Impact of an all-oral capecitabine and vinorelbine combination regimen on functional status of elderly patients with advanced solid tumours: A multicentre pilot study of the French geriatric oncology group (GERICO).

BACKGROUND: Elderly metastatic cancer patients typically have short life expectancy and frequently suboptimal treatment. Goals of therapy should include preservation of functional status as well as clinical response. For elderly patients, oral chemotherapy could be a valuable strategy, avoiding the constraints and risks of intravenous drugs. METHODS: This study assessed effect of an all-oral combination of capecitabine and vinorelbine on functional status (measured by basic Activities of Daily Living [ADL]), toxicity, efficacy and compliance in patients ≥70 years with advanced breast, prostate or lung cancer. RESULTS: Eighty patients were enrolled. After three cycles, 81.8% of patients had stabilised or improved ADL, and 8.6% and 42.9% had a response or stabilised disease. Compliance was excellent (68.8%). The most common grade 3-4 toxicities were haematological (17.9%) and gastrointestinal (7.7%). CONCLUSION: In elderly cancer patients, an all-oral combination of capecitabine and vinorelbine maintains functional status, is well tolerated, and provides good disease control.

Participants' uptake of clinical trial results: a randomised experiment.

BACKGROUND: Participants are showing great interest these days in obtaining the results of clinical trials. The aim of this study was to assess patients' uptake and understanding of the results of the trial in which they have participated and the impact of a letter offering patients the possibility of consulting the trial results on a specific website. METHODS: Breast cancer patients participating in a trial on the efficacy of Trastuzumab were randomly subdivided into an Internet group (who received the letter of invitation) and a control group (who did not receive it). Among 115 HER2-positive women from 21 centres, 107 (93%) answered a self-administered questionnaire. RESULTS: Most of the patients in both groups had access to the Internet (72.0%). The majority (97.2%) stated that receiving information about the trial results would be useful, and the oncologist was the most frequently preferred information provider. The Internet group's declared uptake of the trial results was only slightly higher (47.1% vs 33.9%; P=0.166); however, they understood the results significantly more accurately (18.8% vs 5.6%; P=0.039). INTERPRETATION: Although Internet was not the respondents' preferred source of information, the possibility of using this source slightly increased the uptake and understanding of the results.

Phase I study of high-dose topotecan with haematopoietic stem cell support in the treatment of ovarian carcinomas: the ITOV 01 protocol.

Topotecan has demonstrated activity in ovarian carcinomas. In order to increase the tumour response rate and to define the maximum tolerated dose (MTD) of topotecan, we decided to develop a high-dose phase I regimen supported by stem cell support. High-doses schedules using a 1-day single administration have MTDs of 10.5 (24 h continuous infusion (CI)) or 22.5 mg/m2 (30 min infusion). Five-day CI induces grade IV mucositis at high doses (MTD<12 mg/m2). We chose to administer topotecan in a 5-day schedule with a 30 min daily infusion. Patients were scheduled to receive one cycle of therapy. The first dose level was 4.0 mg/m2/day x 5 days. Limiting toxicities were defined as toxic death, grade IV non-haematopoietic or haematopoietic toxicity >6 weeks. From August 1998 to April 2002, 49 patients were included. Forty-three patients have completed one course and 15 have received two cycles. One patient treated at level 7 mg/m2/day died of sepsis. Median duration of grade IV neutropenia was 9 days. Two episodes of grade IV diarrhoea were observed at level 9.5 mg/m2/day. Pharmacokinetic data were linear within the dose range of 4-9.0 mg/m2/day. The MTD was reached at 9 mg/m2/day x 5 days.

Validation of a specific quality of life questionnaire for functional digestive disorders.

BACKGROUND: Dyspepsia and irritable bowel syndrome are suitable conditions for assessment of quality of life. Their similarities justify the elaboration of a single specific questionnaire for the two conditions. AIMS: To examine the process leading to the validation of the psychometric properties of the functional digestive disorders quality of life questionnaire (FDDQL). METHODS: Initially, the questionnaire was given to 154 patients, to assess its acceptability and reproducibility, analyse its content, and reduce the number of items. Its responsiveness was tested during two therapeutic trials which included 428 patients. The questionnaire has been translated into French, English, and German. The psychometric validation study was conducted in France, United Kingdom, and Germany by 187 practitioners. A total of 401 patients with dyspepsia or irritable bowel syndrome, defined by the Rome criteria, filled in the FDDQL and generic SF-36 questionnaires. RESULTS: The structure of the FDDQL scales was checked by factorial analysis. Its reliability was expressed by a Cronbach's alpha coefficient of 0.94. Assessment of its discriminant validity showed that the more severe the functional digestive disorders, the more impaired the quality of life (p<0.05). Concurrent validity was supported by the correlation found between the FDDQL and SF-36 questionnaire scales. The final version of the questionnaire contains 43 items belonging to eight domains. CONCLUSIONS: The properties of the FDDQL questionnaire, available in French, English, and German, make it appropriate for use in clinical trials designed to evaluate its responsiveness to treatment among patients with dyspepsia and irritable bowel syndrome.

Inhibition of prostaglandin-induced intestinal secretion by igmesine in healthy volunteers.

BACKGROUND & AIMS: Igmesine, a final sigma ligand, has been shown to inhibit intestinal secretion and diarrhea in animal models. The purpose of this study was to measure the inhibitory effect of igmesine on basal and prostaglandin E2 (PGE2)-induced jejunal secretion in normal volunteers. METHODS: Jejunal absorption of water and electrolytes was measured with a three-lumen open-segment perfusion method in 16 volunteers. A double-blind crossover study was performed involving intraluminal infusion of PGE2 after oral administration of placebo or igmesine at two doses. RESULTS: PGE2 induced net secretion of water and electrolytes (P < 0.01 vs. basal conditions). The effect of PGE2 on water and electrolytes was not changed by 25 mg of igmesine but was suppressed by 200 mg of igmesine. This effect lasted at least 3 hours after a single oral dose. Igmesine at a dose of 200 mg also produced a significant decrease in basal rates of water and electrolyte absorption. CONCLUSIONS: Igmesine, a final sigma ligand, inhibits PGE2-induced intestinal secretion in normal humans. Evaluating the drug in chronic diarrheas may be of interest.

Peptide YY inhibition of prostaglandin-induced intestinal secretion is haloperidol-sensitive in humans.

BACKGROUND & AIMS: It is uncertain whether peptide YY (PYY) inhibits human intestinal secretion directly through enterocyte receptors or via indirect neural mechanisms. Thus, the effect of PYY on prostaglandin E2 (PGE2)-induced jejunal secretion in normal volunteers was measured, and it was determined whether a dopamine and sigma antagonist affected PYY effect. METHODS: Jejunal absorption of water and electrolytes was measured by a perfusion method in 6 volunteers. A double-blind crossover study was performed, involving intraluminal infusion of PGE2, intravenous infusion of human PYY, and intramuscular injection of haloperidol or placebo. RESULTS: PGE2 induced net secretion of water and electrolytes (P < 0.01 vs. basal). The effect of PGE2 was reduced by about half with 30 pmol x kg(-1) x h(-1) of PYY (plasma PYY, 96 +/- 12 pg/mL) and suppressed by 90 pmol x kg(-1) x h(-1) of PYY (P < 0.01; plasma PYY, 268 +/- 22 pg/mL). Plasma PYY was correlated negatively (P < 0.01) with net fluxes of water, Cl-, Na+, and K+. Haloperidol suppressed the effect of PYY on PGE2-induced secretion (P < 0.05). CONCLUSIONS: PYY administered in doses producing slightly supraphysiological plasma levels inhibits PGE2-induced secretion in normal humans. Sigma or dopamine receptors (probably neuronal ones) are involved in this effect.

Effect of the kappa agonist fedotozine on perception of gastric distension in healthy humans.

BACKGROUND AND AIM: Gastric hypersensitivity to mechanical distension has been observed in functional dyspepsia, but no drug is available that specifically acts on gastric afferent pathways to decrease gastric nociception. The aim of this study was to assess the effect of fedotozine, a synthetic ligand for peripheral kappa receptors, on human gastric sensitivity. METHODS: Twenty-seven healthy volunteers were randomized to receive either fedotozine (30 mg t.d.s.) or a placebo, for 7 days. On day 7, the effects of fedotozine were tested on discomfort threshold and gastric compliance during graded isobaric and isovolumic distensions. In 16 of these subjects, the effect of this drug was tested on somatic sensitivity. In 10 other healthy volunteers the effect of fedotozine on gastric distension-induced inhibition of the RIII reflex, a process closely related to visceral sensitivity, was also studied. RESULTS: During isobaric distensions, the discomfort threshold was significantly higher in subjects on fedotozine than in those on placebo (14.4 +/- 0.92 vs. 12.0 +/- 1.13 mmHg; P = 0.04). Compared to placebo, fedotozine did not modify gastric compliance and somatic sensitivity. Fedotozine also reduced the inhibition of the RIII reflex induced by gastric distension. CONCLUSION: Fedotozine decreases gastric sensitivity to distension by exerting specific action on gastric afferent pathways.

Endoscopic evaluation of the effect of ketoprofen, ibuprofen and aspirin on the gastroduodenal mucosa.

Endoscopic lesions of the gastric mucosa were evaluated in 12 healthy volunteers after administration of single doses of ketoprofen (25 mg), ibuprofen (200 mg) and aspirin (500 mg) in a randomized, double-blind, cross-over study. The grades of the lesions (according to Lanza's scale) were lower after the administration of ketoprofen than aspirin and were comparable to ibuprofen. An endoscopic score greater than 1 was observed in 3 cases after ibuprofen or ketoprofen, and in 8 cases after aspirin. At a time when low, single doses of NSAIDs are widely used as analgesics, gastroscopy makes it possible directly to assess the local aggressivity of these molecules. In this way it was possible to demonstrate that the local toxicity of NSAIDs was lower than that of aspirin.

Theophylline steady state pharmacokinetics is not altered by omeprazole.

The effect of omeprazole treatment on theophylline pharmacokinetics was studied in eight, non-smoking healthy male volunteers during repeated administration of a slow release formulation of theophylline. In a randomized double-blind cross-over study, the subjects received theophylline 5 mg.kg-1 per day with omeprazole 20 mg per day or identical placebo during two periods, each of 7 days, separated by a washout period of 7 days. The oral clearance of theophylline remained unchanged whether it was administered alone or with omeprazole (54.2 ml.min-1). The average urinary excretion of theophylline and its metabolites, 1,3 dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX), 1-methyluric acid (1-MU) amounted to 9%, 32%, 12% and 22% of the administered dose, respectively, and no significant change occurred during concomitant treatment with omeprazole. Thus, the formation and clearance of the metabolites was not altered by omeprazole. Consequently, omeprazole in the recommended dose of 20 mg daily can safely be administered to patients on theophylline therapy.

Effect of psychological stress on gastric potential difference in man.

This study investigated the effect of three different mental stress tests on gastric transmucosal electric potential difference (GPD). GPD measurement was carried out in six healthy volunteers using the agar-KCl bridges method during dichotomous listening, the ringing of a telephone and 90 dB noise. Cardiac, pulmonary and psychological responses to stress were evaluated at the same time. During the stress period, two of the subjects had no change in GPD as well as no extragastric modification due to the stressor. The four other volunteers had a significant stress-induced fall in GPD (12.5 + 5.6 mV) with a simultaneous acceleration of heart and respiration rates and an increase in systolic blood pressure and anxiety feelings which were evaluated on a visual scale. Such mental stress, possibly mediated by autonomous nervous system, may cause some gastric mucosa changes inducing the retrodiffusion of H+ ions and a fall in GPD. This model could be useful in therapeutic research into the prevention and treatment of stress-induced gastric lesions.

Cystic dilatation of intrahepatic bile ducts in primary sclerosing cholangitis.

A case of primary sclerosing cholangitis associated with cystic dilatations of intrahepatic bile ducts simulating Caroli's disease is described. The diagnosis of primary sclerosing cholangitis was based upon cholangiogram features, liver histologic examination and the association with chronic ulcerative colitis. It may be suggested that the cystic dilatation of intrahepatic bile duct represents an extreme form of the usual mild dilatations (cholangiectases) described in primary sclerosing cholangitis. We suggest that cystic dilatation of intrahepatic bile ducts could be included among the radiologic features of this disease.

Changes in indocyanine green kinetics after the administration of enalapril to healthy subjects.

Enalapril maleate, an angiotensin converting enzyme inhibitor, is a vasodilator liable to modify regional blood flow. The effects of an oral dose of 40 mg enalapril maleate on indocyanine green (ICG) kinetics were assessed in nine healthy subjects. At 4 h after the administration of the drug, a 35% decrease in ICG clearance was observed (P less than 0.01) associated with a 23% decrease in its volume of distribution (P less than 0.02). The half-life of ICG was not altered significantly by enalapril. These results suggest that the administration of enalapril maleate to healthy subjects may reduce apparent liver plasma flow and plasma volume, as a consequence of the pooling of blood in the hepatosplanchnic area.

[Methods for studying the hepatic metabolism of drugs in man]. / Méthodes d'exploration du métabolisme hépatique des médicaments chez l'homme.

Various methods can be used to investigate human hepatic drug metabolism in vivo. a) Indirect methods based on the assessment of atoxic substances metabolism in order to investigate: --hepatic oxidative activity by antipyrine or caffeine clearance and aminopyrine breath test determination. Such an activity can be modified by drug-induced enzyme induction or inhibition and in case of hepatic disease; --genetic polymorphism of hepatic drug metabolism assessed by the determination of debrisoquine or dextrometorphane metabolic ratio and of N-acetylation phénotype. Unusual therapeutic or adverse effects could be explained by such a polymorphism; --hepatic blood flow, which variations could modify hepatic clearance of drugs with a high hepatic extraction ratio, by the assessment of indocyanine green clearance. b) Direct methods based on pharmacokinetics data and their alterations under various circumstances: simultaneous administration of other drugs, liver disease.

[Response in patients with melanoma to immunization using melanoma oncolysates of vaccine virus]. / Réponses de malades atteints de mélanome à l'immunisation par oncolysats de mélanomes au virus de la vaccine.

Thirty-two patients with high risk melanoma (either primary melanoma of the limbs or trunk, or recurrent melanoma) and clinically disease-free following appropriate surgical treatment were immunized with a vaccinia virus oncolysate made from a pool of 4 human melanoma cell lines. Injections were given id weekly for 3 months, and then bi-monthly for a further 21 months or until relapse. Treated patients have been under study for 11-72 months, and 15 of them for more than 36 months. Twelve patients received a full 24-month treatment: 3 relapsed and 10 are alive (9 of them disease-free) with a survival of 34-72 months. One patient is still under treatment. Nineteen patients relapsed during treatment: among the 13 patients that relapsed early during the course of treatment, 9 patients died after a survival of 5-30 months and 4 are alive with a survival of 30-59 months; among the 6 patients that later relapsed, 2 patients died after a survival of 21 and 29 months and 4 are alive with a survival of 16-69 months. An analysis of the patients' disease-free survival and overall survival was made using the actuarial method, and limited to 5 years: the disease-free survival curve shows a 35% plateau reached after 40 months, and the survival curve shows a 60% plateau reached after 30 months. The patients' responses to the immunization antigens expressed by the oncolysate were studied. Lymphocytes from immunized patients do respond in vitro to the stimulation by oncolysate in the presence of low amounts of IL-2, and this response is greater than that of normal individuals. IgG antibody production to gangliosides with N-glycolyl neuraminic acid is of prognostic significance, the increase in IgG anti-ganglioside antibody in patients after 3 and 6 months of treatment being linked to the absence of relapse in these patients. Finally, preliminary results show, in several patients under treatment, the appearance of antibodies directed against a 31 kD protein of the oncolysate not detectable in the vaccinia virus or in melanoma cell lysates. Such results are in accordance with previously reported ones from similar studies conducted by other investigators and tend to indicate the efficacy of vaccinia virus oncolysate immunization in the treatment of high risk melanoma.

Amineptine, a tricyclic antidepressant, inhibits the mitochondrial oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.

Microvesicular steatosis of the liver has been reported in two subjects receiving amineptine (a tricyclic antidepressant metabolized by beta-oxidation of its acyl chain). A similar disease is observed after ingestion of drugs which inhibit hepatic mitochondrial fatty acid beta-oxidation, or in subjects with various inborn defects in this metabolic pathway. We therefore determined the effects of amineptine on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of beta-oxidation products during incubation of palmitic acid with mouse liver mitochondria and the various cofactors necessary for beta-oxidation was inhibited by 27, 33, 46 and 57% respectively, in the presence of 0.25, 0.5, 1 and 2 mM of amineptine. Inhibition was reversible. Tricarboxylic acid cycle activity, assessed by the in vitro formation of [14C]CO2 from [1-14C]acetyl coenzyme A by mouse liver mitochondria, was inhibited by 22, 23, 47, 54, 60 and 62%, respectively, in the presence of 0.0625, 0.125, 0.25, 0.5, 1 and 2 mM of amineptine. In vivo, administration of amineptine, 0.5 and 0.75 mmol.kg-1, inhibited by 70 and 84%, respectively, the exhalation of [14C] CO2 during the first 3 hr after the administration of a tracer dose of [U-14C]palmitic acid. Administration of amineptine, 0.0625, 0.25, 0.5 or 1 mmol.kg-1, 6 hr before the measurement, increased hepatic triglycerides by 73, 139, 295 and 320%, respectively. After 1 mmol.kg-1, accumulation of hepatic triglycerides was maximum at 24 hr, reaching 5-fold the control value; liver histology at that time showed microvesicular steatosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man: possible role in microvesicular steatosis induced by this antibiotic.

Intravenous administration of high doses of tetracycline may produce severe microvesicular steatosis of the liver in man. A similar disease is observed after ingestion of drugs which inhibit hepatic mitochondrial fatty acid beta-oxidation and in subjects with various inborn defects in this metabolic pathway. We therefore determined the effects of tetracycline on the mitochondrial oxidation of fatty acids in mice and in man. In vitro, addition of tetracycline 0.25, 0.5, 1 or 2 mM inhibited by 15, 38, 56 and 65%, respectively, the formation of beta-oxidation products during incubation of palmitic acid with mouse liver mitochondria and the various cofactors necessary for beta-oxidation. Inhibition was reversible. Inhibition appeared even greater with human liver mitochondria. Tricarboxylic acid cycle activity, assessed by the in vitro formation of [14C]CO2 from [1-14C]acetylcoenzyme A by mouse liver mitochondria, was inhibited by 25, 32 and 43%, respectively, in the presence of 0.5, 1 or 2 mM of tetracycline. In vivo, administration of tetracycline, 0.25 or 1 mmole per kg, inhibited by 53 and 84%, respectively, the exhalation of [14C]CO2 during the first 3 hours following the administration of a tracer dose of [U-14C]palmitic acid. Administration of tetracycline, 0.0625, 0.25 or 1 mmole per kg, 6 hr before the measurement, increased hepatic triglycerides by 100, 170 and 250%, respectively. After 1 mmole per kg, accumulation of hepatic triglycerides was maximum at 24 hr, reaching 9-fold the control value; liver histology showed microvesicular steatosis at 6 and 24 hr. We conclude that tetracycline inhibits the mitochondrial oxidation of fatty acids in mice and in man.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of mitochondrial beta-oxidation of fatty acids by pirprofen. Role in microvesicular steatosis due to this nonsteroidal anti-inflammatory drug.

Administration of pirprofen may produce microvesicular steatosis of the liver in humans. The effects of pirprofen on the mitochondrial beta-oxidation of fatty acids have been investigated in mice. In vitro, addition of 2 mM pirprofen decreased by 50% the formation of [14C]acid-soluble beta-oxidation products, and decreased by 70% the formation of [14C]CO2 upon incubation of hepatic mitochondria with [14C]palmitic acid, ATP, carnitine and coenzyme A. In vivo, administration of pirprofen (2 mmol . kg-1 i.p.), 1 hr before that of [U-14C]palmitic acid, decreased by 70% the exhalation of [14C]CO2 during the next 6 hr. Administration of pirprofen (2 mmol . kg-1 i.p.), 1 hr before the measurement, decreased plasma beta-hydroxybutyrate by 60%, plasma acetoacetate by 30% and blood glucose by 40%. Administration of pirprofen (2 mmol . kg-1 i.p.) 6 hr before sacrifice, doubled hepatic triglycerides content and produced microvesicular steatosis of the liver. We conclude that pirprofen inhibits the mitochondrial beta-oxidation of fatty acids in mice, thus explaining the microvesicular steatosis observed in mice and in some human subjects.