2-2''-Pyridylisatogen, a selective allosteric modulator of P2 receptors, is a spin trapping agent

We studied the role of parasympathetic division of vegetative nervous system in regulation of the intestine activity in rats subjected to bilateral subdiaphragmal vagotomy, the response of the neuromuscular apparatus of the small intestine to stimulation by aceclydine taken as an example. Intravenous injection of aceclydine (0.5 mg/kg) into intact animals is accompanied by characteristics changes in the electrical and contractile activities of the intestine, which reflect its enhanced motor activity. Vagotomy leads to changes of response of the intestine to pharmacological stimulation, most expressed within 3, 7, and 30 days. It was proposed that distortion of reactive properties of the intestine contractile system under these conditions is related to functional changes in rhythm-setting neurons of intramural ganglia and M-cholinoreceptors of neuromuscular synapses.     

Sirolimus, a new, potent immunosuppressive agent

Sirolimus (SRL), a potent immunosuppressant, is currently being investigated in phase III trials for prophylaxis of renal transplant rejection. The mechanism of action of SRL is a blockade of the response of T and B cells to cytokines, thereby preventing cell cycle progression in G1 and consequently cell proliferation. There seems to be a good correlation between SRL concentrations, estimated as exposure by the area under the concentration versus time curve, and trough whole blood concentration, so that therapeutic monitoring may be done by trough levels only. Because of the low frequency of allograft rejection, there has been no documented correlation between trough concentrations and efficacy. Trough SRL concentrations of 15 ng/ml or higher seem to be associated with an increased frequency of adverse effects. Drug-associated toxicities include thrombocytopenia, leukopenia, and increases in cholesterol and triglyceride levels. The drug has synergy with cyclosporine (CsA) in vitro as well as in animal and clinical studies. In phase II trials the combination of SRL-CsA therapy reduced the frequency of acute rejection episodes, permit withdrawal of concomitant corticosteroid therapy, and allowed reduction of CsA dosages in nonblack patients.     

Anagrelide in control of myeloproliferative thrombocythemia: long-term experiences in 6 patients

Symptomatic or asymptomatic chronic elevation of platelet count can be observed in all forms of myeloproliferative disorders (MPD). Benefits and limitations of the traditional platelet-reducing agents, such as radioactive phosphorus, alkylating agents, hydroxyurea and interferon alpha, are well known and have been largely described. Anagrelide (Agrelin) is an additional newer drug with a selective platelet-lowering effect. We describe our own long-term experience in 6 patients with MPD who were treated with anagrelide as part of a compassionate-use protocol between April 1991 and August 1997. The median duration of therapy was 54 months (range 17 to 75 months), with an overall response rate of 100% (complete and partial response for at least 4 weeks). The initial median platelet count of 1211 x 10(9)/l (range 847 to 2050 x 10(9)/l) was reduced rapidly and lastingly to 570 x 10(9)/l (range 216 to 667 x 10(9)/l) at the time of the last control. Under treatment with anagrelide 4 of the 6 patients showed a reduction of disease-associated symptoms or complications. Adverse reactions were generally mild and transitory, and no interruption or cessation of therapy was required. Development of drug resistance or late adverse events were not observed. Treatment with anagrelide is effective, safe and in our opinion easy to administer. It also appears to be suitable for long-term administration.     

Pre-clinical evaluation of a novel chloroethylating agent, Clomesone

The in vitro activity of the novel chloroethylating agent, Clomesone, was investigated in a panel of established murine and human tumour cell lines. In vivo anti-tumour activity was examined against three transplantable adenocarcinomas of the mouse colon and in vivo bone marrow toxicity was assessed using a spleen colony forming unit assay. The pharmacokinetic behaviour of the drug in vivo and drug stability in vitro was analysed by gas chromatography with electron capture detection. Clomesone exhibited no activity in vitro against the majority of cell lines derived from solid human colorectal carcinomas. Anti-tumour activity against the murine tumours in vivo was not impressive and was accompanied by myelosuppression. Pharmacokinetic data suggested that the lack of in vivo activity was due to the failure to achieve effective anti-neoplastic drug concentrations at the tumour site. It was concluded that this study found no evidence to suggest that Clomesone was toxicologically more selective than the chloroethylnitrosoureas.     

Thrombotic thrombocytopenic purpura in a previously splenectomized patient

Factors affecting the sealing of foil packages were studied in the sealing of foil packages were studied in three laboratories. The relationship of sealing temperature (with machine speed and pressure kept constant) to the incidence of defective packages was determined. The maximum acceptable limit for defective pouches was 1%. Three tests were employed to detect defects: vacuum-dye, seal strength, and pressurized ammonia vapor. Only the last was sensitive enough to determine the optimum sealing conditions. This test also was capable of detecting leakage sites. Replacement of the cellophane layer of the foil laminate with polyvinylidene chloride-coated polyester improved the barrier properties of the package.     

Degradation chemistry of gemcitabine hydrochloride, a new antitumor agent

The anti-tumor agent gemcitabine hydrochloride, a beta-difluoronucleoside, is remarkably stable in the solid state. In 0.1 N HCI solution at 40 degrees C, deamination of gemcitabine occurs, yielding its uridine analogue. Approximately 86% of the initial gemcitabine remains after 4 weeks under these conditions. Cleavage of the N-glycosidic bond of gemcitabine or conversion to its alpha-anomer in 0.1 N HCI solution is not observed over a 4-week period. However, this work has shown that gemcitabine hydrochloride anomerizes in 0.1 N NaOH at 40 degrees C. Approximately 72% of the initial gemcitabine remains after 4 weeks under the basic conditions used. Uridine hydrolysis products are also formed under these conditions. The anormerization reaction, which is unusual under basic conditions, has been confirmed by characterization of the chromatographically isolated alpha-anomer by NMR and mass spectrometry. A mechanism involving an acyclic intermediate is proposed.     

Idiopathic thrombocytopenic purpura in 5 members of a family

Five cases of idiopathic thrombocytopenic purpura (ITP) appearing on five members of two generations of a family, with autosomal dominant pattern, are presented. The clinico-biologic behaviour of 2 patients (studied and treated by the authors) plus the available data from the 3 others (diagnosed and treated at other hospitals) allowed us to discard any possibility of hereditary non-immunologic thrombocytopenia. The predisposition of ITP patients and their relatives to present clinico-biological features of autoimmune diseases is commented as a possible explanation for the rare forms of familial ITP.     

Repaglinide, a novel, short-acting hypoglycemic agent for type 2 diabetes mellitus

Repaglinide is a new, short-acting, insulin-releasing agent recently approved for the monotherapy of type 2 diabetes mellitus, and in combination with metformin in patients failing repaglinide or metformin monotherapy. Repaglinide appears to trigger insulin release by regulating adenosine triphosphate-sensitive potassium channels on the surface of pancreatic beta cells, which in turn affect calcium influx, the principal mediator of insulin release. Repaglinide mainly affects postprandial plasma glucose concentrations. It reduces glycosylated hemoglobin concentrations by 1-2% U. The agent's short duration of action may lessen the risk of long-lasting hypoglycemia and of down-regulation of beta cell sensitivity (the latter promoting secondary drug failure), although data are sparse in this regard. Its major adverse effect is hypoglycemia. Its role in the therapy of type 2 diabetes is unclear at present, vis-à-vis its use instead of or in combination with other antidiabetic agents other than metformin. The need for multiple daily doses, based on its brief duration of action, may be a barrier to compliance.     

Ticlopidine-induced thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders including infections, connective tissue diseases, and solid organ tumors. It also may coincide with administration of drugs such as mitomycin, metronidazole, oral contraceptives, cyclosporine, and many others. We report the occurrence of TTP in a patient shortly after the initiation of ticlopidine.     

Interaction between enoxacin, a new antimicrobial, and nimesulide, a new non-steroidal anti-inflammatory agent in mice

Convulsions induced by the combination of enoxacin, a new antimicrobial, and nonsteroidal anti-inflammatory drugs including nimesulide, ketoprofen, pranoprofen and loxoprofen sodium, were investigated in mice. The oral administration of nimesulide alone induced clonic convulsions at more than 300 mg/kg. The oral administration of ketoprofen, pranoprofen or loxoprofen sodium induced no convulsion up to 1000 mg/kg, 500 mg/kg and 600 mg/kg, respectively, and that of enoxacin induced no convulsion at more than 5000 mg/kg. The combination of nimesulide at 200 mg/kg and enoxacin at 400 mg/kg induced no convulsion. In contrast, the combination of enoxacin at 100 mg/kg and either ketoprofen at 125 mg/kg or pranoprofen at 500 mg/kg induced clonic convulsions, while that of enoxacin at 400 mg/kg and loxoprofen sodium at 600 mg/kg induced no convulsion. These results suggest that the combination of nimesulide and enoxacin may possibly induce few or less convulsions in the clinical setting.     

Thrombotic thrombocytopenic purpura in a patient with genetic haemochromatosis, liver cirrhosis and an iron-free focus

We report a patient with thrombotic thrombocytopenic purpura and genetic haemochromatosis. The patient was shown by the polymerase chain reaction to be homozygous for the Cys282Tyr mutation of the HFE gene. Liver biopsy showed micronodular cirrhosis and the presence of an iron-free focus which was thought to be pre-neoplastic.     

The alloimmune thrombocytopenic syndromes

We have summarized five thrombocytopenic syndromes caused by platelet-reactive alloantibodies. Increased awareness of these five syndromes, together with the greater availability of highly-specialized laboratory methods to detect and to characterize platelet-reactive alloantibodies, will lead to their more frequent diagnosis. It is important for the clinician to consider unusual alloimmune thrombocytopenic disorders in clinical settings in which alloantigens that could be limited to just one family could cause important disease (ie, NAT caused by a private alloantigen; theoretically, PAT or TAT related to directed donations of blood or bone marrow). These considerations underscore the need for serological investigations to involve the family members rather than to rely on standard platelet typing donor pools.     

Acute pancreatitis as a triggering factor for thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) constitutes a poorly understood multisystemic disease of vascular origin that may involve any organ by thrombotic occlusions of the small vessels. Treatment with plasmapheresis is the best therapeutic option at this present moment. Involvement of the pancreas is a well established feature of this disease, which has generally been interpreted as a consequence of pancreatic vascular compromise. However, there are a few cases in the literature in which the clinical signs of TTP developed well after the clinical and laboratory demonstration of acute pancreatitis (AP). Therefore, the possibility of pancreatic inflammation as a triggering factor of TTP may need to be considered. This cause-effect relationship between AP and TTP remains unclear. We report a patient with chronic pancreatitis presenting with two episodes of TTP, triggered by acute relapses of pancreatitis. TTP may, thus, constitute a hematological complication of AP. We discuss the pathophysiological aspects of this association, along with therapeutical options.     

Chronotropic effects of cilostazol, a new antithrombotic agent, in patients with bradyarrhythmias

Size and asymmetry (size difference between the left and right sides) of inner ear otoliths of larval cichlid fish were determined after a long-term stay in moderate hypergravity conditions (3g; centrifuge), in the course of which the animals completed their ontogenetic development from hatch to freely swimming. Neither the normal morphogenetic development nor the timely onset and gain of performance of swimming behaviour were impaired by the experimental conditions. However, both utricular and saccular otoliths (lapilli and sagittae, respectively) were significantly smaller after hyper-g exposure compared to 1g control specimens raised in parallel. The asymmetry of sagittae was significantly increased in the experimental animals, whereas the respective asymmetry of lapilli was pronouncedly decreased compared with the 1g controls. These findings suggest that growth and development of bilateral asymmetry of otoliths are guided by the environmental gravity vector. Some of the hyper-g animals revealed a kinetotic behaviour on transfer to normal 1g earth conditions, which was similar to the behaviour observed in previous experiments on the transfer from 1g to microgravity (parabolic aircraft flights). The lapillar asymmetry of kinetotic samples was found to be significantly higher than that of normally behaving experimental specimens. No differences in asymmetry of sagittae were obtained between the two groups. This supports an earlier theoretical concept, according to which human static space sickness might be based on asymmetric utricular otoliths.