Phase II study of oral topotecan in advanced non-small cell lung cancer. (49/1675)

This study was designed to assess the activity of oral topotecan (TPT) in patients with advanced non-small cell lung cancer previously untreated with chemotherapy. Eligible patients had inoperable stage III or stage IV non-small cell lung cancer and were chemotherapy-naive. Other inclusion criteria were Eastern Cooperative Oncology Group performance status 0, 1, or 2, adequate bone marrow, and renal and hepatic function. Of 30 patients, 29 were assessable for response. Oral TPT was administered for 5 days every 21 days for up to six cycles unless disease progression or unacceptable toxicity occurred. Patients received a dose of 2.3 mg/m2/day for the first cycle. Dose modification for subsequent cycles was based on tolerability. Patients completed symptom questionnaires every 3 weeks. Pharmacokinetics were evaluated in all patients during cycle 1. Three patients had radiological responses with a reduction in tumor size of 30-40%. No patients achieved complete or partial responses to treatment. Thirteen patients had a stable disease (43.3%), and the median survival was 39.9 weeks with a 1-year survival of 33.3%. At the time of analysis, 27 patients had died. Median time to progression was 12.3 weeks. Treatment was well tolerated. A total of 125 cycles of treatment were completed. Twelve patients (40%) experienced grade III/IV neutropenia. Five patients (16.6%) had grade III/IV anemia. There were two episodes of grade III/IV thrombocytopenia. The main nonhematological toxicities consisted of grade III nausea (13%) and grade III vomiting (13%). The most frequently reported disease-related symptoms at baseline were dyspnea, cough, and fatigue. There was a subsequent improvement in patient scores of dyspnea in 17% of patients, 31% showed improvement in cough, and 32% showed improvement in fatigue. The mean area under the curve of TPT following 2.3 mg/m2 p.o. was 51.6 ng.h/ml (%SD, 25%). The area under the curve of TPT on day 1 of the first cycle was correlated with the percentage fall in leukocytes. Although oral TPT at the applied dose and schedule showed modest activity as a single agent, almost one-half of the patients had a stable disease, and median time to progression was 12.3 weeks. The overall median survival was a promising 39.9 weeks, and useful palliation of symptoms was seen.  (+info)

The emetic reflex in a reptile (Crocodylus porosus). (50/1675)

The emetic (vomiting) reflex in a crocodilian, Crocodylus porosus, was characterised for the first time using the plant alkaloid veratrine (5 mg kg(-)(1) i.v. or i.p.) as an emetic stimulus. The latency to the onset of vomiting was 8.0+/-0.9 min (mean +/- s.e.m., N=5 animals). Vomiting was preceded by a clearly defined set of prodromal behaviours including, in temporal sequence, rhythmic contraction of the pharynx, sneezing and jaw snapping. Expulsion of vomitus was not particularly forceful and was accompanied by lateral shaking of the head. Physiological studies revealed that vomiting was accompanied by oscillatory (9.1+/-0.7 oscillations over 29.7+/-3. 6 s, N=9 episodes in three animals) increases in intraperitoneal pressure (7.0+/-0.9 kPa, cf. 0.7+/-0.1 kPa during respiration). The significance of these results is discussed in the context of the role(s) of vomiting as a protective reflex and as a mechanism for removal of indigestible food residues (e.g. fur, claws) from the gut.  (+info)

Topotecan lacks third space sequestration. (51/1675)

The objective of this study was to determine the influence of pleural and ascitic fluid on the pharmacokinetics of the antitumor camptothecin derivative topotecan. Four patients with histological proof of malignant solid tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on several occasions in both the presence and absence of third space volumes. Serial plasma and pleural or ascitic fluid samples were collected during each dosing and analyzed by high-performance liquid chromatography for both the intact lactone form of topotecan and its ring-opened carboxylate form. The apparent topotecan clearance demonstrated substantial interpatient variability but remained unchanged within the same patient in the presence [110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven courses)]. Similarly, terminal half-lives and area under the concentration-time curve ratios of lactone:total drug in plasma were similar between courses within each patient. Topotecan penetration into pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range, 1.37-1.86 h), and ratios with plasma concentration increased with time after dosing in all patients. The mean ratio of third space topotecan total drug area under the concentration-time curve to that in plasma was 0.55 (range, 0.26-0.87). These data indicate that topotecan can be safely administered to patients with pleural effusions or ascites and that there is substantial penetration of topotecan into these third spaces, which may prove beneficial for local antitumor effects.  (+info)

Novel marine-derived anticancer agents: a phase I clinical, pharmacological, and pharmacodynamic study of dolastatin 10 (NSC 376128) in patients with advanced solid tumors. (52/1675)

Dolastatin (DOLA)-10 is a pentapeptide isolated from the mollusc Dolabella auricularia with clinically promising antitumor activity documented in various in vitro and in vivo tumor models. The objectives of this Phase I study were to determine the maximum tolerated dose, evaluate toxic effects, and document any antitumor activity of this novel agent. Using an electrospray ionization mass spectroscopy system, we also characterized the clinical pharmacokinetics, pharmacodynamics, and metabolism of DOLA-10. The maximum tolerated dose was reached at 300 microg/m2. Granulocytopenia, the dose-limiting toxicity, was documented in 33% of the patients treated at that dose level. There were no episodes of thrombocytopenia or severe anemia (Hgb < 8), and no major nonhematological toxicity was observed. Stabilization of tumor growth was observed in four patients, but no objective responses were seen. Whereas a two-compartment model described the DOLA-10 plasma concentration-time data reasonably well, a three-compartment model consistently performed better. After a rapid distribution phase, DOLA-10 plasma levels declined with mean beta and gamma half-lives of 0.99 and 18.9 h, respectively. Significant interpatient and intrapatient variability in DOLA-10 plasma clearances was observed. The mean area under the concentration-time curve increased proportionally as the dose was escalated, but there was significant overlap between dose levels. The area under the concentration-time curve and the percentage of decline in neutrophils were correlated. A single DOLA-10 metabolite was detected in five patients. Unlike the in vitro studies of DOLA-10, the principal metabolite detected was an N-demethyl derivative, confirmed by mass spectroscopy. In all five subjects, the concentration of this metabolite never exceeded 2% of the simultaneously measured parent drug concentration. The available preclinical, pharmacological, and clinical data suggest that further study of escalated DOLA-10 dosing with cytokine support is warranted.  (+info)

A multicenter phase II trial of losoxantrone (DuP-941) in hormone-refractory metastatic prostate cancer. (53/1675)

Our purpose in this study was to determine the efficacy and toxicity of losoxantrone (DuP-941), an anthrapyrazole, in patients with metastatic hormone-refractory prostate cancer. Patients with metastatic prostate cancer progressing on androgen ablation therapy without demonstrable antiandrogen withdrawal response were treated with losoxantrone 50 mg/m2 i.v. bolus every 21 days. All of the patients had elevated serum prostate-specific antigen (PSA) before study entry and had no prior chemotherapy. Forty-three assessable patients were entered. The median age was 70.6 years (range, 53.9-85.9), median Karnofsky performance scale (KPS), 70% (50-90%), and the median serum PSA, 173 microg/liter (12.5-11,140). The median number of courses was 4 (1-9). Five patients (25%) had a partial response as defined by >50% decline in the serum PSA. Two of nine patients with measurable disease had partial responses and three had minor responses. Thirty percent of patients had improvement in KPS and 37% had an improvement in symptoms with decrease in pain and/or decrease in analgesic requirement. Nonhematological grade 3 and 4 toxicities were one each of grade 3 headache, grade 4 hypocalcemia, grade 3 hyperbilirubinemia, and grade 3 dyspnea. Twenty-six patients (60%) had grade 3 or 4 absolute neutropenia. In conclusion, losoxantrone demonstrated a partial biochemical response rate of 25%, response in measurable disease sites in 22%, and improvement in clinical symptoms in one-third of patients. In this study, PSA increase was not necessarily associated with lack of palliative response.  (+info)

The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel. (54/1675)

This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics.  (+info)

Cisplatin-induced early and delayed emesis in the pigeon. (55/1675)

1. Intravenously injected cisplatin at a dose of 4 mg kg(-1) induced early and delayed emesis in all pigeons without occurrence of lethality during a 72 h observation period. The early emetic response occurred with a latency of 81.3+/-8.0 min (n=15) and reached a peak at 2 - 3 h, and decreased gradually within 8 h after injection. Then the delayed emetic response, whose peak was found between 10 to 23 h, lasted up to 48 h. The emetic response markedly declined after 48 h. 2. Reserpine markedly reduced monoamine levels in both brain and intestine and completely abolished the early and delayed emesis. Dexamethasone markedly reduced not only the early but also the delayed emetic responses. p-Chlorophenylalanine decreased the level of serotonin in brain and intestine without affecting noradrenaline and dopamine and partly reduced the early emetic response, but did not affect delayed emesis. 3. Bilateral vagotomy prolonged the latency time to the onset of early emesis, and reduced the emetic responses in both the early and delayed phases. 4. The above results suggest that the cisplatin-induced early emesis in the pigeon is partially mediated via the vagal nerve and reserpine-sensitive monoaminergic systems including the serotonergic system; the delayed emesis is associated with monoaminergic but not the serotonergic systems.  (+info)

Vaginal misoprostol alone for medical abortion up to 9 weeks of gestation: efficacy and acceptability. (56/1675)

Misoprostol and mifepristone have been shown to be effective for medical abortion up to 9 weeks of gestation. When used alone, the successful complete abortion rate dropped to approximately 60%. It has been demonstrated that by adding water to misoprostol, the success rate rose to 92%. This is the first randomized study to investigate the efficacy of misoprostol and water versus misoprostol alone for first trimester medical abortion in women at +info)