Protective effects of FK506 against glutamate-induced neurotoxicity in retinal cell culture

Nanomoles of neuropeptide Y (NPY) and noradrenaline (NA), administered i.v. to pentobarbital-anesthetized rats, caused nearly equipotent dose-dependent pressor responses in normotensive rats. However, in renovascular Goldblatt hypertensive rats, the dose-response curves for both NPY and NA were significantly displaced to the left, approximately threefold. Intravenous administration of BIBP 3226 (30-180 microg/kg) did not consistently lower blood pressure, per se, but did evoke competitive antagonism of the NPY pressor response in both rat populations. The magnitude of the NPY antagonism evoked by BIBP 3226 was comparable in normotensive and hypertensive rats. The absence of NA antagonism demonstrates the selectivity of the BIBP 3226 blockade.     

Protective effect of hyperin against myocardial ischemia and reperfusion injury

AIM: To study the protective and antiperoxidative effects of hyperin (hyperoside; quercetin-3-O-galactoside; Hyp) on myocardial ischemia/reperfusion. METHODS: The rabbit anterior descenging branch of left coronary artery was occluded for 60 min and then released to allow reperfusion for 20 min. Hemodynamics (LVP, LV +/- dp/dt) and electrocardiogram (ECG, lead II) were monitored continuously with polygraph. After reperfusion, the blood sample and myocardium were taken to assay plasma creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and cations in myocardium. Using a Langendorff system, the isolated heart of rat was initiated by ischemia for 40 min followed by 30 min of reperfusion. Malondialdehyde (MDA) contents of cardiac effluent and myocardium were measured with fluorescence spectrophotometer. RESULTS: Hyp 10 mg.kg-1 i.v. depressed changes in LVP, LV +/- dp/dtmax, ECG, plasma CPK, LDH, and cations (Ca2+, Mg2+, Na+) in myocardium induced by ischemia/reperfusion in rabbits. Hyp 10 and 100 mumol.L-1 markedly reduced the increase in MDA production in isolated rat hearts after ischemia/reperfusion. CONCLUSION: Hyp possesses a protective effect against myocardial ischemia/reperfusion injury via attenuating lipid peroxidation.     

The enhanced immunosuppressive efficacy of newly developed liposomal FK506 in canine liver transplantation

Local delivery of immunosuppressants to the graft and lymphatic tissue is a potential appraoch to enhance the immunosuppressive efficacy and to alleviate systemic adverse effects simultaneously. By taking advantage of this method, we developed liposomal FK506. Previous pharmacokinetic study of liposomal FK506 indicated increased FK506 levels in the liver and spleen. Because the liver is the site of the allograft in liver transplantation and the spleen is a major lymphoid tissue, we hypothesized that liposomal FK506 would increase immunosuppressive efficacy in liver transplantation. We evaluated this hypothesis in a canine model. Orthotopic liver transplantation was performed using beagle dogs, and the recipients were divided into the following groups: group I, no immunosuppression (n = 5); group II, 0.05 mg/kg/day of FK506 i.v. in a commercially available i.v. formulation for 14 days (n = 5); and group III, 0.05 mg/kg/day of FK506 i.v. in a liposomal formulation for 14 days (n = 5). All recipients in group I died within 2 weeks. Recipients in group II died within 33 days. In contrast, three recipients in group III survived for more than 200 days (P < 0.05 versus group I or group II). In DNA analysis, splenocyte proliferation activity in group III was significantly suppressed in comparison with group II. These results suggest that liposomal FK506 markedly increase the immunosuppressive efficacy of FK506 in liver transplantation. A local immunosuppressive effect in the grafted liver and significant suppression of splenocyte proliferation might contribute to enhancement of the immunosuppressive efficacy of liposomal FK506.     

Pharmacokinetics of tacrolimus (FK506) in primary orthotopic heart transplant patients

STUDY OBJECTIVES: Local recurrence is high when sublobar resection is chosen as primary management of stage I non-small cell lung carcinoma. Postoperative external-beam radiotherapy may reduce this local recurrence problem. A technique of intraoperative brachyradiotherapy following thoracoscopic wedge resection is described as an alternative to adjuvant external-beam radiotherapy for high-risk patients who are not candidates for pulmonary lobectomy. PATIENTS: Fourteen patients with significant impairment in cardiopulmonary function having small peripheral solitary pulmonary nodules underwent video-assisted thoracoscopic (VATS) wedge resection and were found to have non-small cell cancer. Surgical margins were pathologically clear and mediastinal nodes were benign-stage I (T1NO). INTERVENTIONS: A custom polyglyconate mesh (Vicryl) containing 125I seeds was applied to pulmonary resection margins following wedge resection of peripheral lung cancers. A total dose of 100 to 120 Gy at 1 cm was applied to the target area. RESULTS: All patients had histologically clear surgical margins. Postoperative dosimetry confirmed adequate resection margin coverage. There was neither operative mortality nor morbidity related to the VATS wedge resection or the brachytherapy implants. Implants did not migrate, and there were no cases of significant radiation pneumonitis or local recurrence at mean follow-up of 7 months (range, 2 to 12 months). CONCLUSIONS: Intraoperative brachytherapy appears to be a safe and efficient alternative to external-beam radiation therapy when adjuvant radiotherapy is considered following therapeutic wedge resection of stage I (T1NO) lung cancers. The impact on local recurrence, disease-free interval, and survival will require additional follow-up.     

Protective effects of taurine against reperfusion-induced arrhythmias in isolated ischemic rat heart

The usefulness of computed tomography (CT) in the diagnosis of fish bone impaction in the oesophagus was evaluated. Thirty-two patients were examined by plain X-ray followed by direct oesophagoscopy for suspected fish bone impaction. Among 25 cases in which fish bones were actually removed, foreign bodies were not clearly demonstrated by plain X-ray in 14 cases (56 per cent). Eleven cases underwent CT prior to the oesophagoscopic examination. Fish bones were clearly demonstrated by CT in all patients. CT also clearly visualized secondarily-induced inflammatory changes in the neighbouring structures. In order to confirm this result, we made a simulation model of oesophageal fish bone impaction, using fish bones of three different species surrounded by a water bag. In comparison with plain X-ray, CT depicted a superior image of fine fish bones and provides extremely useful information for the management of impacted fish bones in the oesophagus.     

Effect of xinmaitong capsule on damage of lipid peroxidation in coronary heart disease patients with myocardial ischemia

The authors show the results of the "Curricular Evaluation Program" of University of S?o Paulo Medical School pertaining to the year of 1996. This program (PAC-II) is based on teachers' opinions regarding the subjects taught (1st to 4th grades) and hospital intern courses. The opinions collected concerning such programs were definitely favorable. Most of the teachers considered the programs to be either good or very good. It was also identified that the hospital intern courses were a little more valued than the other courses taught in the first four grades.     

Evidence that SMS 201-995 enhances the immunosuppressive effect of FK506

Somatostatin (SS) was originally described as a growth hormone release inhibiting factor synthesised in the hypothalamus. Recently, SS and its receptor (SSTR) have been demonstrated in lymphoid tissues and seem to play a regulatory, largely inhibitory, role in immune responses. The aim of the present study was to check the immunosuppressive effect of a SS derived peptide, the octreotide (SMS 201-995) and to verify whether this molecule acted synergistically with FK506. An immunosuppressive effect of SMS was observed on the proliferation of rat spleen cells induced in vitro, either by polyclonal mitogens such as PHA or by alloantigens. With PHA stimulation, 10(-14) M SMS significantly enhanced the immunosuppressive action of 0.00001 microg/ml FK506. The addition of SMS in MLR (10(-11)-10(-9)M) increased the antiproliferative effect of both 0.0001 microg/ml and 0.00001 microg/ml FK506. In consideration of the extremely low concentration of both drugs that was required to obtain a good immunosuppression in vitro, we verified the association of FK506 and SMS in vivo in an allogeneic skin graft model that used Lewis (Lew) rats as donors and Brown Norway (BN) rats as recipients. BN treated with 0.1 mg/kg FK506 and 0.5-10 microg/kg SMS showed a significant increase in mean skin allograft survival time when compared to either a monotherapy or control group. None of the animals died or showed signs of drug-related toxicity. In conclusion, a combined therapy of SMS and FK506, administered at lower dosages than those that are considered therapeutic, led to an effective immunosuppression without any undesirable side effects.     

Protective effects of API0134 on myocardial ischemia and reperfusion injury

A rare case of gangrenous cystitis is described. The questions of the incidence of this pathology are discussed, considering its rareness after the antibiotics age. The etiology of this disease is probably multifactorial and it is never possible to identify a unique cause. The gangrenous cystitis doesn't present with any typical symptomatology, out with urinary troubles common to many urologic diseases. Surgery is often performed in emergency without a preoperative defined diagnosis. Surgical treatment has changed with time from a simple bladder cavity draining to the resection of the necrotized bladder wall. In our case a total cystectomy with uretero-ileocutaneostomy, in two times, was performed. This procedure allowed the patient a good quality of life (1 year of follow-up).     

Single-center randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of acute myocardial rejection

BACKGROUND: To compare the efficacy and safety of tacrolimus and cyclosporine in heart transplantation, this single-center, prospective, randomized, open-label clinical trial was undertaken. METHODS: Seventy-three adult patients were randomly assigned at the time of transplantation to receive either tacrolimus (n=43) or cyclosporine (n=30) as the primary immunosuppressant. Ten of the 43 patients in the tacrolimus group received the drug intravenously in the perioperative period; all other patients received only oral tacrolimus. RESULTS: With a mean follow-up of 27 months, patient survival rates (tacrolimus 83%, cyclosporine 81%) were similar. Fewer patients experienced acute rejection in the tacrolimus group (79%) than in the cyclosporine group (100%), but the difference was not statistically significant. The number of infections and dialysis and insulin requirements were similar for the 2 treatment groups, but the proportion of patients requiring multidrug antihypertensive regimens was lower in the tacrolimus group (12.5% vs 50.0% at month 6; p=.025). The interpatient variance in pharmacokinetic parameters in a subset of 10 patients was much higher after the first oral dose of tacrolimus than at steady-state (eg, first-dose time at which maximal concentration is reached (t(max)): 3.5+/-2.5h, steady-state t(max): 2.0+/-0.7h), and patients treated with intravenous tacrolimus (n=13) rather than oral tacrolimus (n=30) reached target concentrations faster and with less interpatient variability (eg, at day 0: 9.72+/-10.9 ng/mL intravenously vs 3.31+/-8.1 orally). CONCLUSIONS: Tacrolimus was associated with similar efficacy and safety profiles compared with cyclosporine. The higher interpatient variance in absorption associated with oral tacrolimus during the first few days after transplantation would suggest that intravenous tacrolimus should be used during the perioperative period.     

Endothelial protective effect of stobadine on ischaemia/reperfusion-induced injury

A pedagogical network has been developed at University Hospital of Rennes from 1996. The challenge is to give medical information and informatics tools to all medical students in the clinical wards of the University Hospital. At first, nine wards were connected to the medical school server which is linked to the Internet. Client software electronic mail and WWW Netscape on Macintosh computers. Sever software is set up on Unix SUN providing a local homepage with selected pedagogical resources. These documents are stored in a DBMS database ORACLE and queries can be provided by specialty, authors or disease. The students can access a set of interactive teaching programs or electronic textbooks and can explore the Internet through the library information system and search engines. The teachers can send URL and indexation of pedagogical documents and can produce clinical cases: the database updating will be done by the users. This experience of using Web tools generated enthusiasm when we first introduced it to students. The evaluation shows that if the students can use this training early on, they will adapt the resources of the Internet to their own needs.     

Effect of immunosuppressant FK506 on ischemia-induced degeneration of hippocampal neurons in gerbils

To evaluate the effect of FK506 on delayed neuronal death in gerbils after forebrain ischemia, 84 adult Mongolian gerbils were used in this study. Transient forebrain ischemia was induced by clipping common carotid arteries bilaterally for 5 minutes. One hour after reperfusion we intraperitoneally injected FK506 (1.0 mg/kg), cyclosporin A (CsA) (10.0 mg/kg) or the vehicle solution into each gerbil. In one group, each agent was additionally administered daily 3 more times at 24, 48 and 72 hours after ischemia. The gerbils were killed 4 days or 10 days after transient ischemia, and damage to their hippocampal pyramidal cells was histologically assessed. Additionally, the body temperature was measured following administration of each drug to investigate drug-induced hypothermia. Post-ischemic repeated treatment with FK506 significantly (p < 0.01) reduced degeneration of hippocampal neurons. However, partial treatment did not modify neuronal degeneration. CsA did not show a neuroprotective effect in this study. Drug-induced mild hypothermia (35-37 C) was observed following administration of FK506 or CsA. There was no significant difference in the time course of the body temperature between the FK506 and CsA group. We demonstrated that the repeated FK506 treatment, but not the CsA treatment, reduced ischemia-induced degeneration of hippocampal neurons in gerbils. Although FK506-induced hypothermia might have modified neuronal degeneration, a comparison with CsA indicated that the neuroprotective effect of FK506 was not solely due to hypothermia per se.     

Endothelin-1 does not contribute to ischemia/reperfusion-induced vasoconstriction in skeletal muscle

The experiment reported was designed to investigate whether endothelin-1 (ET-1) contributes to vasospasm and poor perfusion during the reperfusion after prolonged ischemia in skeletal muscle. Male Sprague-Dawley rats weighting 100 to 120 g were anesthetized with Nembutal. The vascular isolated rat cremaster muscle, coupled with local interarterial infusion, was the model used in this study. The diameters of feeding arterioles and terminal arterioles were measured utilizing intravital microscopy. The number of terminal arterioles with temporary cessation of flow were counted in each cremaster. Group 1: ET-dose response (8 rats)--various concentrations of ET-1 (from 10(-8) M to 10(-5) M) were infused into the cremaster to test whether this muscle was responsive to the agent in a dose-dependent manner. Group 2: ET-antagonist response (12 rats)--PD-142893, 10(-4) M (ETab receptor antagonist) plus ET-1 10(-7) M were infused into the cremaster to test whether vasospasm caused by exogenous ET-1 could be prevented by pretreatment with this specific ETab receptor antagonist. Group 3: ischemia/reperfusion response (12 rats)--PD-142893, 10(-4) M was infused into the cremaster before ischemia (4 hr warm ischemia) and during reperfusion to test whether ETab receptor antagonism was effective in preventing the vasospasm associated with ischemia/reperfusion injury. The results from this study show that a mixed ETab endothelin antagonist, PD-142893, infused before ischemia and during reperfusion at a dose which virtually abolished the vasoconstriction produced by a high concentration of exogenous endothelin-1, had no effect on ischemia/reperfusion-induced vasoconstriction in this model. These results suggest that ET-1 probably does not contribute to the ischemia/reperfusion-induced vasoconstriction and poor reflow in rat skeletal muscle.