Serum protein binding kinetics of phenytoin in monotherapy patients

Objectives: To determine the binding characteristics of phenytoin to serum proteins in the Japanese population and to compare these with those reported by other investigators. Method: Serum samples examined in the study were obtained from 72 patients (35 males, 37 females) receiving phenytoin monotherapy. The patients' ages ranged from 1 to 73 years (1–15 years, 36 subjects; 16–44 years, 20 subjects; 45–64 years, 13 subjects; ≥65 years, 3 subjects). Results: The in vivo population binding parameters of phenytoin to serum proteins and theoretical minimal unbound serum phenytoin fraction ( fu ) were determined using the Scatchard equation. The association constant ( K ) was 0·020 l/μmol, while the total concentration of binding sites ( n ( Pt ) was 556 μmol/l. The number of binding sites per albumin molecule ( n ) was 0·85, while binding ability ( n · K ) was 0·017 l/μmol. The fu was 0·083. The n · K is approximately 1·1 times higher in patients of Pospíšil et al . ( 26 ) (i.e. 0·0191 l/μmol) than in all our patients. The association contant is approximately 1·1 times higher in our study than in the in vitro study of Monks et al . ( 23 ) (i.e. 0·0186 l/μmol), while n is similar between the two studies. The fu in our patients is similar to the unbound serum phenytoin fraction in adult patients receiving phenytoin therapy reported by Richens ( 2) (i.e. 0·1). Conclusion: Our results suggest that there may be small differences in the binding characteristics of phenytoin to serum proteins between Japanese and non-Japanese subjects. The unbound serum fraction of phenytoin in our patients with epilepsy can be assumed to be relatively constant in the therapeutic concentration range of phenytoin.     

Influence of acute viral hepatitis on disposition and pharmacologic effect of warfarin.

Five patients received a small oral dose of warfarin during and after recovery from acute viral hepatitis. Mean (+/- SD) clearance, volume of distribution, and half-life of the drug were 6.1 +/- 0.9 ml/hr/kg, 0.09 +/- 0.04 L/kg, and 23 +/- 5 hr, respectively, during the acute period. After apparent recovery, observed values were 6.1 +/- 0.7 ml/hr/kg, 0.21 +/- 0.02 L/kg, and 25 +/- 3 hr. These differences were not significant. Pattern of renal elimination of warfarin metabolites and drug protein binding did not change between the two phases. During the acute period of illness, prothrombin time increased in 2 of the 5 subjects, but remained within normal limits in all participants during the recovery period. This study shows that warfarin disposition may not change as a consequence of mild or moderate hepatic impairment.     

Isoprinosine in classical acute viral hepatitis.

A prospective double-blind controlled study was performed on the effects of isoprinosine in 81 patients with clinical and histological features of classical acute viral hepatitis. Appetite was assessed daily. Serum alanine aminotransferase, aspartic aminotransferase, and bilirubin levels were assessed weekly. Changes in biochemical parameters, number of deaths, number of patients showing rise of aminotransferase levels despite treatment, and duration required for appetite to return to normal in each group were compared. Observation was continued for 4 weeks. Contrary to preliminary reports, no therapeutic benefit was demonstrated in any of these parameters. We concluded that isoprinosine was ineffective in the acute phase of classical acute viral hepatitis.     

Plasma alpha-lipoprotein pattern in acute viral hepatitis.

In the present study, the plasma levels of lipoproteins, triglycerides, and cholesterol were followed serially in a group of 57 patients with acute viral hepatitis. Mean plasma triglyceride levels were found elevated at the onset of the disease and gradually returned to normal, while mean plasma cholesterol values, low initially, gradually increased, alpha-lipoprotein was absent at the early stage of hepatitis in 41 out of 46 patients with mild or moderate course and reappeared gradually during the course of the disease. In 11 cases of viral hepatitis with impending or overt coma, alpha-lipoprotein was absent for the whole duration of the acute stage and never reappeared in those who eventually died, while it eventually returned to normal in those who survived. The reappearance of alpha-lipoprotein in acute viral hepatitis appears to be a sensitive index of improvement and a significant prognostic sign.     

Aplastic anemia after acute viral hepatitis

The authors describe 4 patients with grave aplastic anemia that developed after acute virus hepatitis. In two cases aplasia occurred at the icteric period of hepatitis, in one during convalescence, and in one 5 months after the recovery from hepatitis. The counter electrophoresis technique failed to reveal the Australian antigen in all the 4 cases. Ninety per cent of patients out of over 200 reported cases of aplastic anemia that developed after acute virus hepatitis died. Of the 4 cases followed up by the authors, 3 patients died. One of the female patients was subjected to splenectomy 3 weeks after the occurrence of grave aplasia with fatty bone marrow with a purpose of immunodepression. Splenectomy entailed a considerable decrease in hemorrhagic diathesis. Later on the patient was treated with caprine antilymphocytic globulin. At present the patient is in a state of remission. The problems of the pathogenesis of aplastic anemia following acute virus hepatitis and potentialities of the disease treatment are under discussion.     

Behavior of gamma-glutamyltranspeptidase in acute viral hepatitis

The value of serum gamma-glutamyltransferase activity has been serially evaluated in 63 patients with acute viral hepatitis at four different periods of the disease (i.e. 0-10, 10-20, 20-30, 30-40 days from the onset of symptoms). The values of serum alanine-aminotransferase, serum alkaline phosphatase and total bilirubin have been evaluated in the same patients at the same period of time. At the first determination the gamma-glutamyltransferase activity was high in acute viral hepatitis, independently from aetiology (A, B, non-A, non-B), although the single values recorded in acute viral hepatitis type non-A, non-B, were higher than those observed in the other types. This activity exhibited a monoesponential pattern of decrease in all types of acute viral hepatitis; and it was still found high in the recovery phase when the others biohumoral indices (alanine-aminotransferase, alkaline phosphatase, total bilirubin) reached a normal level. Therefore gamma-glutamyltransferase activity could be considered of importance in the follow-up of acute viral hepatitis patients, although strictly in conjunction with alanine-aminotransferase, alkaline phosphatase determination.     

Impaired plasma protein binding of phenytoin in uremia and displacement effect of salicylic acid.

The plasma protein binding of phenytoin (DPH) was studied by equilibrium dialysis at 37 degrees C in plasma from uremic patients and healthy subjects. Scatchard plot analyses demonstrated a decreased association constant Ka for the DPH-albumin interaction in the uremic plasma (mean 1.76 - 10(3) M-1 +/-SD 0.12 and a mean 4.10 - 10(3) M-1 +/- SD 0.24 in normal plasma). Studies on separated fractions of serum did not indicate any significant binding of DPH to proteins other than albumin. The nonlinear mathematical relationship between bound DPH and serum albumin could be linearized at low drug concentrations by plotting the ratio of bound/unbound DPH against albumin concentration. The displacement effect of salicylic acid at a concentration of 276 mug/ml (2mM) and DPH was considerable in plasma from normal subjects. In uremic plasma the effect was of much smaller magnitude.     

替比夫定对慢性乙型病毒性肝炎患者血清细胞因子及超敏C反应蛋白的影响

目的探讨替比夫定对慢性乙型病毒性肝炎(乙肝)患者血清细胞因子及超敏C反应蛋白(hs-CRP)的表达的影响。方法选取2011年1月—2012年1月80例接受抗病毒治疗的慢性乙肝患者设为实验组,同时选取60例同期健康体检志愿者设为对照组,检测实验组治疗前后外周血白细胞介素(IL)-2、γ干扰素(IFN-γ)、IL-4、IL-10及hs-CRP的表达水平变化,与对照组比较。结果治疗前实验组血清IL-2、IFN-γ水平显著低于对照组(P0.01),IL-4、IL-10及hs-CRP水平则显著高于对照组(P0.01);治疗后IL-2、IFN-γ水平显著升高,IL-10及hs-CRP水平显著下降(P0.01),与对照组比较,除IFN-γ外,其余各指标差异仍有统计学意义(P0.01)。结论慢性乙肝患者辅助性T细胞(Th)平衡紊乱,Th1分泌的细胞因子下调,Th2呈现优势应答,且机体存在炎症环境,替比夫定抗病毒治疗可有效纠正其免疫紊乱及炎症反应。     

Reaferon treatment in acute HBsAG-positive viral hepatitis

Clinical, biochemical and serological examinations of 412 patients with acute HBsAg-positive virus hepatitis were conducted to assess therapeutic efficacy of Soviet recombinant alpha 2-interferon (reaferon). There were 309 cases of acute virus hepatitis B, 103 of delta infection (71--coinfection, 32--superinfection). The study and control groups were assigned randomly. Reaferon i.m. administration started on jaundice day 1-5 and lasted for 10-11 days. The treatment proved effective in acute hepatitis B running a moderately severe and severe course up to the development of acute hepatic encephalopathy. In delta infection reaferon produced response in coinfection only. In fulminant hepatitis the treatment was uneffective.     

Ultrasound evaluation of uncomplicated and complicated acute viral hepatitis

Seven hundred ninety-one consecutive patients with acute viral hepatitis, 17 of whom had liver failure, and 97 healthy volunteers were examined by ultrasound. No specific patterns were found in either the uncomplicated or the complicated forms. Only 19 subjects showed a typical "bright liver" pattern, which is correlated with significant vacuolar hepatocellular degeneration. The increased brightness and clear visualization of portal vein radicle walls, previously described in this disease, were detected in only 32.2% of the hepatitis patients but were also seen in 30.9% of the normal controls.     

Influence of protein binding on therapeutic efficacy of cefoperazone.

The effect of protein binding of cefoperazone (89.3% bound to rabbit serum) on antibacterial activity in serum was tested in a model that simulated a closed-space infection in a neutropenic host. Four gram-negative bacilli were tested in the model with cefoperazone doses of 20 and 200 mg/kg administered intramuscularly every 6 h for 16 doses. Cefoperazone efficacy was measured at 92 h by determining the log10 decrease in bacterial count from that of the control for five paired studies with three isolates. A significantly better response was demonstrated when the free (non-protein-bound) drug concentration exceeded the MICs and MBCs for the infecting microorganisms at the infection site at all times (P less than 0.005). This supports the concept that free (unbound) drug is the active component in treating bacterial infections.     

Serum albumin binding capacity values in the clinical evaluation of endogenous intoxication in acute viral hepatitis

The fluorescence technique was used to determine the effective albumin concentration (EAC) and albumin binding reserve (ABR) in 130 patients with acute viral hepatitis A and B in order to establish their values in the evaluation of endogenous intoxication (EI). The most considerable EAC and ABR reduction was found in patients with previous comorbidity and with negative responsiveness changes underlying a high baseline EI level. Despite the resolution of the clinical symptoms of intoxication, the long existence of EAC and ABR changes in the course of the disease in these patients is associated with the tension of the body's key systems in impaired somatic regulation and determines the increased consumption of defense reserves and their rapid exhaustion. Thus, the informative value of the study biochemical parameters of EI increased within the multifactor system of its clinical evaluation.     

Nuclear deformity of hepatocytes in acute viral hepatitis

Nuclear deformity of hepatocytes was measured using two parameters, the form factor and the axial ratio, in liver biopsy specimens from 29 patients with acute viral hepatitis (AVH). Another 13 patients with chronic persistent hepatitis (CPH) were added as control. Nuclear deformity of hepatocytes was morphometrically confirmed to increase in AVH compared to that in CPH. This was related to the regeneration of hepatocytes.