[The contribution of teleconsultation and isolation of symptomatic cases in control of the COVID-19 outbreak a military base]. / Apport de la téléconsultation et de l'isolement des cas symptomatiques dans la maîtrise de l'épidémie COVID-19 au sein d'une base militaire.

BACKGROUND: The first wave of COVID-19 swept over France during the first quarter of 2020, leading to saturation of the health care system. We wished to study, in a French military medical unit assisting one of the country's largest armed forces populations, the impact of teleconsultation and the systematic isolation of all possible, probable and confirmed cases of COVID-19. METHODS: This is a retrospective study carried out from March 9 to May 31, 2020 on the basis of our activity register. The variables collected included type of medical consultation procedure, occupational status, classification of cases and date of onset of first symptoms. We have paralleled our activity with that of SOS Médecins and the emergency departments of the Île-de-France region. RESULTS/DISCUSSION: During this period, 1719 episodes of care (teleconsultations or physical consultations) were recorded, of which 91% (n=1561) were linked to COVID-19. We identified 598 "suspected" (possible and probable) and confirmed cases. "Isolated" teleconsultations (not followed by a face-to-face medical consultation, sample taking or necessitating the dispatch of prompt assistance) represented 86% of episodes of care (n=1482). Comparison of our activity and the number of new cases with the databases of SOS Médecins and the Île-de-France emergency services suggests that our isolation strategy was timely and effective. CONCLUSION: The contribution of teleconsultation was substantial and reassuring. Teleconsultation makes it possible to absorb a large volume of patients, is easy to implement, and entails no nosocomial risk. Isolation of infected patients should be a priority during an outbreak. Once it has become a priority to rapidly bring an epidemic under control, this attitude must be extended to all symptomatic patients.

Polychlorinated biphenyl congeners in the aquatic environment of the Mekong River, South of Vietnam.

Polychlorinated biphenyl compounds (PCBs) were analyzed in sediments and clams' soft tissues from sampling sites in the Mekong River delta from the border with Cambodia to the coast of South China Sea. Concentrations of 13 individual PCB congeners are reported. Median concentration of SigmaPCB congeners was 0.279 ng g(-1) dry weight (range 0.106-2.016 ng g(-1) dry weight) in sediments, and 5.20 ng g(-1) dry weight (range 1.89-19.37 ng g(-1)) in clams. Distribution and bioaccumulation of PCBs in the delta are discussed. It is concluded that in the Mekong River delta PCB concentrations were generally lower than in other regions of Vietnam and their likely sources have been waste discharges from repair workshops and other facilities in the delta cities.

Agrochemical and polychlorobyphenyl (PCB) residues in the Mekong River delta, Vietnam.

An environmental survey on pesticide residues and polychlorobyphenyl compounds (PCBs), encompassing more than 70 polar and non-polar compounds quantifiable by the techniques used, was performed in the Mekong River delta based on analyses of water, sediment and bivalve mollusc samples. Few polar compounds, such as diazinon and fenotrothion, were detected in water but a high number of non-polar chlorinated compounds, such as DDT, HCH, endosulfan and PCBs, were detected in sediments and biota. The highest concentrations measured were of DDT with an average 6.3 ng g(-1) dry weight (range 0.32-67 ng g(-1)) in sediments and 38.6 ng g(-1) (range 5.5-123 ng g(-1)) in molluscs' soft tissues. Amongst chlorinated compounds, DDT concentrations were followed in decreasing order by those of PCB, endosulfan, hexachlorocyclohexane and chlordane. Residues of organochlorine compounds originate from local usage of agrochemicals although with a likely contribution also of atmospheric deposition of residues (not measured) originated elsewhere. Concentrations of PCB and pesticide residues in the aquatic environment of the Mekong River delta are lower than values reported for other regions of Vietnam and Asia. Nevertheless, current concerns about the effects of chlorinated compounds on public health advise improved control of chemical residue discharges in order to abate environmental contamination.

Cytochrome P450 and liver diseases.

Cytochrome P-450 (CYPs) are involved in the metabolism of drugs, chemicals and endogenous substrates. The hepatic CYPs are also involved in the pathogenesis of several liver diseases. CYP-mediated activation of drugs to toxic metabolites induces hepatotoxicity. Well-known examples include acetaminophen and halothane. In some instances, covalent binding of the toxic metabolite to CYP leads to the formation of anti-CYP antibodies and immune-mediated hepatotoxicity (hydralazine, tienilic acid). Anti-CYP2D6 antibodies are also present in the serum of patients with type II autoimmune hepatitis, but the mechanism leading to their presence and their pathogenic significance remains unclear. Several studies support a role for CYP2E1 in the pathogenesis of alcoholic liver disease and non-alcoholic steatohepatitis. In these conditions, enhanced CYP2E1 activity is associated with lipid peroxidation and the production of reactive oxygen species with secondary damage to cellular membranes and mitochondria. Because of its ability to activate carcinogens, a role for CYP2E1 as a cofactor for hepatocellular carcinoma has also been postulated. On the other hand, drug metabolism is impaired in patients with liver disease, particularly that mediated by CYPs. The content and activity of CYP1A, 2C19 and 3A appear to be particularly vulnerable to the effect of liver disease while CYP2D6, 2C9 and 2E1 are less affected. The pattern of CYPs isoenzymes alterations also differs according to the etiology of liver disease. A strong relationship between the activity of CYPs and the severity of cirrhosis has been demonstrated, but the usefulness of measuring CYP activity to assess hepatic functional reserve remains uncertain.

Toxaphene residues from cotton fields in soils and in the coastal environment of Nicaragua.

Toxaphene (camphechlor) was intensively used in the cotton growing fields of Nicaragua for decades with application rates as high as 31 kg ha(-1) in 1985. Although the use of this compound has recently been discontinued in the country, its intensive use in the past and its long persistence in soil allowed for the build up of large reservoirs of toxaphene in agriculture soils and a wide dispersal of residues in the environment. Measurements of toxaphene in coastal areas on the coast of the Pacific Ocean show that environmental concentrations are particularly high in the district of Chinandega, the traditional cotton growing region. Toxaphene residues measured in soils attained 44 microg g(-1) (dry weight) while concentrations in lagoon sediments attained 6.9 microg g(-1) (dry weight) near the mouth of the rivers flowing across the agricultural region. Measurements in aquatic biota showed concentrations as high as 1.6 microg g(-1) (dry weight) in the soft tissues of clams. The toxaphene reservoir in soils combined with the obvious persistence of this compound in soils and lagoon sediments allows predicting that toxaphene will remain in the coastal ecosystem at relatively high concentrations for many years. Toxic effects in lagoon fauna are likely to be observed especially in benthic species that may recycle this compound from sediments. Consumption of seafood, in particular of clams (Anadara spp.) from the more contaminated areas, may expose the population to unacceptably high intake of toxaphene, 30 microg d(-1) per person, with the diet.

Global intercomparison for the determination of chlorinated pesticides, PCBs and petroleum hydrocarbons in sediment sample IAEA-417.

A world-wide interlaboratory comparison exercise was organised using a lagoon sediment as sample material (IAEA-417) for the analyses of chlorinated pesticides, PCB congeners and petroleum hydrocarbons. The sample material was analysed by 97 laboratories from 46 countries, representing a rather wide distribution for such an interlaboratory comparison exercise. Whereas quite variable results were reported for most chlorinated pesticides, more consistent interlaboratory results were obtained for PCB congeners and polycyclic aromatic hydrocarbons (PAHs). Nevertheless, many laboratories reported results in sufficiently dose agreement that after statistical screening of the data, consensus values were obtained for the concentration of several analytes in this sediment sample. The results allow reference concentration values to be assigned for several analytes. Thus, the sediment sample IAEA-417 can be used as a reference material for quality control of data in the determination of chlorinated compounds and petroleum hydrocarbons in moderately polluted sediments.

Distribution, fate and effects of pesticide residues in tropical coastal lagoons of northwestern Mexico.

Analyses of pesticide residues in sediments, water and biota of the Altata-Ensenada del Pabellon coastal lagoon system in Sinaloa, Mexico, showed the presence of organochlorine and organophosphorus compounds. For all the compounds analysed, concentrations in sediments were higher near the points of water discharge from ponds and drainage from the agricultural area. Among the organochlorines, total DDTs displayed the largest sedimentary reservoir, followed by total endosulfans and chlorpyrifos. In sediments, as well as in biota, pp'-DDT concentrations were lower than those of DDT metabolites, which confirms the reduction in the previous massive use of this compound in agriculture. Endosulfan is currently used in the region and endosulfan residues in lagoon sediments attained levels considered to be toxic to meiofauna, therefore constituting an ecological risk to lagoon ecosystems. There was a large sedimentary reservoir of chlorpyrifos but its ecotoxicological risk is difficult to assess due to lack of adequate comparative data. Nevertheless, concentrations of chlorpyrifos which approach acute toxic levels for shrimp were recorded in lagoon water. This suggests that drainage from agricultural fields during high runoff may, on occasion, cause mass mortality of shrimp and fish Organophosphorus pesticides are widely regarded to degrade very rapidly in aquatic systems. Experimental research performed with 14C-labelled chlorpyrifos and parathion has shown that they may be stabilised for relatively long periods of time through sediment-water partitioning. This extension of their environmental half-lives increases their potential for impacting on coastal ecosystems. Since organophosphorus pesticides are highly toxic for aquatic organisms at concentrations generally lower than organochlorines, their presence in the lagoon water and sediment is a matter for much concern. The increased use of tropical coastal lagoons for shrimp and fish farming requires the implementation of environmental management practices to protect these ecosystems from the impact of agricultural activities. Environmental management aims to preserve the ecosystem integrity of these coastal lagoons and, through improving the water quality, to allow the development of aquaculture and reduce human exposure to pesticide residues in food.

Development of a risk-based TMDL assessment approach using the integrated modeling system GIBSI.

Using the integrated modeling system GIB SI and a case study, this paper presents the development of a risk-based TMDL assessment approach that links wet (nonpoint/diffuse) and dry weather (point) sources to a probability of exceeding water quality standards (WQS) governing wateruses. The case study focused on determining whether WQS defining recreational uses of water requiring direct and prolonged contact were attainable if the waste water effluent of a small town was treated using aerated lagoons and if the agricultural nonpoint source (NPS) loads were reduced using different fertilization rates. Dry weather sources were assumed to solely contribute to bacteriological impairment of the studied river reach. Meanwhile, both wet and dry weather sources were assumed to contribute to aesthetic impairment. Simulation results showed that treating the waste water effluent while reducing the agricultural NPS loads by 27% allowed on average over a four-year study period for attainment of the bacteriological WQS 100% of the summer time while lowering the probability of exceeding the aesthetic WQS from 0.32 to 0.19 (30 to 18 days). The results of this study showed this risk-based assessment approach was well suited to establish TMDL. These probabilities should be evaluated using long meteorological series.

Persistent organochlorine residues in sediments from the Black Sea.

The extent of contamination of the Black Sea by selected organochlorine compounds has been assessed through the analysis of surficial sediments taken from throughout the region. Concentrations of HCHs at sites influenced by the Danube delta are among the highest recorded on a global basis (up to 40 ng g(-1) dry wt). The ratio between the alpha- and gamma-isomers was relatively low indicating contamination through the use of lindane. Concentrations of DDTs (0.06-72 ng g(-1) dry wt) and PCBs (0.06-72 ng g(-1) dry wt) were not especially high in comparison to levels reported from throughout the world. The DDE/DDT ratio was, however, low indicating fresh inputs and hence current usage of DDT within the Black Sea region.

Petroleum and PAH contamination of the Black Sea.

Concern has been expressed regarding the extent of contamination of the Black Sea. Analyses of coastal sediments taken from throughout the region indicate, however, that levels of petroleum hydrocarbons (2-300 microg g(-1) dry wt total hydrocarbons) are generally comparable to those encountered in the Mediterranean and are lower than concentrations reported for highly contaminated areas such as the Gulf, Hong Kong, Taiwan and New York Bight. Highest concentrations of total hydrocarbons (>100 microg g(-1) dry wt) were associated with discharges from Odessa, Sochi and the River Danube. Chronic/degraded petroleum was the major contributor at these sites. Samples from the Ukrainian coastline were comparatively clean (<10 microg g(-1) dry wt total hydrocarbons). Major contributions of fresh oil (as indicated by sigma n-C14-34) occur through the River Danube. Concerning total PAH, concentrations (7-638 ng g(-1) dry wt) compare to relatively unpolluted locations in the Mediterranean and are much lower than levels reported for polluted UK estuaries (e.g. Mersey, Tyne, Thames). Both pyrolytic and petrogenic PAH are present in most samples, although petroleum derived PAH are dominant at Sochi and pyrolytic sources are prevalent in the Bosphorus region. The absence of a correlation between total hydrocarbons and PAH (R2 = 0.04) indicates different primary sources for the two.

An unusual case of hepatic abscess.

A case of recurring primary hepatic actinomycosis is reported. A 50-year-old man presented with fever, weight loss and multiple hepatic masses. A diagnosis was obtained by cytological examination of a biopsy sample taken from the largest hepatic mass, which revealed the presence of Actinomyces species. The patient was treated with penicillin for 12 months and did well. Seven years later, he presented with similar symptoms but with a single large liver mass and a pulmonary infiltrate in the right lower lobe. Liver biopsy showed an inflammatory pseudotumour, and lung biopsy showed the presence of Actinomyces species. Again, the patient was treated with penicillin. Five months later, the patient was doing well, and a follow-up computed tomography scan showed partial regression of the hepatic pseudotumour. This case indicates that hepatic actinomycosis can recur several years after an appropriate treatment and stresses the need for careful follow-up in such patients.

Chlorinated pesticides and PCBs in sediments and molluscs from freshwater canals in the Hanoi region.

The concentrations of organochlorine pesticides and PCBs were determined in surface sediments and freshwater molluscs (Angulyagra sp.) from water canals in the region of Hanoi city. Results obtained show that the concentration of sigma DDT compounds in sediments range from 7 to 80 ng/g (dry weight) and from 6 to 864 ng/g (dry weight) in the soft tissues of molluscs. The concentrations of sigma DDTs were higher in populated sites and much lower in rural sites, indicating that the DDT has been used for mosquito control and not as a crop protection chemical. Hexachlocyclohexanes (HCHs) have also been widely used in the region but the current environmental concentrations are much lower than those of DDT's, which is due to the less persistence of those compounds. Polychlorinated biphenyls (PCBs) were measured, for example as aroclor 1254, in concentrations up to 40 ng/g (dry weight) and up to 76 ng/g (dry weight) in sediments and molluscs, respectively. Molluscs from water canals are a very popular food in the region. Taking into consideration the high DDT levels measured in these molluscs their consumption is worrisome and may expose the population to high levels of endocrine disrupting substances. Current PCB levels in sediments are lower than usually measured in industrialized countries. Therefore, PCB concentrations in aquatic molluscs are still also relatively low. These snails do not have enzyme ability to metabolize most of the CB congeners and, thus, are passive accumulators and a significant transfer pathway of CBs to consumers. Therefore, measures to phase out the use of these persistent and bioaccumulable chemicals should be adopted in order to prevent further environmental contamination.

Transjugular intrahepatic portosystemic shunt (TIPS) versus endoscopic variceal ligation in the prevention of variceal rebleeding in patients with cirrhosis: a randomised trial.

BACKGROUND AND AIMS: The transjugular intrahepatic portosystemic shunt (TIPS) is a new therapeutic modality for variceal bleeding. In this study we compared the two year survival and rebleeding rates in cirrhotic patients treated by either variceal band ligation or TIPS for variceal bleeding. METHODS: Eighty cirrhotic patients (Pugh score 7-12) with variceal bleeding were randomly allocated to TIPS (n=41) or ligation (n=39), 24 hours after control of bleeding. RESULTS: Mean follow up was 581 days in the ligation group and 678 days in the TIPS group. The two year survival rate was 57% in the TIPS group and 56% in the ligation group (NS); the incidence of variceal rebleeding after two years was 18% in the TIPS group and 66% in the ligation group (p<0.001). Uncontrolled rebleeding occurred in 11 patients in the ligation group (eight were rescued by emergency TIPS) but in none of the TIPS group. The incidence of encephalopathy at two years was 47% in the TIPS group and 44% in the ligation group (NS). CONCLUSIONS: TIPS did not increase the two year survival rate compared with variceal band ligation after variceal bleeding in cirrhotic patients with moderate or severe liver failure. It significantly reduced the incidence of variceal rebleeding without increasing the rate of encephalopathy.

Furosemide-induced natriuresis as a test to identify cirrhotic patients with refractory ascites.

The diagnosis of refractory ascites in cirrhotic patients carries a poor prognosis and liver transplantation should always be considered in this situation. Identification of patients who will not respond to diuretic therapy usually requires several weeks of observation during which a trial of diuretics is instituted using stepwise increases in dosage in order to classify ascites as refractory. In the present study we evaluated the effect of a single dose of 80 mg intravenous furosemide on urinary sodium excretion over 8 hours in cirrhotic patients with ascites responsive to diuretic treatment (group 1; n = 14) and patients with refractory ascites (group 2; n = 15). The test was performed after 3 days without diuretics and patients were on a 80 mEq sodium/day diet. Refractory ascites was defined by the absence of response after 3 months of high doses of diuretics (spironolactone 200 mg/d + furosemide 80 mg/d + metolazone 2.5 mg/d) and the need for repeated paracentesis. The two groups had similar degrees of liver and renal dysfunction as assessed by the Pugh score and creatinine clearance. The effects of furosemide on 8-hour natriuresis was much higher in patients with responsive ascites as compared with patients with refractory ascites (125 +/- 46 vs. 30 +/- 16 mEq; mean +/- SD; P <.0001). A natriuresis lower than 50 mEq/8 hours was observed in all group-2 patients as compared with none from group 1. The present study shows that patients with refractory ascites can be identified quickly and accurately by using this simple furosemide-induced natriuresis test, which could be very useful to select patients for liver transplantation.

Differential alteration of cytochrome P450 isoenzymes in two experimental models of cirrhosis.

Liver diseases are associated with a decrease in hepatic drug elimination, but there is evidence that cirrhosis does not result in uniform changes of cytochrome P450 (CYP) isoenzymes. The objective of this study was to determine the content and activity of four CYP isoenzymes in the bile duct ligation and carbon tetrachloride (CCl4)-induced models of cirrhosis. The hepatic content of CYP1A, CYP2C, CYP2E1, and CYP3A was measured by Western blot analysis. CYP activity in vivo was evaluated with breath tests using substrates specific for different isoenzymes: caffeine (CYP1A2), aminopyrine (CYP2C11), nitrosodimethylamine (CYP2E1), and erythromycin (CYP3A). Bile duct ligation resulted in biliary cirrhosis; CYP1A, CYP2C and CYP3A content was decreased and the caffeine, aminopyrine, and erythromycin breath tests were reduced whereas CYP2E1 content and the nitrosodimethylamine breath test were unchanged compared with controls. CCl4 treatment resulted in cirrhosis of varying severity as assessed from the decrease in liver weight and serum albumin. In rats with mild cirrhosis, CYP content was comparable with controls except for a decrease in CYP2C. The activity of CYPs was also unchanged except for an increase in CYP2E1 activity. In rats with more severe cirrhosis, the content of all four CYP isoenzymes and the caffeine, aminopyrine, and erythromycin breath tests were reduced whereas the nitrosodimethylamine breath test was unchanged. In both models of cirrhosis, there was a significant correlation between the breath tests results and the severity of cirrhosis as assessed from serum albumin levels. These results indicate that content and the catalytic activity of individual CYP enzymes are differentially altered by cirrhosis in the rat and also suggest that drug probes could be useful to assess hepatic functional reserve.

Genotypic succession of mutations of the hepatitis B virus polymerase associated with lamivudine resistance.

BACKGROUND/AIMS: Hepatitis B mutant strains of virus emerging during treatment with the nucleoside analog lamivudine are being increasingly recognized. In the majority of lamivudine-resistant isolates the mutations have been reported to occur within the YMDD motif of the viral polymerase, either as a single mutation M552I or as M552V concomitant with L528M. We analyzed the time course and genetic succession pattern during the emergence of lamivudine resistance. METHODS: Seven patients with breakthrough viremia in the setting of chronic hepatitis (n=5) or recurrent HBV after liver transplantation (n=2) were investigated. Pre- and post-breakthrough serum samples were evaluated by single- or second-round PCR amplification and sequencing analysis. RESULTS: Genotypic succession of the virus populations was observed to occur from M552I to M552I/L528M (n=2) and from L528M to M552V/L528M (n=1). The double mutations M552I/L528M (n=4) or M552V/L528M (n=2) were found in six out of seven patients, and represented the stable virus populations throughout the follow-up period. Breakthrough viremia was not associated with the single L528M mutation. The mean duration of uninterrupted treatment with lamivudine until breakthrough was 422 days (range 182-642) and was longer in the setting of chronic hepatitis B than in recurrent hepatitis B after liver transplantation. HBV DNA levels after breakthrough were lower than pretreatment levels in the majority of patients with chronic hepatitis but higher after liver transplantation. CONCLUSION: Our observations show that the virus populations conferring resistance to lamivudine can evolve from single to double mutations at amino acid 552 and 528 of the HBV polymerase, and that M552I/ L528M or M552V/L528M seem to be the predominant mutations arising during long-term antiviral therapy with lamivudine.

Decreased in vivo metabolism of drugs in chronic renal failure.

Chronic renal failure (CRF) is associated with a decrease in renal excretion of drugs, but its effects on the liver metabolism of xenobiotics are poorly defined. The objectives of this study were to determine the effects of CRF on hepatic cytochrome P450 (CYP450) and its repercussions on in vivo hepatic metabolism of drugs. Two groups of rats were studied: control paired-fed and CRF. CRF was induced by subtotal nephrectomy. Total CYP450 activity and protein expression of several CYP450 isoforms (CYP1A2, CYP2C11, CYP3A1, CYP3A2) were assessed in liver microsomes. In vivo cytochrome P450 activity was evaluated with breath tests using substrates for different isoenzymes: caffeine (CYP1A2), aminopyrine (CYP2C11), and erythromycin (CYP3A2). Creatinine clearance was reduced by 60% (P <. 01) in rats with CRF. Compared with control paired-fed rats, total CYP450 activity was reduced by 40% in rats with CRF. Protein expression of CYP2C11, CYP3A1, and CYP3A2 was considerably reduced (more than 45%, P <.001) in rats with CRF, whereas the levels of CYP1A2 were unchanged. In rats with CRF, there was a 35% reduction in the aminopyrine (CYP2C11) and the erythromycin (CYP3A2) breath tests compared with control animals (P <.001). The caffeine (CYP1A2) breath tests remained comparable to controls. Creatinine clearance correlated with the aminopyrine and erythromycin breath tests (r(2) = 0.73 and r(2) = 0.81, respectively, P <.001). In conclusion, CRF is associated with a decrease in total liver CYP450 activity in rats (mainly in CYP2C11, CYP3A1, and CYP3A2), which leads to a significant decrease in the metabolism of drugs.

Ineffectiveness of hepatitis B vaccination in cirrhotic patients waiting for liver transplantation.

Cirrhotic patients who undergo liver transplantation are at risk of acquiring de novo hepatitis B virus (HBV) infection at the time of transplantation. It is common practice to immunize these patients against HBV, but the efficacy of vaccination is uncertain. The response to vaccination with a recombinant HBV vaccine was examined in 49 patients with cirrhosis before liver transplantation. Patients received three doses (20 mg) of Engerix-B (SmithKline Beecham) at zero, one and two months before transplantation, and their response was measured on the day of liver transplantation (9.3+/-1.2 months after the initial dose of vaccine). Results were compared with those reported in healthy adults vaccinated according to the same schedule. Fourteen of 49 cirrhotic patients (28%) developed antibodies to hepatitis B surface antigen (anti-HBs) levels of more than 10 U/L after vaccination compared with 97% of healthy controls. Four patients (8%) had anti-HBs levels of more than 100 U/L compared with 83% in healthy individuals. Mean anti-HBs titre in the 14 responders was 62 U/L compared with 348 U/L in controls. No factor was identified that predicted response to vaccination. One of 49 patients acquired de novo HBV infection at the time of liver transplantation. Current HBV vaccination of cirrhotic patients waiting for liver transplantation is ineffective, and new strategies need to be developed to increase the response rate.

Fulminant hepatitis A in patients with chronic liver disease.

Fulminant hepatitis is a rare complication of acute hepatitis A virus (HAV) infection. We report three cases of fulminant hepatic failure with death due to HAV infection in patients with pre-existing chronic liver disease. Data from the literature also indicate a high case fatality rate during HAV superinfection in patients with chronic hepatitis B, particularly those with cirrhosis, and in patients with alcoholic cirrhosis. In patients with chronic hepatitis C, results are conflicting with some reports indicating a high fatality rate of HAV superinfection and others not, irrespective of the presence or absence of cirrhosis. Based on our observations and this review of the literature, we suggest that patients with chronic liver disease should be vaccinated against hepatitis A.

Prediction of cyclosporine clearance in liver transplant recipients by the use of midazolam as a cytochrome P450 3A probe.

BACKGROUND: Interindividual differences in the kinetics of cyclosporine (INN, ciclosporin) result in part from variations in the activity of cytochrome P450 3A (CYP3A). The biotransformation of midazolam to 1'-hydroxymidazolam is also catalyzed by CYP3A. The objective of this study was to examine the usefulness of midazolam as a CYP3A probe to predict cyclosporine clearance. METHODS: Twenty-six stable liver transplant recipients receiving immunosuppressive therapy with oral cyclosporine (Neoral) were studied. Midazolam (0.015 mg/kg) was administered intravenously and a blood sample was obtained 1 hour later. The plasma concentration of midazolam and 1'-hydroxymidazolam was measured by gas chromatography-mass spectrometry. Blood concentration of cyclosporine was measured by a fluorescence polarization assay. Cyclosporine clearance was calculated as daily dose divided by trough level. RESULTS: There were large interindividual variations in cyclosporine clearance and in midazolam metabolism. Cyclosporine blood levels correlated poorly with dose (r = -0.016). However, there was a significant correlation between cyclosporine clearance and the plasma concentration of 1'-hydroxymidazolam (r = 0.559; P < .001) or the midazolam/1'-hydroxymidazolam plasma concentration ratio (r = 0.668; P < .001). CONCLUSION: Heterogeneity in CYP3A activity contributes to interpatient differences in cyclosporine dosage requirements after liver transplantation. Midazolam metabolism correlated with cyclosporine clearance, but it accounted for only about 40% of the variability in the apparent oral clearance of cyclosporine and this relationship is not tight enough to be useful in the prediction of cyclosporine dosage requirements in the clinical setting.