Lactic acidosis: relationship between metformin levels, lactate concentration and mortality.

AIM: The role of metformin in lactic acidosis is regularly questioned. Arguments against a causal role for metformin in lactic acidosis occurrence are the lack of correlation between plasma metformin and lactate levels, as well as between metformin plasma levels and mortality. We aim to analyse these correlations in a large series of lactic acidosis cases recorded in the French nationwide pharmacovigilance database. METHODS: All cases of lactic acidosis spontaneously reported between 1985 and October 2013 associated with metformin exposure were extracted from the pharmacovigilance database. We assessed the statistical correlations between prescribed daily doses of metformin, plasma concentrations of metformin and lactate, pH and plasma creatinine, as well as the relationship between mortality and these variables. RESULTS: Seven hundred and twenty-seven cases of lactic acidosis were reported during the period. Metformin plasma concentration was documented for 260 patients, lactate plasma concentration for 556 patients, pH for 502 patients, creatinine for 397 patients and the vital outcome for 713 patients. Metformin plasma concentration, lactate concentration, pH and plasma creatinine were all correlated (P < 0.001). There were significant differences between surviving and deceased patients in terms of metformin plasma levels (25.2 vs. 37.4 mg/l, P = 0.002) and lactate concentrations (10.8 vs. 16.3 mmol/l, P < 0.001). Thirty per cent of patients died when metformin concentration was > 5 mg/l compared with 11% for patients with concentration < 5 mg/l (P = 0.003). CONCLUSIONS: Our data suggest that metformin accumulation contributes to the pathogenesis and prognosis of lactic acidosis.

Screening for multiple endocrine neoplasia type 1 and hormonal production in apparently sporadic neuroendocrine tumors.

Screening was performed in 130 consecutive patients with apparently sporadic neuroendocrine tumors (NET) to assess the prevalence of multiple endocrine neoplasia type 1 (MEN1) and hormonal production. Screening for MEN1 included measurement of serum calcium and PTH [PTH-(1-84)], gastrin, PRL, and insulin-like growth factor type I (IGF-I) levels. MEN1 genetic testing was performed in patients with two components of the MEN1 syndrome. Screening for hormonal production included measurement of serum neuron-specific enolase (NSE), calcitonin (CT), glycoprotein alpha-subunit (GP alpha), hCG beta-subunit (free hCG beta), and somatostatin levels. Twenty-four-hour urinary free cortisol (UFC) and 5-hydroxyindolacetic acid (5-HIAA) determinations were also performed. Four patients had hyperparathyroidism, none of whom had pituitary or familial disease. Hyperprolactinemia was compatible with a pituitary disease in one patient. No acromegalic feature or any increase in IGF-I was found. Hypergastrinemia, compatible with an associated pancreatic NET, was found in one patient. Genetic screening of the MEN1 gene was performed in five of the six patients with two components of the MEN1 syndrome. A nonsense mutation (Arg108stop) was identified in the tumor of one patient. Elevated NSE, 5-HIAA, CT, GP alpha, free hCG beta, SMS, and nonsuppressible UFC were found in 47%, 46%, 14%, 19%, 12%, 3%, and 6% of NET patients, respectively. Production of CT, GP alpha, and free hCG beta was highly related to the primary site: all but two of these secretions originated in foregut NET. 5-HIAA secretion was found in 27% of foregut-derived and 85% of midgut-derived NET. In conclusion, MEN1 is a rare event in patients presenting with apparently sporadic NET. It occurred mainly in foregut NET and should be screened for by serum calcium and PTH-(1-84) measurements. Routine hormonal measurements should depend on the primary site. NSE, 5-HIAA, CT, and alphaGP should be routinely measured in foregut-derived NET; only serum NSE and 5-HIAA measurements are recommended in midgut-derived NET.

Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours.

Circulating neuron-specific enolase (NSE) and chromogranin A (CgA) were measured in 128 patients with neuroendocrine tumours (NET) to compare their sensitivity and specificity, to investigate factors associated with elevated serum levels and to determine the usefulness of these markers in the follow-up of NET patients. NSE (Cispack NSE, Cis Bio International, Gif-sur-Yvette, France; normal <12.5 microg l(-1)), and chromogranin A (CgA-Riact, Cis Bio International, normal <100 microg l(-1)) were measured in 128 patients without renal insufficiency. There were 99 patients with gastroenteropancreatic (GEP) NET, 19 with medullary thyroid carcinoma and ten with phaeochromocytoma. Fifty-three patients with non-NET were studied as controls. Serum NSE and CgA levels were elevated in 48 (38%) and 76 (59%) of the 128 NET patients respectively. In all groups of NET patients, CgA proved to be more sensitive than NSE. NSE and CgA had a specificity of 73% and 68% respectively. Immunostaining for NSE was positive in three out of eight controls with elevated CgA levels, whereas immunostaining for CgA and synaptophysin was negative in all cases. Elevated CgA levels were significantly associated with two independent parameters, namely the presence of other secretions (P = 0.0001) and a heavy tumour burden (P = 0.001). Elevated NSE levels were exclusively associated with poor tumour differentiation (P = 0.01). Among six patients with NET followed for 11-37 months, CgA appeared to be a better marker of tumour evolution than NSE. We suggest that CgA ought to be the only general marker screened in NET patients.

Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience.

BACKGROUND: Patients with thyroid microcarcinoma (TMC) have favorable long term prognoses. However, recurrences in the neck and distant metastases have been reported. The authors investigated independent factors associated with recurrence in an effort to define therapeutic guidelines. METHODS: Two hundred eighty-one patients (207 females, 74 males; mean age, 41.9 years) with a differentiated thyroid carcinoma < or = 1 cm in greatest dimension (mean size +/- standard deviation, 5.9+/-3.3 mm) were analyzed. The median follow-up time was 7.3 years. RESULTS: TMC diagnosis was incidental in 189 patients, and metastases were the first manifestation of the disease in the other 92 patients. Therapy included near-total thyroidectomy for 195 patients, lymph node dissection for 195, and therapeutic administration of radioiodine for 124. Eleven recurrences (3.9%) were observed 4.3+/-2.7 years (mean +/- standard deviation) after initial treatment: all had locoregional recurrence (4 in the thyroid bed and 7 in the lymph nodes), and in one of these the local recurrence was associated with lung metastases. Multivariate analysis showed that two parameters significantly influenced TMC recurrence, namely, the number of histologic foci (P < 0.002) and the extent of initial thyroid surgery (P < 0.01). Only 3.3% of patients with unifocal TMC treated with loboisthmusectomy had tumor recurrence. CONCLUSIONS: The recurrence rate for TMC appears to be low (3.9%). In the authors' view, loboisthmusectomy is the treatment of choice for patients with TMC when only one focus of cancer is found histologically, and total thyroidectomy is the optimal treatment for patients with multiple foci.

Red blood cell glutathione levels before and during treatment with neoadjuvant chemotherapy cisplatin/5-fluorouracil in patients with head and neck squamous cell carcinoma.

The purpose of this study was to find out whether the glutathione (GSH), in red blood cells could predict the response to neoadjuvant chemotherapy cisplatin/5-fluorouracil (CDDP/5-FU) in patients with head and neck squamous cell carcinoma (HNSCC). Three courses of induction chemotherapy with CDDP/5-FU were administered and followed by surgery and radiotherapy or radiotherapy alone, in 51 patients with HNSCC. GSH was measured by spectrophotometry in red blood cell before any treatment (Sample 1: S1), after each course of chemotherapy (S2, S3, S4). Our results showed that GSH was the same at diagnosis in patients with complete or partial response (OR) compared to those with stable or progressive disease (NR). With regard to evolution of the GSH during the 3 courses of CT a significant difference was found between courses (S2: 5.06 +/- 0.35 vs S4 = 3.61 +/- 0.4 mumol/g haemoglobin, p < 0.05). When we separated our patients into OR and NR, a significant difference was found over the 3 courses of chemotherapy for GSH content. Non responder patients showed decreased GSH content at the end of the treatment, (S2: 5 +/- 0.5 vs S4: 2.2 +/- 0.4 mumol/g haemoglobin, p < 0.05) while OR were stable. In conclusion, red blood cell GSH seems to have no early predictive value for chemoresponse to neoadjuvant chemotherapy CDDP/5-FU in HNSCC.

Cancer mortality in the commune of Pargny sur Saulx in France.

Radioactive thorium wastes were found in April 1997 at the former industrial site of 'Orflam-Plast' in the commune of Pargny sur Saulx in the Northeast of France, where industrial activity began in 1934. On this site, between 1934 and 1970, cerium for lighter stones and thorium nitrate were extracted from imported monazite sand, a mineral containing elevated levels of natural radioactivity. We decided to study cancer mortality in the surrounding population. We found an excess of mortality due to lung and bladder cancer in the commune of Pargny sur Saulx and its neighbours, between 1968 and 1994. This excess did not seem to be linked to the river of Saulx which was a possible source of contamination. We conclude that a cancer incidence study of the former workers of this industrial site is necessary in order to investigate the role of natural radioactivity from monazite processing in the risk of cancer mortality among this workforce.

Quantification of tumor uptake of iodized oils and emulsions of iodized oils: experimental study.

PURPOSE: To optimize use of iodized oil for diagnostic computed tomography (CT) enhanced with iodized oil and for interstitial radiation therapy with iodine-131-labeled iodized oil, the authors quantified the distribution of iodized oil after injection of different formulations of iodized oil into the hepatic artery. MATERIALS AND METHODS: I-125-labeled iodinated ethyl ester of poppyseed oil in two viscosities (iodized oil ultrafluid [viscosity, 0.04 Pa/sec] and iodized oil fluid [viscosity, 0.17 Pa/sec]) was injected (pure forms and three different emulsions of each) into the hepatic artery of rabbits bearing VX2 tumors in the liver. All rabbits received a radiation dose of 4 MBq per kilogram of body weight in 0.1 mL/kg iodized oil. Animals were killed 4 days later, and iodized oil uptake was evaluated in the tumor, nontumorous liver, and lung. RESULTS: There were no statistically significant differences in uptake between pure iodized oil ultrafluid or fluid or between the same type of emulsions made with each type of iodized oil. Lung uptake was significantly higher with pure iodized oil ultrafluid and fluid (19.75 kBq/g +/- 3.25 [standard error of the mean] vs 19.48 kBq/g +/- 6.15, respectively) than with any emulsions (range, 3.72-8.14 kBq/g; mean, 5.68 kBq/g) except the small-droplet oil-in-water emulsion (10.51 kBq/g +/- 1.18). The ratio of tumor to nontumorous liver uptake of iodized oil was significantly higher with large-droplet water-in-oil emulsions made of iodized oil ultrafluid or fluid (10.26 +/- 2.88 and 9.53 +/- 0.64, respectively) than with any other product (range, 4.07-5.38; mean, 4.49). CONCLUSION: Use of large-droplet water-in-oil emulsions limited lung uptake and increased tumor uptake of iodized oil after intraarterial hepatic injection in rabbits bearing VX2 tumors in the liver.

Influence of dofetilide on QT-interval duration and dispersion at various heart rates during exercise in humans.

BACKGROUND: The objective of this study was to assess the influence of heart rate on QT-interval duration and dispersion during administration of the new selective potassium-channel blocker dofetilide in normal subjects. METHODS AND RESULTS: Dofetilide 0.25 and 0.75 mg was administered for 4 days to 12 subjects in a randomized-sequence, double-blind, three-period, placebo-controlled, crossover study. QT-RR pairs were measured on study day 4 over a wide range of RR intervals obtained at rest and during an exercise test. QT-interval durations were calculated at seven predetermined RR intervals ranging from 400 ms (150 bpm) to 1000 ms (60 bpm) by use of monoexponential nonlinear curve fitting. QTmax and QTmin were calculated similarly, and QT-interval dispersion was measured as QTmax-QTmin at each predetermined RR interval. Minimal effects were found with 0.25 mg dofetilide. Two hours after administration of 0.75 mg dofetilide, QT interval was prolonged by 16.7 +/- 8.7% at a heart rate of 60 bpm (P < .01) and by 7.4 +/- 8.2% at a heart rate of 150 bpm (P < .05). QT prolongation at a heart rate of 150 bpm was less pronounced than at lower heart rates. Neither placebo nor dofetilide at either dose significantly increased QT-interval dispersion at any heart rate. CONCLUSIONS: Dofetilide increases QT-interval duration but does not increase QT-interval dispersion in healthy subjects. QT-interval prolongation remains significant at high heart rates, although some degree of reverse rate dependence is observed at high concentrations.

Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study.

PURPOSE: The purpose of this study was to determine the bioavailability (F) of etoposide (E;VP-16) after oral administration of the water-soluble prodrug etoposide phosphate (EP;BMY-40481) during a phase I trial in cancer patients. PATIENTS AND METHODS: Twenty-nine patients received oral EP (capsules, 50 to 150 mg/m2/d of E equivalent) for 5 days in week 1 (course 1), followed every 3 weeks thereafter by a daily intravenous (i.v.) infusion for 5 days of E (80 mg/m2, 1-hour i.v. infusion; course 2); in three patients, the i.v. E course was given before oral EP. Plasma and urine E pharmacokinetics (high-performance liquid chromatography [HPLC]) were performed on the first day of oral EP administration and on the first day of i.v. E. RESULTS: Twenty-six of 29 patients completed two courses or more, whereas three patients received only one course due to toxicity. Myelosuppression was dose-dependent and dose-limiting, with grade 4 leukoneutropenia in four of 15 patients at 125 mg/m2 and in five of seven patients at 150 mg/m2. One patient died of meningeal hemorrhage related to grade 4 thrombocytopenia. Other toxicities were infrequent and/or manageable. No objective response was observed. The maximum-tolerated dose (MTD) is therefore 150 mg/m2, and the recommended oral dose of EP for phase II trials in this poor-risk patient population is 125 mg/m2. Twenty-six patients had pharmacokinetic data for both oral EP and i.v. E, whereas three had pharmacokinetic data on the i.v. E course only. After oral administration of EP, the pharmacokinetics of E were as follows: mean absorption rate constant (Ka), 1.7 +/- 1.7 h-1 (mean +/- SD); lag time, 0.3 +/- 0.2 hours; time of maximum concentration (t(max)), 1.6 +/- 0.8 hours; and mean half-lives (t1/2), 1.6 +/- 0.2 (first) and 10.3 +/- 5.8 hours (terminal); the increase in the area under the plasma concentration-versus-time curve (AUC) of E was proportional to the EP dose. After the 1-hour i.v. infusion of E, maximum concentration (C(max)) was 15 +/- 3 micrograms/mL; mean AUC, 88.0 +/- 22.0 micrograms.h/mL; mean total-body clearance (CL), 0.97 +/- 0.24 L/h/m2 (16.2 mL/min/m2); and mean t1/2, 0.9 +/- 0.6 (first) and 8.1 +/- 4.1 hours (terminal). The 24-hour urinary excretion of E after i.v. E was significantly higher (33%) compared with that of oral EP (17%) (P < .001). Significant correlation was observed between the neutropenia at nadir and the AUC of E after oral EP administration (r = .58, P < .01, sigmoid maximum effect [E(max)] model). The mean F of E after oral administration of EP in 26 patients was 68.0 +/- 17.9% (coefficient of variation [CV], 26.3%; F range, 35.5% to 111.8%). In this study, tumor type, as well as EP dose, did not significantly influence the F in E. There was no difference in F of E, whether oral EP was administered before or after i.v. E. Compared with literature data on oral E, the percent F in E after oral prodrug EP administration was 19% higher at either low ( < or = 100 mg/m2) or high ( > 100 mg/m2) doses. CONCLUSION: Similarly to E, the main toxicity of the prodrug EP is dose-dependent leukoneutropenia, which is dose-limiting at the oral MTD of 150 mg/m2/d for 5 days. The recommended oral dose of EP is 125 mg/m2/d for 5 days every 3 weeks in poor-risk patients. Compared with literature data, oral EP has a 19% higher F value compared with oral E either at low or high doses. This higher F in E from oral prodrug EP appears to be a pharmacologic advantage that could be of potential pharmacodynamic importance for this drug.

[Absence of labetalol interference on urine metanephrine determination in hypertensive patients]. / Absence d'interférence du labétalol sur la détermination des métanéphrines urinaires chez l'hypertendu.

The dosage of urinary catecholamines and their metabolites is a main element of diagnosis in the research of a pheochromocytoma in patients with high blood pressure. The literature reports high values of these compounds in patients treated with labetalol (an alpha/beta-blocker). An analytical interference has been evoked to explain these misleading results, which have not been observed with other beta-blockers. The goal of this work was to look for this eventual analytical interference in the dosage of urinary metanephrine by reversed phase liquid chromatography coupled with electrochemical detection, in patients with high blood pressure. Eighteen hypertensive patients, 52 +/- 14 years old, were included in the study. In 8 patients, a dosage of metanephrine, normetanephrine and creatinine on a 24 hours urine sample was performed before (D1) and 24 hours after (D3) the prescription of labetalol (200 mg twice a day). In the other group, labetalol was not prescribed but dosage was made in the same conditions. Urinary excretion of these compounds (metanephrine+normetanephrine) divided by urinary creatinine was not modified in the treated group (0.16 +/- 0.08 vs 0.14 +/- 0.04), nor in the reference group (0.17 +/- 0.08 vs 0.17 +/- 0.08). This study shows that administration of labetalol in patients with essential hypertension does not interfere with urinary metanephrine and normetanephrine determination after 48 hours of treatment. This implies that research for a pheochromocytoma is possible in patients with hypertension and receiving labetalol, by using reversed phase liquid chromatography coupled with an electrochemical detector for the dosage of urinary metanephrine and normetanephrine.

[Critical analysis of drug interactions with cyclosporine. Evaluation of interactions with cyclosporine]. / Analyse critique des interactions médicamenteuses de la ciclosporine. Evaluation des interactions de la ciclosporine.

Cyclosporine A is a potent immunosuppressive agent, widely used in organ transplantation, in bone marrow transplantation and in the treatment of some autoimmune diseases. Changes of its absorption, a metabolism mainly processed by the liver and a concentration-related nephrotoxicity lead to the need of a careful drug monitoring, allowing to obtain blood levels that must be low and nevertheless sufficiently efficient. Cyclosporin A may additionally yield some numerous drug interactions. Those with potentially serious issue must be mandatory avoided and distinguished from those less severe that only have to be followed up. The strategy differs according to the nature of the interaction (i.e. pharmacokinetic/pharmacodynamic): the posology will have either to be adjusted or the risk/benefit ratio will have to be taken into account to decide any change in the dosage regimen.