Insulin glargine provides greater improvements in glycaemic control vs. intensifying lifestyle management for people with type 2 diabetes treated with OADs and 7-8% A1c levels. The TULIP study.

AIM: To determine whether earlier administration of insulin glargine (glargine) vs. the intensification of lifestyle management (LM) improves glycaemic control in type 2 diabetes patients with A1c 7-8% treated with oral therapy. METHODS: TULIP [Testing the Usefulness of gLargine when Initiated Promptly in type 2 diabetes mellitus (T2DM)] was a 9-month, 12-visit, open-label, multinational, multicentre, randomized study to evaluate starting glargine or intensifying LM in T2DM patients aged 40-75 years, body mass index (BMI) 24-35 kg/m2 and A1c 7-8%, treated with maximum doses of metformin and sulphonylurea for > or = 2 years. Glargine was injected once daily (evening) and titrated to fasting blood glucose 0.7-1.0 g/l. In the LM arm, dietary and physical activity counselling recommended stable weight for people with BMI < 27 kg/m2 or weight loss of 3 kg for patients with BMI > or = 27 kg/m2. A total of 215 patients were randomized to glargine (n = 106) or LM (n = 109). The primary objective was patients achieving A1c < 7% at endpoint. Secondary endpoints included changes in A1c, in fasting plasma glucose (FPG), body weight and hypoglycaemia incidence. RESULTS: Two hundred and eleven (52.6% male) patients were randomized and treated; mean (+/- s.d.) age 60.7 +/- 7.9 years, weight 84.5 +/- 13.1 kg, BMI 29.9 +/- 3.5 kg/m2 and A1c 7.6 +/- 0.4%. More patients reached A1c < 7% (66 vs. 38%; p < 0.0001) or < 6.5% (34 vs. 11%; p = 0.0001) with glargine vs. LM. The change in FPG from baseline to study endpoint was significantly greater in the glargine vs. the LM arm (-0.50 +/- 0.47 vs. -0.05 +/- 0.39 g/l respectively; p < 0.0001). Compared with the glargine group, the LM group showed a decrease in weight (+0.9 +/- 2.9 vs. -2.5 +/- 3.2 kg; p < 0.0001), as well as the expected lower symptomatic hypoglycaemia (55.3 vs. 25.0%; p < 0.0001) and nocturnal hypoglycaemia (20.4 vs. 5.6%; p = 0.0016). No significant changes were observed from baseline to study endpoint in any of the lipid parameters tested. CONCLUSIONS: In patients with T2DM with A1c 7-8%, who were previously treated by conventional LM and OAD therapy, adding glargine resulted in greater improvements in glycaemic control vs. intensifying LM.

A call to incorporate the prevention and treatment of geriatric disorders in the management of diabetes in the elderly.

The prevalence of type 2 diabetes increases with age. However, the management of diabetes in the elderly has received surprisingly little attention. Diabetes in the elderly is associated with a high risk of geriatric syndromes including malnutrition and sarcopenia, functional impairments, falls and fractures, incontinence, depression and dementia. Tight glycaemic control for the prevention of vascular complications is often of limited value in the elderly. However, glycaemic control and non-pharmacological therapy may prevent diabetes symptoms and delay geriatric syndromes. The prevention, screening and treatment of both conventional diabetic complications and geriatric syndromes should be integrated in a management plan to optimize the patients' overall health status and quality of life.

Diabetic nephropathy in the elderly.

Renal impairment is frequent in aged diabetic patients, notably with type 2 diabetes. It results from a multifactorial pathogeny, particularly the combined actions of hyperglycaemia, arterial hypertension and ageing. Diabetic nephropathy (DN) is associated with an increased cardiovascular mortality. DN often leads to end stage renal failure (ESRF) which causes specific problems of decision and practical organization of extra-renal epuration in diabetic and aged patients. In the absence of renal biopsy, clinical signs are often insufficient to assess the diabetic origin of a nephropathy in an elderly diabetic patient. Prevention of DN is principally based on tight glycaemic and blood pressure control. The progression of renal lesions can be retarded by strict blood pressure control, notably by blocking of the renin-angiotensin system, if well tolerated in aged patients. It is absolutely necessary to avoid the worsening of renal lesions by potentially nephrotoxic products, notably non steroidal anti-inflammatory drugs (NSAIDs) and iodinated contrast media. At the stage of renal failure, it is important to adapt the antidiabetic treatment, and in the majority of the cases, to switch to insulin when glomerular filtration rate (GFR) is below 30 ml/mn/1.73 m2.

Type 2 diabetes mellitus: epidemiology, pathophysiology, unmet needs and therapeutical perspectives.

In France, prevalence of drug-treated diabetes reached 3.60% in 2005, with 92% of type 2 diabetic patients. In 2007, there are probably nearly 3000 000 diagnosed or undiagnosed diabetic patients. Ageing of the population and increase in obesity are the main causes of this "diabetes epidemic". Type 2 diabetes is a multifactorial disease, defined as resulting from defects in insulin secretion (including abnormalities in pulsatility and kinetics, quantitative and qualitative abnormalities of insulin, beta-cell loss progressing with time) associated with insulin resistance (affecting liver, and skeletal muscle) and increased glucagon secretion. The lack of compensation of insulin resistance by augmented insulin secretion results in rise in blood glucose. To achieve satisfactory glycaemic control in order to prevent diabetes related complications, drug therapy is generally required in addition to life style changes. Currently available oral therapies offer a large panel of complementary drugs, but they have several contraindications and side effects. In spite of major advances in the management of type 2 diabetes, and the strictness of new guidelines, some goals remain unachieved and the new family of insulin-secretors (DPP-IV inhibitors, GLP-1 analogues) should enrich therapeutic approaches.

Thiazolidinediones for the treatment of type 2 diabetes.

Thiazolidinediones (TZD), or glitazones, represent a new generation of antidiabetic drugs that have recently been introduced in Europe. They improve insulin resistance, one of the key anomalies involved in the pathogenesis of type 2 diabetes mellitus, by activating the nuclear peroxoxisome proliferator activated receptor-gamma (PPAR-gamma), leading to crucial metabolic alterations in adipose tissue. Rosiglitazone and pioglitazone have been shown to be active as monotherapy, in combination therapy with metformin or sulfonylureas, and even in triple therapy. They are generally well tolerated but can induce fluid retention. Cardiac failure is a contraindication for the use of TZDs, as is the concomitant administration of insulin. Aside from their effect on glycemic control, TZDs act on several cardiovascular risk factors and may protect pancreatic beta cells from apoptosis. The cardiovascular protective effect of TZDs has recently been demonstrated with the results of the PROactive study, and long-term preservation of beta-cell function is currently under further investigation.

Meglitinide analogues: a review of clinical data focused on recent trials.

Glinides represent a chemically heterogeneous new class of insulin-secreting agents characterized by a rapid onset and short duration of action. They act by closure of the ATP-dependant K channel. Repaglinide, the only glinide available in France, has an equivalent HbA1c lowering effect to conventional sulfonylureas but reduces predominantly postprandial glucose levels. Several studies indicate a decreased risk of hypoglycaemias, particularly nocturnal or in case of a shift or omission of a meal. This drug appears particularly useful in early stage type 2 diabetes or in combination with metformin. The only significant drug-drug interaction concerns gemfibrozil. Due to its hepatic metabolism and biliary elimination, repaglinide can be used in patients with renal insufficiency. Nateglinide has a even shorter duration of action and has almost no effect on fasting plasma glucose levels. For this reason, this drug is only indicated in combination with metformin in the countries where it is licensed. Several experimental data suggest that glinides could preserve B cell function over time better than hypoglycaemic sulfonylureas, and that the improvement of post-prandial glucose levels could exert a long term protective cardiovascular effect.

Hematological response to short-term oral cyanocobalamin therapy for the treatment of cobalamin deficiencies in elderly patients.

OBJECTIVES: The aim of this trial was to demonstrate the efficacy of one month of oral cobalamin (vitamin B12) therapy in elderly patients with cobalamin deficiency related to food-cobalamin malabsorption (FCM). PATIENTS AND METHOD: Twenty elderly patients (mean age: 78+/-17 years) with established cobalamin deficiency related to FCM were included in an open-label, non-randomized, non-placebo trial. They were treated with a maximum of 1,000 microgram per day of oral crystalline cyanocobalamin for at least 1 month. Serum cobalamin levels (primary endpoint), blood count abnormalities and reticulocytes count (secondary endpoints) were determined at baseline and during the first month of treatment. RESULTS: 85% of the patients normalized their serum cobalamin levels with a mean increase of+167 pg/ml (p<0.001 compared with baseline). 100% of the patients corrected their initial macrocytosis and 25% their anemia; 100% of the patients had medullar regeneration with a mean increase of reticulocytes count of 32+/-11.3 x 106/l (p=0.03 compared with baseline). CONCLUSIONS: Our findings support the view that one month of oral crystalline cyanocobalamin is effective to correct serum vitamin B12 levels and to obtain hematological responses in elderly patients with cobalamin deficiency related to FCM.

Management of hypertension in elderly diabetic patients.

Hypertension is a major vascular risk factor in the elderly diabetic. The benefit of proper management is well recognized, even if treatment has no influence on overall mortality or might even tend to increase it in very elderly subjects. Globally, the efficacy of the major classes of antihypertensive drugs, diuretics, beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin II receptor antagonists appears to be equivalent so that the therapeutic choice depends on the type of hypertension, systolic or systolic-diastolic, and the rapidity of the desired effect, co-morbid conditions, particularly coronary or renal disease, or drug tolerance. Blood pressure goals are similar to those in middle-aged persons, except in very old, frail or sick subjects.

[A urachus cyst revealing a torpid Crohn's disease in a young adult with chronic fever]. / Kyste de l'ouraque révélateur d'une maladie de Crohn torpide chez un adulte jeune atteint d'une fievre nue chronique.

INTRODUCTION: This case report describes a rare situation in which a superinfected cyst of the urachus complicated initially unknown and inactive Crohn's disease. CASE: A 21-year-old man presented a chronic fever finally attributed to a superinfected urachal cyst. Six months after ablation of the cyst, progressive Crohn's disease was diagnosed. DISCUSSION: The association of Crohn's disease and a superinfected urachal cyst is extremely rare. The case reported here is original in two aspects: the slowly progressive Crohn's disease was diagnosed after its complication; the superinfection developed through local bacterial translocation (ileal loop adjacent to the urachal cyst).

Clinical pharmacokinetics of cefotiam.

Cefotiam, a semisynthetic parenteral cephalosporin of the aminothiazole group, exhibits interesting properties: stability against hepatic metabolism and excellent solubility, accounting for an apparent volume of distribution 2 to 3 times higher than that of most other cephalosporins. Its degree of protein binding is about 40%. High concentrations of cefotiam are observed in several tissues (kidney, heart, ear, prostate and genital tract) as well as in fluids and secretions (bile, ascitic fluid). In healthy subjects, the serum elimination half-life is about 1 hour. The pharmacokinetics are linear only for doses lower than 1g. Cefotiam is mostly (and rapidly) eliminated in unchanged form in urine; 50 to 70% of the dose is recovered during the 12 hours following administration, and only severe renal failure, with creatinine clearance less than 5 ml/min, significantly alters the elimination half-life. Although the drug has no proven nephrotoxicity in man, a reduction of the dose is recommended when creatinine clearance is less than 30 ml/min.

[Pharmacological treatment of postprandial hyperglycemia]. / Les traitements pharmacologiques de l'hyperglycémie postprandiale.

Every diabetes treatment contributes to the control of postprandial blood glucose, yet some agents more specifically target this goal. Alpha-glucosidase inhibitors, led by acarbose, mainly address postprandial glucose control. These agents inhibit intestinal disaccharidases through a competitive effect and can be used either as the sole treatment or in combination with other antidiabetic drugs. Other agents improve insulin secretion kinetics. This is the case for repaglinide et nateglinide, which are efficient in controlling postprandial blood glucose, and to a lesser degree, fasting blood glucose. These agents shortly and quickly stimulate insulin secretion and should be available soon. In oral therapy secondary failures, trials are currently being conducted to clarify the role of fast-acting insulin analogs, as monotherapy or in combination. Finally, insulin sensitizing agents are being investigated as a way to improve postprandial glucose efflux by potentiating insulin effects. The optimal strategy for the use of these different therapeutic agents remains to be established, as well as their long-term effects on diabetic complications.

[Should type 2 diabetes prevention pharmacological studies prompt us to change our prescription habits?]. / Les études de prévention médicamenteuse du diabète de type 2 doivent-elles nous amener à changer nos prescriptions?

Type 2 diabetes (T2D), a major public health problem in all parts of the world, is preceded by an identifiable phase of impaired glucose tolerance (IGT) during which a therapeutic intervention aimed at preventing the glycaemic decompensation can be considered. The efficacy of a diet resulting in a weight loss and even more of an exercise program has been clearly established, but the long term continuation of these measures is difficult in real life conditions. So, pharmacological interventions on insulin resistance and B cell dysfunction, the major pathophysiologic components of the disease have been tested. A relative risk reduction of conversion from IG to T2D has been obtained with metformin in the Diabetes Prevention Program, but this effect seems to be directly linked to the antihyperglycaemic effect of the drug. Likewise, the relative risk reduction of 25% with acarbose in the Stop-NIDDM trial results more from a short term therapeutic effect than from an action in depth on the mechanisms leading to the glycaemic decompensation. This might does not be the case with troglitazone in the TRIPOD trial, since the protection conferred by this drug largely exceeds the treatment period and the B cell function appears to be preserved. However, these results should be confirmed in larger and more common populations of IGT. Finally, the practical carrying out of a prevention program at the scale of a whole population raises several unsolved problems.

[Thiazolidinediones: clinical data and perspectives]. / Thiazolidinediones: données cliniques et perspectives.

This brief review realizes a synthesis of the main clinical studies of the three thiazolidinediones (TZDs) which have been launched elsewhere, troglitazone, rosiglitazone and pioglitazone. At optimal dose, the three molecules have a similar effect, although slightly weaker for the first, on the fasting plasma glucose and HbA1c levels. They exhibit identical activity, or even higher for troglitazone, in combination with sulfonylureas, metformine and insulin. On the contrary, the three TZDs seem to differentiate according to their effects on lipid metabolism. While rosiglitazone only moderately and inconstantly reduces plasma triglycerides, troglitazone and pioglitazone decreases them by 15 to 25%. LDL-cholesterol levels are almost unaffected by pioglitazone while they increase by 6 to 8% with troglitazone and by more than 10% with rosiglitazone. On the other hand, HDL-cholesterol strongly increases with rosiglitazone and pioglitazone and only slightly on troglitazone. Besides these metabolic effects, TZDs have several properties which could be of therapeutical interest, particularly a possible beta cell protective effect. Except for the severe problems of hepatotoxicity which appear specific to troglitazone and have led to its withdrawal, TZDs are well tolerated. They share as major undesirable effects a risk of peripheral oedema, of anemia due to plasma volume expansion and of weight gain due to the development of subcutaneous adipose tissue. Until now, the European Product licence of rosiglitazone and pioglitazone is limited to the combination with metformin in case of failure of a monotherapy with metformin in obese type 2 diabetic patients and to the combination with a sulphonylurea only in case of intolerance or contra-indication to metformin in type 2 diabetics insufficiently controlled by sulphonylurea therapy at maximal tolerated dose. These indications will probably be enlarged to earlier treatments when long term study results will be available.

Contribution of total and intact proinsulins to hyperinsulinism in subjects with obesity, impaired glucose tolerance or type 2 diabetes.

The recent development of specific radioimmunoassays of insulin (Ins) and proinsulin (PI) led some authors to question the classical data on insulinosecretion in patients with abnormal glucose tolerance. The aim of this work was to determine the participation of intact proinsulin (iPI) and its split fragments to total insulinsecretion in obese subjects and in various stages of glucose intolerance determined by an oral glucose load according to the WHO recommendations. Five groups were constituted: non obese controls (C), obese subjects with normal glucose tolerance (O), non obese subjects with impaired glucose tolerance (I), obese subjects with impaired glucose tolerance (OI) and diabetic patients (D). The basal level of total Proinsulin (tPI) of D and OI was significantly higher than that of C, but the tPI/Ins ratio did not differ between the five groups. After glucose load, this ratio tended to be higher in D, but not significantly. No statistical difference between groups was observed for the iPI/Ins ratio. These results indicate that the determination of tPI is at least as informative or more than that of iPI. Furthermore, the proportionally constant participation of PI to insulin secretion observed in various stages of glucose intolerance suggests that the results obtained in the past with non specific insulin radioimmunoassays remain valid.

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.

Amputations among diabetics in Reunion Island.

OBJECTIVES: Our study allowed us to exhaustively list up all the cases of lower limb amputation carried out in the hospitals of the island from May 1st, 2000 to April 30, 2001. METHODS: We studied the medical files of all the diabetic patients having undergone a non traumatic amputation and they all had an interview with an inquiring doctor. RESULTS: 406 amputations (including 11 traumatic ones) have been carried out over the 12 months of our study. On a total of 395 non traumatic amputations, 70% were made among diabetics and concerned 278 patients among whom 179 are type 2 diabetics. Men are more concerned than women. If the distribution of amputation levels does not differ between diabetics and non-diabetics, the former more often undergo multiple interventions. 72% of the patients have a level of primary education, 59% have difficulties reading, and most of them have a very limited knowledge on their disease and do not practise any prevention for podologic traumatism. CONCLUSION: In a region where 718 220 inhabitants live and where the rate of diabetes prevalence is high (17.7% for 30-69 years), we could be afraid for the years to come of an important increase of the prevalence and diabetes chronic complications incidence rates. Authorities have to become aware of the current risks and of increasing equipments and personnel for the prevention and the follow-up of this insidious pathology. Programmes for the prevention of podologic complications should be supported by taking into account local specificities.

Heterogeneity of diabetes phenotype in patients with 3243 bp mutation of mitochondrial DNA (Maternally Inherited Diabetes and Deafness or MIDD).

OBJECTIVE: In patients with maternally inherited diabetes and deafness (MIDD), due to 3 243 A > G mutation of mitochondrial DNA (mtDNA), diabetes may present with variable phenotypes. OBJECTIVE: To ascertain the existence of two distinct phenotypes, MIDD1 and MIDD2, in a series of patients with MIDD. DESIGN: Multicenter prospective study. PATIENTS: 77 patients with diabetes and the mtDNA 3243 mutation and 139 control patients with type 1 (T1D) or type 2 (T2D) diabetes, matched according to initial presentation of diabetes, age at onset, sex, and duration of diabetes (24 T1D and 115 T2D, including 55 treated with insulin). MEASUREMENTS: Anthropometric characteristics (height, body weight, body mass index [BMI], sex), family history of diabetes, and characteristics of diabetes (age at onset, treatment, hemoglobin A1c [HbA1c]), extrapancreatic manifestations. RESULTS: In 13 cases (17%, MIDD1), diabetes presented as insulin-dependent from the onset, with ketoacidosis in 6 cases. In 64 cases (83%, MIDD2), diabetes resembled T2D, and was treated with diet in 12 cases, oral hypoglycemic agents in 21 cases, or insulin in 31 cases. Compared with patients with MIDD2, patients with MIDD1 were characterized by lower age at onset of first manifestation of MIDD (25.4 +/- 9.6 vs 33.7 +/- 13.2 Years, P<0.0005), lower body weight (49.1 +/- 7.4 vs 56.3 +/- 10.9 kg, P<0.0025), lower BMI (18.2 +/- 2.3 vs 20.9 +/- 3.6 kg/m2, P<0.0005), and higher HbA1c levels (9.5 +/- 2.0 vs 7.5 +/- 1.6%, P<0.0005). Frequency of family history of diabetes and of extrapancreatic manifestations was the same in both MIDD subtypes. No difference was found within the MIDD2 subtype when comparing patients treated with or without insulin. Compared with matched controls, patients with MIDD had a lower BMI (MIDD1/T1D 18.2 +/- 2.3 vs 24.0 +/- 3.6 kg/m2 and MIDD2/T2D 20.9 +/- 3.6 vs 30.2 +/- 5.9 kg/m2, P<0.0025). Lastly, male patients with MIDD had a shorter height than controls (MIDD1/T1D: 166.1 +/- 3.2 vs 177.3 +/- 6.6 cm and MIDD2/T2D: 168.4 +/- 7.2 vs 173.6 +/- 6.6 cm P<0.025). CONCLUSIONS: These results confirm the existence of two different phenotypes in MIDD, MIDD1 and MIDD2, which may be related to the severity of the mitochondrial disease. The role of other genetic and/or environmental factors in the variable phenotype of MIDD remains to be elucidated.

Multicenter randomized evaluation of a nutritional education software in obese patients.

OBJECTIVE: To study the efficacy of the nutritional education software, Nutri-Expert, in the management of obese adult patients. MATERIAL AND METHODS: Two groups of obese patients were followed up over one year in a randomized study: the first group received close traditional management (seven nutritional visits over the year, with physicians and dietitians conjointly) and the second one also used at home by Minitel the Nutri-Expert system. 557 patients were enrolled in the study by 16 French centers of diabetology and nutrition. Body mass index (BMI), tests of dietetic knowledge, dietary records and centralized biological measurements were assessed at inclusion, 6 and 12 months. 341 patients were evaluable at the end of the year. RESULTS: The group using Nutri-Expert scored significantly better in the tests of dietetic knowledge than the control group. For all patients, nutritional education led to a significant improvement in BMI, dietary records and biological measurements, without significant difference between the two groups. Five years after the end of the study, the weight of 148 patients was recorded; mean BMI was significantly lower than the initial value but there was no significant difference between the two groups. CONCLUSION: In the management of obese patients, Nutri-Expert system has a role to play in reinforcing nutritional knowledge; if regular follow-up is not possible, or if a large series of obese patients is to be treated, Nutri-Expert could partly replace traditional management, for example between visits.

Genetically engineered insulin: five years of experience.

Genetically engineered insulin is the first application of recombinant DNA technology which has gone into industrial production and wide clinical use. Four years after the first clinical trials, it appears that there are only minor pharmacokinetic differences from purified pork insulin; in particular, a faster subcutaneous absorption for both regular and NPH forms. The hypoglycaemic potency of genetically engineered insulin is identical to that of purified pork insulin but a weaker effect on counterregulatory hormones has been reported. However, the main advantage of biosynthetic human insulin is its species specificity, which reduces its immunogenicity. Convincing results were obtained in patients suffering from insulin-produced adverse reactions such as insulin resistance or allergy, although biosynthetic human insulin does have some immunological properties and crossreacts with beef or pork insulin antibodies.

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)