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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

[Present status in the treatment of type 2 diabetes mellitus. Insulin-secreting agents].

The functional defect of the pancreatic beta cell represents one of the main therapeutic targets in type 2 diabetes mellitus. Among the currently available oral antidiabetic drugs, only hypoglycaemic sulfonylureas exhibit beta cell stimulating properties. However, their use has some limits, particularly those related to the risk of hypoglycaemia and the frequent secondary therapeutic failure. These drugs have largely contributed to the knowledge of the mechanisms of insulin secretion. Besides some galenic modifications of existing sulfonylureas and the development of new drugs of this family with original properties, like glimepiride, the research is essentially focused on drugs derived from the non sulfonylurea moiety of some sulfonylureas, particularly the meglitinide family, which will probably be available for the clinician in the near future. These drugs act however grossly by the same mechanism than sulfonylureas, even if their binding site on a protein coupled with the ATP sensitive K channel appears different. Among the other possible approaches suggested by the theoretical data concerning the mechanisms of insulin secretion, GLP-1 derivatives probably represent good candidates, if stable analogues are developed.

Adenosine Triphosphate↗
PubMed1999

[Current status of the treatment of type 2 diabetes mellitus. The revival of insulin-resistance drugs].

The relief of insulin resistance is one of the two therapeutic targets of the treatment of type 2 diabetes. Insulin-sensitizers are therefore complemental with other oral diabetic drugs. The treatment of insulin resistance was for a long time limited to dietary and exercise programmes, a biguanide, metformine, and benfluorex, a phenylethylamine derivative; the mechanisms of action of both drugs are now better understood and their indications more precisely targeted. A new therapeutic class, the thiazolidinediones (troglitazone, rosiglitazone, pioglitazone) has recently completed the family of insulin-sensitizing agents. These drugs, which should be soon available in France, act by a different way than metformin, which has been recently identified as the peroxisomes proliferator-activated receptor. The role of antilipolytic agents, which might increase glucose uptake by reducing free fatty acid production and oxidation is under evaluation, as well as the potential benefit of orlistat, an inhibitor of lipid digestion which has been proved effective, in addition to hypocaloric diet, in the management of obese patients.

Administration, Oral↗
PubMed1999

[Current status of the treatment of type 2 diabetes mellitus. Alpha-glucosidase inhibitors].

The development of antidiabetic drugs with complementary mechanisms of action appears more and more necessary in order to achieve durable glycaemic control in type 2 diabetes. By inhibiting in a reversible way the hydrolysis of disaccharides and the ultimate steps of the digestion of dietary polysaccharides, alpha-glucosidase inhibitors reduce postprandial blood glucose raise in diabetics. This therapeutic class, limited in Europe until recently to acarbose, has been enlarged with the marketing of miglitol, whose pharmacokinetic properties might lead to better long term tolerance. The improvement of glycaemic control obtained with alpha-glucosidase inhibitors is now better evaluated and appears similar whatever the combinations with other antidiabetic drugs, including insulin. The role of alpha-glucosidase inhibitors in the overall therapeutic strategy of type 2 diabetes and their benefit on the evolution of long term complications remains to be clarified.

1-Deoxynojirimycin↗
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↗
PubMed1999

[Biliary diffusion of tazocillin in man].

The objective of this study was to determine the extent of biliary excretion of tazocillin, a combination of piperacillin and tazobactam administered as an intravenous infusion in a dose of 4 g of piperacillin and 0.5 g of tazobactam. In 10 patients, piperacillin and tazobactam levels were determined in serum, main bile duct bile, gallbladder bile, and gallbladder wall specimens harvested during a cholecystectomy procedure 1 h after completion of a tazocillin infusion. In five other patients, piperacillin and tazobactam levels were determined in bile collected from a main bile duct T-tube during 12 h following a tazocillin infusion given seven days after cholecystectomy. HPLC was used to assay both compounds. Piperacillin and tazobactam levels in the intraoperative specimens were as follows: 69.1 +/- 13.8 and 9.9 +/- 1.7 micrograms/ml, respectively, in the serum; 630 +/- 133 and 11.9 +/- 2.2 micrograms/ml, respectively, in the main bile duct bile; 342 +/- 114 and 7.7 +/- 2.3 micrograms/ml, respectively, in the gallbladder bile; and 49.3 +/- 20.2 and 2.9 +/- 0.6 micrograms/g, respectively, in the gallbladder wall. In the T-tube bile specimens, peak piperacillin and tazobactam levels were 358 +/- 281 and 9.9 +/- 3.3 micrograms/ml, respectively, after 1 h; total biliary excretion over 12 hours was 28.3 +/- 18.0 mg and 1.0 +/- 0.5 mg, i.e., 0.7 +/- 0.4% and 0.2 +/- 0.1% of the dose, respectively. The levels of piperacillin and tazobactam found in bile and gallbladder wall specimens in this study suggest that tazocillin may prove valuable for the prevention and treatment of biliary infections.

Bile↗
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↗