Clinical and pharmacokinetic study of praziquantel in Egyptian schistosomiasis patients with and without liver cell failure.

The pharmacokinetics and therapeutic efficacy of praziquantel (Distocide; Epico, El-Asher-Men-Ramadan City, Egypt) were studied in 40 patients with schistosomiasis mansoni and various degrees of hepatic dysfunction. The patients were allocated into four groups: the first included 10 patients with simple active schistosomiasis while the other three were made up of patients with schistosomiasis associated with liver cirrhosis and splenomegaly according to Child's classification of hepatocellular function. Every patient was treated with 40 mg/kg of praziquantel as a single oral dose. The efficacy of the drug was evaluated after two months by rectal snip examination. The pharmacokinetic parameters did not differ significantly between patients with simple active schistosomiasis (group 1) and those with hepatosplenomegaly with liver involvement but without ascites and jaundice (group 2). However, as liver cell dysfunction became more evident (groups 3 and 4), pharmacokinetic parameters of praziquantel such as the half-life of elimination, the half-life of absorption, the maximum concentration, the time to maximum concentration, and the area under the concentration-time curve increased proportional to the degree of hepatic insufficiency. Linear correlations were found between each of the these parameters on the one hand and hepatic function test results (total bilirubin, direct bilirubin, and serum albumin) on the other. In spite of these pharmacokinetic differences, the cure rates were 70%, 80%, 90%, and 90% in the four groups, respectively. Although the incidence of side effects was high (53%), such effects were transient and mild.

Pharmacokinetics of aztreonam in patients with liver cirrhosis and ascites.

The pharmacokinetics of aztreonam were studied in six healthy male subjects (group I) and 12 male patients with post-hepatitis liver cirrhosis and ascites. Patients were allocated into two groups according to serum creatinine; group II included nine patients with serum creatinine. < or = 15 mg/L while group III included three patients with serum creatinine > 15 mg/L. Aztreonam 1 g was given as iv bolus injection. Aztreonam reached a peak concentration in the ascitic fluid (AF) of 6.2 +/- 2.3 mg/L at 4 h, and of 8.7 +/- 4.4 mg/L at 6 h in groups II and III respectively. The level of the drug in AF 24 h post-dosing was still higher than MIC90 for Enterobacteriaceae in most patients. The half-life of elimination from serum increased significantly (P > 0.001) from 1.82 +/- 0.14 h in group I to 6.6 +/- 2.1 h and to 8.87 +/- 0.2 h in groups II and III, respectively. Both the central and the terminal volumes of distribution were higher in cirrhotic patients than in healthy volunteers. Liver cirrhosis and ascites resulted in a significant increase (P < 0.001) of the total body clearance (Cl) of aztreonam from 84 +/- 8 mL/h/kg in group I to 209 +/- 87 mL/h/kg in group II. However, the concomitant association of mild renal impairment in group III abolished this increase; Cl in group III was 122 +/- 50 mL/h/kg. The AUC0-infinity serum was 137.5 +/- 12.2, 78.5 +/- 24.9 and 151 +/- 42 mg.h/L in groups I, II and II, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of cefodizime in patients with liver cirrhosis and ascites.

The pharmacokinetics of cefodizime were studied in 6 healthy male volunteers (group A) and 6 patients with liver cirrhosis and ascites (group B) receiving 1 g of the drug as an i.v. bolus. Cefodizime was assayed in serum and ascitic fluid (AF) samples by a microbiological assay. The serum concentration-time curve fitted a two-compartment open model in group A and a three-compartment open model in group B. Initially, the serum level of cefodizime in group A exceeded that in group B for about 10 h; thereafter the reverse occurred until 24 h post-dosing. Cefodizime penetrated rapidly into the AF, reaching a peak at 6 h, and its AF level was still above the MIC90 for Enterobacteriaceae in most patients at 24 h post-dosing. The half-life of distribution did not differ significantly between the two groups, while the elimination half-life was prolonged significantly (p < 0.001) from 2.7 +/- 0.2 h in group A to 5.4 +/- 0.8 h in group B. The central volume of distribution (Vc) did not differ significantly in the two groups, while the terminal volume of distribution (Vp) was significantly smaller (p < 0.01) in group A (0.172 +/- 0.30 l/kg) than in group B (0.55 +/- 0.20 l/kg). The area under the serum concentration-time curve (AUC0-infinity serum) was significantly larger (p < 0.001) in group A [322 +/- 34 (micrograms/ml).h than in group B (180 +/- 34 (micrograms/ml).h]. The area under the AF concentration-time curve (AUC0-infinity ascites) in group B was 141 +/- 37 (micrograms/ml).h.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of ceftazidime in patients with liver cirrhosis and ascites.

The pharmacokinetics of ceftazidime were studied in 18 male individuals, including six healthy volunteers and 12 patients with liver cirrhosis and ascites. Each participant received 1 g of ceftazidime as a single intravenous bolus injection. The elimination half-life was longer in cirrhotic than in control patients (5.40 +/- 1.02 h) vs. (1.98 +/- 0.24 h), P less than 0.01; probably due to slow return from the ascitic compartment. Nevertheless, total body clearance did not differ significantly between the two groups (81.4 +/- 30.3 ml/h/kg vs. 83.6 +/- 24.9 ml/h/kg). Dose reduction is not necessary when treating systemic infection in cirrhotics. Ceftazidime attained a concentration of 1 microgram/ml in the ascitic fluid in most patients 15 to 30 min after the injection, and maintained this level, which is higher than the MIC90 of Enterobacteriaceae, for 24 h. An intravenous bolus injection of 1 g ceftazidime every 24 h is sufficient to treat patients with spontaneous bacterial peritonitis caused by a susceptible organism other than Pseudomonas aeruginosa.

Re-evaluation of the value of ascitic fluid pH lactate dehydrogenase and total proteins in the diagnosis of spontaneous bacterial peritonitis (SBP).

In view of high mortality, variable clinical presentation, and late results of bacterial culture, early diagnosis of SBP and treatment are based on indirect parameters of infection. Forty-two patients with ascites and liver cirrhosis were studied. Ascitic fluid (AF) was examined for total protein content, pH, lactate dehydrogenase, amylase, absolute polymorphonuclear cell count (PMN) and for presence of bacteria by examining a fresh smear of the deposit and culture of the fluid under aerobic and anaerobic conditions. AF/serum gradient of total proteins and LDH was calculated. One patient proved to have a malignant ascites and was excluded. The remaining 41 patients fell into two groups: Group I PMN less than 250 cell mm-3, culture negative, sterile ascites, 36 patients. Group II PMN greater than 250 cell mm-3. (a) Culture positive neutrophilic ascites (SBP), three patients. (b) Culture negative neutrophilic ascites (CNNA), two patients. In both CNNA and SBP:AF/serum total LDH gradient greater than 0.75 In the sterile group: AF/serum total LDH gradient less than 0.58 There was no correlation between presence of infection and ascitic fluid pH, protein content and AF/serum total protein gradient. Therefore AF PMN greater than 250 mm and AF/serum total LDH gradient greater than 0.6 should be considered reliable, indirect parameters of infection, and CNNA a variant of SBP with a small bacterial inoculum size.