and CYP2D6 phenotype were not altered. CONCLUSION: The metabolism of antipyrine is increased in patients with type 1 diabetes. Based on in vitro reports of antipyrine metabolism and current caffeine metabolic index data, the predominant effect of type 1 diabetes appears to be an increase in CYP1A2 activity. Assessment of the effect of the disease on other specific CYP metabolic pathways is warranted.

Acetylation↗
PubMed1998

Calcium channel antagonists: morbidity and mortality--what's the evidence?

Recent studies have shown an association between the use of calcium channel antagonists for the treatment of hypertension and an increased risk of myocardial infarction, gastrointestinal hemorrhage and cancer. The interpretation of the results of these studies and their application to clinical practice requires an understanding of study design constraints, conflicting results and limitations in extrapolating study findings to other dosage strengths, formulations or agents within the calcium channel antagonist class. A review and critique of these studies provides background information on the controversial subject of using calcium channel antagonists for the treatment of hypertension. Despite the limitations of these studies, clinicians may want to select other classes of agents, including diuretics and beta blockers, as first-line therapy until the morbidity and mortality effects related to the use of calcium channel antagonists are clearly known.

Administration, Sublingual↗
PubMed1996

Magnitude and nature of noncompliance with treatment using isosorbide dinitrate in patients with ischemic heart disease.

Isosorbide dinitrate is one of the most commonly prescribed medications for the treatment of ischemic heart disease. It has been demonstrated to be ineffective relative to placebo when taken inappropriately. This study objectively documents the magnitude and nature of compliance in 68 ambulatory patients who were prescribed isosorbide dinitrate three times a day. Each patient received a 9-week supply of medication in a vial equipped with a computerized monitor (MEMS-4 cap; APREX Corporation, Fremont, CA) and were informed as to the purpose of the study. Of the patients, 74% were classified into the low and 16% into the high compliance category, defined as compliant < 70% and > or = 85% of study days, respectively. The mean (+/- SD) percent days in which isosorbide dinitrate was taken three times was 66% (+/- 29), and the mean number of days in which it was taken three times with a 10-hour "nitrate free period" was 53% (+/- 31). It is concluded that the magnitude of noncompliance in patients prescribed isosorbide dinitrate three times daily is substantial (74%). The nature of this noncompliance is often due to failure to observe a 10- to 12-hour nitrate free period. Given the need to take isosorbide dinitrate appropriately and given the demonstrated magnitude of noncompliance, physicians should take these factors into consideration when selecting this agent for the management of coronary artery disease relative to other pharmacologic options.

Aged↗
PubMed1996

Predominance of slow acetylators of N-acetyltransferase in a Hmong population residing in the United States.

Pharmacogenetics can be an important determinant of pharmacologic response. To learn more about interpopulation differences in drug metabolism between ethnically diverse populations of subjects cared for by an International Clinic, a study was conducted to describe the prevalence of fast or slow acetylators of N-acetyltransferase (NAT2) in a population of Hmong residing in Minnesota. Ninety-eight healthy Hmong refugees from Laos volunteered to take caffeine as an oral probe drug to establish acetylator phenotype. Participants were classified as either rapid or slow acetylators based on the urinary molar ratio of select metabolites of caffeine. Assignment of phenotype was based on results from analysis of urine collected subsequent to ingestion of caffeine. The ratio of 5-acetylamino-6-formylamino-3-methyluracil (AFMU) to the combined products of the 7-demethylation pathway of paraxanthine (AFMU, 1-methylxanthine (1X), and 1-methylurate (1U)] formed the basis for this determination. A probit plot of the data collected in our subjects qualified a metabolic ratio of 0.34 as an acceptable cut point for phenotype assignment. Participants with an AFMU/(AFMU + 1X + 1U) ratio of < 0.34 were classified as slow acetylators and all others as rapid acetylators. Analysis of the data suggested a bimodal distribution with an excess (74.5%) of slow acetylators in the population. The predominance of slow acetylators found in the Hmong contrast with the prevalence of slow acetylators seen in other ethnic groups. These findings may have important clinical implications given the large number of Hmong treated each year in our International Clinic and the increasing use of medications metabolized by NAT2 in this population.

Acetylation↗
PubMed1996

Chronopharmacologic considerations when treating the patient with hypertension: a review.

Recognition of the existence of circadian variation in exacerbation of cardiovascular disease may have relevance to clinical use of cardioactive agents. Physiologic rational for the chronobiology of cardiac disease exists and can provide a basis on which to examine the efficacy of agents to manage cardiac disease. The use of 24-hour ambulatory blood pressure monitoring (ABPM) devices have advanced our ability to describe the interplay of chronobiologic rhythms and pharmacodynamic response to antihypertensive medications. This review summarizes the studies evaluating the use of various antihypertensive medications in the context of using 24-hour blood pressure monitoring devices. The studies are described in an attempt to increase awareness of chronobiology and potential implications of designing chronotherapeutic regimens.

Adrenergic Antagonists↗
PubMed1995

Comparison of the prevalence of the poor metabolizer phenotype for CYP2D6 between 203 Hmong subjects and 280 white subjects residing in Minnesota.

Genetic polymorphism of the P450IID6 (CYP2D6) enzyme system can be an important component of the variability in response to drug therapy. Interpopulation differences in the prevalence of deficiencies of drug-metabolizing enzymes may be clinically important in the selection and dosage of drug therapies for patients. Since 1980, the State of Minnesota has had more than a 1000% increase in population of Hmong refugees from Laos. The Hmong are frequently treated in our institution's international clinic with virtually no systematically acquired knowledge about the ability of this relatively ethnically pure population to metabolize commonly used Western medications. To further our knowledge of drug metabolism in this population, we identified the prevalence of the poor metabolizer phenotype for CYP2D6 in a sample population of Hmong subjects and compared this prevalence to that in a sample population of white subjects. Urine collected after ingestion of dextromethorphan in 237 healthy Hmong and 280 healthy white volunteers was analyzed by HPLC. Based on probit plots of the metabolic ratios (dextro-methorphan/dextrorphan), 8.9% of Hmong subjects and 6.1% of white subjects were assigned the poor metabolizer phenotype (difference not significant). Weak associations were found between body surface area and metabolic ratio for both Hmong and white men and between smoking status and metabolic ratio for white subjects only. We conclude that the prevalence of poor metabolizers for the CYP2D6 enzyme system is similar between Hmong subjects and white subjects residing in Minnesota and that an antimode of 0.3 for metabolic ratio appears to be reasonable for the populations studied.

Adolescent↗
PubMed1992

Determination of dextromethorphan and its O-demethylated metabolite from urine.

A high-performance liquid chromatography (HPLC) assay for the simultaneous quantitation of dextromethorphan and its O-demethylated metabolite dextrorphan from urine is described. A cyano analytical column was used with a mobile phase consisting of MeOH 16%, acetonitrile 3%, and triethylamine 0.06% at pH 2.8 and a flow rate of 1.0 ml/min. Betaxolol was used as the internal standard. Standard curves from 50 ng/ml to 10,000 ng/ml (dextrorphan), and from 50 ng/ml to 8,000 ng/ml (dextromethorphan) were developed. The peaks eluted at 7.8 min (dextrorphan), 12.2 min (betaxolol), and 17.8 min (dextromethorphan). The coefficients of variance ranged from 1.3 to 4.5% at 250 ng/ml and 0.9 to 2.5% at 5,000 ng/ml. This assay was used to determine dextromethorphan/dextrorphan molar ratios in healthy male volunteers for the purpose of determining phenotype status for the P450IID6 isozyme.

Chromatography, High Pressure Liquid↗
PubMed1990

Analysis of metoprolol enantiomers in human serum by liquid chromatography on a cellulose-based chiral stationary phase.

Metoprolol is a lipophilic, cardioselective beta-adrenergic blocking agent commercially available as a racemic compound. A normal phase high-performance liquid chromatographic method was developed to directly determine individual enantiomeric concentrations of metoprolol in human serum. Separation of the enantiomers was accomplished by a cellulose-tris(3,5-dimethylphenylcarbamate) chiral stationary phase. Metoprolol enantiomers were detected by means of fluorescence with excitation and emission wavelengths of 275 and 315 nm, respectively. Standard curves were linear over the concentration range 12.5-400 ng/ml for each enantiomer. Within-day coefficient of variation was less than 15% at all concentrations and the between-day coefficient of variation ranged from 4.1 to 11.2%. The limit of detection was determined to be 5 ng/ml for each enantiomer and the stereoselective resolution (alpha) of R- and S-metoprolol was 3.08. The assay was employed to determine enantiomeric serum concentrations of metoprolol in healthy male volunteers.

Cellulose↗
PubMed1990

Improved selectivity of a high-performance liquid chromatography assay for debrisoquine and its 4-hydroxy metabolite from urine.

Debrisoquine is an antihypertensive drug that displays polymorphic metabolism and has been used to determine hydroxylator status in human subjects. A high-performance liquid chromatographic method for the simultaneous urine analysis of debrisoquine (D) and its primary metabolite, 4-hydroxydebrisoquine (4-OHD), is described. A cyanopropyl (CN) extraction column and CN analytical column were used with a mobile phase consisting of 20% acetonitrile/20 mM sodium dihydrogen orthophosphate (pH = 7.1) at a flow rate of 1.5 ml/min. The peaks of interest, as well as the internal standard, were eluted from the column in less than 14 min. The method described was validated for within-day and between-day accuracy and precision for both D and 4-OHD. Coefficients of variation at all concentrations tested were less than 4.1% for D and less than 9.3% for 4-OHD. The assay was used to evaluate D/4-OHD ratios, thereby determining hydroxylation status in 65 healthy male volunteers.

Chromatography, High Pressure Liquid↗
PubMed1988

Measurement of underivatized propranolol enantiomers in serum using a cellulose-tris(3,5-dimethylphenylcarbamate) high-performance liquid chromatographic (HPLC) chiral stationary phase.

A commercially available high-performance liquid chromatographic (HPLC) chiral stationary phase (HPLC-CSP) has been used to measure serum levels of d- and l-propranolol. The HPLC-CSP is based upon cellulose-tris(3,5-dimethylcarbamate) and is able to stereochemically resolve d- and l-propranolol without precolumn derivatization using a mobile phase composed of hexane:2-propranol:N,N-dimethyloctylamine (92:8:0.01, v/v/v). Under these conditions the observed stereochemical resolution (alpha) of the two enantiomers was alpha = 2.2. A subject's concentration-time curve of the two isomers was determined following the ingestion of 160 mg racemic propranolol.

Cellulose↗
PubMed1988

Nonlinear accumulation of propranolol enantiomers.

The accumulation of (+)- and (-)-propranolol was investigated in nine subjects who received 160 mg of racemic propranolol as a single dose and then once daily for 7 days. The serum concentrations of propranolol enantiomers were measured by h.p.l.c. using a novel chiral stationary phase allowing direct resolution of underivatized propranolol. The (+)-propranolol AUC increased from 412 +/- 223 ng ml-1 h after single doses (0-infinity) to 584 +/- 279 ng ml-1 h at steady-state (0-24 h) (P less than 0.05). Similarly, (-)-propranolol AUC increased from 609 +/- 304 to 777 +/- 370 ng ml-1 h (P less than 0.05). The AUC ratio (-)/(+) was 1.52 +/- 0.36 and 1.32 +/- 0.17 after single doses and steady-state, respectively (P greater than 0.05). Therefore, nonlinear accumulation occurs with both enantiomers although there is a trend for the (-)/(+) ratio to decrease at steady-state.

Adult↗
PubMed1987

Nonlinear pharmacokinetics of unbound propranolol after oral administration.

After multiple oral doses, propranolol has been reported to accumulate to a greater degree than expected based on its terminal elimination rate constant and dosage interval. To determine whether the decrease in presystemic elimination can be attributed solely to a decrease in unbound intrinsic clearance or possibly a decrease in unbound fraction, we studied the pharmacokinetics of unbound propranolol in nine healthy subjects who were given 160 mg of regular or sustained-release propranolol orally as single doses, and once daily for 7 d. Unbound propranolol concentrations were calculated by HPLC and equilibrium dialysis on each serum sample. With regular propranolol, the mean unbound oral clearance (CLoral) decreased 29%, from 503 +/- 281 after a single dose to 359 +/- 143 mL/min/kg at steady state (p less than 0.05). Similarly, CLoral decreased 33% with sustained-release propranolol from 1077 +/- 514 to 721 +/- 385 mL/min/kg (NS). The corresponding accumulation ratios for regular and sustained-release propranolol were 1.39 +/- 0.49 and 1.61 +/- 0.81, respectively (NS). Therefore, the mean bioavailability of sustained-release relative to that of regular propranolol was 0.52 +/- 0.23 and 0.54 +/- 0.17 for single doses and at steady-state, respectively. The percent unbound of propranolol ranged from 6.8 to 14.0 with an average of 10.1. Neither the percent unbound nor alpha 1-acid glycoprotein (AAG) serum concentrations were statistically different between single and multiple doses. The binding ratio was significantly correlated to AAG concentration (r = 0.776, p less than 0.05). The data support a decrease in unbound intrinsic clearance of propranolol with no change in unbound fraction, leading to an increase in bioavailability at steady state.

Administration, Oral↗
PubMed1987

Propranolol pharmacokinetics and pharmacodynamics after single doses and at steady-state.

The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0-24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.

Administration, Oral↗
PubMed1987

Propranolol pharmacodynamic modeling using unbound and total concentrations in healthy volunteers.

In an attempt to evaluate the propranolol (P) concentration-effect relationship, percentage reduction in exercise heart rate was modeled as a function of unbound and total P concentrations using the linear, Emax, and sigmoid Emax models. Nine volunteers underwent repeated treadmill exercise tests over 48 hr during a control period, after receiving 160 mg of P orally and again after receiving 160 mg once daily for 7 days. Beta blockade was assessed as the percentage reduction in exercise heart rate compared to control. Total serum P concentrations were determined by HPLC and unbound fractions by equilibrium dialysis. Using nonlinear least-squares regression, the Emax model was best in describing the concentration-effect relationship in each subject. Mean parameters for combined single dose and steady state were Emax 33.6 +/- 4.5% and EC50 18.2 +/- 15.6 ng/ml for total P and Emax 33.5 +/- 4.3% and EC50 1.66 +/- 1.56 for unbound P. Model fits were not significantly better for unbound versus total P and EC50 values showed similar intersubject variability. The observed unbound EC50 values are consistent with reported receptor dissociation constants. Therefore the large intersubject variability in EC50 could not be accounted for by variability in P protein binding.

Adult↗
PubMed1987

Liquid chromatography and fluorescence polarization immunoassay methods compared for measuring flecainide acetate in serum.

We analyzed 99 patients' serum samples for concentrations of a new antiarrhythmic agent, flecainide acetate, by fluorescence polarization immunoassay (FPIA) and "high-performance" liquid chromatography (HPLC). Within-day and between-day coefficients of variation at concentrations in the low and high ends of the therapeutic range were less than 7% for HPLC and less than 9% for FPIA. There was no statistical difference in the mean (+/- SD) concentrations of the clinical serum samples measured by the two methods (607 +/- 334 micrograms/L by HPLC, 602 +/- 344 micrograms/L by FPIA), but results by each differed by a mean of 0.13%. FPIA and HPLC measurements correlated significantly (r = 0.98, P less than 0.05), and were linearly related (slope = 0.970, intercept = 13 micrograms/L) as assessed by orthogonal regression. Both assay methods produced similar concentration measurements and were sufficiently accurate and precise to be used in therapeutic drug monitoring.

Anti-Arrhythmia Agents↗
PubMedDate not supplied

Antihypertensive drug use in the long-term care facility: a pilot study and review of the literature.

The overuse and cost of drugs in long-term care facilities are of significant concern. To quantify potential overuse of antihypertensive agents, we conducted a retrospective chart review in four long-term care facilities. We analyzed data in 550 patient records to identify residents receiving drugs for the sole indication of hypertension. Of the 550 records, 49 (9%) residents qualified. Of these, 20 (41%) had all recorded blood pressures less than 140/90 mm Hg for the 6 months before review, and 32 (65%) had all blood pressures less than 160/90 mm Hg. Given this degree of blood pressure control and the reported success of withdrawing antihypertensive drugs from the elderly in whom the disorder is well controlled, a reevaluation of antihypertensive therapy in residents of long-term care facilities appears to be justified.

Aged↗