Phase I clinical study of LL-D49194α1 with retrospective pharmacokinetic investigations in mice and humans

Summary LL-D491941 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m². One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D491941 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.     

Phase II studies of Elsamitrucin in breast cancer, colorectal cancer, non-small cell lung cancer and ovarian cancer

PURPOSE:: To test the antitumor activity of Elsamitrucin in metastaticcancer of the breast, colon and rectum, non-small cell lungand ovary. PATIENTS AND METHODS:: Eligibility required histologically proven cancer. Patientswith colorectal or non-small cell lung cancer could not havereceived prior chemotherapy. Patients were entered if WHO PSwas 2 and organ functions were normal. Treatment consisted ofElsamitrucin 25 mg/m²/week given as a 5–10 min infusionfor at least 3–6 weekly doses. RESULTS:: One hundred and five patients entered the studies, 97 were eligible,94 are evaluable for toxicity and 75 for response. Toxicitymainly consisted of mild nausea/vomiting, and less frequentlyreversible hepatotoxicity and malaise. No objective responseswere seen. CONCLUSION:: Elsamitrucin at this dose and schedule is not an active drugin metastatic breast cancer, colorectal cancer, non-small celllung cancer or ovarian cancer. Elsamitrucin, phase II, breast, colorectum, nonsmall cell lung, ovary     

Factors leading to local recurrence or death after surgical resection of phyllodes tumours of the breast

BACKGROUND: Local recurrence and death from metastases are occasional, but consistent, themes in reports of patients with phyllodes tumours. Factors that might contribute to these outcomes were sought. METHODS: Data from 38 patients with a phyllodes breast tumour were reviewed retrospectively, reclassifying the pathological material using the Pietruszka and Barnes criteria. RESULTS: At a median of 12 months, nine patients had developed a local recurrence and four had died from metastases. Following local excision in 24 patients (for diagnosis in 13, for 'fibroadenoma' in nine and for phyllodes tumour in two patients), 13 had no further surgery and five had local recurrence (three of eight benign tumours, two of two malignant tumours). Wide local excision or mastectomy in 18 patients was followed by four recurrences (one of eight borderline tumours, three of ten malignant tumours). All patients with recurrence had margin involvement on histological examination, but not all patients with margin involvement developed recurrence. Lack of statistical correlation between local recurrence and age, delay, size, grade or type of surgery was confounded by selection bias for more extensive surgery for malignant tumours. Death correlated with size (P = 0.05) and grade (P = 0.03) of tumour. CONCLUSION: Inadequate preoperative diagnosis ('fibroadenoma' or failure of triple assessment) frequently led to local excision with positive margins. Without revision this often resulted in local recurrence. Local recurrence of any grade was usually followed by further recurrence. Death was related to tumour size and histological grade, confirming these as prognostic factors.     

Prevalence and symptomatology of comorbid obsessive-compulsive disorder among bulimic patients

This study sought to assess the prevalence and symptomatology of comorbid obsessive-compulsive disorder (OCD) among Japanese subjects who met the DSM-III-R criteria for bulimia nervosa (BN). The Structured Clinical Interview for DSM-III-R Patient Version was used to distinguish 26 BN patients with concurrent OCD from 52 BN patients without OCD. Obsessive-compulsive symptoms in BN subjects with concurrent OCD were evaluated using the Japanese version of the Yale-Brown Obsessive-Compulsive Scale. There were no differences in the prevalence of concurrent OCD between BN subjects with and without a lifetime history of anorexia nervosa. Among BN subjects with concurrent OCD, symptoms related to symmetry and order were most frequently identified, followed by contamination and aggressive obsessions, and checking and cleaning/washing compulsions. Bulimia nervosa subjects with concurrent OCD were more likely than subjects without OCD to have more severe mood and core eating disorder psychopathology. Comorbid OCD is a common phenomenon in Japanese bulimics (33%) similar to that suggested in BN subjects in the Western countries. Obsessive-compulsive symptoms related to symmetry and order were most frequently observed in BN subjects with concurrent OCD, which was a similar finding to that reported among restricting anorexic subjects.     

Comparative Effects of N(omega)-L-Nitro-L-Arginine Methyl Ester and N(omega)-L-Nitro-L-Arginine Benzyl Ester in the Mesenteric Circulation of the Rat

Comparative effects of the nitric oxide (NO) synthase inhibitors, N(omega)-L-nitro-L-arginine methyl ester, and N(omega)-L-nitro-L-arginine benzyl ester on baseline arterial tone and on vasodilator responses to acetylcholine, isoproterenol, prostaglandin E(1), histamine, and nitroglycerin were investigated in the isolated mesenteric vascular bed of the rat. Under constant-flow conditions, intra-arterial (IA) injections of acetylcholine (100 ng--1 &mgr;g), isoproterenol (100 ng--1 &mgr;g), prostaglandin E(1) (0.3--3 &mgr;g), histamine (300 ng--3 &mgr;g), and nitroglycerin (100 ng--1 &mgr;g) caused dose-related decreases in mesenteric arterial perfusion pressure and decreases in systemic arterial pressure. Following administration of the NO synthase inhibitors, N(omega)-L-nitro-L-arginine methyl ester or N(omega)-L-nitro-L-arginine benzyl ester, mesenteric vascular resistance, and systemic arterial pressure were increased and mesenteric vasodilator responses to acetylcholine were significantly decreased, whereas N(omega)-L-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine benzyl ester did not significantly decrease vasodilator responses to nitroglycerin, histamine, isoproterenol, or prostaglandin E(1). The inhibitory effects of N(omega)-L-nitro-L-arginine methyl ester and N(omega)-L-nitro-L-arginine benzyl ester on vasodilator responses to acetylcholine suggest that acetylcholine-induced vasodilation in the mesenteric circulation of the rat is dependent on the release of NO from the endothelium. The increase in mesenteric vascular resistance following administration of N(omega)-L-nitro-L-arginine methyl ester and N(omega)-L-nitro-L-arginine benzyl ester suggest that tonic production of NO by the endothelium serves to maintain the mesenteric vascular bed of the rat in a dilated state.     

Situational management

In this paper, the organizational theory of situational planning is used to establish a decentralized management model for complex health units. Because of cultural limitations imposed on a perspective of change and rationalization, considerations are made in relation to a given form of dealing with culture, keeping in mind the feasibility of the management model. A particular type of communicative management emerges as a general need revealed by the analysis of the object at issue: the management of professional organizations.     

Anti-social personality disorder and response to methadone maintenance treatment

A sample of 183 current methadone maintenance patients were interviewed on their drug use history, criminal history, current drug use, and symptoms of Anti-social Personality Disorder (ASPD). Thirty-nine percent of patients met the DSM-III-R criteria for a diagnosis of ASPD. ASPD patients had an earlier onset of drug use, drug injecting, heroin use, had wider polydrug using histories and had been arrested earlier and more frequently than other patients. Despite the different pretreatment histories of ASPD and other patients, there were no differences between the two groups in retention in treatment, methadone dosage or heroin use. It is concluded that heroin-dependent ASPD patients can be successfully retained in methadone treatment, on similar methadone doses and with similar in-treatment drug use patterns as those of non-ASPD heroin dependent patients.