Male reproductive hormones in patients treated with pretomanid.

BACKGROUND: Pretomanid (Pa) is a nitroimidazole-class drug recently approved by the US Food and Drug Administration and other regulatory authorities as part of a regimen for treating highly drug-resistant pulmonary Mycobacterium tuberculosis infections. Studies in rodents identified the testis as a target organ of concern, which led to monitoring of reproductive hormones in >800 male patients enrolled in four clinical trials of Pa-containing regimens and the HRZE (isoniazid+rifampin+pyrazinamide+ethambutol) control regimen.METHODS: Serum hormone levels relevant to male reproductive health - follicle stimulating hormone (FSH), luteinizing hormone (LH), inhibin B (InhB) and total testosterone (T) - from the four clinical trials were summarized numerically and analyzed by repeated-measures modeling.RESULTS: Hormone levels generally behaved similarly in Pa-containing and HRZE arms. Relative to baseline, serum T and InhB levels generally increased at the end of treatment and follow-up. FSH and LH levels were variable, but were generally at or below baseline levels by follow-up. Before treatment, many patients were borderline hypogonadal, with T levels near the lower limits of the normal range.CONCLUSION: Changes in male hormones in four clinical trials studying patients with TB indicate that Pa-containing treatment was not associated with testicular toxicity but rather led to improvement in the underlying hypogonadism.

Pretomanid with bedaquiline and linezolid for drug-resistant TB: a comparison of prospective cohorts.

BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B-L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Benefits of implementing a link nurse group across both an acute and a primary care trust.

This paper describes how two tissue viability nurses, one from an acute trust and one from a primary care trust, joined forces to set up a link nurse group. This helped raise the profile of wound care and improve standards of care.

Drug-resistant tuberculosis clinical trials: proposed core research definitions in adults.

Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.

The neglected medical history and therapeutic choices for abdominal pain. A nationwide study of 799 physicians and nurses.

A random national sample of 501 physicians and 298 nurse practitioners was presented a case vignette describing a patient with epigastric pain and endoscopy showing diffuse gastritis. Respondents were encouraged to request further information and then were asked for recommendations. History available if requested included substantial use of aspirin, coffee, cigarettes, and alcohol, and severe psychosocial stress. More than one third of the physicians chose to initiate therapy without seeking a relevant history. Nearly half of all physicians indicated that a prescription would be the single most effective therapy; 65% recommended a histamine antagonist. By contrast, only 19% of nurse practitioners opted to treat without taking further history; the nurse sample asked an average of 2.6 questions vs 1.6 for physicians; only 20% of the nurses recommended a prescription medication. These findings raise concerns about the adequacy of basic history taking in this setting and the underuse of nonpharmacologic approaches in favor of excessive reliance on prescription drugs, even when not indicated by clinical circumstances.

Anticholinergic drug use and bowel function in nursing home patients.

BACKGROUND: We sought to measure the relationship between the use of anticholinergic drugs and bowel dysfunction in nursing home patients. METHODS: The study population consisted of 800 residents (average age, 84.7 years; range, 65 to 105 years) from 12 intermediate-care facilities in Massachusetts. Patient characteristics and actual medication use were documented during a 1-month observation period. Neuropsychological and functional testing was performed on all residents receiving psychoactive medications. Constipation was assessed by measuring the frequency of laxative use. RESULTS: Laxatives were used daily by 74% of residents; 45% received more than one laxative a day. After adjusting for potential confounding by logistic regression modeling, we found that daily laxative use was significantly more common in residents taking highly anticholinergic antidepressants such as amitriptyline (odds ratio, 3.12), diphenhydramine (odds ratio, 2.18), highly anticholinergic neuroleptics such as thioridazine (odds ratio, 2.01), and in the very old (odds ratio, > or = 85 years = 2.23). Gender, decreased functional status, impaired cognitive function, and the use of benzodiazepines or antiparkinsonian agents were not associated with increased use of laxatives. CONCLUSIONS: A strong association exists in institutionalized elderly between the use of specific anticholinergic medications and constipation, as reflected in the increased use of laxatives. This effect was not seen with nonanticholinergic sedatives, nor was it explained by the patients' cognitive or functional status. These drugs may be responsible for substantial iatrogenic effects on bowel function in elderly patients.

Clinical assessment of extrapyramidal signs in nursing home patients given antipsychotic medication.

BACKGROUND: We sought to quantify the relationship between antipsychotic drug use and clinical evidence of extrapyramidal dysfunction in a large population of elderly nursing home patients. METHODS: Subjects were 251 residents (mean age, 84.1 years; range, 65 to 105 years) who were taking psychoactive drugs in 12 long-term care facilities. Patient characteristics and all medication use (both scheduled and as needed) were measured during a 1-month observation period. We then performed neuropsychological and functional testing on residents who received any psychoactive medications during the study month. The presence of rigidity, bradykinesia, or masklike facies was assessed in each patient by a research assistant who was unaware of diagnoses and medication use. RESULTS: The parkinsonian signs studied were found in 127 (50.6%) of these residents. Using logistic regression modeling to adjust for potential confounding, we found this outcome to be increased more than threefold in patients who took low-potency neuroleptics (odds ratio [OR], 3.49 for > or = 50 mg/d of chlorpromazine-type drugs; 95% confidence interval [CI], 1.28 to 9.57) and more than sixfold for use of 1 mg/d or more of haloperidol (OR, 6.42; 95% CI, 2.16 to 19.04). Age, gender, and use of nonneuroleptic psychoactive drugs were not associated with an increase in parkinsonian signs. CONCLUSIONS: Clinical evidence of extrapyramidal dysfunction is three to six times more common in institutionalized elderly patients given antipsychotic medication than in comparable patients not using such drugs. Its risk is substantially increased even in patients given low-potency chlorpromazine-type drugs, as well as those taking haloperidol. The effect is not explained by age or mental status and is not seen with other psychoactive medications. The expected frequency of parkinsonian symptoms can help to inform the balancing of risks vs therapeutic effect when the use of all drugs in this class is considered.

Urinary excretion of 6 beta-hydroxycortisol as an in vivo marker for CYP3A induction: applications and recommendations.

OBJECTIVE: To evaluate the usefulness of 6 beta-hydroxycortisol as a screen for CYP3A induction in early-phase drug development. METHODS: Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily, (2) placebo once daily, (3) 40 mg SB 216469 twice a day, (4) 60 mg SB 216469 twice a day, or (5) 40 mg SB 216469 three times a day. All medications were taken orally and administered for 7 consecutive days. Urine was collected over a 24-hour period for each subject before administration and on the last day of administration for each respective regimen for measurement of 6 beta-hydroxycortisol and 17-hydroxycorticosteroid concentrations. RESULTS: Subjects in the rifampin group had a significant increase from predose value in the 24-hour urinary excretion of 6 beta-hydroxycortisol and the ratio of 6 beta-hydroxycortisol to 17-hydroxycorticosteroid. All 12 subjects in the rifampin group had increases in 6 beta-hydroxycortisol excretion, whereas 11 of 12 had an increase in the ratio. The placebo and three active treatment groups did not show significant changes in either parameter. CONCLUSIONS: Urinary excretion of 6 beta-hydroxycortisol may be useful as a screening tool in early-phase development to assess the potential for an investigational drug to induce CYP3A.

Clinical decision-making in the evaluation and treatment of insomnia.

We interviewed a representative random sample of 501 office-based general physicians and 298 nurse practitioners to evaluate their approach to the symptoms of insomnia. Clinicians were presented with a standard case of a patient complaining of difficulty sleeping, with the age of the patient depicted as either 37 years or 77 years. Historical information was provided in response to practitioners' questions. In evaluating the history, physicians asked an average of 2.5 questions and were most likely to ask about psychologic problems. Only 47% of the physicians who were presented with the elderly case vignette elicited a sleep history. By contrast, nurse practitioners asked an average of 3.2 questions, and 60% of them took a sleep history. Despite many possible non-pharmacologic therapies for the patients presented, 46% of physicians identified a prescription medication as the single most effective therapy for the older patient, compared with 17% of nurse practitioners. These findings suggest that physicians place inadequate emphasis on history-taking in the evaluation of insomnia and resort to the use of psychoactive drugs even when non-pharmacologic approaches might be more effective.

Neuroleptic drug exposure and treatment of parkinsonism in the elderly: a case-control study.

PURPOSE: Despite the widespread use of neuroleptic medications for the elderly, little is known about the frequency of treatment for drug-induced parkinsonian syndromes in this age group, particularly with L-dopa-type drugs, which are more appropriate for the treatment of true idiopathic Parkinson's disease. PATIENTS AND METHODS: We identified 3,512 patients aged 65 to 99 enrolled in a large state Medicaid program who were newly prescribed a drug to treat parkinsonian symptoms. Controls were comparable program enrollees of similar age who had not been prescribed an antiparkinsonian drug. In a case-control study, we evaluated the use of neuroleptic drugs in the 90 days before initiation of antiparkinsonian therapy. RESULTS: Patients taking neuroleptics were 5.4 times more likely to begin antiparkinsonian medication than were nonusers (95% confidence interval [CI] 4.8 to 6.1). They also had a greater than two-fold increase in risk of beginning therapy with a dopaminergic drug specific for idiopathic Parkinson's disease, not generally indicated for treatment of drug-induced parkinsonism (adjusted odds ratio 2.2, 95% CI 1.9 to 2.7). Clear dose-response relationships were demonstrated, as were differences among neuroleptics. Among all patients started on dopaminergic drugs in this population, 37% of such therapy was attributable to prior neuroleptic use. Continuation of the neuroleptic persisted in 71% of patients so treated. CONCLUSION: Neuroleptic use is a common cause of extrapyramidal dysfunction in the elderly, and the side effect is frequently treated by adding an anticholinergic or dopaminergic drug to the regimen. The use of anticholinergic drugs presents risks of additional drug side effects; the use of dopaminergic drugs, generally not appropriate for drug-induced parkinsonian syndrome, suggests that extrapyramidal neuroleptic side effects may often be mistaken for idiopathic Parkinson's disease in older patients.

Inhibition of vascular K(ATP) channels by U-37883A: a comparison with cardiac and skeletal muscle.

1 The aim of this study was to investigate the selectivity of the ATP-sensitive potassium (K(ATP)) channel inhibitor U-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-1-cyclohexyl). Membrane currents through K(ATP) channels were recorded in single muscle cells enzymatically isolated from rat mesenteric artery, cardiac ventricle and skeletal muscle (flexor digitorum brevis). K(ATP) currents were induced either by cell dialysis with 0.1 mM ATP and 0.1 mM ADP, or by application of synthetic potassium channel openers (levcromakalim or pinacidil). 2 U-37883A inhibited K(ATP) currents in smooth muscle cells from rat mesenteric artery. Half inhibition of 10 microM levcromakalim-induced currents occurred at a concentration of 3.5 microM. 3 Relaxations of rat mesenteric vessels caused by levcromakalim were reversed by U-37883A. 1 microM levcromakalim-induced relaxations were inhibited at a similar concentration of U-37883A (half inhibition, 1.1 microM) to levcromakalim-induced KATP currents. 4 K(ATP) currents activated by 100 microM pinacidil were also studied in single myocytes from rat mesenteric artery, skeletal muscle and cardiac ventricle. 10 microM U-37883A substantially inhibited K(ATP) currents in vascular cells, but had little effect in skeletal or cardiac myocytes. Higher concentrations of U-37883A (100 microM) caused a modest decrease in K(ATP) currents in skeletal and cardiac muscle. The sulphonylurea K(ATP) channel antagonist glibenclamide (10 microM) abolished currents in all muscle types. 5 The effect of U-37883A on vascular inward rectifier (KIR) and voltage-dependent potassium (KV) currents was also examined. While 10 microM U-37883A had little effect on these currents, some inhibition was apparent at higher concentrations (100 microM) of the compound. 6 We conclude that U-37883A inhibits K(ATP) channels in arterial smooth muscle more effectively than in cardiac and skeletal muscle. Furthermore, this compound is selective for K(ATP) channels over KV and KIR channels in smooth muscle cells.

Medicaid data as a resource for epidemiologic studies: strengths and limitations.

Large claims databases from third-party insurance programs such as Medicaid have attracted the interest of epidemiologists because of their enormous size and apparent comprehensiveness. Over 20 million people are covered by the various state Medicaid programs and most states maintain detailed computerized records of all reimbursed health care encounters on a recipient-specific basis. For states covering medication costs, data on drug exposures are particularly complete and accurate. However, Medicaid claims data also have many limitations that can pose major methodological difficulties. Foremost among these is the uneven validity and completeness of the diagnoses appearing on claims. Likewise, the unique identification of specific program participants is not straightforward, although useful approaches can often be developed to track individuals over time. Consideration of the limitations as well as the possible strengths of claims-based data makes it possible to choose appropriate study hypotheses as well as to attempt solutions, where possible, to the biases of this methodology.

Resident behavior and staff distress in the nursing home.

Newly enacted Federal regulations have focused increasing attention on the use of psychoactive drugs and on the treatment of disruptive behavior in the nursing home. To study the interaction between resident behavior and staff distress in nursing homes, we measured the frequency of seven types of behavior problems among 346 residents of intermediate care facilities who were receiving some form of psychoactive medication. Nurses were interviewed on two shifts to determine their perception of the frequency and severity of each behavior in each patient as well as the level of distress it caused among caregivers. The most common behavior problems noted were agitation (42%), withdrawal (33%), and noisiness (27%). Only half of the reported instances of behavior disorders were considered distressful by nursing home staff. While physical abuse caused distress 92% of the time and verbal abuse 90% of the time, wandering was seen as distressful to staff only 50% of the time. Nearly a third of "wandering" patients were restrained; they produced less distress than non-restrained wanderers. There was substantial disagreement, ranging from 6% to 22% for individual residents, over the presence of distress-causing behavior, although day and evening nursing shifts rated the frequencies of behavior and the degrees of distress equally on average. Residents with higher cognitive function were less likely to cause distress for all behaviors, except for verbal abuse where the reverse was true. Age and dependency in activities of daily living were not associated with problematic behavior or staff distress. These findings indicate that the existence of "problematic" behaviors in a given resident is often perceived differently by different staff, and its impact on staff also differs widely.

Pygmalion in the nursing home. The effects of caregiver expectations on patient outcomes.

Several characteristics of nursing home care can diminish rather than enhance the clinical status of older residents. In view of evidence from other settings that "interpersonal expectancy effects" can influence outcomes in a variety of relations, we conducted a randomized controlled trial to test the effects of caregiver expectations on the clinical status of nursing home residents. Within 2 weeks of admission, 63 older residents at six nursing homes were given a comprehensive assessment of cognitive, functional, and emotional status. Residents were then randomly assigned to a "high-expectancy" or "average-expectancy" condition. Nurses and aides were told that, in comparison with other residents having similar problems, residents in the high-expectancy group were predicted to perform above average in their rehabilitation. The assessment was repeated 3 months later; information on the health and psychosocial status of residents was drawn from their medical records covering the same period. Aides reported having higher expectations for treatment group residents. When assessed by a blinded research assistant, residents in the high-expectancy group experienced greater relief of depressive symptoms but showed greater decrements in functional independence in comparison with control residents. Treatment group residents were admitted significantly less frequently to hospitals despite a comparable number of emergency ward visits, suggesting a lower incidence of severe illness despite comparable medical surveillance. There was also a trend toward improved performance in mental status testing among the high-expectancy residents compared with controls (P = .08). Additional research is needed to define further the magnitude and mechanisms of expectancy effects in relations between nursing home caregivers and residents.

Changing surgical antimicrobial prophylaxis practices through education targeted at senior department leaders.

Prescribing antibiotics for perioperative prophylaxis in common surgical procedures presents an ideal target for educational intervention. In this situation, antibiotics are often used inappropriately, with consequent excess expense and risk of morbidity. We developed an educational intervention aimed at the choice and appropriate dosing of antibiotics for the prophylaxis of cesarean sections. Person-to-person educational messages targeted at authoritative senior department members were supplemented by brief reminders on a structured antibiotic order form. Time-series analyses were conducted on 34 months of antibiotic use data for 2,783 cesarean sections to estimate the trend of magnitude and significance of discontinuities associated with the start of the program. Prior to the intervention, 95% of sections receiving prophylaxis were given cefoxitin and 3% were given cefazolin. After the intervention, these proportions were reversed, with the shift in use occurring immediately after the intervention (p less than .001). Two years after the intervention, virtually all patients undergoing cesarean sections who receive antibiotic prophylaxis are given cefazolin. Savings from this change alone accounted for over $26,000 each year, or $47.36 per patient-day of prophylaxis. Substantial changes in prescribing practices for routine procedures can be accomplished through the implementation of a coordinated educational program that enlists influential senior staff members in a department in which policy-making is highly centralized, coupled with a structured educational ordering system. Lasting improvements in clinical practices may be brought about by means that are noncoercive, inexpensive and well-accepted by medical staff.

Categories of family-mediated abuse and neglect of elderly persons.

The records of 22 cases of family-mediated abuse and neglect of elderly persons were retrospectively reviewed by the physician and nurse responsible for their care using a modification of the OARS Multidimensional Functional Assessment form. Cases were divided into three categories: Category I cases (n = 4) involved extremely impaired elders who received extensive care from the individuals responsible for the abuse or neglect. Category II cases (n = 9) involved impaired elders who received inadequate or intermittent care. Category III cases (n = 9) involved independent elders whose only care needs resulted from threats or violence from relatives. Among the statistically significant differences found between these categories were the age of the abuser, the manifestations of abuse or neglect, the interventions offered, the durations of abuse, and the outcomes of the cases. The results suggest that these three categories represent different subgroups of abused and neglected elderly persons, all with different implications for identification, intervention, and outcome.

The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) may alter blood pressure through their inhibitory effects on prostaglandin biosynthesis. Such potential hypertensive effects of NSAIDs have not been adequately examined in the elderly, who are the largest group of NSAID users. METHODS: We performed a randomized, double-blind, two-period crossover trial of ibuprofen (1800 mg per day) vs placebo treatment in patients older than 60 years of age with hypertension controlled with hydrochlorothiazide. While continuing their usual thiazide dosage, subjects were randomized to a 4-week treatment period (ibuprofen or placebo) followed by a 2-week placebo wash-out period and a second 4-week treatment period with the alternative therapy. Supine and standing systolic and diastolic blood pressures were measured weekly. RESULTS: Of 25 randomized subjects, 22 completed the study protocol (mean age = 73 +/- 6.7 years). Supine systolic blood pressure and standing systolic blood pressure were increased significantly with ibuprofen treatment, compared with placebo. Mean supine systolic blood pressures were 143.8 +/- 21.0 and 139.6 +/- 15.9 mmHg on ibuprofen and placebo, respectively (p = .004). Mean standing systolic blood pressures were 148.1 +/- 19.9 and 143.4 +/- 17.9 mmHg on ibuprofen and placebo, respectively (p = .002). CONCLUSION: We conclude that 1800 mg per day of ibuprofen does induce a significant increase in systolic blood pressure in older hypertensive patients treated with hydrochlorothiazide. NSAID therapy may negatively impact the control of hypertension in elderly patients.

Effect of intravenous fenoldopam on intraocular pressure in ocular hypertension.

Intravenous fenoldopam, a selective dopamine-1 receptor agonist, was compared with placebo in this randomized, double-blind, two-period crossover study to evaluate its effects on intraocular pressure, aqueous dynamics, and macular blood flow in patients with elevated intraocular pressure or primary open-angle glaucoma. Doses of fenoldopam were titrated up to a maximum of 0.5 microgram/kg/min. Intraocular pressure, measured by pneumotonometry, was the primary outcome variable. Other outcomes included macular blood flow assessed by blue field examination, visual field examined by automated perimetry, aqueous outflow facility measured by tonography, and aqueous humor production determined by fluorophotometry. During infusions of fenoldopam, intraocular pressure increased from a mean baseline level of 29.2 mmHg to a mean maximum level of 35.7 mmHg. During the placebo infusions, pressure increased from a mean baseline of 28.4 mmHg to a mean of 29.0 mmHg at the time point that corresponded to the mean maximum intraocular pressure on the day intravenous fenoldopam was administered, to yield a mean difference in pressure between study days of 6.7 mmHg (P < 0.05). There were no apparent changes in macular blood flow, visual fields, or production or outflow of aqueous humor associated with fenoldopam infusion. The increase in intraocular pressure seen in this population of patients with ocular hypertension during infusions of fenoldopam is consistent with fenoldopam-associated increases in intraocular pressure reported in previous studies of healthy volunteers and of patients with accelerated systemic hypertension. These results further suggest that dopamine-1 receptors play a role in the regulation of intraocular pressure.

Comparative effects of nabumetone, sulindac, and indomethacin on urinary prostaglandin excretion and platelet function in volunteers.

Nonsteroidal antiinflammatory drugs differ with respect to their effects on prostaglandin metabolism in various tissues, a property that may be partly responsible for some of the differences in the pharmacologic activities and side-effect profiles that are associated with their use. The effects of nabumetone on urinary prostaglandin excretion have not been reported. Fourteen healthy females, age 21-43 years, were treated with nabumetone (NAB) 1000 mg daily, sulindac (SUL) 200 mg every 12 hours, and indomethacin (IND) 50 mg every 12 hours for 7 days in a randomized period-balanced crossover study. The effects of drug treatment on urinary prostaglandin excretion (PGE2, 6-keto-PGF1 alpha, PGF2 alpha, thromboxane [TX] B2) and platelet function (collagen-induced whole blood platelet aggregation [CIPA] and template bleeding time) were determined on day 1 and day 7. For each treatment regimen, mean baseline urinary PG excretion values were comparable for each prostanoid, but the pattern of excretion differed in response to each drug. Treatment with NAB significantly increased the urinary excretion rates of PGE2 and PGF2 alpha, but 6-keto-PGF1 alpha and TXB2 excretion were unchanged. IND treatment did not result in a significant change in PGE2 excretion but did significantly reduce urinary 6-keto-PGF1 alpha and TXB2 excretion rates. Reduced excretion of PGF2 alpha was observed on both study days during treatment with IND and SUL. SUL treatment also resulted in increased urinary PGE2 excretion while significantly reducing 6-keto-PGF1 alpha excretion on day 7. Significant differences were observed between the NAB and SUL regimens with respect to PGF2 alpha excretion and between the NAB and SUL regimens for PGE2, PGF2 alpha, 6-keto-PGF alpha 1 (on day 1 only) and TXB2 (on day 1 only). Neither NAB nor SUL caused inhibition of CIPA or bleeding time although platelet aggregation was inhibited during IND treatment. That NAB treatment was neither associated with alterations in platelet function nor decreases in the urinary excretion of the vasodilatory prostaglandins, PGE2 and 6-keto-PGF1 alpha, suggests that NAB possesses renal sparing properties.