Comparison of the effect of levodopa and bromocriptine on naloxone-precipitated morphine withdrawal symptoms in mice

In this study, the effect of l-dopa and bromocriptine on morphine withdrawal syndrome was compared. Both l-dopa (125, 250 mg/kg, i.p.) and low doses of bromocriptine (0.04, 0.08 mg/kg, i.p.) potentiated naloxone-induced morphine withdrawal symptoms such as jumping, climbing and rearing in mice. Higher doses of bromocriptine (0.16, 0.32 mg/kg, i.p.) attenuated these naloxone-induced symptoms. SKF 83566, D(1) dopamine antagonist (0.4, 0.8 mg/kg, i.p.) and sulpiride, D(2) dopamine antagonist (5, 10 mg/kg, i.p.) when used alone, also produced inhibitory effects on naloxone-induced morphine withdrawal symptoms. Pretreatment with sulpiride (5, 10 mg/kg, i.p.) and SKF 83566 (0.4, 0.8 mg/kg, i.p.) attenuated the potentiating effects of l-dopa on withdrawal symptoms significantly. Pretreatment with sulpiride also decreased the potentiating effect of bromocriptine and reinforced the inhibitory action of it, but SKF 83566 pretreatment just reinforced the effect of higher doses of bromocriptine. Concurrent pretreatment of animals with sulpiride (10 mg/kg, i.p.) and SKF 83566 (0.8 mg/kg, i.p.) markedly decreased the potentiating effects of l-dopa and bromocriptine and reinforced the inhibitory action of bromocriptine on the naloxone-induced morphine withdrawal syndrome. Prazosin, alpha(1) antagonist (1, 2 mg/kg, i.p.) decreased the naloxone-induced morphine withdrawal syndrome significantly. Pretreatment with yohimbine, alpha(2)-antagonist (5 mg/kg, i.p.) reversed the inhibitory effects of bromocriptine (0.16, 0.32 mg/kg, i.p.) on naloxone-induced morphine withdrawal syndrome significantly. In conclusion, our results show that bromocriptine at lower doses (0.04, 0.08 mg/kg, i.p.) acts similar to l-dopa, but at higher doses (0.16, 0.32 mg/kg, i.p.) shows different effects on naloxone-induced morphine withdrawal syndrome which may be due to the interaction of bromocriptine with alpha-adrenoceptors. Copyright 2000 John Wiley & Sons, Ltd.     

Carzelesin phase II study in advanced breast, ovarian, colorectal, gastric, head and neck cancer, non-Hodgkin's lymphoma and malignant melanoma: a study of the EORTC early clinical studies group (ECSG)

Purpose: In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed. Patients and methods: Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 μg/m². A total of 140 patients were entered and a total of 285 courses were administered. Results: In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen. Conclusions: At this dose and schedule carzelesin did not yield activity in the types of tumors studied. Received: 8 December 1999 / Accepted: 10 April 2000     

Dipeptidyl(amino)peptidase IV and aminopeptidase M metabolize circulating substance P in vivo.

Recent studies have demonstrated that Fischer-344 rats from Japanese Charles River Inc. specifically lack dipeptidyl(amino)peptidase IV (DAP IV-negative; EC 3.4.14.5), whereas Fischer-344 rats from sources within the United States (DAP IV-positive) possess normal DAP IV activity. In the present study, plasma from DAP IV-positive rats metabolized substance P (SP) (5.37 +/- 0.25 nmol/min/ml) via the actions of angiotensin-converting enzyme (EC 3.4.15.1) (1.86 +/- 0.50 nmol/min/ml) and DAP IV (2.56 +/- 0.42 nmol/min/ml). DAP IV sequentially converted SP to SP[3-11] and SP[5-11]. The SP[5-11] metabolite was then rapidly hydrolyzed by plasma aminopeptidase M (AmM; EC 3.4.11.2) (36.2 +/- 4.2 nmol/min/ml). In contrast, SP metabolism by plasma from DAP IV-negative rats was less than half that of control animals (2.14 +/- 0.06 nmol/min/ml), due to a complete lack of DAP IV hydrolysis. The absence of DAP IV was not associated with any differences in angiotensin-converting enzyme-mediated hydrolysis of SP (1.45 +/- 0.11 nmol/min/ml) or AmM-mediated hydrolysis of SP[5-11] (37.1 +/- 0.9 nmol/min/ml). Consistent with this deficiency in SP metabolism, SP was more potent in vivo in stimulating salivary secretion in DAP IV-negative rats compared to DAP IV-positive animals. Potentiation was specific in that SP[5-11], an SP fragment resistant to DAP IV, was equipotent in DAP IV-negative and positive animals. SP[5-11]-induced salivary secretion was potentiated in both strains when AmM-mediated hydrolysis was inhibited by amastatin (20 nmol/min, i.v.). These data provide direct evidence for a significant role for DAP IV and AmM in the in vivo processing of SP and active SP metabolites.     

Cholecysto-hydatid cyst fistula.

A 27-year-old woman developed recurrent hydatid of liver. CT scan showed unilocular cysts in segments IV and VII. Intraoperatively, there was a fistulous communication between the gall bladder and the cyst in segment IV. Partial pericystectomy along with cholecystectomy was done for the segment IV cyst; percutaneous aspiration, instillation and re-aspiration using hypertonic saline was done for the cyst in segment VII. This was followed by albendazole treatment.     

Variable effects of weight loss on serum lipids and lipoproteins in obese patients

After a 500 calorie diet and 6 months of low fat, maintenance diet, weight, serum lipid, and lipoprotein levels were compared to baseline in 46 obese patients. Mean weight decreased by 25.9 percent (29.2 kg). Mean total (TC) and low density lipoprotein cholesterol (LDL-C), and triglycerides (TG) decreased by 5.5 percent (12.1 mg/dl), 11 percent (15.5 mg/dl) and 23.6 percent (34.5 mg/dl); mean high density lipoprotein cholesterol (HDL-C) increased by 20.6 percent (10.3 mg/dl) and TC/HDL-C decreased by 25 percent (1.2), P less than 0.01. Females and males had equal increases in HDL-C. The decrease in TG and TC in patients who continued to lose 4.2 kg during the 6 month maintenance period was significantly greater than in those who regained 7.8 kg (P less than 0.015). Greater changes in HDL-C and TC/HDL-C occurred in younger individuals (r = -0.35 and r = -0.37); in those with more abnormal initial values (r = -0.60, r = 0.64); and for HDL-C, a larger increase occurred in those with greater weight loss (r = 0.32; P less than 0.04).     

The role and value of oral metronidazole in acute appendicitis

A prospective, randomized study was undertaken in 246 patients 4 – 15 years of age with simple or complicated appendicitis and local peritonitis to determine the efficacy of oral metronidazole (OM) threrapy. Those referred on odd days were chosen as the study group (SG) and those on even days as a control group (CG). The SG received OM 10 mg/kg per dose 2 h preoperatively and every 8 h after operation according to the following intraoperative findings: inflamed (mild to severe), 3 doses; gangrenous or perforated with no pus, 3 days, the same with pus, 5 days. The CG received 20 mg/kg cephalexin 2 h before operation and, if the appendix was inflamed, 6-hourly for 3 doses postoperatively. The routine combination in our center of penicillin, chloramphenicol, and gentamicin was given to the patients in the CG with complicated appendicitis, as in the SG, for 3 or 5 days. All cases with generalized peritonitis were excluded from the study. Serum concentrations of metronidazole after one postoperative dose were in the bactericidal range in 18 of 20 patients in whom the measurement was performed. The incidences of wound infection and intraabdominal abscess were quite similar in both groups with the same degree of pathology. However, in patients with complicated appendicitis the hospital stay in the SG was about 1 day less than in the CG. Moreover, hospital costs per patient day were less in the SG. We conclude that OM is a cost-effective drug, more convenient for the patient and nursing staff, and can be used as an effective antibiotic even in complicated appendicitis.     

Differential requirements for co-stimulatory signals from B7 family members by resting versus recently activated memory T cells towards soluble recall antigens

The interaction between CD28 on T cells with CD80 (B7-1) andCD86 (B7-2) on APCs is considered to be of critical importancefor primary T cell activation both in vivo and in vitro. Therelative importance of this co-stimulatory signal in memoryT cell activation is, however, less clear, and was thereforestudied by in vitro experiments on T cell responses to solublerecall antigens using peripheral blood mononuclear cells orT cell clones. Our data demonstrate that B7-2 represents themajor co-stimulatory signal for the activation of resting peripheralblood memory T cells with recall antigens, as evidenced by theeffects of anti-B7-1 and anti-B7-2 on T cell proliferation aswell as on IL-2 and INF-y production. Since CTLA-4-lg and anti-CD28Fab fragments had similar inhibitory effects to the combinationof anti-B7-1 plus anti-B7-2, the involvement of a third co-stimulatoryCD28/CTLA-4 ligand is unlikely. Despite the strong effects ofB7-blocking agents, a variable fraction of the memory T cellswas resistant to inhibition. Moreover, T cell clones or in vitropreactivated T cells could efficiently be restimulated by solubleantigens on autologous APCs in the absence of B7-1 or B7-2 co-stimulation.These data show that most memory T cells that are freshly isolatedfrom the blood are still dependent on CD28 triggering for theiractivation. However, recently activated T cells can apparentlybypass the requirement for B7 and use other co-stimulatory signalsfor reactivation, a finding with important implications forthe development of immunosuppressive strategies.     

Familial fatal Parkinsonism with alveolar hypoventilation and mental depression.

The clinical, pathological, and neurochemical characteristics of a newly recognized inherited neurological disorder are reported. Lethargy and mental depression are early symptoms, followed by mild parkinsonism and progressive weight loss. Failure of automatic respiratory control develops and may result in sudden death. Advanced degeneration of the substantia nigra, cell loss and gliosis of the basal ganglia, and focal gliosis in the medulla are seen on pathological study. Degeneration of the nigrostriatal dopaminergic system is evidenced by low levels of tyrosine hydroxylase, dopamine, homovanillic acid, and L-dopa decarboxylase in postmortem brain samples. Taurine concentrations in fasting plasma and CSF are somewhat depressed; brain contents of taurine are within normal limits.