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Biomedical subjects

J M Brogard

Publications and source records attributed to J M Brogard.

At least 19 recordsLinked to original sources
PubMed1999

Biliary tract infections: a guide to drug treatment.

Initial therapy of acute cholecystitis and cholangitis is directed towards general support of the patient, including fluid and electrolyte replacement, correction of metabolic imbalances and antibacterial therapy. Factors affecting the efficacy of antibacterial therapy include the activity of the agent against the common biliary tract pathogens and pharmacokinetic properties such as tissue distribution and the ratio of concentration in both bile and serum to the minimum inhibitory concentration for the expected micro-organism. Antimicrobial therapy is usually empirical. Initial therapy should cover the Enterobacteriaceae, in particular Escherichia coli. Activity against enterococci is not required since their pathogenicity in biliary tract infections remains unclear. Coverage of anaerobes, in particular Bacteroides spp., is warranted in patients with previous bile duct-bowel anastomosis, in the elderly and in patients in serious clinical condition. In patients with acute cholecystitis or cholangitis of moderate clinical severity, monotherapy with a ureidopenicillin--mezlocillin or piperacillin--is at least as effective as the combination of ampicillin plus aminoglycoside. In severely ill patients with septicaemia, an antibacterial combination is preferable. Therapy with aminoglycosides, mostly for Pseudomonas aeruginosa-related infections, should not exceed a few days because the risk of nephrotoxicity seems to be increased during cholestasis. Relief of biliary obstruction is mandatory, even if there is clinical improvement with conservative therapy, because cholangitis is most likely to recur with continued obstruction. Emergency invasive therapy is reserved for patients who fail to show a clinical response to antibacterial therapy within the first 36 to 48 hours or for those who deteriorate after an initial clinical improvement. Immediate surgery is indicated for gangrenous cholecystitis and perforation with peritonitis. Long-term administration of antibacterials is required for recurrent cholangitis, as seen in bile duct-bowel anastomosis. Oral cotrimoxazole (trimethoprim/sulfamethoxazole) is the preferred agent. Wound infection rates after biliary tract surgery can be significantly reduced by preoperative administration of prophylactic antibacterials. Newer generation beta-lactams have not proven to be of greater benefit than older agents such as cefuroxime or cefazolin. Antibacterial prophylaxis before endoscopic retrograde cholangiopancreatography (ERCP) should be reserved for patients with obstructive jaundice, since the risk of infectious complications seems to be strongly associated with this clinical condition. Failure to achieve full biliary drainage is the most important factor in predicting septicaemia, and prophylaxis should be prolonged until the bile duct is unobstructed. Piperacillin, cefazolin, cefuroxime, cefotaxime and ciprofloxacin are effective for this indication.

Acute Disease↗
PubMed1998

Short-term variations of serum glycated apolipoprotein B.

Serum glycated apolipoprotein B (apo B-G) levels were determined in 31 non-insulin-dependent diabetic patients and 13 control subjects by an enzyme-linked immunosorbent assay. Apo B-G was increased in diabetic patients compared to non-diabetic subjects, whether expressed as a serum concentration (57.7 vs 36.1 mg/l) or a percentage of total apolipoprotein B (4.42 vs 3.14%). Apo B-G, together with other markers (mean daily plasma glucose, serum fructosamines, triglycerides, total cholesterol, glycated haemoglobin), was measured before and after 5 days of therapeutic adjustment in diabetic patients. In 20 patients with a favourable course of glycaemic control, the mean decrease of apo B-G concentration reached nearly 16%. In 11 patients with an unfavourable course, the increase of apo B-G concentration was about 14%. Therefore, variation of serum apo B-G concentration could serve as an additional short-term marker for glycaemic control, although possible concomitant variations of serum triglycerides or total apolipoprotein B concentrations should also be considered.

Aged↗
PubMed1998

[New therapies in type 2 diabetes].

The progress of knowledge relating to non-insulin-dependent diabetes mellitus (NIDDM) is associated with new therapeutic developments. Their different respective targets allow to classify them in drugs stimulating insulin secretion (glimepiride, repaglinide, glucagon-like peptide 1), medications reducing insulin resistance (thiazolidinediones) or in insulinmimetic agents (vanadium). Alpha glucosidase inhibitors, available in France since 1993, constitute another therapeutic approach, reducing postprandial hyperglycemia by delaying the digestion of complex carbohydrates. These new medications, safer and sometimes effective in a single daily administration, represent an alternative to classic oral antidiabetic agents allowing therapeutic combinations and a more global management of NIDDM.

Diabetes Mellitus, Type 2↗
PubMed1997

Assessment of biliary excretion of piperacillin-tazobactam in humans.

Piperacillin-tazobactam concentrations in serum and bile were measured intraoperatively in 10 patients undergoing cholecystectomy (group 1) and 5 cholecystectomized patients provided with external bile duct drainage (group 2). Each patient received a single intravenous dose of piperacillin at 4 g plus tazobactam at 0.5 g over 30 min. Drug concentrations in both serum and bile were measured by high-performance liquid chromatography. In group 1 patients, serum and bile specimens and gallbladder wall fragments were collected at mean times of 70 and 83 min postinfusion, respectively. The mean concentrations of piperacillin and tazobactam were, respectively, 69.1 +/- 41.5 (standard deviation) and 9.9 +/- 5.1 microg/ml in serum, 630.4 microg/ml (range, 24.8 to 1,194 microg/ml) and 11.8 microg/ml (range, 3.6 to 22 microg/ml) in choledochal bile, 342.3 microg/ml (range, 1.1 to 1,149 microg/ml) and 7.7 microg/ml, (range, 0.2 to 23.1 microg/ml) in gallbladder bile, and 49.3 microg/g (range, 9.7 to 223 microg/g) and 2.9 microg/g (range, 0.1 to 5.9 microg/g) in the gallbladder wall. In group 2 patients, the amounts of drugs recovered in bile drainage obtained over 12 h were 28.4 +/- 18.0 and 1.0 +/- 0.5 mg for piperacillin and tazobactam, respectively. Peak piperacillin and tazobactam concentrations in bile reached 358 +/- 242 and 10.8 +/- 4.2 microg/ml, respectively. Comparison of drug levels in serum and bile suggests an underlying active secretion process for piperacillin elimination into the bile, unlike that of tazobactam. From a therapeutic viewpoint, given the concentrations of tazobactam recorded in bile fluid and tissue, the addition of this beta-lactamase inhibitor to piperacillin therapy might be of interest in the management of biliary tract infections, mostly in patients at risk of mixed aerobic-anaerobic infections due to beta-lactamase-producing organisms.

Adult↗
PubMed1997

Drug administration in chronic liver disease.

Cirrhosis encompasses a range of pathophysiological changes that may alter drug disposition. Drugs that are dependent primarily on the liver for their systemic clearance are more likely to be subject to reduced elimination and subsequent accumulation. Drug accumulation may lead to excessive plasma drug concentrations and adverse effects, if the adverse effects of the drug are concentration-dependent. The effects of hepatic insufficiency on the pharmacokinetics of drugs are not consistent or predictable. Furthermore, the influence of hepatic disease on the disposition of various drugs can vary, even though those drugs may share the same apparent metabolic pathway. Problems in forecasting drug kinetic behaviour are further enhanced by the additional impairment of kidney function (frequently encountered in patients with advanced liver disease) and by the unpredictability of the glomerular filtration rate using customary methods in patients with cirrhosis. Accordingly, dosages are generally adapted empirically, with the help of serum drug concentrations, when applicable. However, drugs eliminated predominantly by hepatic metabolism are not among those most commonly inducing adverse drug reactions or causing severe complications in patients with cirrhosis. Electrolyte disturbances and the hepatorenal syndrome produced by furosemide (frusemide)-the disposition of which is not substantially modified in liver disease-appear to be the most frequent adverse drug reactions in patients with liver disease. Furthermore, clinically significant alterations in the action of medications at concentrations generally considered to be in the normal therapeutic range are not uncommon. Tissue responsiveness to the pharmacological action of some drugs may be modified, as evidenced by the increased susceptibility of the brain in patients with cirrhosis to the action of many psychoactive agents. Another example is the greater susceptibility of such patients to the nephrotoxic potential of aminogly-cosides, which should not be used in this patient group. Drugs may also interfere with adaptive physiological processes induced by liver disease. ACE inhibitors and nonsteroidal anti-inflammatory drugs counteract the enhanced activity of the renin-angiotensin system in advanced liver disease, thereby generating a high risk of excessive hypotension or acute renal failure, respectively. These drugs are best avoided in patients with cirrhosis. Finally, there may be pharmacological effects that overlap with some pathophysiological modifications related to the process of liver disease, such as increased portal pressure produced by some calcium antagonists, or hypoprothrombinaemia related to the inhibition of synthesis of vitamin K-dependent clotting factors by some beta-lactam antibacterials (especially moxalactam and cefamandole). Accordingly, the use of these drugs should be avoided in advanced liver disease. It is noteworthy that reduced drug metabolism in patients with liver disease does not seem to have a significant impact on the frequency of hepatotoxicity. Special caution should be exercised, however, in patients with alcoholic liver disease because excessive alcohol intake may potentiate the hepatotoxic effect of paracetamol (acetaminophen).

Adverse Drug Reaction Reporting Systems↗
PubMed1996

[Refsum disease].

Refsum's disease, firstly described almost 50 years ago by the Norvegian neurologist Sigvald Refsum, is an autosomic recessive disease affecting mostly the Scandinavians and the populations originating from Northern Europe. The disease results from a specific enzyme deficiency of the first step of phytanic acid catabolism pathway. This deficiency leads to an accumulation of this C20 fatty acid in the serum and the tissues with a preference for adipose tissue, liver and kidneys. The clinical picture includes retinitis pigmentosa, peripheral neuropathy, ataxia and elevated cerebrospinal fluid protein concentration. Other less frequent manifestations include cranial nerves deficiency, myocardiopathy, renal tubular dysfunction and ichtyosis. The diagnosis relies on serum phytanic acid measurement. The treatment consists of a phytanic-acid free diet sometimes associated with plasmapheresis. This treatment is generally effective on neuropathy but not on cranial nerves dysfunction and retinitis pigmentosa.

Humans↗
PubMed1995

Amoxicillin intestinal absorption reduction by amiloride: possible role of the Na(+) -H+ exchanger.

Intestinal absorption of beta-lactam antibiotics has been shown to use the dipeptide carrier system. In vitro experiments have established that the efficiency of uptake by enterocytes depends on an inwardly directed proton gradient--dipeptides and beta-lactam antibiotics being cotransported along with hydrogen ion. This gradient is thought to result from the sodium-hydrogen (Na(+)-H+) exchanger located on the brush-border membrane. The aim of the present study was to assess the in vivo relevance of these data in humans by examining the effect of amiloride, a well-known inhibitor of the Na(+) -H+ exchanger, on the bioavailability of amoxicillin in eight healthy volunteers. The results show that amiloride reduces significantly amoxicillin absorption rate (mean time to maximum concentration increases from 1.0 to 1.6 hours, p < 0.05) and absolute bioavailability (by 27%, p < 0.01) and that amiloride-induced inhibition of the intestinal Na(+) -H+ exchange could be associated with an additional inhibitory effect on (Na/K)-ATPase activity. The present data seem to confirm the role of Na(+) -H+ exchange in the uptake of beta-lactams by the intestine and to support the indirect sodium dependence of this carrier system in vivo.

Adult↗
PubMed1995

[Etiopathogenesis of non-insulin-dependent diabetes].

Two major mechanisms, peripheral insulin resistance and impaired insulin secretion participate concomitantly but to a variable extent to the pathogenesis of non-insulin-dependent diabetes, whose heterogeneity, suspected for a long time, is now confirmed by the recent discoveries of the molecular biology. Mutations of several genes governing key-steps of the recognition of the glucose signal, insulin secretion or its peripheral effect have been found in some particular cases, but presently not at a large scale among non insulin-dependent diabetic patients. The tendency to worsening of the metabolic disturbances with the time, even under adequate therapy, can be explained by the vicious circle of glucose toxicity, but other mechanisms like amylin, responsible of the deposition of amyloid in the islets, may play a role. So, despite the acquisition of many new knowledges, the pathogenesis of non-insulin-dependent diabetes keeps nowadays a part of its mystery.

Diabetes Mellitus, Type 2↗
PubMed1995

[Assessment of the role of enterocyte ion exchange in the intestinal absorption of amoxicillin, based on a study of the interaction with amiloride].

Intestinal dipeptide carrier system has been shown in vitro to be involved in intestinal absorption of betalactam antibiotics. Given that efficiency of this transport system depends on a pH gradient (extracellular pH < intracellular pH) at the brush-border membrane of enterocytes, we assessed the effects of amiloride, a known inhibitor of the Na-H exchange, on the bioavilability of oral amoxicillin in eight normal volunteers. Following a single 10 mg oral dose of amiloride, the absolute bioavailability of oral amoxicillin turned out to decrease by 27% (p < 0.01). The extent of reduction of oral amoxicillin AUC appeared to significantly correlate (p = 0.005) with the extent of decrease in potassium renal excretion but not with variations in antibiotic renal clearance under amiloride effect. Such patterns seem to confirm in vivo the role of the Na-H exchange in betalactam absorption and to suggest the underlying regulatory function of intracellular Na concentration, the latter depending on the (NaK)-ATPase activity.

Administration, Oral↗
PubMed1994

Hepatic side-effects of antibiotics.

Although the liver is particularly exposed to drugs and their metabolites, hepatic side-effects of antibiotics are far less frequent than other adverse effects such as gastrointestinal disorders or cutaneous reactions. However, the potential severity of hepatic side-effects for some drugs is stressed. Antibiotic related liver injuries cover most of the clinical and pathological expressions of hepatic dysfunction, including cytotoxic hepatitis (isoniazid), intrahepatic cholestasis (macrolides, penicillins, clavulanic acid), mixed hepatitis (sulphonamides), chronic active hepatitis (nitrofurantoin), or microvesicular steatosis (tetracycline). In most cases, toxicity is idiosyncratic, reactions occurring only in some susceptible individuals. The mechanisms underlying toxicity may be primarily metabolite-dependent (isoniazid), hypersensitivity-mediated (beta-lactams), or result from both processes (sulphonamides, erythromycin derivatives). In some cases, the liver is not the primary target organ for toxicity but appears to mediate the clinical expression of some adverse effects induced by antibiotics. The most significant example of this is hypoprothrombinaemia due to the inhibition of hepatic gamma-carboxylation of vitamin K-dependent clotting factors by sulphydryl group-containing cephalosporins. Inhibition of bilirubin conjugation or transport by rifampicin or fusidic acid may also be viewed as hepatic side-effects of antibiotics. Ascertaining the casual relationship of a given drug to an hepatic adverse effect may prove particularly difficult, because of the potential contribution of host status and concurrent medications. Diagnosis is based mainly on circumstantial evidence, i.e. the temporal relationship between drug administration (or withdrawal) and the time-course of liver dysfunction. Improving morbidity related to drug hepatotoxicity relies on a free flow of information between manufacturers and practitioners in order to optimize detection of potentially serious liver damage, and advances in pharmacogenetics toward a better identification of those at particular risk for developing drug-related liver toxicity.

Animals↗
PubMed1994

Biliary elimination and hepatic disposition of an association of piperacillin and tazobactam: experimental evaluation.

Biliary elimination and hepatic disposition of tazocillin, an association of a highly bile-excreted ureido-penicillin, piperacillin, with a beta-lactamase inhibitor, tazobactam, have been assessed applying an isolated perfused rabbit liver experimental model. Six investigations were performed, each during a 3 h period, using reconstituted blood circulating in a closed circuit. Piperacillin and tazobactam concentration in all specimens were determined by high performance liquid chromatography. Blood samples and cumulative bile secretion were collected every 30 min, and liver fragments were isolated at the end of each experiment for dosage purposes. Following the simultaneous administration of piperacillin 80 mg and tazobactam 10 mg (dose ratio 8/1) in the perfusion device, theoretical initial serum concentrations were respectively 414 micrograms/ml and 32.1 micrograms/ml. Maximal biliary concentrations of 4431 +/- 1541 (s.d.) of piperacillin and 21.3 +/- 7.8 micrograms/ml of tazobactam were reached between 0.5-1 h and 2.5-3 h, respectively. Cumulative biliary excretion (0-3 h) amounted to 37.6 +/- 17.7% of the administered dose for piperacillin and 1.5% for tazobactam. At the end of the perfusion, respectively 22.1% and 50.7% of piperacillin and tazobactam doses remained in the circulating blood, while 1.1% and 5.6% were found in the liver. On the basis of these data, the calculated percentages of piperacillin and tazobactam doses having undergone hepatic biotransformation, were 6.5% and 1.2%, respectively. Under such experimental conditions, concentrations and excretion of piperacillin in bile prove to be substantial. Of note, tazobactam concentrations turn out to be stable both in serum and in bile whereas they stay at a relatively constant level of 20 micrograms/ml during nearly all the perfusion time.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

[Evaluation of the participation of proinsulin in hyperinsulinism in patients with obesity and glucose intolerance].

The comparison of the results of two insulin assays, a RIA using a polyclonal antibody and a EMIA using two monoclonal antibodies in blood samples collected during an oral glucose load in normal, obese, glucose intolerant and type II diabetic patients indicated that hyperinsulinemia of obese and glucose intolerant patients is not associated to increased proinsulin/insulin ratio.

Adult↗
PubMed1993

Role of intrahepatic protein binding in the hepatobiliary extraction profile of cefixime in humans.

The hepatobiliary extraction profile of cefixime, a dianionic cephalosporin antibiotic, was studied in 10 patients, each of whom was provided with T-tube drainage of his or her common bile duct after cholecystectomy. After a single 200 mg oral dose, cefixime biliary clearance proved to be nonlinear, mostly in its initial phase, which is consistent with a concentrative uptake and intracellular protein binding for the drug. The latter process appears to be saturable and to operate at a rate that correlates with the total amount of cefixime recovered in the 24-hour bile drainage. Such findings seem to confirm the significant role played in vivo by hepatic ligandin in the hepatobiliary extraction of organic anions. The data also show that a single 200 mg oral dose of cefixime yields drug levels in bile substantially higher than the minimal inhibitory concentrations for the most frequent Enterobacteriaceae in biliary tract infections. Accordingly, this cephalosporin could be an interesting alternative in both prophylaxis and treatment of biliary tract infections.

Bile↗