Excretion mass balance evaluation, metabolite profile analysis and metabolite identification in plasma and excreta after oral administration of [14C]-meloxicam to the male cat: preliminary study.

The objective of this study was to investigate the metabolic pathways and routes of excretion of oral meloxicam in the cat. [(14)C]-meloxicam was administered orally to three fasted male cats. Urine, faeces, vomit and cage washes were collected over the following 144 h period. Blood was collected predosing and at 3 and 12 h postdosing. Metabolites were identified by HPLC/MS/MS. When possible a metabolic structure was proposed for each metabolite detected. Only unchanged meloxicam was identified in plasma. Five major metabolites were detected in urine and four in faeces, which were identified by HPLC/MS/MS as products of oxidative metabolism. No conjugated metabolites were detected. Elimination occurred early (61% during the first 48 h). A total of 21% of the recovered dose was eliminated in urine (2% as unchanged meloxicam, 19% as metabolites) and 79% in the faeces (49% as unchanged meloxicam, 30% as metabolites). The results indicate that after oral administration the major route of excretion of meloxicam in the cat is faecal and that the main pathway of biotransformation of meloxicam in the cat is oxidation.

[Pulmonary hypertension in patient with beta-thalassemia major]. / Hypertension artérielle pulmonaire chez un patient porteur d'une bêta-thalassémie majeure.

We report a case of pulmonary hypertension (PH) in a 35-year old patient with beta-thalassemia major; he had commenced blood transfusions after the age of 4 years and had been splenectomised at the age of 6 years. PH clinical presentation was not uncommon. Hemodynamic study revealed precapillary PH with high cardiac output; vasodilators agents led to significant pulmonary responsiveness. In beta-thalassemia, whereas congestive heart failure is common and due to cardiac hemosiderin deposition, PH appears to be non rare but its etiopathogenic mechanism remain unclear and probably non univoqual. Hypoxemia as well as hemodynamic changes related to chronic anemia including increased pulmonary flow might play an important role. Management should include blood transfusions to correct anemia, the indication and the choice of vasodilator agents need to be evaluated.

[Acute blood pressure elevations]. / Elévations aiguës de la pression artérielle.

Blood pressure (BP) elevations may correspond to different clinical situations. Hypertensives emergencies are situations that require immediate reduction in BP because of acute or rapidly progressing target organ damage: accelerated malignant hypertension, hypertensive encephalopathy, acute myocardial infarction, acute aortic dissection, acute left ventricular failure, and eclampsia. Hypertensive urgencies are those with marked elevated BP in which it is desirable to reduce BP progressively within few hours, such as severe hypertension, progressive target organ damage, perioperative hypertension. Cerebrovascular accidents have to be individualized. In most patients in the immediate post-stroke period, BP should not be lowered. Caution is advised in lowering BP in these patients because excessive falls may precipitate cerebral ischemia. In situations without symptoms or progressive target organ it is necessary to exclude proximate causes of elevated BP such as pain and elevated BP alone rarely requires antihypertensive treatment. Among parenteral antihypertensive (AH) drugs labetalol, nicardipine, urapidil, and nitroprussiate are generally used, and the choice of AH drug depends on the clinical situation. It is not required to normalize BP immediately but to reduce mean BP no more than 25%, then toward 160/100 mmHg as recommended by JNC VI, in order to avoid an impairment of renal, cerebral or coronary ischemia. Oral long-acting dihydropyridines are often subsequently administrated, except in myocardial ischemia. Therapeutic attitudes vary considerably according to the clinical situation: abstention, immediate decrease or progressive decrease in BP have to be decided.

Direct matrix-assisted laser desorption/ionization mass spectrometric analysis of glycosphingolipids on thin layer chromatographic plates and transfer membranes.

Results are reported for analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) of native glycosphingolipids (GSLs) after development on thin layer chromatographic plates and after heat transfer of the GSLs from the plates to several types of polymer membranes. The spectral quality is better for membrane-bound analytes, in terms of sensitivity, mass resolution and background interference. The sensitivity gain compared with liquid secondary ion mass spectrometry (LSIMS) of GSLs on thin layer plates is 1-2 orders of magnitude (detection limits of 5-50 pmol vs. 1-10 nmol). Resolution and mass accuracy (0.1%) are limited by the irregular membrane surfaces and this effect cannot be entirely compensated by delayed extraction. The best results were obtained with a polyvinylidene difluoride (PVDF) P membrane, with irradiation from a nitrogen laser. Although the Nafion membrane could not be used for molecular weight profiling, its acidic character led to sample hydrolysis at the glycosidic linkages, thus yielding a series of fragments that could be used to determine the sequence of carbohydrate residues. Structural information could also be obtained by post-source decay (PSD) experiments on mass-selected precursor ions. Samples containing both neutral and acidic components were characterized in a 1:1 combination of 2, 5-dihydroxybenzoic acid and 2-amino-5-nitropyridine. GSLs that exhibited binding to antibodies in an overlay assay on the TLC plate were transferred to membranes and analyzed by MALDI-TOFMS without interference from the antibody or the salts and buffers used during the binding and visualization steps. Taking advantage of the insights into sample preparation gained from these studies, future research will extend this approach to analysis by matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICRMS) with an external ion source.

[Ambulatory blood pressure, intima media thickness, global cardiovascular risk and therapeutic decisions]. / Mesure ambulatoire de la pression artérielle, épaisseur intima média carotidienne, risque cardiovasculaire global et décision thérapeutique.

OBJECTIVE: To determine the influence of ambulatory blood pressure monitoring (ABPM), carotid intima media thickness (IMT) and global cardiovascular risk on the therapeutic strategies issued from our hypertension unit. METHODS: All essential uncomplicated and never treated hypertensive patients referred to our hypertension unit between 1996 and 1997 for etiologic or target organ damage evaluation were considered eligible. We excluded diabetics and patients with renal disease who need a specific therapeutical approach. 54 patients (44.7 +/- 10.1 years) were included (40 men). All patients underwent an ABPM measurement. The right common carotid IMT measurement had been performed (0.06 +/- 09 mm). The global cardiovascular risks were assessed with the Framingham prediction chart taking into account age, sex, total cholesterol, smoking status and systolic office blood pressure. According to the therapeutic decision three groups were made up: group 1 lifestyle counselling (n = 13), group 2 single drug therapy (n = 31), and group 3 combination therapy (n = 10). RESULTS: No significant difference was found in age, sex ratio, prevalence of severe hypertension, office systolic blood pressure, body mass index, global cardiovascular risk between the three groups. In contrast ABP (24 h ABP mmHg: group 1: 128.23 +/- 6.91/79.7 +/- 6.4; group 2: 140.48 +/- 9.7/97.48 +/- 8.17; group 3: 152.4 +/- 15.35/99.4 +/- 12.14 p < .0001) and IMT (group 1: 10.55 +/- .09, group 2: .59 +/- .07, group 3: .66 +/- .11 p = .02), were significantly higher in group 3 than in group 2 and in group 1. The percentage of white coat hypertensives was higher in group 1 than in group 3 (group 1: 61.5%, group 2: 3.2%, group 3: 0%). In the whole population, the higher was the global cardiovascular risk, the higher was the common carotid intima media thickness. In this study the global cardiovascular risks are not related to therapeutic decisions. Therapeutic strategies are influenced by ABP level and by the vascular remodeling which depends partly on the global cardiovascular risk.

[Conceptual basis and diagnosis of primary hyperaldosteronism]. / Conception et diagnostic des hyperaldostéronismes primaires.

Primary aldosteronism comprises two different conditions, the tumoral form usually caused by an adenoma and the idiopathic form due to nodular hyperplasia of the two adenals. More rarely, an adenoma of the adrenal cortex, glucocorticosteroid-sensitive hyperplasia, and angiotensin-sensitive adenoma or an autonomous nodule transformed to primary tumoral hyperplasia, may be observed. Primary alderosteronism may be conceived as a spectrum of genetic abnormalities which express themselves either by hyperplasia or by a tumour. A defect in steroid genesis and prolonged stimulation of the cortex would lead to the formation of nodules which may become autonomous and generate a tumour. Hypertension may be isolated. Detection requires three sampling of serum potassium in all hypertensive patients, a study of the aldosterone-renin axis when the value is less than 3.6 mEq, or whenever the hypertension is severe or resistant to treatment. The diagnosis is made by the association of an increased plasma aldosterone level before getting up in the morning and a plasma renin unaffected by orthostatism. The choice of medical or surgical treatment depends on the uni- or bilateral anatomic substrate. Computerised tomography, very sensitive but not specific, like hormonal studies, often provides incomplete answers. Adrenalectomy is indicated in the presence of a mass of centimetric proportions with concordant results of the dynamic test. In other situations, investigations are continued with the search for an aldosterone gradient by selective venous sampling. This is very valuable to determine the lateralisation but fails in 25% of cases, and its results have to be compared with those of imaging techniques: CT scan, venography and, when necessary, scintigraphy.(ABSTRACT TRUNCATED AT 250 WORDS)

Matrix-assisted laser desorption ionization time-of-flight mass spectrometry of DNA-Pt(II) complexes.

Matrix-assisted laser desorption ionization (MALDI) time-of-flight mass spectrometry has been used to characterize the reaction products of the 18-mer deoxyribonucleotide d(AACGGTTAACCGTTAATT) with [Pt(NH3)3(H2O)]2+ and cis-[Pt(NH3)2(H2O)2]2+. Characteristic peaks corresponding to different monofunctional adducts (18-mer+n[Pt(NH3)3]) (n = 1, 2, 3 and 4) have been observed with the triamino-monoaqua complex. With the diamino-diaqua cis-Pt complex, formation of a chelate (18-mer+[Pt(NH3)2]) involving two adjacent guanines has been demonstrated. A good correlation between MALDI and polyacrylamide gel electrophoresis results is observed.

[Acromegaly and bronchial carcinoid tumor. Apropos of a case]. / Acromégalie et tumeur carcinoïde bronchique. A propos d'une observation.

Acromegaly due to ectopic secretion of growth hormone-releasing hormone (GHRH) is rare. A 29-year-old woman with acromegaly secondary to ectopic GHRH secretion by a bronchial carcinoid tumor is presented. Normalization of GHRH levels, reversal of pituitary hyperplasia and regression of acromegaly followed resection of the bronchial tumor. The authors stressed the interest of GHRH dosage in patients with acromegaly and pituitary hyperplasia.

[Value of the study of electrocardiographic P wave in pheochromocytoma]. / Intérêt de l'étude de l'onde P de l'électrocardiogramme en cas de phéochromocytome.

The diagnostic value of electrocardiographic P wave analysis in the frontal plane was assessed with respect to previously reported abnormalities: right atrial hypertrophy-dilatation; an enlarged, crenalleted summit without criteria of right atrial hypertrophy. Two observers studied the ECG recordings of 20 hypertensive patients with pheochromocytomas: 10 men and 10 women, aged 45.5 +/- 16 years, and in 30 patients with essential hypertension, 15 men and 15 women, aged 48.9 +/- 9 years (NS). The duration of hypertension was 2.6 +/- 2 years versus 4.7 +/- 4 years (p = 0.02). Right atrial hypertrophy-dilatation was observed in 5 patients in the pheochromocytoma group and in none of the essential hypertensive patients: an isolated abnormality of the summit of the P wave was observed in 5 other cases of pheochromocytoma and by 1 observer in 1 of the essential hypertension. These abnormalities disappeared after ablation of the tumour. These changes were not recorded in 3 patients who had predominant noradrenaline hypersecretion; nevertheless, comparison of the urinary adrenaline, noradrenaline, normeta- and metanephrine levels were inconclusive. No relationship was established between these concentrations, global urinary catecholamines and meta block, the duration of hypertension, the frequency and level of hypertensive crises, or the presence of "ischaemic" ST-T wave changes. P wave changes are thought to be related to high plasma catecholamine levels irrespective of the clinical impact; the sensitivity of these changes is modest (10/20) but the specificity is better within a group of hypertensive patients. An experienced observer can orient the diagnostic investigations to the search for a pheochromocytoma or to a secondary recurrence of the tumour from the surface ECG. The role of marker of a very high noradrenaline or adrenaline secretion cannot be confirmed from a series limited in separated plasma concentration measurements.

[Outcome of "white coat reaction" induced by nurse and physician in patients with hypertension treated with a beta blockader (bisoprolol)]. / Devenir sous bêta-bloquant (bisoprolol), de l'effet "blouse blanche" induit chez l'hypertendu par l'infirmière et le médecin.

The aim of the study was to assess the evolution of Alerting reaction (AR) under beta blocker treatment and to discuss its incidence on the management of arterial hypertension (AH). In 28 patients (pts), 19 men, 9 females, 46 +/- 12 years old, suffering from a mild to moderate AH, blood pressure (BP) was measured, according to a ritual circuit by a nurse (N), then a 12-minutes recorded monitoring, then a physician (Ph) using a mercury sphygmomanometer in upright, then in supine position at the end of the visit (165 +/- 18/108 +/- 13 mmHg, 161 +/- 14/100 +/- 9 mmHg). Pts received a cardioselective beta blocker, bisoprolol (B), 10 mg once daily and BP was evaluated after 1 and 2 months (D30; D60) under identical conditions. When compared to monitoring BP, there was a significant increase in systolic (S) and diastolic (D) BP, taken by the nurse and the physician, attributed to AR (delta SBP; delta DBP). Under B, AR remained unchanged, even increased regarding upright DBP at D30, D60 in spite of its efficacy: (formula; see text) The study demonstrates that there is no incidence of beta blocker on alerting reaction and that AR must be considered to evaluate the treatment and avoid an unnecessary or overtreatment. In case of discrepancies, it is suggested to perform an ambulatory BP monitoring.

[Neurogenic arterial hypertension in humans]. / Hypertension artérielle neurogène de l'homme.

The purpose of this study was to investigate baroreflex activity in hypertensive patients with orthostatic hypotension (OH) due to sinoaortic baroreceptor denervation. The study concerned 3 patients (pts), 58-63 years, mean age 60.6 +/- 2 with both arterial hypertension (paroxysms recorded at 250/130 mmHg) and OH. They received radiation therapy to the entire cervical area for neoplasm, 9.6 +/- 2.8 years ago and had a carotid murmur without significant stenosis. Every pt had a severe and symptomatic OH: blood pressure (BP) and heart rate (HR) were respectively 163 +/- 17/105 +/- 7, 82 +/- 5 b/mn in lying position and 82 +/- 16/53 +/- 9 mmHg, 99 +/- 1 b/mm in standing position. The standing-induced increase in HR was lower (delta HR = + 17.3 b/mn) than expected; atropine (0.02 mg/kg) infusion and cold pressor test were ineffective; the massage of sinocarotid receptors induced a slight decrease in HR (delta HR = - 8 b/mn) and BP was not modified by Valsalva's maneuver. Infusion of norepinephrine (0.016 mg/mn) performed in one pt, increased BP without effect on HR. Platelet alpha 2-adrenoreceptors (alpha 2AR) evaluated by (3H) Yohimbine binding showed a significant increase in alpha 2AR number (Bmax), without any significant change in affinity (KD) when compared with normotensive and essential hypertensive pts: (table; see text) This study described an unusual etiology of a paroxysmal hypertension with orthostatic hypotension, demonstrated the impairment of baroreflex activity and suggested the potential interest of platelet alpha 2 adrenoceptors measurement to evaluate sympathetic tone in these patients.

[Treatment of deep venous thrombosis. Comparative study of a low molecular weight heparin fragment (Fragmin) by the subcutaneous route and standard heparin by the continuous intravenous route. A multicenter study]. / Traitement des thromboses veineuses profondes constituées. Etude comparative d'un fragment d'héparine de bas poids moléculaire (Fragmine) administrée par voie sous-cutanée et de l'héparine standard administrée par voie intraveineuse continue. Etude multicentrique.

This open, randomised multicenter trial compares the efficacy and safety of Fragmin administered subcutaneously twice daily with standard heparin administered by continuous infusion in the treatment of deep vein thrombosis (DVT). The initial dose of Fragmin is 100 U anti-Xa/kg/12 h and the further doses are adjusted according to the anti-Xa activity between 0.5 and 0.8 U/ml, 3 hours after the morning injection. The initial dose of standard heparin is 240 UI/kg/12 h. The dose adjustments are based on the daily results of APTT (1.5 - 3 times the control). Treatments efficacy are appreciated when comparing the venography performed before and after 10 days of treatment. The safety is evaluated on clinical parameters and iterative biological tests. Sixty-six patients have been included in this study. Efficacy of the two treatments is equivalent with a phlebographic improvement in respectively 79.3 p. 100 (Heparin Group) and 71.0 p. 100 (Fragmin Group) of the cases and an aggravation in 3.4 p. 100 and 6.4 p. 100 (NS) respectively. The frequency of dosage adjustments is lower and the stability of biological tests is better in the Fragmin group. In conclusion, the administration of Fragmin twice daily by subcutaneous route seems to be equivalent at least to standard heparin continuous infusion in the treatment of recent DVT. The better convenience and safety of Fragmin have to be verified on a larger panel of patients.

[Treatment of deep venous thrombosis in the presence of a congenital antithrombin III deficiency. Apropos of the use of purified concentrates]. / Traitement d'une thrombose veineuse profonde en présence d'un déficit congénital en antithrombine III. A propos de l'utilisation de concentrés purifiés.

The authors report the case of an active 32 year old man who developed right leg DVT. Before heparinisation, he was discovered to have a low antithrombin III level (biological activity (B) 60%, immunological level (I) 50) and a further inquiry showed the same abnormality in 4 members of the family, leading to a diagnosis of a congenital deficit: a 35 year old sister with a bilateral post-DVT changes had antithrombin III levels of 70% (B) and 45% (I); two nephews, sons of the affected sister: the one aged 5 years was asymptomatic despite antithrombin III levels of 50% (I) and 70% (B); the other had experience DVT at the age of 2 and, on oral anti-vitamin K drugs, had antithrombin III levels of 55% (I) and 67% (B) at the age of 15 years; the patient's brother died at the age of 29 of cerebral vein thrombosis after pulmonary embolism. The recurrence of local signs of DVT after 12 day's heparin therapy with AT III levels (B) of 40%, led to a change in management with infusion of purified AT III concentrate at a dose of 40 U per kg (2 500 U per hour). This induced a rise in AT III activity to over 100% and enabled early introduction of anti-vitamin K therapy. The patient remains asymptomatic after 6 months follow-up. This case illustrates the value of determining AT III activity in all patients who developed DVT without obvious reason.(ABSTRACT TRUNCATED AT 250 WORDS)

[Role of the TRF test in the study of atrial dysrhythmia]. / Place du test au TRF dans l'enquête d'une dysrythmie auriculaire.

The aim of this retrospective study of 43 patients (32 females) aged 26 to 84 years old (mean 62 +/- 14,5) was to assess the value of the TRF test in cases with normal static endocrine levels and isolated arrhythmias: 25 atrial fibrillations, 3 atrial flutters, 10 sinus tachycardias, 2 junctional tachycardias, 2 focal atrial tachycardias and 1 atrial extrasystoles. There was underlying cardiac disease in 24 patients. Thyroid function was assessed by T4, T3 and the TRF test. There was no relationship between cardiac disease and arrhythmias with the levels of TSH 25 minutes after TRF. The reactivity to TRF was low: 5,8 +/- 5,6 microU/ml. Nineteen patients were hyperthyroid (TSH at O and 25 min: 1,7 +/- 0,5 and 2 +/- 1 microU/ml respectively), in the following three eventualities: - Clinical hyperthyroidism and raised hormonal levels, the TRF confirmed the diagnosis in 10 out of 11 cases; - Clinical hyperthyroidism and normal hormone levels: the TRF confirmed the diagnosis in 8 out of 14 cases; - Normal clinical examination and normal hormone levels: the TRF test showed a hyperthyroid reaction in 1 out of 18 cases. T3 and T4 measurements are often misleading. The TRF test with 2 blood samples would appear to be essential, especially in patients over 60 years of age. The hyperthyroid population was older (68,5 +/- 8 years) and the mean values of the thyroid investigations (T3, T4 and STH at 25 minutes) were significant. Underlying cardiac disease was detected in over half these cases. Atrial fibrillation was the commonest arrhythmia. Each case of arrhythmia, whether or not related to hyperthyroidism, justifies echocardiography.

[A study of antithrombin systems during heparin therapy]. / Etude du système des antithrombines au cours de l'héparinothérapie.

Plasma levels of three thrombin inhibitors (antithrombin III--AT-III-, alpha 2 macroglobulin - alpha 2M -; alpha 1 antitrypsin - alpha 1 AT-) were measured, together with total plasma antithrombin activity (Howie's method), in 19 hospital patients with venous thromboembolic disease before and during heparin therapy. A decrease in AT III levels was observed during treatment and found to correlate significantly with heparin plasma levels, but there were no significant changes in alpha 2M and alpha 1 AT levels. Variations in total plasma antithrombin activity were not significant. In 9 patients whose AT III levels were under 60% a significant increase in alpha 2M level was noted. The therapeutic problems associated with this category of patients are discussed.

Modulation of leukaemia blast colony growth by steroid hormones.

The effect of steroid hormones on in vitro colony growth of human myelogenous leukaemia cells was examined. beta-Oestradiol, testosterone and 5-beta-dihydrotesterone had little effect on HL60 promyelocytic leukaemia cells of blast colony forming cells (CFC) from eight patients with acute non-lymphocytic leukaemia (ANLL). These compounds inhibited blast colony growth at very high concentrations (10(-6)-10(-4) M). In contrast, hydrocortisone (HC) had highly variable effects on blast colony growth. HL60 cells were resistant to HC at concentrations up to 10(-4) M but blast CFC showed a wide range of response. Some patients were resistant to HC at all concentrations treated, while others were inhibited by concentrations as low as 10(-8) M. The inhibitory effect of HC was also observed on 3H-TdR incorporation by stimulated peripheral blood blasts. Inhibition by HC was not blocked by progesterone, suggesting this effect was not mediated by specific hormone receptors. These data indicate differences in the response of blast cells in ANLL and normal progenitors to steroid hormones. Cells from patients with ANLL display variable inhibition by HC which is probably not mediated by specific receptors.