Pharmacodynamic Modeling for Change of Locomotor Activity by Methylphenidate in Rats

Purpose. The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed. Methods. MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis. Results. The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (K_i) of MPD for DA reuptake was estimated to be 41.3 ± 73.8 nM (mean ± SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model. Conclusions. The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may be useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.     

Pharmacobezoar complicating treatment with sodium alginate

We encountered a gastric bezoar that had developed in a 9-year-old girl treated with sodium alginate (Alloid G) for acute gastritis associated with systemic lupus erythematosus. A hard mass palpated in the left upper abdomen proved, upon gastric endoscopy, to be an intragastric foreign body. Sodium alginate was detected in an analysis of a sample from this bezoar. In an in vitro simulation, sodium alginate solidified when mixed with the patients other medicines. The bezoar caused no complications, and disappeared spontaneously after discontinuation of the medications. This case indicates that this sodium alginate preparation, Alloid G, can be a cause of pharmacobezoar.     

Clinical Characteristics of Portal Hemodynamics in Alcoholic Liver Cirrhosis

Background: Low incidence of reversal blood flow at the portal vein has been reported by measurement in larger and extrahepatic blood vessels but not in intrahepatic blood vessels in patients with liver cirrhosis. Moreover, there is little information regarding the incidence of reversal blood on the basis of the cause of liver cirrhosis. The aim of this study was to measure the reversal blood flow in the portal vein including intrahepatic branches in patients with alcoholic and viral cirrhosis.
Methods: The blood flow in the portal vein and existence of portosystemic shunt were studied in 52 and 27 patients with alcoholic and viral cirrhosis, respectively, by Doppler ultrasonography. The parameters of liver function test and the prevalence of ascites and esophageal varices were compared between patients with and without reversal blood flow.
Results: Reversal blood flow at the portal vein was found only in patients with only alcoholic cirrhosis (17 of 52 patients) but not in any patients with viral cirrhosis (0 of 27 patients; p < 0.05). The incidence of portosystemic ascites and red color of esophageal varices was also higher in patients with alcoholic cirrhosis with reversal blood flow in the portal vein compared with patients without reversal blood flow ( p < 0.05).
Conclusions: Reversal blood flow in the portal vein is a characteristic feature of alcoholic cirrhosis. The presence of reversal blood flow indicates severe liver diseases, and this feature may have prognostic importance for patients with alcoholic cirrhosis.     

Pneumothorax after diagnostic laparoscopy

Here we want to call laparoscopist's attention to pneumothorax after diagnostic laparoscopy. Diagnostic laparoscopy has less complications, compared with laparoscopic surgery. In our experience, only one case (0.04%) developed pneumothorax during routine diagnostic laparoscopic procedure. This complication is presented in a 50-year-old female. She complained of dyspnea just after the decrease of intraabdominal pressure and deflation of intraperitoneal gas. The chest roentgenogram showed a right pneumothorax, and a right chest tube was inserted with immediate relief of tension. Pneumothorax during diagnostic laparoscopy is relatively rare but a major complication; Medline literature research showed six reported cases of pneumothorax after diagnostic laparoscopy from 1983 to 1998 including our case. The etiology was idiopathy in 5 and diaphragmatic injury in 1. Hypotension, elevation of inspiratory pressure, dyspnea, a decrease in systemic oxygen saturation, and loss of breath sounds suggest tension pneumothorax. The clinical condition of the patients improved rapidly because of the easy diffusion of the gas used in laparoscopy. Diagnostic laparoscopists should be aware of this complication and treat ventilatory problems.     

Osteodystrophy in patients with chronic hepatitis and liver cirrhosis

Bone mineral density (BMD) of the lumber vertebrae and factors related to bone metabolism were determined in patients with chronic viral hepatitis and patients with liver cirrhosis to clarify correlations between hepatic dysfunction, considered to be one of the causes of hepatic osteodystrophy, and decrease in bone mass. BMD of the second to fourth lumbar vertebrae was determined with a Lunar (Madison, WI, USA) DPX, a dual-energy X-ray absorptiometry diagnostic system. BMD was significantly lowest in patients with liver cirrhosis, followed by patients with chronic hepatitis, and healthy subjects, in this order. There was a significantly positive but weak correlation between albumin and BMD. Levels of 25(OH)D and 1,25(OH)₂D were significantly lower in patients with liver cirrhosis than in those with chronic hepatitis. BMD and vitamin D were decreased in all patients whose cholinesterase (ChE) was below 0.3ΔpH. Urinary pyridinoline(Upyr) was significantly higher in the patients with liver cirrhosis, in whom bone mass was decreased, than in the patients with chronic hepatitis, whereas serum osteocalcin levels were distributed in the upper normal range in patients with chronic hepatitis and those with liver cirrhosis. There was a positive correlation between 25(OH)D and serum osteocalcin levels in patients with liver cirrhosis. These results indicate that osteogenesis is decreased and suggest that the decrease in BMD which occurs in viral liver cirrhosis, probably related to decreased, bone formation and slight promotion of bone resorption, reflects deranged hepatic function. This is the first report of Upyr and urinary deoxypyridinoline (UDpyr) determination in patients with liver cirrhosis and patients with chronic hepatitis. The negative correlation of Upyr and UDpyr with ChE is a novel finding.     

Neurotoxicodynamics of the Interaction between Ciprofloxacin and Foscarnet in Mice

The potential for convulsions induced by the coadministration of ciprofloxacin (CPFX) and foscarnet (PFA) may be due not to a change in the distribution of CPFX to the brain but to a potential CPFX-induced inhibition of γ-aminobutyric acid (GABA)-GABA_A receptor binding in the presence of PFA.     

Content and classification of clinical trials at a university hospital in Japan

"Standards on the Implementation of Clinical Trials on Drugs (New GCP)" is a Japanese government policy established in April 1998 with the aim of satisfying scientific and ethical requirements for industry-sponsored research, i.e., registration-directed clinical trials and clinical trials intended to support reexamination or reevaluation applications. Since then, efforts for more effective implementation of clinical trials have been promoted, including establishment of a system to invite more active participation of subjects in clinical trials and improvement of a network of medical institutions conducting clinical trials. These efforts should help to reactivate clinical trials in Japan, which reportedly have become stagnant. Although the New GCP addresses the quality of industry-sponsored clinical trials, investigators also construct study protocols without industry involvement. We reviewed clinical trials submitted by investigators at Gunma University Hospital to institutional review boards (IRBs) from June 1999 to February 2002. Ten clinical research coordinators contributed to the present survey. A total of 151 investigator-initiated clinical trials reviewed included a wide variety of content; and investigators from many institutions and organizations conducted trials. Most of the ethical guidelines for approving proposed trials represented the provisions of the Declaration of Helsinki. However, additional guidelines prepared by the Japanese Ministry of Health, Labour and Welfare were also helpful. Development of a support system for clinical trails requires the contribution of clinical research coordinators. Flexible management and careful attention to both the protocol and its execution by the investigators were also important for promoting clinical trials on the basis of meticulous patient care.     

Immuno-gene therapy with adenoviruses expressing fms-like tyrosine kinase 3 ligand and CD40 ligand for mouse hepatoma cells in vivo

Introduction of genes encoding immuno-stimulatory cytokines into cancer cells is known to enhance antitumor immunity. CD40 ligand (CD40L, CD154) and fms-like tyrosine kinase 3 ligand (Flt3L) are recently identified cytokines, which have been demonstrated to stimulate antitumor immunity in several cancer models. However little is known about antitumor activity of Ftl3L and CD40L against hepatocellular carcinoma (HCC). In the present study, we constructed replication-defective adenoviruses expressing Flt3L and CD40L and examined their therapeutic efficacy on mouse HCC, MH134 cells. Subcutaneous injection of MH134 cells genetically engineered to express Flt3L and/or CD40L developed tumors in all the syngeneic immunocompetent mice, but tumor growth was significantly delayed as compared to control mice. Partial inhibition of this antitumor effect in athymic nude mice suggests that both innate and adaptive immunity appear to play a role. It was shown by immunodepletion of NK cells with anti-asialo-GM1 antibody that the effector cells involved in innate immunity are NK cells. In a therapeutic setting, however, injection of adenovirus expressing Flt3L or CD40L into pre-established MH134 tumors exhibited no efficacy. These data demonstrate that Flt3L and CD40L induce significant, but only weak, antitumor immunity against MH134 cells presumably through both innate and adaptive immunity. Our results suggest that immuno-gene therapy with Flt3L and CD40L may need adjuvant modalities to achieve strong immune response.     

Pharmacokinetic/pharmacodynamic analysis of anti-hyperprolactinemic effect of terguride based on dopamine D2 receptor occupancy

Terguride has been widely used for the treatment of hyperprolactinemia via partial agonistic action on dopamine D2 receptors in the pituitary. The present study analyzed retrospectively the dopamine D2 receptor binding occupancy (phi) of terguride. The average phi value was estimated to be 14.1% after oral administration of the average/standard therapeutic dose of terguride. Taking the intrinsic activity (alpha) into consideration, the value of alpha. phi was 2.33%. These results suggest that the antihyperprolactinemic effect of terguride was elicited despite the low receptor occupancy. Furthermore, we developed a pharmacokinetic/pharmacodynamic model for ascertaining the serum prolactin-lowering effect of terguride, considering both the reversible binding to D2 receptors and the effect on the increase rate in the prolactin level. The developed model fit well with the actual data. Although this model could be improved, it could explain the long duration of the antihyperprolactinemic activity of terguride and might be useful for designing its rational dosage regimen.     

Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects

Objective Losartan is metabolized to the active carboxylic acid metabolite EXP3174 by CYP2C9. In this study, we determined the effects of the single CYP2C9*3 variant on the pharmacokinetics and pharmacodynamics of losartan.Methods Seven healthy Japanese subjects (CYP2C9*1/*1, n=4 and CYP2C9*1/*3, n=3) were phenotyped with a single dose of losartan (25 mg). Blood and urine samples were collected and assayed for losartan and EXP3174. Blood pressure and pulse rate were also measured using a sphygmomanometer.Results The maximum plasma concentration of EXP3174 was significantly (P<0.05) lower in the CYP2C9*1/*3 (n=3) group than in the CYP2C9*1/*1 (n=4) group. Diastolic blood pressure in the CYP2C9*1/*1 group, but not that in the CYP2C9*1/*3 group except for at 6 h and 8 h, was reduced from 1.5 h to 12 h compared with the baseline level. Systolic blood pressure in the CYP2C9*1/*1 group, but not that in the CYP2C9*1/*3 group, was reduced from 1 h to 12 h compared with the baseline level. The metabolic ratio (MR) of EXP3174 concentration to the losartan concentration in plasma at 6 h post-dosing and the 4-h to 8-h urinary EXP3174/losartan MR were significantly lower in the CYP2C9*1/*3 group than in the CYP2C9*1/*1 group. The plasma 6-h MR and the 4-h to 8-h urinary MR were significantly (P<0.05) correlated with the plasma AUC ratio (AUC_EXP3174/AUC_losartan), with Spearman rank correlation coefficients of 0.75 and 0.89, respectively.Conclusion The single CYP2C9*3 variant reduces the metabolism of losartan and its hypotensive effect. Plasma MR, as well as urine MR, may be useful for phenotyping assays of CYP2C9 activity.