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Biomedical subjects

I Robieux

Publications and source records attributed to I Robieux.

30 records · Page 2Linked to original sources
PubMed1991

Cytochrome P450IID subfamily in non-human primates. Catalytical and immunological characterization.

Interindividual variations of debrisoquine metabolism was recently identified in non-human primates tested in vivo. The catalytical and immunological characterization of cytochrome P450IID subfamily was undertaken in hepatic microsomes from extensive metabolizer primates. The NADPH/O2 mediated metabolism of debrisoquine, dextromethorphan and bufuralol was similar to the kinetics reported in humans. The CuOOH mediated metabolism of bufuralol suggested that at least two enzymes are responsible for bufuralol 1'-hydroxylation. Eleven compounds were tested for their capacity to modify P450IID function in vitro. Eight competitive inhibitors of P450IID6 in man were all and exclusively competitive inhibitor of P450IID subfamily in non-human primates. Quinidine, which is the strongest competitive inhibitor in man, exhibited the higher inhibitory potency in monkey (Ki = 0.75 microM). Anti-LKM antibody against P450IID subfamily cross-reacted with two proteins of 49 and 47 kDa, and sera containing anti-LKM antibody against these two proteins inhibited dextrorphan formation in vitro. These data provide evidence for catalytical and immunological similarities between human and monkey microsomes and indicate that the primate system could be a model for enzymatic studies of P450IID.

Animals↗
PubMed1991

Diurnal variation of methotrexate disposition in children with acute leukaemia.

There is recent evidence that survival is improved when maintenance therapy for acute lymphocytic leukaemia in children is given at night. We have examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In 6 children with leukaemia there was a significant fall in methotrexate plasma clearance at night (from 5.6 to 4.7 ml.kg-1.min-1). Renal clearance of methotrexate tended to fall at night and unbound renal clearance fell significantly (from 17.5 to 8.5 ml.min-1.kg-1 P less than 0.05). Creatinine clearance did not exhibit diurnal variation, whereas there was a significant fall in the non-glomerular clearance of methotrexate (from 14.8 to 6 ml.min-1.kg-1). Since methotrexate is a weak organic acid, its tubular secretion depends on urinary pH. At night urinary pH is more acidic, and this may result in more reabsorption and hence reduced renal clearance.

Acute Disease↗
PubMed1991

Decreased protein binding of salicylates in Kawasaki disease.

Because patients with Kawasaki disease have low serum concentrations of salicylates despite high doses, and because the free (unbound) drug is responsible for the pharmacologic effects of salicylates, we assessed salicylate protein binding in patients with Kawasaki disease. During the acute phase of the disease, protein binding of salicylate in 36 children with Kawasaki disease was 73 +/- 12%, significantly lower than during the subacute phase (90.4 +/- 8.7%; p less than 0.0005). Mean serum albumin concentration was 29.2 +/- 6.4 gm/L during the acute phase and 36.7 +/- 7.8 gm/L during the subsequent subacute phase (p less than 0.005). Salicylate protein binding was affected independently by both serum albumin and total salicylate levels. During the acute phase of Kawasaki disease, children had an average twofold increase in free salicylate compared with normoalbuminemic control subjects. A nomogram has been devised to derive free salicylate levels from the known total salicylate and serum albumin concentrations.

Acute Disease↗
PubMed1990

[Analgesia-sedation in pediatric resuscitation: indications, modalities].

Recently in pediatric intensive care, sedative and analgesic drugs are being used more frequently, not only for painful and stressful procedures, but also to improve the techniques of intensive care and the patient's comfort. Benzodiazepines are the most common drugs used for sedation, and narcotics for pain.

Analgesics↗
PubMed1990

Pharmacokinetics of midazolam in critically ill neonates.

Midazolam is a water soluble benzodiazepine, with a short elimination half-life in adults and children. An IV bolus of midazolam 0.2 mg.kg-1 was administered to 10 critically ill neonates receiving intensive care who required sedation. The plasma clearance was 6.85 ml.min-1 and the elimination half-life was 6.52 h. Midazolam was well tolerated during and after administration. Because of its short half-life compared to diazepam, midazolam could be used during the neonatal period to produce brief rapid sedation.

Chromatography, High Pressure Liquid↗
PubMed1990

Morphine excretion in breast milk and resultant exposure of a nursing infant.

We report the case of an infant who was breastfed while his mother was receiving low doses of morphine. Morphine concentration in his serum was in the analgesic range (4 ng/ml), while concentrations in the milk varied substantially in three samples collected within 2 hours (10, 100, 12 ng/ml). The calculated dose that the infant must have received to achieve the observed serum concentration had to be between 0.8 to 12% of maternal dose, based on reference literature values of clearance and bioavailability. The current perception that maternal morphine exposure is safe for the breastfed infant is based on a 50 year old data which were determined by an analytical method 1000 fold less sensitive than the present HPLC, thus leading to a likely erroneous conclusion.

Adult↗
PubMed1989

Seizures presenting as apnoea.

Between the ages of 3 and 6 months a baby boy presented with repeated, non-specific episodes of cyanosis, apnoea, bradycardia, and abnormal movements of the limbs. The episodes were severe and required resuscitation and several admissions to hospital. Initial investigations showed only signs of oesophagitis. Despite treatment of the oesophagitis the symptoms recurred, and electroencephalography and polygraphy eventually showed evidence of minor seizures. Severe epilepsy with tonic-clonic seizures developed when he was 6 months old.

Apnea↗
PubMedDate not supplied

Interactions of antineoplastic chemotherapy with zidovudine pharmacokinetics in patients with HIV-related neoplasms.

To evaluate the perturbations in zidovudine (ZDV) pharmacokinetics as a consequence of antineoplastic chemotherapeutic treatments, we performed a prospective crossover study in 13 HIV-infected patients with cancer. The subjects received 2-day regimens of ZDV (250 mg x 2/day). On the first day ZDV was administered alone, whereas on the second day it was combined with antitumor chemotherapies specific for the histological type (ZDV + chemotherapy). Blood sample and urine collections were performed over a 12-hour period following oral administration of the antiretroviral agent. ZDV was measured with high-performance liquid chromatography. Pharmacokinetic parameters of ZDV were calculated by a noncompartmental model. The mean ZDV area under curve (AUC) was not significantly different in the patients treated with ZDV alone and ZDV + chemotherapy. Comparison of plasma elimination half-life (t((1/2))), apparent systemic clearance (CL/F), and apparent volume of distribution (Vd/F) of ZDV did not show any significant difference before and after chemotherapy. Conversely, some significant differences were observed for both mean peak concentration (C(max)) of ZDV and the corresponding time (T(max)). There was a 57% reduction in C(max) (p<0.05) and a 66% increase in T(max) (p<0.05) after chemotherapy compared with treatment with ZDV alone. No differences were observed in the urinary excretion of ZDV and ZDV glucuronide and urinary metabolic ratio, as a consequence of antineoplastic treatment. In conclusion, this study demonstrates that some minor perturbations in ZDV pharmacokinetics (i.e. C(max) and T(max)) derived from antineoplastic chemotherapy. Based on the observation that antineoplastic chemotherapy had no significant effect on plasma ZDV concentration expressed as AUC, the observed pharmacokinetic interaction would not warrant by itself a change in the ZDV dosage during chemotherapy.

Adolescent↗
PubMedDate not supplied

Pharmacology of chronic oral daily administration of idarubicin.

Idarubicin (4-demethoxydaunorubicin) (IDA) is a daunorubicin analogue with substantial activity in hematologic malignancies and solid tumors. Among several reasons, IDA is of interest because of its main metabolite derivative, the C-13 alcohol analogue, idarubicinol (IDOL). Previous studies have suggested that IDOL, unlike other anthracycline metabolic derivatives, possesses a striking growth-inhibitory activity in tumor cell lines. This suggests that IDOL, like IDA could be useful in circumventing MDR. IDA is bioavailable in an oral dosage form. After oral administration of IDA to the patients, the concentration of IDOL quickly exceeds that of IDA and is retained in the plasma for a longer period. Hence, administration of IDA to cancer patients results ina much greater overall exposure of the tumor to IDOL than to the parent compound. At the Oncology Center (CRO) in Aviano we performed a dose-finding and pharmacokinetic (PK) study of chronic daily oral IDA with intrapatient escalation in patients with metastatic breast cancer (MBC). All the patients were pretreated with anthracyclines (the cumulative dose was 530 mg and 264 mg, respectively, for epirubicin and (DOX) and had at admittance a PS < or = 2 and a left ventricular ejection fraction > 50%. IDA (1 mg capsules) was administered orally twice a day for 21 days every two weeks. Treatment was continued at escalating doses until progression or intolerance. Twenty-five patients were enrolled. MTD has not yet been reached and clinical results are reported in Table 1. Treatment was well-tolerated in all but one patient (300 ANC at day 28). Three patients had tox G3 ANC for more than three weeks after 3, 6, and 7 mg doses, respectively. Two of them stopped chemotherapy after 1 cycle and 1 patient stopped after 2 cycles (6 mg doses). Despite previous treatments with anthracyclines (the mean cumulative dose before entering the study was 530 and 264 mg, respectively, for epirubicin and DOX) no cardiotoxicity due to IDA treatment was observed. This trial demonstrates the feasibility of chronic daily IDA administration. At the dosage reported, treatment was generally well tolerated. The PK findings (high IDOL concentrations) and the unexpected G4 myelotoxicity in patients with the highest IDOL plasma concentrations suggest that IDOL is clinically relevant.

Administration, Oral↗