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The financial effects of the coronavirus disease 2019 (COVID-19) pandemic have fundamentally changed the healthcare environment, with hospitals expected to have lost billions in 2021. A preexisting nationwide nursing shortage became drastically worse during the pandemic amid dramatically increasing labor costs. We examined the evolution and financial effects of these changes during repeated pandemic surges within a vascular surgery division at a tertiary medical center.Operating room, inpatient unit, and outpatient clinic financial data were examined retrospectively. The monthly averages for a 14-month control cohort before COVID-19 (January 2019 to February 2020) were compared to the averages for seven interval groups of sequential, 3-month cohorts from March 2020 through November 2021 (groups 1-7).The monthly relative value unit (RVU) generation had returned to the mean before the COVID-19 pandemic (2520 RVUs) after an isolated decrease early in the pandemic (group 1; 1734 RVUs). The RVUs ranged from 2540 to 2863 per month for groups 2 to 5, with a slight decline in groups 6 and 7. The average monthly RVUs in the COVID-19 period (2437 RVUs) were nearly equivalent (P = .93) to those for the pre-COVID-19 cohort. An analysis of payor mix demonstrated an increase in commercial and Medicaid payors, with a respective decrease in Medicare payors, during COVID-19. The contribution to indirect, or profit, from inpatient hospital and outpatient clinical revenue showed a drastic decrease in group 1, followed by a swift rebound when the government restrictions were eased (group 2). The total monthly vascular nursing unit expense demonstrated a marked increase with each sequential group during COVID-19, with an average monthly upsurge of +$82,171 (+47%; P .001). An increase in the nursing labor expenses of +$884 per vascular case (from $1630 to $2514; +54%; P .001) was observed in the COVID-19 era. The nursing labor costs per patient day had increased from $580 to $852 (+$272; +53%; P .001). The nursing labor cost per RVU had increased from $69.5 to $107.7 (+$38.2; +55%; P .001). On a system-wide level, the agency-related nursing costs had increased from $4.9 million to $13.6 million per month (+178%; P .001) in 2021 compared with 2020.The COVID-19 pandemic has had severe, nationwide effects on healthcare delivery, exacerbating the deleterious effects of an existing, critical nursing shortage. To the best of our knowledge, the present study is the first detailed analysis of this phenomenon and its effects on a surgical division. Our results have demonstrated a progressive, drastic increase in nursing labor costs during the pandemic, with a resultant sustained erosion of financial margins despite a level of clinical productivity, as measured in RVUs, equal to the prepandemic standards. This precarious trend is not sustainable and will require increased, targeted government funding.

Background In the current era of cost containment, the financial impact of high-cost procedures such as endovascular aneurysm repair (EVAR) remains an area of intensive interest. Previous reports suggested slim to negative operating margins with EVAR, prompting widespread initiatives to reduce cost and to improve reimbursement. In 2015, the Centers for Medicare and Medicaid Services (CMS) announced the reclassification of EVAR to more specific diagnosis-related group (DRG) coding and predicted an overall increase in hospital reimbursement. The potential impact of this change has not been described. Methods Patients undergoing elective EVAR at a single institution between January 2014 and December 2018 were identified retrospectively, then stratified by date. Group 1 patients underwent EVAR before DRG change in 2015 and were classified with DRG 237/238, major cardiovascular procedure. Group 2 patients underwent EVAR after the change and were classified as DRG 268/269, aortic/heart assist procedures. The total direct cost included implant cost, operating room (OR) labor, room and board, and other supply costs. Net revenue reflected real payer mix values without extrapolation based on standard Medicare rates. Hospital profit was defined as the contribution to indirect (CTI), subtracting total direct cost from net revenue. Results A total of 188 encounters were included, 67 (36%) in group 1 and 121 (64%) in group 2. Medicare patients composed 84% of group 1 and 81% of group 2. CTI (profit) increased by $4447 (+123%) from $3615 in group 1 to $8062 in group 2. Net revenue per encounter increased by $2054 (+7.1%). In group 1, the higher reimbursement DRG code 237 was applied in 5 of 67 (7.5%) patients, whereas DRG code 268 was assigned in 19 of 121 (15.1%) patients in group 2. Total direct cost per encounter decreased by $2012 (−7.9%). This decrease in cost was driven by a reduction in implant cost, from a mean $16,914 per encounter in group 1 to a mean $15,655 in group 2 (−$1259 or −7.4% per encounter) and by a decrease in OR labor cost, $2838 in group 1 to $2361 in group 2 (−$477 or −17.0% per encounter). Conclusions A significant improvement in hospital CTI was observed for elective EVAR during the course of the study. The increased DRG reimbursement after the Centers for Medicare and Medicaid Services coding changes in 2015 was a major driver of this salutary change. Notably, efforts to reduce implant and OR cost as well as to improve coding and documentation accuracy over time had an equally important impact on financial return.

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 (el***) was 1.92±1. The pharmacokinetic parameters (AUC, Ke1, t.1/2el (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.

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.

To examine whether the risk of some selected adverse effects increases with the number of systemic non-steroidal anti-inflammatory (NSAID) drugs. The French Pharmacovigilance database was examined for an association between drug reaction reports and the exposure to one and two or more NSAIDs using a case/non-case study design. In the analysis, 54,583 spontaneous reports of adverse drug reactions were included, consisting of 2270 reports of hepatic injury, 994 reports of acute renal failure, 194 reports of gastrointestinal bleeding and 525 reports of angioedema, among others. Use of NSAIDs significantly increased the risk of hepatic injury, gastrointestinal bleeding, acute renal failure and angioedema. The odds ratios tended to increase with the number of NSAIDs for hepatic injury, gastrointestinal bleeding and acute renal failure but not for angioedema. In comparison with reports that did not mention any use of NSAIDs, the odds ratios associated with the use of a single NSAID and two or more NSAIDs were respectively 1.2 (95%CI: 0.9–1.5) and 2.2 (95%CI: 1.3–3.8) for hepatic injury, 7.3 (95%CI: 4.9–10.9) and 10.7 (95%CI: 2.9–40.2) for gastrointestinal bleeding, 3.2 (95%CI: 2.5–4.1) and 4.8 (95%CI: 2.6–8.8) for acute renal failure. For angioedema, the odds ratios were roughly similar when a single NSAID (OR=2.7; 95% CI: 2.2–3.4) or two or more NSAIDs (OR=2.0; 95%CI: 0.7–6.0) were used. The risk of severe ADRs (hepatic injury and acute renal failure) was six- to sevenfold higher in reports mentioning concomitant use of two NSAIDs or more than in those that did not. This study shows that concomitant use of two or more NSAIDs was associated with an excess risk of adverse effects such as hepatic injury, acute renal failure and gastrointestinal bleeding. Although simultaneous use of several systemic NSAIDs has no pharmacological justification, this may raise a serious public health problem with the increasing use of over-the-counter non-steroidal anti-inflammatory agents.

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 observed1--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.

Chronic cyclosporine A (CsA) nephrotoxicity has been widely assessed but only few studies have described acute nephrotoxicity. As CsA is now used for short periods, we developed an experimental model of acute CsA-induced nephrotoxicity. Renal clearances of inulin and para-aminohippurate were assessed in 35 New Zealand rabbits. Group 1: control, no treatment; group 2: CsA 25 mg/kg per day in 0.5 ml/kg per day for 5 days; group 3: vehicle Cremophor-EL, 0.5 ml/kg per day for 5 days; group 4: follow-up, the same as group 2, then CsA discontinuation for 31 days. Compared with group 1, CsA significantly decreased glomerular filtration rate (GFR), renal blood flow (RBF), and diuresis, with a significant increase in renal vascular resistance (RVR). The proportional fall in GFR (-32.3%) and RBF (-33.1%) suggests both pre- and postglomerular vasoconstriction. Discontinuation of CsA in group 4 led to normalization of RVR with improvement of other renal function parameters. Compared with group 1, Cremophor-EL induced no significant changes but an increased RBF. Microvacuolization of proximal tubule epithelial cells was the sole histological abnormality observed only in group 2. The overall results suggest that CsA induced a vasomotor acute renal failure which was not due to Cremophor-EL. This effect was partly reversible after discontinuation of treatment.

National audience; Les intoxications par le méprobamate sont relativement moins fréquentes que les intoxications par benzodiazépines, mais elles sont généralement beaucoup plus graves. Les méthodes de dosages ne recourant pas à la chromatographie en phase gazeuse sont peu nombreuses et délicates. Nous décrivons ici une adaptation de la technique colorimétrique de Ludwig et Hoffmann pour doser le méprobamate sérique. Dans cette technique, le benzène peut être avantageusement remplacé par le toluène dont la toxicité médullaire est beaucoup plus faible

To investigate the glucuronidation of the R- and S-enantiomers of the nonsteroidal antiinflammatory drug, flurbiprofen, by liver microsomes of several mammals, including humans, a new and reliable HPLC method for the separation and quantification of the corresponding diastereoisomeric glucuronides has been developed. Interspecies comparison revealed that the glucuronidation of flurbiprofen was highly efficient with liver microsomes of humans, monkeys, rats, and guinea pigs (in decreasing ranking order). Gunn rats, which present a genetic defect in the bilirubin UDP-glucuronosyltransferase (UGT) isoforms, were still able to glucuronidate the drug. The R-enantiomer was glucuronidated faster than the S-form by liver microsomes of rats and humans. Although the KM of glucuronidation of R- and S-enantiomers by rat liver UGT were in same order of magnitude (apparent KM 0.52 and 0.57 mM, respectively), the apparent Vmax's were significantly different (9.34 and 5.48 nmol/min.mg of protein). Regardless of the enantiomer considered, the glucuronidation of flurbiprofen was strongly increased up to 5-fold by treatment of rats with phenobarbital and, at a lower extent, by 3-methylcholanthrene. In contrast, the treatment of rats with ciprofibrate markedly decreased the activity. Glucuronidation of R-flurbiprofen was more enhanced by phenobarbital than that of the S-antipode. Each flurbiprofen enantiomer could weakly inhibit the glucuronidation of its antipode in a noncompetitive way. The apparent Ki was 0.51 mM with R-flurbiprofen as a substrate, and 0.37 mM with S-enantiomer. On the other hand, the rat liver UGT2B1 isoform, stably expressed in V79 cells, could glucuronidate flurbiprofen in an appreciable amount.(ABSTRACT TRUNCATED AT 250 WORDS)

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.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.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.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.

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 μm. 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 < 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 < 0·05). The pulmonary concentration of THP-DXR reached 0·032 ± 0·01 μmol g−1 60 min after the beginning of a perfusion of 1 μm of the drug. This concentration increased to 0·379 ± 0·11 μmol g−1 when the initial dose concentration was 10 μm. Corresponding lung concentrations for DXR were 0·013 ± 0·001 and 0·150 ± 0·04 μmol g−1, respectively (P < 0·05). The perfusate concentration/initial concentration ratio decreased by the same amount whether a 1 or 10 μm initial concentration of either drug was used. An initial concentration of 100 μm 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. These findings suggest: (1) a higher lung affinity for THP-DXR; (2) a correlation between lung uptake and dose consistent with a passive diffusion transport mechanism for both drugs; (3) a higher acute toxicity induced by THP-DXR; (4) the absence of metabolic activity in the lung with regards to both anthracyclines.

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.

1. Simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl CoA reductase, lowers the plasma cholesterol level and has been approved for treatment of hyperlipoproteinaemia. 2. Simvastatin has been studied for its effects on hepatic microsomal drug metabolism in rat. No induction of 7-ethoxyresorufin-O-deethylase (EROD), ethoxycoumarin-O-deethylase (ECOD) and of UDP-glucuronosyltransferases were found, in vitro, after administration of 0.5, 1.5 and 10 mg/kg per day for 22 days. 3. Epoxide hydrolases (microsomal and cytosolic) were also unchanged after treatment with simvastatin. 4. No increase of the palmitoyl CoA oxidase activity or of mitochondrial glycerol phosphate dehydrogenase activity occurred. 5. Fatty acid distribution in rat liver microsomal phosphatidylcholines showed a significant decrease of C16:1 and a significant increase of C20:4 acids.

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).

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.

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.

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.

In these studies we examined the kinetics of amiodarone (Am) uptake and efflux in/from the lung, and the influence of other amphiphilics on these processes. We used single-pass perfused isolated lungs from rats. Medium containing Am (30 microM + 1 microCi of [14C]Am) was perfused through the lung for 20 min (uptake), followed by 20 min of perfusion with drug-free medium (efflux). Lack of metabolism enabled us to follow Am by measuring the amount of radioactivity in perfusate and lung. Other concentrations of Am (3, 60 and 120 microM; n = 2-4 each) were also examined. Inhibited uptake and accelerated efflux of Am were attempted with the pneumophilic amphiphilics chlorimipramine, chlorphentermine, chlorpromazine, verapamil and with the main metabolite of Am: desethylamiodarone (60 and/or 240 microM; n = 3-4 lungs each). Lung extracted Am extensively during uptake. The amount of Am accumulated at 20 min (inflowing concentration: 30 microM) averaged 1307 +/- 109 (S.E.) nmol/g, corresponding to a tissue to medium ratio of 43.3 +/- 1.6. Spontaneous efflux of Am was incomplete. At 40 min, 862 +/- 105 nmol of Am remained bound per g of lung, suggesting sequestration of Am in a slowly effluxable pool in which calculations show that more than 50% of the drug will ultimately persist. Uptake and efflux rates obey biexponential kinetics, indicating storage into two pools. Uptake rate and the amount of Am accumulated in lung at 20 min increased in proportion to inflowing concentration up to 60 microM. At 120 microM the increase was less. Neither amphiphilic was capable of inhibiting Am uptake, whereas only chlorphentermine significantly accelerated Am efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The influence of thyroid hormones upon the inductive effects on microsomal enzymes and the hepatic proliferation produced by different fibrates was studied in the male rat. A pharmacological dose of triiodo-L-thyronine significantly lowers the total cytochrome P450 content induced by some equi-effective doses of clofibrate, ciprofibrate, bezafibrate and fenofibrate. The ethoxycoumarin O-deethylase activity (ECOD) is concomitantly decreased. On the contrary, L-T3 accentuates the specific inductive effect of fibrates on bilirubin-UDPGT activity. Hypothyroid has little or no influence upon the effect of fibrates towards cytochrome P450 content and ECOD activity. On the other hand, this thyroid status significantly lowers the CN- palmitoyl coenzyme A dehydrogenase, which is a marker enzyme of the peroxisome proliferation caused by the different fibrates. These results indicate a possible modulation of thyroid hormones within the fibrates induction mechanism in the rat.

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.