Differential action of thyroid hormones and chemically related compounds on the activity of UDP-glucuronosyltransferases and cytochrome P-450 isozymes in rat liver.

The effect of thyroid hormones and chemically related compounds, on the activity of UDP-glucuronosyltransferases (EC 2.4.1.17) and cytochrome P-450-dependent monooxygenases in rat liver microsomes was investigated. The animals were thyroidectomized and treated with different doses of the drugs for 3 weeks. Opposite effects were observed depending on the isoenzyme of UDP-glucuronosyltransferase considered. While 3,3',5-triiodo-L-thyronine, 3,3',5-triiodothyroacetic acid, 3,3',5-triiodothyropropionic acid, isopropyldiiodothyronine and L- and D-thyroxine strongly increased 4-nitrophenol glucuronidation in a dose-dependent fashion, they decreased markedly bilirubin glucuronidation. However, the activity toward nopol, a monoterpenoid alcohol, was not significantly changed regardless of which compound or dose was used. Variation of UDP-glucuronosyltransferase observed with 4-nitrophenol and bilirubin was related to the thyromimetic effect of the drugs estimated from the increase in alpha-glycerophosphate dehydrogenase. Thyronine and 3,5-diiodo-L-tyrosine, which did not enhance this activity, also failed to affect glucuronidation. Variations in UDP-glucuronosyltransferase activity were more likely due to changes in protein expression rather than changes in enzyme latency, since lipid organization of the microsomal membrane, as estimated from the mean anisotropy of 1,6-diphenyl-1,3,5-hexatriene by fluorescence polarization was not significantly modified by the drug administration. Although some of the drugs could significantly decrease the triacylglycerol and cholesterol contents in plasma, all failed to affect lauric acid hydroxylation. The activities of catalase, palmitoyl-CoA dehydrogenase (CN- insensitive) and carnitine acetyltransferase in the fraction enriched in peroxisomes were also not significantly affected by treatment with the thyroid hormone LT3. In contrast, the activity of 7-ethoxycoumarine O-deethylase was increased by large doses of thyronine and by 3,3',5-triiodothyropropionic acid. The concentration of total cytochrome P-450 was decreased in a dose-dependent fashion by all the compounds used, except thyronine. Finally, significant correlations were observed between glucuronidation of bilirubin and 4-nitrophenol and the content in cytochrome P-450. This suggests a possible coordinate regulation of the two processes, which depends on the physicochemical characteristics of the thyroid hormones and related compounds.

Urinary beta 2-microglobulin: early indicator of high dose cisdiamminedichloroplatinum nephrotoxicity? Influence of furosemide.

To evaluate the efficacy of beta 2-microglobulin as an indicator of cisplatinum nephrotoxicity, creatinine clearance and urinary beta 2-microglobulin were measured in 19 patients during 5 h after administration of a single dose of 80 mg/m2 cisplatinum. Eleven patients received furosemide as a concomitant therapy. Serum creatinine and beta 2-microglobulin remained unchanged. A decrease of creatinine clearance was observed. Urinary beta 2-microglobulin increased between 1 and 3 h after administration. This suggests transient tubular damage immediately after the treatment course. The concomitant administration of furosemide does not modify these results. However, patients who developed long-term nephrotoxicity had no early rise of urinary beta 2-microglobulin excretion; thus, it is not possible to predict cumulative nephrotoxicity by measuring beta 2-microglobulin immediately after the first course of high-dose cisplatinum.

Influence of hydration on ultrafilterable platinum kinetics and kidney function in patients treated with cis-diamminedichloroplatinum(II).

It has been reported that hypertonic saline provides protection against the renal toxicity of cisplatin (CDDP). We therefore evaluated its influence on the plasma and urinary pharmacokinetics of ultrafilterable platinum and kidney function as estimated by creatinine, inulin and PAH clearance. We undertook a randomized trial including two groups of ten patients receiving 100 mg/m2 CDDP in isotonic (group 1) or hypertonic saline (group 2) by a 20-min infusion. The hydration consisted of dextrose in group 1 and isotonic saline in group 2. Maximal concentration (Cmax), protein binding and cumulative urinary excretion were significantly higher in the dextrose group. Urinary flow decreased in this group but not in the other one. Inulin clearance was higher in the dextrose group than in the saline group and P-aminohippuric acid (PAH) clearance was not significantly different in these groups of patients. Hyponatremia was observed in the dextrose group. These results suggest that hypertonic saline infusion and saline hydration may enhance the diffusion of CDDP into tissues, lowering Cmax and renal excretion of platinum. The reduction of protein binding may indicate a diminution of aquation of CDDP in plasma. Our results suggest that the infusion of CDDP in hypertonic saline with salt hydration could exert a protective effect on the kidney. Moreover, there is a lessening of the risk of cellular hyperhydration. However, the better influence of dextrose hydration on glomerular filtration leads us to recommend a combination of the two methods of hydration for better tolerance and efficacy.

Evaluation of the effect of furosemide on ultrafilterable platinum kinetics in patients treated with cis-diamminedichloroplatinum.

It has been reported that furosemide can prevent platinum nephrotoxicity by dilution of the toxic drug in the tubule or by another unknown mechanism. To evaluate its influence on ultrafilterable platinum pharmacokinetics, we undertook a randomized prospective trial of cis-diamminedichloroplatinum (CDDP) (80 mg/m2 by a 20-min infusion) administered to 20 patients with hydration-induced diuresis. Ten patients received 20 mg/m2 furosemide 1 h before CDDP administration, and 10 patients received no diuretic drug. Plasma and urinary pharmacokinetics of platinum and creatinine were compared in both groups of patients. Plasma total and ultrafilterable platinum was always higher in the furosemide group. However, protein binding, urinary concentrations, cumulative urinary excretion, renal clearance and creatinine clearance/renal clearance ratio (fractional clearance) were not statistically different. Moreover, the fractional clearance was successively lower, equal and higher than one in both groups. These results suggest that: (1) furosemide probably causes water depletion leading to a rise in plasma concentrations; (2) its protection by a pharmacokinetic interaction is doubtful, since all other parameters (especially urinary parameters) are not significantly modified; (3) renal clearance and fractional clearance suggest a bidirectional transport of platinum in the tubule not influenced by the diuretic drug.

Liver microsome phospholipids and cytochrome P.450 concentration in phenobarbital treated rats fed on different diets.

Liver microsomal concentration of cytochrome P.450 is increased in animals which are fed diets rich in polyunsaturated fatty acids. On the other hand, the effects of phenobarbital are more important when the dietary fat is more unsaturated. The unsaturation index in liver microsomal phosphatidylcholines depends on the unsaturation of the dietary fats. The treatment with phenobarbital constantly results in a decrease of the unsaturation index of fatty acids both in lecithins and cephalins. The importance of the liver microsomal cytochrome P.450 increase and the importance of the unsaturation index decrease in liver microsomal lecithins, both promoted by phenobarbital, are in good agreement.

Inductive effects of fenofibrate and metabolism of phenobarbital.

The inductive effects of fenofibrate (FF) and phenobarbital (PB) were investigated in male Wistar rats. FF treatment produced an inductive effect on liver weight, cytochrome P450 content, and aniline hydroxylase (AH) and bilirubin UDP-glucuronosyltransferase (UDP-GT) activities in liver microsome fraction. PB and FF inductive effects were additive on liver weight but were not additive on P450 microsomal concentrations. On the contrary, FF administration decreased the inductive effect of PB on bilirubin UDP-GT activity. When FF and PB treatment were coupled, plasma and liver PB concentrations were not affected, whereas OHPB concentrations, especially in liver homogenate, were greatly decreased. Thus it can be concluded that the production of OHPB from PB was probably not accelerated, but the elimination of OHPB, the main metabolite of PB, was considerably enhanced. These results are to be compared with recent reports of structure-dependent induction of bilirubin glucuronidation by arylcarboxylic acids chemically related to clofibrate.

Comparison of creatinine and inulin clearances in multiple trauma.

Creatinine clearance (Ccr) is a good predictor of renal dysfunction. However, numerous analytical interferences have been observed with the classical measurement of creatinine by Jaffé's procedure. This prospective study was conducted to compare 4 methods for determining creatinine; and also endogenous creatinine clearance with inulin clearance (Cin) to estimate the glomerular filtration rate. The 4 different techniques for measuring creatinine were: 1) 2 techniques using Jaffé's colorimetric reaction: one with rapid and the other with slow kinetics: 2) 2 more selective methods: enzymatic procedure and high performance liquid chromatography (HPLC). Measurements were performed in 13 multiple trauma patients after stabilization and in 5 comatose patients (control group) over a 3-day period, with strict 24-h urine collection. On the second day, inulin clearance and para-aminohippuric acid clearance (Cpah) were measured. Measurement of creatinine by Jaffé's procedure yields significantly higher levels than those obtained by the other methods. Higher levels of both plasma and urinary creatinine were observed in the multiple trauma patients with all the methods used. There were no significant differences in Ccr, Cin, Cpah between the multiple trauma patients and the control patients. The best correlations between inulin clearance and creatinine clearance were observed for Jaffé's rapid kinetics (r = 0.90) in the control group and for the enzymatic procedure in the multiple trauma group (r = 0.55). Plasma creatinine is not a useful indicator in multiple trauma. The correlation between creatinine clearance and inulin clearance is not very strong in multiple trauma, indicating that the relative evolution (not the absolute values) of creatinine clearance is of interest.

Comparative pharmacokinetics of tetrahydropyranyl-doxorubicin and doxorubicin in rat isolated lung.

Rat isolated perfused lungs (Sprague-Dawley rats, n = 20) were studied to compare the pulmonary uptake of a new anthracycline, tetrahydropyranyl-doxorubicin (THP-DXR) with that of doxorubicin (DXR). Lung perfusions were initiated with a constituted medium containing either drug at concentrations of 1, 10 or 100 microM. Lungs were perfused by recirculation for 60 min. Thirteen perfusate samples were collected over 60 min and subjected to HPLC for assay. The perfusate concentration of THP-DXR decreased to 24 +/- 5% of the initial concentration and to 8 +/- 2%, 20 and 60 min after the beginning of the infusion, respectively. Corresponding values for DXR were 77 +/- 16 and 52 +/- 15%, respectively (P less than 0.05). During the THP-DXR perfusion, the area under the perfusate concentration vs time curve (AUC) was decreased to one-third and the clearance was increased 3-fold (P less than 0.05). The pulmonary concentration of THP-DXR reached 0.032 +/- 0.01 mumol g-1 60 min after the beginning of a perfusion of 1 microM of the drug. This concentration increased to 0.379 +/- 0.11 mumol g-1 when the initial dose concentration was 10 microM. Corresponding lung concentrations for DXR were 0.013 +/- 0.001 and 0.150 +/- 0.04 mumol g-1, respectively (P less than 0.05). The perfusate concentration/initial concentration ratio decreased by the same amount whether a 1 or 10 microM initial concentration of either drug was used. An initial concentration of 100 microM of THP-DXR, unlike DXR, consistently induced oedema in the perfused lung. No metabolite of either drug was revealed during the course of our study.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Mercaptopurine pharmacokinetics after use of azathioprine in renal transplant recipients with intermediate or high thiopurine methyl transferase activity phenotype.

Prevention of allograft transplant rejection by the immunosuppressive 6-thiopurine drug azathioprine is limited by haematological toxicity (leucopenia or agranulocytosis). This toxicity is particularly apparent in subjects with low thiopurine methyltransferase activity (TPMTase) phenotype (1% in the Caucasian population). The thiopurine derivative 6-mercaptopurine is the active metabolite of azathioprine, and it would be of interest to measure, after validation of plasma measurements, the mean values of the pharmacokinetic parameters in transplant patients with high or intermediate TPMTase phenotypes (85 and 14% of the Caucasian population, respectively). We measured erythrocyte TPMTase activity in 103 kidney transplant recipients of high or intermediate phenotype and calculated, after a test dose of azathioprine, the mean values of the pharmacokinetic parameters for 6-mercaptopurine. We also compared these values with the same parameters from one subject with low TPMTase activity phenotype. The mean observed area under the plasma concentration-time curve (AUC) was 190+/-140 ng mL(-1) h and the elimination rate constant (Kel) was 1.92+/-1. The pharmacokinetic parameters (AUC, Kel, t1/2el (the elimination half-life)) of 6-mercaptopurine in transplant patients are normally distributed and suitable for acceptance as a gold standard value for this population of Caucasian transplant patients. It seems useful to calculate these parameters, representative of the systemic exposure of individual patients to the drug, before prescribing these subjects azathioprine immunosuppressive treatment. In subjects with low TPMTase phenotype these pharmacokinetic measurements could also be an index of dose reduction.

Nutritional factors of microsomal enzymatic induction: influence of lipidic components of the diet.

We compared the ability of two different diets containing 6 per cent of maize oil and 6 per cent of fish oil to modify: firstly the enzyme induction by phenobarbital and secondly the phenobarbital hydroxylation by the liver either in vivo or during in vitro perfusions. The presence of fish oil in the diet increased the cyt P 450 content and the bilirubin glucuronosyl transferase activity. The two induction effects promoted by the association of the phenobarbital treatment and the eating of the fish oil were not additive and it was found that the phenobarbital induction effect was decreased by the fish oil consumption. Phenobarbital and p-hydroxyphenobarbital kinetics were different in the two groups of animals. Phenobarbital was more slowly eluted in the fish oil fed than in the maize oil fed rats while p-hydroxyphenobarbital was more slowly eluted by the fish oil-fed rat livers.

Influence of frusemide on cis-dichlorodiammineplatinum (II) pharmaco-kinetics.

Cis-dichlorodiammineplatinum (CDDP) pharmacokinetics were evaluated in eighteen patients with cancer who received 80 mg/m2 CDDP as a 20 min infusion. One hour before, 10 of them had 20 mg/m2 frusemide. Fifteen blood samples and fifteen urine samples were collected over the 5 hours following the infusion of CDDP. Platinum was assayed by flameless atomic absorption. The data did not detect any difference between patients with or without frusemide for the following platinum parameters: plasma concentration, urinary concentration, cumulative urinary excretion, renal clearance. These results suggest that frusemide has no influence upon cisplatin (CDDP) pharmacokinetics and if it protects the kidneys, it is not via kinetic modifications.

[Side effects of fibrates (except liver and muscle)]. / Effets indésirables des fibrates (hors foie et muscle).

If the iatrogenic acute muscular syndromes (rhabdomyolysis) and hepatic diseases following hypolipidemic drugs therapy are very well known, the other unwanted effects associated with fibrate therapy are not well established. It is the reason why we have selected, in the computerised data base of side effects from the French Network of "Centres de Pharmacovigilance" organisation, the pathological events associated with fibrate therapy during five years (1985 to 1989) (with exception for the acute muscular and hepatic diseases). The 277 side effects represent 67% of the side effects in which the product is regarded as "suspect" (S). These effects were observed in 132 men (mean age = 57 years) and 145 women (mean age = 61 years). The most frequently encountered products are: fénofibrate (Lipanthyl) for 30%; ciprofibrate (Lipanor); gemfibrozil (Lipur); bézafibrate (Befizal); each for about 10%. The mean doses used were the same that suggested in the french therapeutic dictionary ("Vidal"). The unwanted effects observed were: Skin reactions: 22.8% Blood disturbances (and hemorrhage): 9.8% Gl diseases (pancreatitis), Libido and psychic disturbances, nervous system disorders: about 6% each. All clotting disturbances (5.8%) are interactions with coumarin derivatives. The incidence of serious side effects was low and the recovery very good in 80.9% of cases: no death. In conclusion, the toxicity of fibrates (with exception for rhabdomyolysis and hepatic reaction) appears unimportant: the most frequently observed side effects are skin reactions and blood disturbances (interactions) and rarely nervous system, psychic or libido disturbances. The recovery is good, and the general toxicity of all products appear to be of the same order of magnitude.

Cyclosporine determinations in heart and liver transplant recipients: comparison of HPLC and FPIA methods on whole blood and plasma.

One hundred and eighty five whole blood samples were analysed for cyclosporine levels by fluorescence polarization immunoassay (FPIA) and high performance liquid chromatography (HPLC). 123 came from 4 heart transplant recipients (mean age +/- SD: 47.50 +/- 20.56 years) and 62 from 4 liver transplant recipients (44.50 +/- 16.52 years). FPIA was done on plasma and whole blood in heart transplant recipients, on plasma in the liver recipients. HPLC was always done on whole blood. The results show a good correlation between FPIA on plasma (y) and HPLC (x) in liver recipients (n = 62, r = 0.935, y = 1.23x + 70 ng/ml), slightly worse between FPIA on plasma (y) and HPLC (x) in heart recipients (n = 64, r = 0.610, y = 0.78x + 189 ng/ml) and mediocre for FPIA on whole blood (y) and HPLC (x) in heart recipients (n = 123, r = 0.566, y = 1.35x + 594 ng/ml).

[Retrospective of national pharmacovigilance surveys on drug-induced bullous, vesicular eruptions: methods and results ]. / Rétrospective d'enquêtes nationales de pharmacovigilance sur les toxidermies: méthodologies et résultats.

UNLABELLED: The academic interest for pharmacovigilance appears to be very low, because of the judged weakness of a "significant" relationship between drug utilisation and pathological events. We have tried to collect the relevant surveys of the French pharmacovigilance network on cutaneous toxic reactions to show the use of this work for current medical knowledge. This study was limited to the most relevant reports: 1--Cutaneous disorders induced by local reactions to ketoprofen, bufexamac, paracetamol (i.v.) 2--Cutaneous disorders observed in systemic hypersensitivity syndromes: allopurinol, chlormezanone, pristinamycine 3--Photosensitisation (toxicity), including: Individual characteristics of patients Nature of the observed syndromes Induction time and evolution of the disease Imputation and apparent incidence of the cases observed RESULTS: 1--Concerning "contact" dermitis, erythematous skin reactions are the most frequently observed. The causality link is proved in 272 patients of the cases. The mean age of the patients is 40-50 and the induction time from one to ten days. 2--In the hypersensitisation syndromes, severe skin reactions, combined with general reactions (fever), are the most frequently observed. The mean age is 50-60 and the number of serious cases is high (4.5%). 3--Severe burns with bullous skin reactions are observed in phototoxicity cases. The mean age of the patients is 50. Time induction is short (ten days), the cases are frequently serious, but evolution appears good. In conclusion, the synthesis of pharmacovigilance surveys shows the value of this epidemiological approach to drug-induced skin reactions. It is regrettable that the results of this work are not more widely distributed.

[Erythema multiforme induced by the combination of phenytoin and cerebral irradiation]. / Erythème polymorphe induit par l'association phénytoïne et irradiation cérébrale.

The authors report the case of erythema multiforme characterized by its cephalic onset and its rise after association phenytoin and cranial irradiation, for glioblastoma with epileptic fits. Eight similar cases are observed in literature with the same timing. Benign outcome is not always the rule because 2 patients died. This type of reaction being not forseeing, and outcome very varying, we suggest to avoid phenytoin in patients having a cerebral tumor revealed by epilepsy and needing a cranial irradiation.

[Drug-induced respiratory complications. Study of 27 cases]. / Accidents respiratoires médicamenteux. Etude de 27 observations.

Over 8 1/2 years, we observed 27 patients with drug-induced respiratory disease (DIRD). The inducer drugs were mainly those used in cardiology (9 patients, of whom 8 had amiodarone pneumonitis), in oncology (8 patients), in rheumatology (4 patients; 3 from d-penicillamine and 1 from gold), and in neurology (4 cases from ergoline derivatives). The main pattern of DIRD was a diffuse interstitial lung disease having either a rapid, a slowly progressive or a chronic course. Only the two former patterns offered clearing following withdrawal of the drug. Severe bronchiolitis obliterans from d-penicillamine (2 cases) and pulmonary eosinophilia (2 cases) was also observed. The onset of DIRD occurred earlier, i.e. following shorter periods of drug administration (months), in the acute interstitial lung disease variant, while it occurred after years of drug exposure in subacute and chronic forms. In contrast to other reports, bronchoalveolar lavage lymphocytosis was not a prominent feature in amiodarone pneumonitis. The outcome was favourable in 16 patients; deaths was encountered during the florid phase of DIRD in 3; incapacitating sequelae were noted in 6 patients, leading to subsequent death in 2; the underlying disease accounted for 7 additional deaths. Therefore, DIRD are relatively common, develop often in patients with severe underlying conditions, and interstitial pneumonitis is their pattern of predilection. Amiodarone emerges as a common inducer, and accounted for more cases than all chemotherapeutic agents grouped together in our series.

[Course of blood creatinine during repeated injections of cisplatin. Influence of drug combinations]. / Evolution de la créatininémie lors d'injections répétées de cisplatine. Influence des associations médicamenteuses.

Cisplatin (CDDP) is known to induce nephrotoxicity. In this retrospective study, we have investigated the evolution of plasma creatinine in long term therapy with CDDP. We have studied case history, mode of administration of CDDP and associations with other chemotherapeutic agents or drugs which could potientiate CDDP renal damage (non steroidal anti-inflammatory agents, analgesics, antibiotics, antihypertensive agents, diuretics and contrast media). Mean creatinine concentration versus time rises significantly. This elevation is significantly higher in patients with hypertension, diabete, one functional kidney, or abdominoperineal irradiation. The association with other drugs has not proved a real influence on creatinine evolution.

[Local anesthetics: simultaneous HPLC determination of lidocaine (Xylocaine) and bupivacaine (Marcaine) in human serum]. / Anesthésiques locaux: dosage simultané par CLHP de lidocaïne (Xylocaïne) et de bupivacaïne (Marcaïne) dans le sérum humain.

In order to monitor loco-regional anaesthesia in the upper limbs with a combination of two anaesthetics, the authors participated in a clinical pharmacology study. They describe a method of simultaneous assay of bupivacaine and lignocaine by direct phase HPLC. In particular, the use of heptane sulfonic acid (counter-ion) in the mobile phase allows the elution of the local anaesthetics to be controlled. The criteria of reliability studied enable this technique to be considered for routine use.

[Secondary hyperparathyroidism in hospitalized aged patients: apropos of 200 assays of intact parathyroid hormone]. / Hyperparathyroïdie secondaire chez le sujet âgé hospitalisé: à propos de 200 dosages de parathormone intacte.

Plasma intact parathyroid hormone (PTH) determinations were performed in 200 elderly patients admitted in a geriatric care unit. Abnormally high levels of PTH were observed in 40 subjects. There was a significant correlation between plasma ionized calcium determinations or creatinine clearance and PTH levels. Subjects with high PTH levels exhibited constantly reduced levels of 25 OH-D3. A calcium and vitamin D supplement, performed in 13 patients, was constantly followed by a decrease of the PTH level.

[Secondary hyperparathyroidism in the elderly. Apropos of 200 assays of intact parathormone]. / L'hyperparathyroïdie secondaire du sujet âgé. A propos de 200 dosages de parathormone intacte.

OBJECTIVES: To evaluate the frequency of high levels of intact parathormone in an elderly population of hospitalized patients and to determine whether there are any correlations with different factors involved in phosphocalcium metabolism, nutritional status and renal function. METHODS: Intact parathormone was assayed in all patients admitted to a geriatric ward (n = 200). Other laboratory tests included serum phosphorus, calcium, total albumin, prealbumin, ionized calcium, creatinine with calculation of the clearance and in 50 patients radioimmunoassay for 25 hydroxyvitamin D. RESULTS: Intact parathormone was abnormally high (> 65 pg/ml) in 40 patients. Mean levels increased significantly with age and reached 70.5 pg/ml in patients 90 years of age and over. No correlation was found between intact parathormone and total serum calcium, corrected serum calcium, albumin or prealbumin. Inversely there was a significant correlation with serum phosphorus and creatinine and creatinine clearance. Serum levels of 25 hydroxyvitamin D were abnormally low in 82% of the patients. There was a constant and significant decrease in intact parathormone level 15 days after calcium and calcifediol substitution therapy in 13 patients. CONCLUSION: The frequency of hyperparathyroidism increases with age to affect nearly 1 out of 2 subjects over 90. It would be useful to determine a threshold level for elderly subjects with a major risk of bone fracture.