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Biomedical subjects

J Cavanaugh

Publications and source records attributed to J Cavanaugh.

At least 19 recordsLinked to original sources
PubMed2001

International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16.

Numerous familial, non-Mendelian (i.e., complex) diseases have been screened by linkage analysis for regions harboring susceptibility genes. Except for rare, high-penetrance syndromes showing Mendelian inheritance, such as BRCA1 and BRCA2, most attempts have failed to produce replicable linkage findings. For example, in multiple sclerosis and other complex diseases, there have been many reports of significant linkage, followed by numerous failures to replicate. In inflammatory bowel disease (IBD), linkage to two regions has elsewhere been reported at genomewide significance levels: the pericentromeric region on chromosome 16 (IBD1) and chromosome 12q (IBD2). As with other complex diseases, the subsequent support for these localizations has been variable. In this article, we report the results of an international collaborative effort to investigate these putative localization by pooling of data sets that do not individually provide convincing evidence for linkage to these regions. Our results, generated by the genotyping and analysis of 12 microsatellite markers in 613 families, provide unequivocal replication of linkage for a common human disease: a Crohn disease susceptibility locus on chromosome 16 (maximum LOD score 5.79). Despite failure to replicate the previous evidence for linkage on chromosome 12, the results described herein indicate the need to further investigate the potential role of this locus in susceptibility to ulcerative colitis. This report provides a convincing example of the collaborative approach necessary to obtain the sample numbers required to achieve statistical power in studies of complex human traits.

Chromosome Mapping↗
PubMed1998

Effects of oral and intravenous terazosin and head-up tilt on blood pressure responses in patients with hypertension.

Terazosin is a selective alpha1-adrenoceptor antagonist. A double-blind, randomized, placebo-controlled, two-period study evaluated the effects of posture and of oral and intravenous administration of terazosin on blood pressure and heart rate in patients with hypertension. At least one week after withdrawal of all antihypertensive medications, 31 patients with sitting diastolic blood pressure of 95 to 114 mmHg were enrolled in the study. After a 24-hour, single-blind, placebo lead-in phase, the patients were randomized to receive either oral terazosin (1 mg on day 1, 2 mg on day 2, and 5 mg on days 3 and 4), a 12-hour intravenous infusion of terazosin (2.5 mg, 5 mg, or 7.5 mg), or placebo for 4 consecutive days. Head-up tilt (60 degrees for 20 minutes) evaluations were performed before and 0.5, 1.5, 2.5, 6, 12, and 16 hours after start of administration during the placebo lead-in phase and on each of the 4 days of the double-blind treatment phase. Blood pressure and heart rate were monitored every 2 minutes during the 20-minute tilt. Statistically significantly larger mean changes in blood pressure and heart rate were observed with the 7.5-mg intravenous dose of terazosin compared with those after oral terazosin or placebo. With respect to intravenous terazosin, the orthostatic changes were maximal on the first day of the 4-day treatment and increased with increasing doses of terazosin. Maximum orthostatic changes in blood pressure after oral administration of terazosin were not significantly different from those observed with placebo. The most common treatment-emergent adverse events during tilt were dizziness and nausea. Dizziness occurred more frequently with intravenous terazosin than with oral terazosin. The results of this study indicate that oral dose titration of terazosin rather than a slower rate of terazosin infusion minimized the postural effects on blood pressure and associated symptoms during head-up tilt.

Administration, Oral↗
PubMed1998

The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin.

OBJECTIVE: To investigate the effects of ritonavir on the pharmacokinetics of rifabutin. METHODS: In a multiple-dose, randomized, parallel-group, double-blind study, subjects received 150 mg rifabutin daily for 24 days coadministered on days 15 to 24 with twice-daily doses of either placebo or ritonavir (300 mg on day 15, 400 mg on day 16, and 500 mg on days 17 to 24). Plasma concentrations of rifabutin and 25-O-desacetylrifabutin were measured by HPLC, and the pharmacokinetics were determined after the rifabutin doses on days 14 and 24. RESULTS: For subjects receiving rifabutin and placebo who completed the study (n = 11), there were small but statistically significant differences (< or = 32%) in several rifabutin and 25-O-desacetylrifabutin pharmacokinetic parameters between the regimens of rifabutin alone and rifabutin with placebo. In contrast, the effect of ritonavir on rifabutin pharmacokinetics of subjects completing the study (n = 5) was substantial. Rifabutin mean minimum observed concentration (Cmin), maximum observed concentration (Cmax), and area under the concentration-time curve [AUC(0-24)] increased by approximately sixfold, 2.5-fold, and fourfold, respectively, and 25-O-desacetylrifabutin mean Cmin, Cmax, and AUC(0-24) increased by approximately 200-, 16-, and 35-fold, respectively, when coadministered with ritonavir compared with rifabutin administered alone. The sum of the mean AUC(0-24) of rifabutin and 25-O-desacetylrifabutin increased nearly sevenfold when coadministered with ritonavir. CONCLUSIONS: Ritonavir inhibited the metabolism of rifabutin and 25-O-desacetylrifabutin, suggesting that both are metabolized at least in part by CYP3A. Ritonavir may have enhanced rifabutin bioavailability by reducing either intestinal of hepatic metabolism of both. Clarithromycin is an alternative to rifabutin for antimycobacterial therapy that may be administered concurrently with ritonavir. Administration of ritonavir with a reduced rifabutin dosage regimen (150 mg every Monday, Wednesday, and Friday) is being investigated.

Adult↗
PubMed1998

Pharmacokinetic interaction between ritonavir and clarithromycin.

BACKGROUND: Because ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, and clarithromycin, a macrolide antibiotic used in the treatment of disseminated infection caused by Mycobacterium avium complex, are likely to be administered concurrently for treatment of patients with HIV and acquired immunodeficiency syndrome (AIDS), the drug interaction potential of these 2 agents was evaluated. Both clarithromycin and ritonavir are metabolized to a significant extent through cytochrome P450-mediated biotransformation and are potential inhibitors of these enzymes. OBJECTIVE: To evaluate the pharmacokinetic effects of concomitant administration of multiple doses of ritonavir and clarithromycin. METHODS: This was an open-label, randomized, 3-period crossover study. Ritonavir alone (200 mg every 8 hours), clarithromycin alone (500 mg every 12 hours), and ritonavir and clarithromycin in combination were administered to 22 healthy volunteers. Blood samples were collected on day 4 for determination of ritonavir, clarithromycin, and its metabolite 14-(R)-hydroxyclarithromycin. RESULTS: Ritonavir practically completely inhibited the formation of 14-(R)-hydroxyclarithromycin. The mean area under the plasma concentration-time curve (AUC) for clarithromycin increased by 77% with concomitant ritonavir, and the harmonic mean terminal half-life increased from 5 hours to 14 hours. Statistically significant increases in peak plasma concentration (31%) and minimum plasma concentration (182%) were also observed. The effect of concomitant clarithromycin administration on ritonavir pharmacokinetics was statistically significant but small, with a 12.5% increase in mean AUC and a 15.3% increase in peak plasma concentration. The terminal half-life increased from 3.47 to 3.87 hours with concomitant clarithromycin. CONCLUSIONS: No adjustment of the ritonavir dose is necessary when administered with clarithromycin. In addition, no changes in clarithromycin dose are warranted in patients with normal renal function.

AIDS-Related Opportunistic Infections↗
PubMed1997

Are prophylactic antibiotics required for elective laparoscopic cholecystectomy?

BACKGROUND: Some clinicians administer prophylactic antibiotics routinely before laparoscopic cholecystectomy, and the results of some of the studies in the literature support this practice. We conducted a prospective randomized trial to determine whether administration of prophylactic antibiotics is necessary during routine laparoscopic cholecystectomy in low-risk patients. STUDY DESIGN: Two hundred fifty patients without evidence of acute inflammation, common duct stones, or other indications for antibiotics were randomized to receive three perioperative doses of cefazolin or no prophylaxis and followed up for complications up to 30 days postoperatively. The primary end point was the occurrence of a major infectious complication, defined as that causing a systemic response, delaying discharge, or leading to readmission. Minor infectious problems were also noted, defined as those causing local symptoms only. RESULTS: One hundred twenty-eight patients were randomized to receive prophylactic antibiotics (PA group), 122 to receive none (NONE group; two patients in this group were actually given preoperative antibiotics). Only one major complication occurred (in a patient in the NONE group), an abscess in the presence of a bile leak, despite the administration of antibiotics when the leak was discovered several days before infectious problems arose. There were four minor problems: two lower urinary tract infections and one superficial wound infection in a NONE patient and one urinary tract infection in a PA patient (not significant); all were easily managed. The prophylactic antibiotics did not sterilize the bile, and infectious complications were not associated with weight, inflammation found at the time of operation, reported stone or bile spill-age, or conversion to open operation. CONCLUSIONS: Prophylactic antibiotics are not necessary for elective laparoscopic cholecystectomy in low-risk patients.

Antibiotic Prophylaxis↗
PubMed1997

Evaluation of the effect of fluconazole on the pharmacokinetics of ritonavir.

The effects of fluconazole on the pharmacokinetics of the HIV protease inhibitor ritonavir were investigated after multiple dosing in an open-label study. In this randomized, two-period crossover study, eight healthy subjects received ritonavir alone (200 mg every 6 hr for 4 days) and ritonavir with fluconazole (400 mg on day 1, 200 mg every day on days 2-5) with a 2-week washout period. Ritonavir plasma concentrations were measured during the final four ritonavir dosing intervals (24 hr) and a 12-hr washout period. There were statistically significant increases in ritonavir C(max) and AUC0-24 (p < 0.02), with concurrent administration of fluconazole compared with administration of ritonavir alone. The difference between regimens in C(min) was marginally statistically significant (p = 0.089), and t(max) and beta were not statistically significantly different. Although some ritonavir parameters were affected by fluconazole, mean increases in C(max) and AUC were < or = 15% for the 24-hr period, and only 7-19% for individual dose intervals. Thus, the pharmacokinetics of ritonavir may be influenced only to a small extent when administered with fluconazole. These changes are probably of limited clinical significance and do not necessitate dosage adjustment of ritonavir when fluconazole is added to the regimen.

Adult↗
PubMed1996

Assessment of the pharmacokinetic-pharmacodynamic interaction between terazosin and finasteride.

The pharmacokinetic-pharmacodynamic interaction between terazosin and finasteride was evaluated in an 18-day, parallel, open-label, randomized study. Forty-eight non-smoking, healthy, adult male volunteers entered the study. One third of the participants received terazosin alone, one third received terazosin and finasteride, and one third received finasteride alone. Multiple-dose coadministration of terazosin and finasteride did not alter the central values of steady-state pharmacokinetic parameters of either drug in a statistically significant manner. Compared with the single-agent groups, however, the group taking finasteride and terazosin had higher variability in the pharmacokinetic parameters of both drugs. Testosterone concentrations were not altered after administration of finasteride and terazosin alone or in combination. Terazosin administered alone did not affect the dihydrotestosterone concentrations. The significant reduction in dihydrotestosterone concentrations induced by administration of finasteride was not affected by coadministration of terazosin. Mean changes in blood pressure and pulse rate in these normotensive volunteers were generally slight; therefore, concurrent administration of multiple doses of terazosin and finasteride did not produce significant clinical concern.

Adrenergic alpha-Antagonists↗
PubMed1996

Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics.

BACKGROUND: Divalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phase of bipolar syndrome. Because amitriptyline is also prescribed in these patient populations, data are needed on their potential for interaction. METHODS: The effect of concomitant administration of divalproex sodium on the pharmacokinetics of amitriptyline and its active metabolite, nortriptyline, was investigated in an open-label, sequential, two-period phase I study. Ten healthy male and five healthy female subjects received 50 mg amitriptyline hydrochloride on two occasions: (1) alone (period 1) and (2) 2 hours after receiving the ninth dose of 500 mg divalproex sodium (Depakote) administered once every 12 hours (period 2). RESULTS: Amitriptyline area under the curve was increased 31% from the combined effect of decreased first-pass metabolism and inhibition of systemic metabolism. The elevated nortriptyline plasma levels reflected primarily the increase in amitriptyline concentrations but also appeared to involve modest inhibition of nortriptyline elimination. For the sum of amitriptyline and nortriptyline concentrations, the peak plasma concentration mean was 19% higher with concomitant divalproex dosing. The mean area under the curve for the sum of amitriptyline and nortriptyline concentrations was 42% higher with concomitant divalproex dosing than it was for dosing with amitriptyline alone. CONCLUSION: These results suggested that a lower dose of amitriptyline might be considered when divalproex is administered concomitantly.

Adult↗
PubMed1995

Computerized documentation in home health.

Computerized documentation in community health nursing is only now receiving the attention it deserves. The authors explain one agency's experience with adapting a computerized clinical documentation system to visiting nurses' needs and the nurses' responses to the process.

Attitude to Computers↗
PubMed1992

Absolute bioavailability of clarithromycin after oral administration in humans.

The absolute bioavailability of clarithromycin, a new macrolide antimicrobial agent, was assessed in a three-way, randomized, single-dose, crossover study conducted with 22 healthy volunteers, 19 of whom provided analyzable study data. The bioavailability parameters of two 250-mg oral tablet formulations were calculated with reference to an identical dose administered by intravenous infusion of the lactobionate salt. After adjustment for formulation potency, the mean absolute bioavailabilities of the two oral formulations were 52 and 55%, on the basis of the appearance of parent compound in the systemic circulation. Metabolite peak concentration and area under the plasma concentration-time curve data after oral dosing were generally greater than those after intravenous infusion, suggesting that marked first-pass metabolism of clarithromycin occurs after oral administration. Pharmacokinetic analysis of the parent drug and the active 14-hydroxy metabolite data suggests complete (or nearly complete) absorption of the drug after oral administration.

Administration, Oral↗
PubMed1990

Gynecomastia and cirrhosis of the liver.

Hepatic cirrhosis is frequently listed as a cause of gynecomastia. We found previously that in hospitalized men the prevalence of gynecomastia was correlated with body mass index and with age. The mean body mass index and the prevalence of gynecomastia in the cirrhotic subjects (nonedematous) did not differ from those in the overall population. Because more severely cirrhotic subjects with ascites, peripheral edema, or both usually are thin, we examined 18 more severely cirrhotic subjects and 18 nonobese (mean body mass index, 20.9 +/- 0.6 kg/m2), age-matched control subjects for the prevalence of palpable gynecomastia. Total testosterone, free testosterone, total estrogen, and estradiol concentrations also were measured. Fifty percent of the control subjects had gynecomastia. Breast tissue diameter was correlated with body mass index. The prevalence of gynecomastia in the cirrhotic subjects was 44%. In these subjects no significant correlation was noted between breast tissue diameter and body mass index, presumably because the body mass index was increased owing to fluid retention. The results could not be accounted for based on medications. Serum free testosterone concentrations were lower in the cirrhotic patients than in the controls (0.11 +/- 0.02 vs 0.22 +/- 0.03 nmol/L). The total estrogen-free testosterone ratio was higher in cirrhotic patients (10.3 +/- 2.5 vs 2.6 +/- 0.5), as was the estradiol-free testosterone ratio (2.2 +/- 0.7 vs 0.5 +/- 0.1). These ratios did not differ significantly in cirrhotic subjects with and without gynecomastia. Therefore, these data indicate that factors other than the estrogen-testosterone ratio are playing a role in the development of gynecomastia in both cirrhotic subjects and controls or that breast tissue sensitivity to an elevated estrogen-testosterone ratio is highly varible.

Age Factors↗
PubMed1989

Psychiatric DRGs: more risk for hospitals?

The diagnosis related group (DRG) system, which replaced the cost-plus system of reimbursement, was implemented in 1983 by Medicare to cover medical expenses on a prospective basis. To date, the DRG system has not been applied to psychiatric illness. The authors compare the likelihood of cost overruns in psychiatric illness with that of cost overruns in medical illness. The data analysis demonstrates that a prospective payment system would have a high likelihood of failure in psychiatric illness. Possible reasons for failure include wide variations in treatments, diagnostics, and other related costs. Also, the number of DRG classifications for psychiatric illness is inadequate.

Data Collection↗
PubMed1987

Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans.

A change in the formulation of the levothyroxine preparation Synthroid (Flint) in 1982 prompted us to reevaluate the replacement dose of this drug in 19 patients with hypothyroidism. The dose was titrated monthly until thyrotropin levels became normal. The mean replacement dose (+/- SD) was 112 +/- 19 micrograms per day, significantly less (P less than 0.001) than the dose of an earlier formulation--169 +/- 66 micrograms per day--used in a similar study (Stock JM, et al. N Engl J Med 1974; 290:529-33). The fractional gastrointestinal absorption of a tablet of the current formulation is 81 percent, considerably higher than the earlier estimate of 48 percent. Using high-performance liquid chromatographic analysis, we found that the current tablet contains the amount of thyroxine stated by the manufacturer. By measuring the bioavailability of the earlier type of tablet in five patients, we inferred that the strength of the previous tablet had been overestimated. In the present study, the thyrotropin levels of patients on replacement therapy returned to normal when serum triiodothyronine concentrations were not significantly different from those of controls (122 vs. 115 ng per deciliter [1.87 vs. 1.77 nmol per liter]), but when serum thyroxine levels were significantly above those of controls (11.3 vs. 8.7 micrograms per deciliter [145 vs. 112 nmol per liter], P less than 0.001). These findings suggest the possibility that in humans, serum triiodothyronine may play a more important part than serum thyroxine in regulating the serum thyrotropin concentration.

Biological Availability↗
PubMed1987

Buffy coat transfusions in early type I diabetes.

Fresh whole-blood buffy coats from American Red Cross volunteers were used to treat early type I diabetes. Attempts were made to adapt to human diabetic patients a protocol successfully used in prediabetic BB rats. Twenty-two type I diabetic patients (duration of disease less than 4 wk) were randomized to treatment or control groups; the treatment patients were given one buffy coat (approximately 0.6 X 10(9) T-lymphocytes) weekly for 5 wk. Plasma C-peptide (stimulated and unstimulated), insulin dose, and hemoglobin A1c were measured before and periodically after the treatment for 24 wk. The control group underwent the same studies. Although there were no significant differences for the parameters studied between the two groups, 2 of 12 patients in the treatment group underwent three complete (normal glycemia without insulin) temporary remissions. One of these patients was given a second course of transfusions after relapse from the first remission and developed a second complete remission that lasted 2 mo. No control patient had remissions during the 24-wk study. Although the future of adoptive immunotherapy in the treatment or prevention of diabetes is not known, several probable limitations of the current protocol, as discussed here, can explain the differences in results between this trial and the rodent studies.

Adolescent↗