Disposition of ropinirole in animals and man.

1. The disposition and metabolic fate of ropinirole, a novel compound indicated for the symptomatic treatment of Parkinson's disease, was studied in the mouse, rat, cynomolgus monkey and man, following oral and intravenous administration of ropinirole hydrochloride. 2. In all species, nearly all of the p.o. administered dose (94%) was rapidly absorbed from the gastrointestinal tract following administration of 14C-ropinirole hydrochloride. In rat and monkey, the compound distributed rapidly beyond total body water and was shown to cross the blood-brain barrier. Blood clearance of the compound was high, approximately equal to one-half the hepatic blood flow in the monkey and similar to the hepatic blood flow in rat. Terminal phase elimination half-lives for the compound were relatively short (0.5 and 1.3 h in rat and monkey respectively), although there was evidence of a second elimination phase in the monkey with an elimination half-life of approximately 5-11 h. Plasma concentrations of ropinirole after the intravenous dose were not determined in the mouse and were below the lower limit of quantification in man (0.08 ng/ml) at the doses used in the studies described in this paper. 3. In both animals and man, ropinirole was extensively metabolized. In the rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole. In mouse, monkey and man, the major pathway was via N-depropylation. The N-despropyl metabolite was metabolized further to form 7-hydroxy and carboxylic acid derivatives. Metabolites formed in all species were generally metabolized further by glucuronidation. 7-Hydroxy ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo. In all species, the major route of excretion of ropinirole-related material after oral or intravenous administration of the compound was renal (60-90% of dose).

Phase II trial of topotecan as a 21-day continuous infusion in patients with advanced or metastatic adenocarcinoma of the pancreas.

The aim of this study was to determine the efficacy and toxicity of topotecan administered as a 21-day continuous intravenous infusion in patients with advanced or metastatic adenocarcinoma of the pancreas. 26 previously untreated patients with advanced or metastatic pancreatic adenocarcinoma received topotecan at a dose of 0.5 mg/m2/day or 0.6 mg/m2/day as a continuous intravenous infusion for 21 days. Courses were repeated every 28 days. 26 patients were assessable for response and toxicity on an intent-to-treat basis. The initial 8 patients at a starting dose of 0.6 mg/m2/day experienced unacceptable myelosuppression and dose delays. The subsequent 18 patients, therefore began therapy at a dose of 0.5 mg/m2/day. The major toxicity of topotecan at this dose and schedule was myelosuppression, which was reversible and non-cumulative. There were no complete responses and two partial responses for a total response rate of 8% (95% confidence interval, 1-25%). Response durations were 17 and 45 weeks. Stable disease was seen in 3 patients. The median time to progression for all patients was 8 weeks and the median survival was 20 weeks. Topotecan given as a 21-day continuous intravenous infusion has a similar response rate and median survival to our previously reported study of the 5-day short infusion regimen in pancreatic carcinoma.

Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.

PURPOSE: Topotecan and paclitaxel were evaluated in a randomized, multicenter study of patients with advanced epithelial ovarian carcinoma who had progressed during or after one platinum-based regimen. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 112) or paclitaxel (175 mg/m2) infused over 3 hours every 21 days (n = 114). Patients had bidimensionally measurable disease and were assessed for efficacy and toxicity. RESULTS: Response rate was 23 of 112 (20.5%) in topotecan-treated patients and 15 of 114 (13.2%) in paclitaxel-treated patients (P = .138). Disease stabilization for at least 8 weeks was noted in 30% of patients with topotecan and 33% of patients with paclitaxel. Median durations of response to topotecan and paclitaxel were 32 and 20 weeks, respectively (P = .222) and median times to progression were 23 and 14 weeks, respectively (P = .002). Median survival was 61 weeks for topotecan and 43 weeks for paclitaxel (P = .515). Response rates for topotecan and paclitaxel were 13.3% versus 6.7% (P = .303) in resistant patients (not responded to prior platinum-based therapy or progressed within 6 months of an initial response) and 28.8% versus 20.0% (P = .213) in sensitive patients (progressed > 6 months after response). Neutropenia was significantly more frequent on the topotecan arm 79% versus paclitaxel arm 23% (P < .01). It was short-lasting and noncumulative in both arms. Nonhematologic toxicities were generally mild (grades 1 to 2) for both agents. CONCLUSION: Topotecan has efficacy at least equivalent to paclitaxel manifested by the higher response rate and significantly longer time to progression.

Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors.

PURPOSE: Topotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: Patients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. RESULTS: Thirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point "t" [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function. CONCLUSION: The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.

Patient-family conflicting issues. Part 1: The case. Part 2: Case analysis.

This article describes an ethical case when the patient's wishes and that of her spouse disagreed and the ethical issues which were involved. Although the patient clearly has the right of choice on treatment, her own choices became ambivalent as she recognized her husbands need for her to fight on.

Effects of oral pantoprazole on 24-hour intragastric acidity and plasma gastrin profiles.

Pantoprazole selectively blocks gastric parietal cell H+,K(+)-ATPase. To define a dosage regimen for clinical trials we compared the effect of pantoprazole 40 and 60 mg daily on 24-h intragastric acidity and plasma gastrin concentrations using a double-blind, randomized, cross-over design. Eleven men took each of the three regimens (placebo, 40, 60 mg) for 5 days. On Day 5, 24-h pHmetry and plasma gastrin profile were performed. A consistent decrease in intragastric acidity with each dosage regimen was shown by a rise in 24-h median pH from 1.4 (1.2-1.8, IQR) on placebo to 2.3 (1.8-4.4, P = 0.0022) during pantoprazole 40 mg and to 3.5 (2.6-4.9, P = 0.0017) during 60 mg. Pantoprazole 40 and 60 mg maintained the intragastric pH above 3 for 33% and 58% of time, respectively, compared with 15% time with placebo. Twenty-four-hour integrated plasma gastrin concentration rose from 478 to 1798 and 1962 pmol.h/L, respectively. The drug was well tolerated. The decrease of acidity was dose related and should result in clinical efficacy similar to other antisecretory drugs. It is not known whether higher doses might abolish acid secretion. The optimal dose of pantoprazole is yet to be established.

Administering pain medication for a terminal patient. Part 1: The ethical case. Part 2: Case analysis.

This is the case of a middle age man who was admitted to the intensive care unit (ICU) in respiratory failure. The nurses questioned their role in giving a medication to help the ventilatory-dependent patient to be more comfortable when the ventilator was removed at his request. Following the case is an ethical analysis of this situation.

Conflict resolution strategies: when ethical dilemmas evolve into conflict.

In critical care, ethical dilemmas arise when all duties, rights, and goals cannot be satisfied by the alternatives that are available. Conflicts evolve from ethical dilemmas due to differences in how nurses, physicians, administrators, and patients or families who are involved in a clinical situation assign priorities or interpret roles and responsibilities. This author presents strategies for critical care nurses to use to resolve conflicts that arise in relation to ethical dilemmas.

Effects of low-dose cimetidine on nocturnal acid secretion in healthy subjects.

The effects of 100 mg and 200 mg bedtime doses of cimetidine on nocturnal gastric acid secretion were examined in nine healthy subjects in a double blind, placebo controlled, randomised three way crossover study. Treatment was given at 23.00 hours and the gastric contents continually aspirated from midnight until 07.00 hours the following morning. Hourly aliquots were analysed for pH and acid output. Relative to placebo the 100 mg and 200 mg doses of cimetidine respectively increased mean pH by 2.22 and 2.63 units/h (P less than 0.001) with mean acid output decreasing by 0.95 and 0.98 mmol/h (P less than 0.001). Whilst mean pH was higher and mean acid output was lower for 200 mg cimetidine compared to 100 mg cimetidine the difference was not statistically significant. Mean hourly pH was consistently above pH 3 for 100% of the time for both doses of cimetidine whereas mean pH failed to reach this value at anytime on placebo. Low doses of cimetidine taken at bedtime effectively reduced nocturnal gastric acid secretion in healthy individuals.

Threshold variability using different Goldmann stimulus sizes.

We tested 10 healthy subjects on the Humphrey Field Analyzer using Goldmann stimulus sizes I-V to determine the effect of varying the area of the stimulus upon threshold fluctuation. Our results show similar components of fluctuation for the size III stimulus as in past studies. However, an increased total fluctuation was observed for Goldmann stimulus sizes I (3.69 decibels) and II (3.17 decibels) and a similar fluctuation for stimulus sizes IV (2.64 decibels) and V (2.51 decibels) as compared to stimulus size III (2.52 decibels). The study suggests no advantage results in reduced threshold fluctuation by changing the Goldmann stimulus from a size III when testing normal individuals on the Humphrey Field Analyzer.

A dose rising study of the safety and effects on serum prolactin of SK&F 101468, a novel dopamine D2-receptor agonist.

1. SK&F 101468, a non phenolic indolone derivative, has been characterised preclinically as a novel, potent and specific dopamine D2-receptor agonist. 2. Its tolerability and effects on serum prolactin were investigated in 14 healthy male volunteers in a study of the first administration of SK&F 101468 to man. 3. Doses between 80 micrograms and 2.5 mg caused statistically significant (P less than 0.05) lowering of basal and food stimulated serum prolactin, relative to placebo, over a 6 h post treatment period. 4. SK&F 101468 was well tolerated up to 1 mg with symptoms of nausea and postural hypotension at higher doses.

Urgency and fecal soiling in people with bowel dysfunction.

The frequency of urgency and fecal soiling in the population and among people with irritable bowel syndrome (IBS), and the association of these symptoms with health care seeking is unknown. Among 1128 students and hospital employees that we surveyed, urgency was reported in 14.4%, fecal soiling in 5.3%, and diarrhea in 9.0%. Most persons with fecal soiling did not report urgency or diarrhea. Although bowel dysfunction compatible with IBS was present in 20% (227), only 29% of this group (65) had seen a physician for bowel complaints. People with bowel dysfunction were more likely to be women, to take laxatives, and to have rectal urgency. Fecal soiling was more likely among those with bowel dysfunction who had been to the doctor, and included almost half of the men in this group. There was no difference in the frequency of diarrhea reported among those with bowel dysfunction regardless of whether they had been to the doctor. These data suggest fecal soiling may influence people with bowel dysfunction to go to the doctor. Physiological studies are needed to determine if anal sphincter dysfunction is a component of IBS.

The detection and prevalence of reactive and physiologic sclerotic dentin, reparative dentin and dead tracts beneath various types of dental lesions according to tooth surface and age.

The pulpo-dentinal complex responds to external injuries with dentin sclerosis (DS), dead tracts (DT), or reparative dentin (RD). This investigation correlates the prevalence of these responses with age, sex, type and surface location of tooth lesions (caries, restorations, attrition, abrasion and erosion) utilizing ground sections, microradiographs and decalcified paraffin-embedded tooth sections treated with the Pollak trichrome stains (270 teeth from 113 patients). The main response to caries, restorations and erosion was DS, followed by RD and DT. DS, RD and DT occurred equally in any tooth, on any tooth surface and even beneath the same lesion. DS did not necessarily prevent RD. Root and furcation DS and RD in the floor of the pulp chamber and root canals were unrelated to particular lesions but did relate to increasing age. Root DS extended from apical to cervical area with increasing age. Beneath caries and restorations DS and RD were more prevalent in males, but DT was more prevalent in females. Pollak staining of decalcified paraffin sections for DS was approximately 80% as accurate as ground sections and microradiography. In pulp studies, where the result is contrary to previous experience, the Pollak stains reveal whether DS has decreased dentin permeability.

Detecting dentinal sclerosis in decalcified sections with the Pollak trichrome connective tissue stain.

The supply of young human teeth for controlled human pulp studies is inadequate. Dentinal sclerosis in older teeth modifies the expected pulpal responses. Decalcification, necessary to interpret pulpal responses, destroys the primary evidence of sclerosis. At present we are unable to detect the degree of sclerosis and the pulp response in the same preparation. Valid interpretations on older teeth cannot be accomplished until this problem is resolved. Fifty-seven teeth, normal and carious, representing a wide age span were fixed, embedded in Bioplastic and sectioned with the Bronwill Model No. 77 through the middle of the M-D plane on the labio-lingual plane to obtain an undecalcified ground section for examination with reflected and transmitted light and Faxitron 805 microradiography. The remaining portions of the tooth were decalcified, processed in paraffin and subjected to a variety of histochemical reactions including the Pollak trichrome stain. The Pollak trichrome and the Pollak trichrome solution No. 6 modification stains provided the greatest correlations with the sclerotic areas in the radiographs of the ground sections. Areas of dentin indicative of sclerosis prior to decalcification stained orange-red with the Pollak trichrome stain and deep orange with the Pollak trichrome solution No. 6 modification.