Residential care and risk of proximal femur fracture.

The risk of hip fracture is higher among persons living in long-term care than among persons living at home. The aim of this study was to explain the difference in risk between the two types of residence by identifying differences in the respective risk factor profiles. Information from the Mediterranean osteoporosis (MEDOS) study questionnaire was used for statistical analyses of 107 non-demented female cases and 225 neighbourhood controls matched for age, sex, and residential area. The statistical analyses incorporated adjustments of the risk estimates by unconditional multivariate logistic regression. Urban background, activity, and morbidity were found to differ between the two types of residence. The detected differences in risk factor profiles were, however, not considered to be sufficient as an explanation for the difference in risk of fracture.

Binding of (+)-PN 200-110 to rat pituitaries and to normal and adenomatous human pituitaries.

Endocrine cells possess voltage-sensitive Ca2+ channels involved in the modulation of hormonal secretion. Using the dihydropyridine, (+)-PN 200-110, we have investigated the binding characteristics of this ligand to pituitary membrane Ca2+ channels from normal rat, normal and adenomatous human pituitaries. [3H]PN 200-110 binds specifically to rat pituitary membranes to one class of sites (Kd = 0.41 +/- 0.10 mM; Bmax = 39 +/- 1.3 fmol/mg protein). At 37 degrees C, equilibrium is reached in 45 min and half-life of the binding is 13 min. No significant changes were observed for either the Kd or Bmax values between normal rat and human pituitaries or between the different types of adenomas (GH- and PRL-secreting and non-secreting). As the secretory activity of the pituitary adenomas, involving Ca2+ mobilization, varies from one adenoma to another, our results could indicate that, if there is a modified regulation of Ca2+ entry in the adenomas, it may not be related to a varying number of calcium channels, at least the channels labeled by the dihydropyridine (+)-PN 200-110.

A prospective multicenter trial of octreotide in 24 patients with visual defects caused by nonfunctioning and gonadotropin-secreting pituitary adenomas. French Multicenter Octreotide Study Group.

OBJECTIVE: The somatostatin analog octreotide has been demonstrated to improve optic tract compression caused by pituitary macroadenomas within hours of its administration and/or reduce tumor size in some patients. We report the results of a prospective multicenter study of the effects of octreotide on visual function and tumor size in patients with nonfunctioning pituitary adenomas or gonadotropin-secreting adenomas. METHODS: Twenty-four patients with visual defects caused by histologically confirmed macroadenomas were administered octreotide via continuous subcutaneous infusion, as follows: 100 micrograms the 1st day and, if necessary, 200 micrograms the 2nd and then 100 or 200 micrograms three times daily if visual function improved. Vision was assessed after 4 days, 1 month, and 2 months, including tumor size evaluation. Visual improvement was defined by a net gain of at least 2/10 in acuity and/or of more than 20% of the surface of one isopter (a reduction in tumor volume of > or = 20% of the initial measurement); opposite changes were defined as deterioration. RESULTS: Visual improvement was noted in 13 of 24 patients, 10 of 23 patients and 9 of 22 patients, and was not noted in 11 of 24 patients, 14 of 23 patients, and 13 of 22 patients after 4 days, 1 month, and 2 months, respectively. After 2 months, three adenomas had shrunk, three had not changed in size, and one had increased; visual function improved in the seven patients with these adenomas. Octreotide was discontinued in 13 patients for lack of efficacy. CONCLUSION: The incidence of visual improvement and tumor shrinkage noted in this study was higher than previously reported. Our data suggest that early onset of visual improvement might help in deciding which patients profit from octreotide. However, concomitant gain in visual acuity with deterioration in visual fields or visual improvement with an increase (moderate) in tumor size can occur.

Blood binding and tissue uptake of drugs. Recent advances and perspectives.

The free drug hypothesis, which states that only the unbound moiety of drug in blood is available for tissue diffusion, is discussed according to recent investigations. In some experimental conditions, it must be assumed that part of the protein-bound drug in plasma is extracted during a single passage through the organ studied. The mechanisms underlying these observations are not unequivocal and remain hypothetical. In the liver, high-affinity binding sites for serum albumin have been demonstrated, and they would explain the high extraction by liver of endogenous and exogenous compounds. However, these experiments measure the unidirectional transfer of a drug from the vascular to the extravascular space in non-steady-state conditions. Hence, in steady-state conditions, the free drug hypothesis cannot be ruled out because it is supported by numerous pharmacokinetic studies.

French multicenter randomized double-blind placebo-controlled trial on nebulized amiloride in cystic fibrosis patients. The Amiloride-AFLM Collaborative Study Group.

The effect of amiloride, a sodium channel blocker, has been evaluated in a multicenter randomized double-blind placebo-controlled trial in cystic fibrosis patients more than 5-years-old (n = 137) whose forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV(1)), and forced mid-expiratory flow (FEF(25-75)) were not below 50%, 50%, and 30% of reference values, respectively. Patients were randomly allocated to two parallel groups. Sixty-four patients were chronically colonized with Pseudomonas aeruginosa; they received either amiloride or placebo as a nebulized solution three times daily for 6 months. Routine treatments were continued. Patients chronically colonized with Pseudomonas received nebulized colimycine twice a day for a month during the third and sixth months of treatment. Bronchopulmonary exacerbations were treated in the usual way. The effects of the amiloride treatment were assessed at the end of the 6-month treatment period. The effects on FVC and secondarily on FEV(1), FEF(25-75), the number of days on antibiotic therapy, the Shwachman score, a nutritional index (weight/height(2)), the change in sputum bacterial flora, and nocturnal cough were assessed. For the patients not chronically colonized with Pseudomonas, the effect of the treatment was also evaluated by counting chronic colonizations with pathogens appearing during the trial period. The present study failed to demonstrate any significant benefit of amiloride over placebo on FVC, FEV(1), and the other secondary endpoints in the studied population. Neither the chronically colonized, nor the noncolonized patients benefited. The confidence intervals of the differences between treatment groups indicated small differences that were most likely of no clinical significance. Complementary analyses taking into account the gender, the type of mutation, the subpopulations whose FVC and FEV(1) were below 80% of normal values at the beginning of the study, and also patients less than 10 years old, did not show any statistically or clinically significant improvements following amiloride therapy.

Nicardipine in the prevention of spasm-induced neurological deficits after subarachnoid hemorrhage: a dose-ranging study.

The tolerability of four doses of intravenous nicardipine (0.03, 0.08, 0.11, and 0.15 mg/kg/h) was assessed in this randomized multicenter, parallel-group study. Fifty-two patients with Hunt and Hess grade I-III aneurysmal subarachnoid hemorrhage were treated with intravenous nicardipine beginning within 4 days of bleeding, for a mean duration of 12.6 days; this treatment was followed by administration of oral nicardipine 90-120 mg until day 30. Hypotension was the main side effect, and it occurred only in the two groups that received the highest doses. However, it was possible to continue nicardipine in all cases at lower doses or even without modification, and hypotension was never responsible for any deleterious clinical effect.

[Essential elements of quality assurance of clinical trials in hospital environment]. / Eléments essentiels de l'assurance de qualité des essais cliniques en milieu hospitalier.

This round table discussion was devoted to describing the present status of clinical trials in the hospital setting, analysing common difficulties in conducting quality clinical research, and proposing realistic solutions to solve or attenuate those difficulties. This analysis was performed on five critical topics: personnel, laboratory tests and investigations, drug supplies, source documents and investigator's procedures.

[Parlodel in early combination with levodopa in the treatment of Parkinson disease. Comparison of 2 dosage forms]. / Introduction du Parlodel en association précoce à la lévodopa dans le traitement de la maladie de Parkinson. Comparaison de deux progressions posologiques.

In order to compare two titrations of Parlodel in early combination with levodopa in the treatment of Parkinson's disease a multicentre randomized open study was performed with a fast titration in group A (15 mg/day for 3 weeks) and slow in group B (15 mg/day for 5 weeks). 153 patients were included: 77 in group A and 76 in group B. The recommended titration was observed in 76% in group A and 88% in group B, the difference was not significant. The efficacy assessed by the Webster Scale was remarkable and similar in the two groups. This study confirms the additive benefit of bromocriptine on the symptoms and long term complications of levodopa therapy, but no absolute conclusion can be drawn regarding the best titration.

[Therapeutic trials in Alzheimer disease. Selection--recruitment and stratification]. / Essais thérapeutiques dans la maladie d'Alzheimer. Sélection--recrutement et stratification.

Therapeutic trials conducted in Alzheimer's disease have benefited from the standardization of diagnostic criteria based on internationally recognized scales (DSM III-R, NINCDS-ADRDA) which ensure more valid inclusions. Well specified exclusion criteria are also of the utmost importance, in particular depression, vascular dementia and concomitant psychotropic drugs. Cognitive and/or functional scales allow an appreciation of the severity of the disease. Due to the heterogeneity of Alzheimer's disease stratification methods on identified prognostic factors i.e. aphasia, extrapyramidal symptoms should be performed. Selection of responders during an enrichment phase has still to be discussed. Multicentric studies become imperative because of the large number of patients required and the difficulties in selecting the adequate patients. These raise the issues of investigators' experience, coordination and between center variability.

[Study of combined anticoagulant (fluindione)-aspirin therapy in patients with atrial fibrillation at high risk for thromboembolic complications. A randomized trial (FFAACS)]. / Etude de l'association anticoagulant (fluindione)-aspirine, chez les patients en fibrillation auriculaire à haut risque de complications thrombo-emboliques. Une étude randomisée (FFAACS).

BACKGROUND: A combination of low-dose aspirin (A) and anticoagulation (AC) may provide better protection against thromboembolic events compared with AC alone in high-risk patients with atrial fibrillation (AF). METHODS: We performed a multicentric placebo-controlled double blind-trial to test the preventive efficacy against thromboembolic events of the addition of aspirin (A) (100 mg) or placebo (P) to anticoagulant treatment in patients with high-risk atrial fibrillation. A total of 157 patients were included, with atrial fibrillation and previous thromboembolic event or older than 65 years with either a history of hypertension, a recent episode of heart failure or a left ventricular dysfunction. All patients received fluindione (F) and P or F and A, with an INR target between 2 and 2.6. The primary endpoint was a combined endpoint of stroke (ischaemic or haemorrhagic), myocardial infarction, systemic arterial emboli or vascular death. RESULTS: The study had to be stopped prematurely owing to a too low recruitment rate. During follow-up (0.84 years) 3 non-fatal thromboembolic events were recorded (1P, 2A) and 6 patients died (3P, 3A), none of them from a thromboembolic complication. However, 3 deaths were secondary to severe haemorrhagic complications (1P, 2A). Non-fatal haemorrhagic complications occurred more often in group A (n = 10, 13.1 pour cent) compared with group P (n = 1, 1.2 pour cent), p = 0.003. CONCLUSION: The FFAACS study was not able to show any therapeutic benefit from the addition of aspirin to anticoagulant in patients with high-risk AF. Such a combination increased the incidence rate of bleeding complications, which therefore greatly reduces its potential overall benefit.

[Clozapine (Leponex) in France]. / La clozapine (Leponex) en France.

Leponex (clozapine) is an atypical neuroleptic indicated in severe schizophrenia, launched in France in December 1991. The safety and efficacy data pertaining to 1,062 patients treated on a compassionate needs basis between May 1989 and December 1991 constitute the first French experience on the drug. The results of an interim analysis pertaining to 602 patients, i.e. available data on 03-15-1992, generally collected on a retrospective basis, by means of a specific questionnaire are reviewed. The population included patients with severe and long-standing schizophrenia i.e. 15.71 +/- 9.3 years, resistant to usual neuroleptic therapy (90.86% of cases), and rarely with a history of intolerance to this class (2.49%). The indication was in the majority of the cases a paranoid schizophrenia (67.2%). The mean maintenance daily dose was 419 mg/d (+/- 152). Overall, with respect to associated drugs, neuroleptics were recorded in 16.4%, another psychotropic drug in 44.7% and symptomatic treatments for extrapyramidal disorders in 21.3% of patients. Of interest is the fact that, for those patients started on Leponex more recently, the drug is more often prescribed on a single basis. Leponex was stopped in 24.3% for the following reasons: adverse events 10.6%, lack of efficacy 6%, non compliance 3.8%, other reasons 3.8%. The adverse event profile is consistent with the literature data, taking into account the fact that certain adverse events were more commonly described: fatigue of lower limbs 11.8%, leucocytosis 19.8% and eosinophilia 4.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

[Use of octreotide in the treatment of digestive endocrine tumors. A French multicenter study]. / Utilisation de l'octréotide dans les tumeurs endocrines digestives. Etude française multicentrique.

Morbidity and mortality in endocrine gastro-enteropancreatic (GEP) tumours are mainly related to the clinical consequences of tumoral peptide hypersecretion. Surgical resection at an early stage is the only curative treatment. However, most tumours are detected only when the hypersecretory state reflects the presence of metastases; surgery and chemotherapy then give only palliative results counterbalanced by serious side-effects. Somatostatin inhibits most endocrine secretions of the GEP tract and thus can alleviate invalidating symptoms. Its use is limited by its short half-life (2 min), the necessity of i.v. infusion and the possibility of a rebound phenomenon. Octreotide, a synthetic somatostatin analogue with a long duration of action, is administered subcutaneously and allows ambulatory treatment. In our series of 78 patients we observed about 80 percent of excellent or good clinical results, enabling the patients to resume normal life. Only minor and transient side-effects were noted. The overall tolerance of the drug was considered excellent or good. Prolonged administration of octreotide is a safe and effective symptomatic treatment in patients without any restriction of anti-tumoral procedures. Furthermore, it prevents the severe carcinoid crises that occur during surgery or embolization in patients with carcinoid syndromes.

Amphiphilic perfluoroalkyl carbohydrates as new tools for liver imaging.

The synthesis of three molecules containing a fluorocarbon chain (either C(6)F(13), C(8)F(17) or C(10)F(21)), a sugar moiety (derived from lactobionic acid) and a chelate (derived from DTPA) is reported. These molecules (C(6)F(13)-Gal-DTPA, C(8)F(17)-Gal-DTPA or C(10)F(21)-Gal-DTPA) have been dispersed in water and their critical micellar concentration (CMC) as well as their size were determined. Their interaction with serum was weak as evaluated by time resolved fluorimetry of europium complexes. The presence of sugar on the surface of the nanoparticles was confirmed by the agglutination test using ricin. Conditions of pH and concentrations were optimised for in vivo studies. Finally, the nanoparticles formed with C(10)F(21)-Gal-DTPA have been complexed with (99m)Tc and injected to rats in order to follow their biodistribution by scintigraphy while following their stability by transmission electronic microscopy. A majority of the compound was found in the liver post-bolus injection.

Hyperosmolarity causes inflammation through the methylation of protein phosphatase 2A.

OBJECTIVE AND DESIGN: We evaluated the role of the osmolarity in the pro-inflammatory responses of epithelial cells. MATERIAL: Twenty-five female Wistar rats and colorectal (HT-29) and bladder (T24) cell lines were used. TREATMENTS: Rats and cells were exposed for 48 hours to hyperosmotic solutions. METHODS: Interleukin-8 (IL-8) production was measured by Enzyme Linked ImmunoSorbent Assay, mRNA transcription of pro-inflammatory cytokines by microarrays or RNase Protection Assay. Nuclear factor-kappa B (NF-kappaB) pathway and Protein Phosphatase 2A (PP2A) activations were measured. Myeloperoxydase (MPO) activation and Macrophage-Inflammatory Protein-2 (MIP-2) transcription were monitored. RESULTS: The exposure to hyperosmotic solutions enhanced the production of IL-8 and induced pro-inflammatory cytokines transcription. In vivo, MPO enhanced activity accompanied by an increased MIP-2 transcription was observed. In vitro, NF-kappaB activation is accompanied by an inhibitor of kappa B-alpha degradation and inhibitor of kappa B kinase (IKK gamma) activation. We demonstrated the induction of IKK gamma after methylation and activation of PP2A. Cytokine induction was inhibited by okadaic acid and calyculin A and stimulated by xylitol. CONCLUSION: Hyperosmolarity can induce pro-inflammatory cytokine responses in colorectal and bladder epithelial cells. Inflammation appears to be the simple consequence of a shift of methylation of PP2A which in turn activates NF-kappaB.

Effect of plasma protein binding on kinetics of PN 200-110 in the isolated perfused rat heart.

The myocardial accumulation and elimination pharmacokinetics of PN 200-110 (PN) were investigated in the single pass isolated perfused rat heart by two methods. A direct method, radioactivity measurement in myocardial tissue after various perfusion times, and an indirect method, concentration determination in coronary effluent, by fractionary collection of samples, during infusion and elimination periods. Both methods showed that the myocardium could be considered as a one-compartment model with regard to PN pharmacokinetics. The perfusion with a modified Krebs-Ringer (MKR) solution containing 1 nM of (+/-)PN 200-110 and [3H]-(+)PN 200-110 as radioactive tracer, led to an accumulation of about 61.4 fmol.mg-1 myocardial tissue at steady-state. The effect of protein binding on the uptake and pharmacokinetic parameters of PN has been investigated in this isolated perfused heart (IPH) model. binding of PN decreased as a function of increasing bovine serum albumin (BSA) levels in the perfusion solution. As a matter of fact, the mean steady state myocardial concentration of PN was decreased by 42.9, 56.2, 76.5, 83.9 and 95.5% for respectively, 1, 2.5, 6, 10 and 40 g.l-1 of BSA. In the same way, the free fraction, the apparent volume of distribution (Vd) and the distribution and elimination half-lives were decreased. On the contrary, the elimination rate constant was increased.

Differences in the serum binding determinants of isradipine and darodipine--consequences for serum protein binding in various diseases.

1. Serum protein binding of isradipine and darodipine, and serum concentrations of alpha 1-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids (NEFA) were measured in three groups of patients, I: healthy subjects (n = 20); II: patients with inflammatory disorders (n = 15) and III: patients with hepatic insufficiency (n = 17). 2. AAG was increased significantly in group II patients (P less than 0.001) and decreased in group III patients (P less than 0.001); HSA was decreased significantly in group II and group III patients (P less than 0.001). 3. The free percentage of isradipine was decreased significantly in group II patients (P less than 0.05) and increased in group III patients (P less than 0.05) and multivariate analysis showed that these variations were inversely related to changes in AAG concentration. 4. The free percentage of darodipine was increased significantly in group II and III patients (P less than 0.05) due to a decrease in HSA concentration, as shown by multivariate analysis. 5. The changes in free serum percentages of isradipine and darodipine were inversely related to concomitant changes in the concentration of the serum protein for which they showed the highest affinity, AAG for isradipine and HSA for darodipine, respectively. 6. The unexplained variability in the binding data was greater when AAG was the major determinant of binding (isradipine).

Comparative binding of two closely related dihydropyridines (isradipine and darodipine) to serum proteins and erythrocytes.

The binding of the two drugs isradipine and darodipine, chemically related to dihydropyridines and potent calcium channel blockers, was studied in vitro to isolated plasma proteins, erythrocytes and human serum. The two drugs were strongly bound to serum proteins (up to 97%), mainly to human serum albumin (HSA), alpha 1-glycoprotein (AAG) and lipoproteins (VLDL, LDL and HDL). Their bindings to AAG were saturable with high affinity constants (isradipine 498,000 M-1, darodipine = 155,000 M-1; n = 1). The binding of these drugs to HSA, VLDL and HDL was unsaturable, but it was saturable on LDL. In blood the drugs partitioned in erythrocytes, 16% for isradipine and 14.8% for darodipine.