Hyperkinetic shock in viral and pneumococcal pneumonias.

Ten patients, suffering from severe viral or bacterial pneumonia had circulatory shock, characterised haemodynamically by normal or high cardiac output (CI = 4.1 +/- 1.2 1/min/m2) and low systemic resistance (SVR = 14 +/- 3.7 mm Hg/1/min/m2). Existence of such a hyperkinetic state greatly complicates the management of patients. Plasma volume expansion, performed in five cases of initial hypovolaemia, and Dopamine infusion (five patients) increased markedly the intra-pulmonary shunting. High level PEEP ventilation was not tolerated, despite the improvement of blood gases it produced. Extra-corporeal membrane lung oxygenation (three cases), whilst giving an initial decrease of shunting and restoring SVR, produced no long term surviors. All ten patients died from intractable shock and severe hypoxaemia. Spontaneous ventilation with positive expiratory pressure (CPAP) is believed to be an attractive alternative, due to its absence of deleterious haemodynamic effects.

[Prevention of myocardial ischemia during exercise 8 hours after use of transdermal nitrate derivatives]. / Prévention de l'ischémie myocardique d'effort 8 heures après l'application de dérivés nitrés transdermiques.

A controlled (placebo) double blind trial of a 20 cm2 transdermal system delivering 10 mg of Trinitrin per 24 hours, was carried out in 18 patients with stable angina and significant coronary artery disease. The exercise stress tests were performed at the same time of day using Bruce's protocol and computerised analysis (Case Marquette) after a 48 hour wash out period. All patients had two basal positive and reproducible exercise tests interrupted because of induced anginal pain and/or greater than or equal to 3.5 mm ST depression. There was no significant difference between the basal exercise stress tests and those performed after placebo. With the active drug the onset of ischaemia was delayed (ST less than -1 mm = 217 +/- 122 sec vs 150 +/- 70 sec with placebo, p less than 0.01); the duration of exercise was prolonged (419 +/- 119 sec vs 328 +/- 94 sec with placebo, p less than 0.01); for the same theoretical maximal heart rate, the ST depression was less (-1.6 +/- 0.9 mm vs -2.1 +/- 0.7 mm with placebo, p less than 0.01). On the other hand, the double rate pressure product was unchanged at rest and on effort. These results obtained after a 48 hour therapeutic window show statistically significant benefits with an increase in exercise tolerance and a decrease in myocardial ischaemia 8 hours after the application of transdermal Trinitrin system.

Pharmacokinetics of oxiracetam in elderly patients after 800 mg oral doses, comparison with non-geriatric healthy subjects.

The pharmacokinetics of oxiracetam have been studied in eighteen elderly patients and in six healthy non-geriatric adults. A 800 mg single oral dose was administered in the morning of the first day and repeatedly, every 12 h, from day 2 evening to day 10 morning, to the elderly patients. The healthy non-geriatric adults were given a 800 mg single oral dose of oxiracetam. In healthy non-geriatric subjects after a single oral administration of 800 mg, the normalized plasma levels of oxiracetam for 1 mg/kg dose were similar to those already recorded after a 2000 mg single dose of oxiracetam. Therefore, there was no tendency towards non-linear pharmacokinetics of oxiracetam between 800 and 2000 mg single doses in healthy subjects. After the single oral dose, the mean area under the plasma concentration-time curve of oxiracetam in elderly patients was increased by a factor of two as compared to that observed in non-geriatric healthy subjects whereas the maximum concentration (Cmax) was almost not modified and slightly delayed. This can be explained by a slower absorption and elimination in the elderly patients. The highest oxiracetam levels were predominantly recorded in the oldest patients. The slower elimination (mean T1/2 = 12.3 h in elderly and 7.7 h in healthy subjects) could be attributed to a physiological decrease of the renal function. The volume of distribution was not significantly modified in the elderly patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of oxiracetam in patients with renal impairment after a 800 mg single oral dose.

The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged from 9 to 95 ml/min among the 20 patients. In plasma, the terminal elimination half-life (T1/2) ranged from 10.6 to 68.1 h, the highest T1/2 corresponding to the patients with a high degree of renal impairment. In urine, the amounts of oxiracetam excreted during the 48 h postdosing represented 8.3 to 82.6% of the dose. They were lower in patients with a high degree of renal impairment. The correlations between the total clearance of oxiracetam, the renal clearance, the terminal apparent elimination rate constant in plasma, and CLcr were estimated by linear regression analysis. The correlation coefficients were 0.916, 0.985 and 0.803 respectively. The apparent volume of distribution of the central compartment V(1) and the total volume of distribution at the steady-state V(SS) were not dependent on the degree of renal impairment. The mean values +/- SD were 25.9 +/- 13.0 litres and 48.3 +/- 21.5 litres respectively. Oxiracetam concentrations in plasma of patients were estimated for repeated administration of 800 mg of oxiracetam.(ABSTRACT TRUNCATED AT 250 WORDS)

[Role of estro-progestational compounds in myocardial infarct]. / Rôle des estroprogestatifs dans l'infarctus du myocarde.

PIP: The association between oral contraceptives (OCs) and infarction is still not very clear. Only an epidemiological approach and statistical studies of known cases could shed light on the problem. Other risks associatd with OCs include arterial hypertension, obesity, glycoregulation problems, and blood coagulation problems. The association between OCs and the risk of thromboembolism during pregnancy is also not proved. Even if the risk of myocardial infarction is 2.7 times higher for a woman on OCs it is still lower than the risk of cardiovascular diseases or the risk of phlebitis. The physician should be aware of all possibilities before prescribing any oral contraceptives.^ieng

[Administration route of natural sex steroids (estradiol, progesterone, testosterone) (author's transl)]. / Les voies d'administration des stéroïdes sexuels naturels (estradiol, progestérone, testostérone).

The natural sex steroids (E2, T, P) may be used in therapeutics. Estradiol and testosterone esters (decanoate and undecanoate) may be administered orally. A local effect always follows the percutaneous application of sex steroids, and this is usually accompanied by a systemic effect. But because of the very important metabolism of progesterone by the skin, it is necessary to administer it by other routes (intravaginal, intrarectal) in order to obtain a systemic effect.

PIP: The effectiveness of natural steroids administered orally is relatively weak. However, estradiol, progesterone, and testosterone, may be administered orally, and with better results, when micronized, i.e. in the form of microcrystals (1-3 micron, instead of the usual 100 micron crystals). Intestinal absorption of such steroids can be modified by the esterification of estradiol with deconoic acid, and of testosterone with undeconoic acid. Intravaginal and intrarectal routes can be effectively used for the absorption of estradiol and of progesterone. Percutaneous absorption depends on the solvents favoring the contact between the steroids and the skin; penetration into the skin is, however, slow and limited.

[Female hyperprolactinaemia. 19 cases (author's transl)]. / Hyperprolactinémies féminines. 19 observations.

The authors were able to confirm the ineffectiveness of vitamin B6. The correction of hyperprolactinaemia by bromocriptine restored ovarian function immediately, or after the failure of surgical treatment. It would still be premature to determine the exact place of surgery in this type of pathology.

[Hypogonadotrophic hypogonadism. Pituitary and testicular reactivity--receptivity to androgens (author's transl)]. / Hypogonadisme hypogonadotrophique. Réactivité hypophysaire et testiculaire. Réceptivité aux androgènes.

Six subjects aged between 19 and 29 years were studied. Gonadotrophins, follicular stimulating hormone or FSH and luteotrophic hormone or LH, were low in all cases. Under the influence of a single dose of 150 microgram of hypothalamic gonadotrophin liberation factor (LHRH), there was a preferential increase in FSH whilst levels of LH were little influenced. The continuous infusion of LHRH was associated with the same phenomenon. Only prolonged administration (for approximately 12 months) of chorionic gonadotrophins, resultes in a significant rise in plasma testosterone levels (low in all cases in the absence of stimulation). The level of urinary 3alpha-androstanediol represents a good parameter of androgenicity. Urinary 3beta-androstanediol is a metabolite of androgens formed in the liver. In hypogonadotrophic hypogonadism, and in particular in de Morsier's syndrome, the essential element would seem to be the absence of solicitation of the pituitary gonadotrophic cells by virtue of inadequate secretion of LHRH. The results of stimulation with chorionic gonadotrophins reflects the existence of inadequate maturation of testicular receptors to these hormones.

[Digestive tract hemorrhages of cirrhotic patients. Relation between hepatic insufficiency and the hemorrhagic lesion]. / Les hémorragies digestives des cirrhotiques. Relation entre l'insuffisance hépatique et la lésion hémorragique

The cause of upper gastrointestinal bleeding was studied in 85 cirrhotic patients by emergency endoscopy. In every patient, one or several lesions were observed and the site of bleeding was ascertained in 59. The two main causes were oesophago-gastric varices (46 p.cent) and acute mucosal lesions(42 p.cent). The source of bleeding appeared to be related to the degree of liver function impairment. In patients with no or moderate liver function impariment, bleeding usually originated from varices or from drug-associated mucosal erosions. Patients with severe impairment of liver function most often bled from spontaneous acute oeso-gastro-duodenal ulcerations. These ulcerations resembled what has been described in "stress" hemorrhage. Because of the relationship between liver function and the cause of hemorrhage, mortality was lower in variceal bleeders (29 p.cent) than in patients with spontaneous ulcerations (83 p.cent). In patients with severely impaired liver function, portacaval shunt was rarely indicated since hemorrhage was generally due to acute mucosal ulcerations.

[Respiratory function study on insulin-dependant diabetics (author's transl)]. / Contribution à l'étude de la fonction respiratoire du diabétique insulino-dépendant.

A present report on insulin dependant diabetics described changes in ventilatory mechanics and a decrease of pulmonary volumes; other studies ended up with different results, i.e. an absence of any spirographic change: the current study agrees with the latter findings. Yet, we noticed an alteration in the CO transfer of the lungs at the alveolar-capillary membrane level which appeared to be due to a reduced pulmonary capillary volume. The duration of the disease and the possible appearance of characteristic complications of diabetes did not seem to have any influence on the functional parameters measured. On the other hand, a broncho-pulmonary disorder independant of diabetes but associated with certain ailments (chronic bronchitis, sequelae of tuberculosis, ... tobacco smoking, etc.) led, as one might have foreseen, to functional ventilatory disturbances. A histological and haematological study would be a logical sequel to our study to clarify the mechanism of the diminished pulmonary transfer capacity.

[Acute post-gravidic Budd-Chiari syndrome. One case (author's transl)]. / Syndrome de Budd-Chiari aigu post-gravidique. Une observation.

The sixth case of post-gravidic Budd-Chiari syndrome is reported. In the acute stage of the disease heparin seems to have given immediate favourable results, and the value of long-term heparin treatment is discussed. Post-mortem findings seven years after the acute episode confirmed the evolution towards a certain type of cirrhosis characterized by macroscopically and histologically heterogenous lesions and by persistent liver congestion. Portal hypertension was associated with arterialization of the portal vein and considerable dilatation of the right diaphragmatic veins. The venous drainage of the liver had undergone complex alterations: the supra-hepatic veins were affected with fairly recent incomplete ostial thrombosis, many intra-hepatic veins were reduced to a vestigial reticulum and others were the seat of recent or old re-canalized thrombosis. Cancerous transformation was found to be present in the larger hepatic nodules.

[Pituitary investigations in idiopathic haemochromatosis (author's transl)]. / L'exploration hypophysaire des hémochromatoses idiopathiques.

Twelve patients with idiopathic hemochromatosis have been studied. Hypogonadotropic hypogonadism with normal prolactin appears to be a most constant finding. Other hypophysal functions are preserved. A rapid exploration of such patients with LHRH-TRH and insulin tolerance test is proposed.

[Contribution of motor nerve conduction velocity and Hoffmann reflex in early detection of neuropathy in diabetics. Results and correlations with duration and other long-term complications in 117 patients (author's transl)]. / Apports de la vitesse de conduction nerveuse motrice et du réflexe d'Hoffmann dans le dépistage de la neuropathie chez le diabétique. Résultats et corrélations avec l'ancienneté et les autres complications dégénératives à propos de 117 malades.

Motor nerve conduction velocity and H. reflex parameters were studied in 85 insulin-treated diabetics classified in groups I to VI, according to the duration of the disease, in 32 maturity-onset diabetics (groupe V) and in 92 healthy control subjects. Each diabetic subject was examined prior to testing for clinical evidence of neuropathy and also had funduscopic examination, fluorescein angiography and an estimation of renal status by serum creatinine measurement and proteinuria. Electrical parameters were significantly different in all groups of diabetics from results in the control group. Neuropathy, as judged by these electrical studies, was frequently present in the absence of clinical expression, worsened with the duration of the disease in groups I to IV and preceeded other degenerative changes of diabetes. H. reflex parameters are an earlier index of neuropathy than motor nerve conduction velocity and may be used as a monitor of diabetic neuropathy.

[Influence of glycemic control on peripheral nerve conduction in insulin-dependent diabetic subjects (author's transl)]. / Influence du contrôle glycémique sur la conduction nerveuse périphérique des diabétiques insulino-dépendants.

In order to better evaluate the influence of glycemic control on diabetic neuropathy, 73 diabetic patients were considered: 42 males and 31 females who had been treated with insulin during 9 years. Twenty-one subjects were examined during 2-12 months. Motor nerve conduction velocity (MCV) was measured on the external sciatic popliteus (ESP). The H reflex parameters from soleus were: latency time for H response (HL), the ratio between the maximum amplitude of the H reflex response and the M motor response: (formula: see text) was determined by a chromatographic method. The reduction of MCV, the rise in HL and the decrease of E in diabetics are more pronounced according to the duration of the disease and are significantly correlated with the rate of HbA1c (respectively MCV: r = -0.39, P less than 0.001; HL: r = 0.42, P less than 0.001; E: r = -0.37, P less than 0.01). There is a slight correlation between HbA1c level and the duration of diabetes. For the 21 diabetics observed during many months there is a very significant correlation between the slope of the evolution curves of HbA2c, MCV and HL.

Pharmacokinetics of cadralazine in a large group of hypertensive patients chronically treated with cadralazine: advantage over a conventional study in a small group of patients.

The concentrations of cadralazine in plasma were studied in 101 hypertensive patients treated with oral doses of 10, 15, or 20 mg of cadralazine once daily. Most of the patients received additionally a beta-blocking drug (n = 87) and a diuretic (n = 52). Few blood samples were collected in each patient on several occasions during the treatment, which usually lasted for more than 6 months. No accumulation of cadralazine in plasma occurred in any of the patients and the maximum concentrations were similar to those recorded in a small sample of healthy volunteers. The terminal half-life of elimination (3.6 h) was longer than that observed in healthy subjects (approximately 2.5 h). Conversely, the total clearance (197 ml/min) was lower (285 ml/min in healthy). The half-life and the total clearance in plasma were not dose dependent. In the patients treated for more than 6 months, no change in the pharmacokinetics of cadralazine was detected. The description of the distribution of concentrations showed that one-half of the patients behaved similarly to healthy subjects concerning half-life and total clearance. The other half presented a slower elimination of the drug (t 1/2 = 4.4 h and ClT = 130 ml/min) and these patients were significantly older (p = 0.01) than the former. This suggests that special attention should be paid to old hypertensive patients when a dose higher than 15 mg once daily is prescribed. Though concentrations were proportional to the dose, the body weight was not found to be a determining factor for dose adjustment.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites.

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated. The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2-2.5-times higher in patients with severe renal impairment (CLCR < 10 ml.min-1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects. The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance. The maximum target dose in patients with slight renal impairment (CLCR > 30 ml.min-1) should not be changed. In patients with moderate renal impairment (CLCR 10-30 ml.min-1) it should be reduced by 50%. In patients with severe renal impairment (CLCR < 10 ml.min-1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.