Inflammatory changes in the urogenital tract and therapeutic possibilities in the course of adjuvant disease in the male rat

The adjuvant disease of the rat is an experimental disease, not only important as an arthritis model, but also as an "urethritis model" in clinical and therapeutical respects. The polyarthritic syndrome in rats following injection of Freund's adjuvant also shows regularly involvement of the genitourinary system. Urethritis, cavernitis, and balanitis are common inflammatory manifestations of the penis, which can mostly be observed. In the peritesticular and periepididymal fat, granulomata and nonspecific inflammatory reactions do occur. Prostata, bladder, kidneys, testes, and epididymis are seldom involved in the inflammatory process. This therapeutical study demonstrated clearly that acetylsalicylic acid (dosage: 80 mg/kg BW/day) cannot be of benefit for these changes. However, it was possible to significantly influence the inflammatory changes by using prednisolone (dosage: 1.5 mg/kg BW/day).     

Health care partnerships must be accountable, based on data

A successful health-care partnership with employers depends on agreeing to goals and measures of success as well as sharing a wide range of clinical and claims information. The following case study tells how Twin County Community Hospital, the only hospital in Galax, VA met the demands of a group of employers for better service, lower costs and a more stable relationship, even though it had what it describes as good relations with the community and a long-standing tradition of minimal pricing.     

Interferon gamma and interleukin 10 levels in preimplantation embryo culture media

Purpose The aim of our study is to elucidate whether human oocyteslembryos secrete IFN and/or IL-10 and whether the fertilization process depends on the balance between these cytokines.Methods A total of 142 embryo culture media from 24 patients were collected and the cytokine levels were tested with ELISA.Results IFN and IL-10 were detectable in 40.1% and 29.6% of culture media respectively. The difference of IFN and IL-10 levels in media from fertilized oocytes between day 1 and day 2 are significant (0.46 vs. 1.47 and 34.2 vs. 12.7, respectively). However there was no significant difference between the IFN levels of the media from fertilized and nonfertilized oocytes 0.46 vs. 0.85 at day 1 and 1.47 vs. 1.49 at day 2, as well as IL-10 levels 34.2 vs. 30.9 at day 1 and 12.7 vs. 9.58 at day 2 respectively.Conclusions Human preimplantation embryos secrete the cytokines IFN and IL-10. No effect of these cytokines on fertilization process could be shown.Presented at the IXth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction, April 3–7, 1995, Vienna, Austria.     

Treatment guidelines for primary nonretentive encopresis and stool toileting refusal

Nonretentive encopresis refers to inappropriate soiling without evidence of fecal constipation and retention. This form of encopresis accounts for up to 20 percent of all cases. Characteristics include soiling accompanied by daily bowel movements that are normal in size and consistency. An organic cause for nonretentive encopresis is rarely identified. The medical assessment is usually normal, and signs of constipation are noticeably absent. A full developmental and behavioral assessment should be made to establish that the child is ready for intervention to correct encopresis and to identify any barriers to success, particularly disruptive behavior problems. Successful interventions depend on the presence of soft, comfortable bowel movements and addressing toilet refusal behavior. Daily scheduled positive toilet sits are recommended. Incentives may be used to reinforce successful defecation during these sits. A plan for management of stool withholding should be agreed on by the parents/caretakers and the family physician before intervention.     

CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding

Metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors characterized by a large, extracellular N-terminal domain comprising the glutamate-binding site. In the current study, we examined the pharmacological profile and site of action of the non-amino-acid antagonist 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt). CPCCOEt selectively inhibited glutamate-induced increases in intracellular calcium at human mGluR1b (hmGluR1b) with an apparent IC50 of 6.5 microM while having no agonist or antagonist activity at hmGluR2, -4a, -5a, -7b, and -8a up to 100 microM. Schild analysis indicated that CPCCOEt acts in a noncompetitive manner by decreasing the efficacy of glutamate-stimulated phosphoinositide hydrolysis without affecting the EC50 value or Hill coefficient of glutamate. Similarly, CPCCOEt did not displace [3H]glutamate binding to membranes prepared from mGluR1a-expressing cells. To elucidate the site of action, we systematically exchanged segments and single amino acids between hmGluR1b and the related subtype, hmGluR5a. Substitution of Thr815 and Ala818, located at the extracellular surface of transmembrane segment VII, with the homologous amino acids of hmGluR5a eliminated CPCCOEt inhibition of hmGluR1b. In contrast, introduction of Thr815 and Ala818 at the homologous positions of hmGluR5a conferred complete inhibition by CPCCOEt (IC50 = 6.6 microM), i.e., a gain of function. These data suggest that CPCCOEt represents a novel class of G protein-coupled receptor antagonists inhibiting receptor signaling without affecting ligand binding. We propose that the interaction of CPCCOEt with Thr815 and Ala818 of mGluR1 disrupts receptor activation by inhibiting an intramolecular interaction between the agonist-bound extracellular domain and the transmembrane domain.     

The N-terminal domain of gamma-aminobutyric Acid(B) receptors is sufficient to specify agonist and antagonist binding.

The recently identified gamma-aminobutyric acid type B receptors (GABA(B)Rs) share low sequence similarity with the metabotropic glutamate (mGlu) receptors. Like the mGlu receptors, the N-terminal extracellular domain (NTED) of GABA(B)Rs is proposed to be related to bacterial periplasmic binding proteins (PBPs). However, in contrast to the mGlu receptors, the GABA(B)Rs lack a cysteine-rich region that links the PBP-like domain to the first transmembrane domain. This cysteine-rich region is necessary for the PBP-like domain of mGlu receptors to bind glutamate. To delimit the ligand-binding domain of GABA(B)Rs, we constructed a series of chimeric GABA(B)R1/mGluR1 and truncated GABA(B)R1 receptor mutants. We provide evidence that despite the lack of a cysteine-rich region, the NTED of GABA(B)Rs contains all of the structural information that is necessary and sufficient for ligand binding. Moreover, a soluble protein corresponding to the NTED of GABA(B)Rs reproduces the binding pharmacology of wild-type receptors. This demonstrates that the ligand-binding domain of the GABA(B)Rs can correctly fold when dissociated from the transmembrane domains.     

A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion

In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m²/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m². Both plasma concentrations achieved during infusion (r² = 0.9) and area under the curve (AUC) (r² = 0.8) were proportional to increase in dose (p < 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m². Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.     

Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkin's lymphoma

Summary Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m² of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 g/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m² with a relatively large apparent volume of distribution at steady-state of 1012 l/m² indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.