In vitro efficacy of platelet glycoprotein IIb/IIIa antagonist in blocking platelet function in plasma of patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an important complication following administration of heparin. Platelet activation and aggregation induced by heparin/platelet factor 4/immunoglobulin complexes are thought to be the underlying mechanism for this condition, so it was hypothesized that abciximab (a humanized murine monoclonal antibody directed against the glycoprotein IIb/IIIa receptor) would prevent heparin-induced platelet aggregation and activation in plasma from patients with HIT. Platelet aggregation was tested in vitro with platelet-poor plasma (obtained from 23 patients with HIT), platelet-rich plasma (from normal donors with known reactivity), heparin (0.5 U/ml), and ascending doses of abciximab (0.07-0.56 microg/ml). The ability of abciximab to prevent platelet activation was also evaluated using flow cytometry (P selectin expression, mepacrine release, microparticle formation) and platelet factor 4 immunoassay. In vitro, abciximab inhibited heparin-induced platelet aggregation in a dose-dependent fashion (IC50 0.103 microg/ml) and inhibited microparticle formation, the expression of P-selectin, release of mepacrine and platelet factor 4. These findings suggest that abciximab may be useful in treatment of patients with HIT and warrants further clinical evaluation.

Phase I prehysterectomy studies of the transcervical administration of quinacrine pellets.

To determine the safety of transcervical administration of quinacrine pellets as a method of voluntary female sterilization, three noncomparative Phase I clinical trials of the administration of 250 mg quinacrine were carried out in 21 women who were scheduled to undergo hysterectomy 24 h or one month later. Detailed results are presented for one of the trials using 10-min pellets. Six of 10 women had minor transitory complaints during the postinsertion 24-h follow-up period. Five women reported pelvic/abdominal cramping, one experienced headache, and one experienced dizziness. Blood chemistry values were not adversely influenced by the quinacrine. The average plasma level of quinacrine peaked at 3 h, 36.1 ng/ml, slightly lower than the value observed 4 h after oral administration of 200 mg in a previous study. An average of 27% of the administered dose was recovered in tampons. Quinacrine was detected in the plasma of two women at the four/six-week visit. Selected results are presented from two other trials that were halted because of slow recruitment. The transcervical administration of 250 mg of 10-min quinacrine pellets was well tolerated. However, based on recent mutagenicity testing and meetings with regulatory officials, it appears unlikely that the use of quinacrine for nonsurgical sterilization could be approved in the United States or Europe.

Esterilizaçäo näo-cirúrgica: estudo do perfil reprodutivo e dos efeitos colaterias de mulheres que recorreram a este método / Non-surgical sterilization: study of the women's reproductive life and the side effects of this contraceptive method

Constitui uma avaliaçäo prospectiva da utilizaçäo do método de esterilizaçäo feminina näo cirúrgica com quinacrina. Estudou-se dez mulheres, atendidas de abril a setembro de 1990, no Ambulatório de Planejamento Familiar do Hospital Sotero del Rio, Santiago, Chile. O perfil reprodutivo das mulheres revela que o início da vida fértil foi, em média, aos 12,1 anos e aos 16.4 anos iniciaram a atividade sexual, sem anticoncepcionais. Verifica-se que a primeira gravidez ocorreu, em média, aos 19,1 anos. Após este evento a maioria iniciou o uso de métodos de planejamento familiar por volta dos 21 anos, resultando numa variada e näo muito bem sucedida história anticoncepcional A decisäo de encerrar a vida reprodutiva com medidas definitivas foi tomada pelo casal, baseado em informaçöes fornecidas pelos profissionais de saúde e referindo razöes de planejamento familiar, história anticoncepcional e obstétrica negativa. Nesta ocasiao as mulheres faziam em média, 34.8 anos e parte de uma família legalmente constituída com 3.2 filhos vivos; 49 por cento delas ainda tinham a opçäo de utilizar métodos reversíveis. O seguimento prospectivo do método näo-cirúrgico mostra que os efeitos colaterais, como os maiores níveis de quinacrina plasmática e urinária, apresentam-se nas primeiras 48 horas, após inserçäo intrauterina das primeira e segunda doses de "pellets" de quinacrina.

Quinacrine and basic amines in human platelets: subcellular compartmentation and effects on serotonin.

Human platelets appear to accumulate quinacrine both in a thrombin-releasable compartment (dense bodies or amine storage vesicles) and in another compartment from which it is released by agents known to collapse pH gradients (possibly lysosomes with an acidic interior). Approximately 61% of the total amount of quinacrine present in human platelets resides in dense bodies and 14+ in lysosomes, with the remainder probably present in the cytoplasm. Other basic amines are accumulated in the three compartments to widely varying extents, suggesting that several factors besides the existence of pH gradients act to determine the distribution of these substances within the cell. The fluorescence emission of quinacrine excited with 420 nm light is completely quenched for quinacrine inside both dense bodies and lysosomes, and the absorption of 440 nm light is decreased by approximately 25%. Quinacrine added to dense bodies at 37 degrees C induces the efflux of 5-hydroxytryptamine (5HT) from the bodies. There is, however, no 5HT loss following quinacrine entry at 0 degree C, and the relationship between the two types of amine movement varies according to incubation time at 0 degree C and 37 degrees C. This action of quinacrine therefore does not appear to be associated with stoichiometric exchange of 5HT and quinacrine, but rather to modulation of the passive permeability of the dense body membrane for 5HT.

Gas chromatographic analysis of chloroquine after a unique reaction with chloroformates.

A specific method for the gas chromatographic determination of chloroquine (CQ) after derivatization with chloroformates, using 9-bromophenanthrene as the internal standard and a column filled with 3% OV-17 on 80-100 mesh Supelcoport is described. Derivatization with chloroformates produced a pyrrolidine derivative, 4-(2-methyl-1-pyrrolidyl)-7-chloroquinoline with CQ, and a carbamate with desethylchloroquine. The chloroformate reaction for CQ is thus selective in the presence of CQ metabolites. The method based on flame ionization detection is highly suitable for quantitation of CQ in urine.

Fluorescent histochemical localisation of quinacrine-positive neurones in the guinea-pig and rabbit atrium.

Quinacrine-fluorescent nerve fibres and nerve cell bodies are described in the right and left atria of the guinea-pig and rabbit. The nerve cells (20 to 35 micrometers in diameter) are found predominantly in the right atrium in both species. The nerve fibres are varicose and innervate both the muscle and many blood vessels. The quinacrine fluorescent neural structures are unaffected by chemical sympathectomy with 6-hydroxydopamine. The distribution of quinacrine-positive nerve fibres and cell bodies are compared to the distribution of adrenergic and acetylcholinesterase-positive nerves in the atrium of both species. Quinacrine fluorescence appears to be selective for non-adrenergic, non-cholinergic nerves and the possibility that it is binding to high contents of ATP discussed.

[Spectral luminescence studies of cells stained with acrichine derivatives]. / Spektral'nye liuminestsentnye issledovaniia kletok, okrashennykh proizvodnymi akrikhina.

Excitation and fluorescence spectra are given of quinacrine derivative solutions, of buccal epithelium cell nuclei, of peripheral blood cells, and of isolated chromosomes treated with propyl-quinacrine mustard. It is confirmed that the differential cell treatment with quinacrine derivates may be observed in aqueous solutions only. Data obtained allow us to give some recommendations for employment of optimal filters and dichroic beam-splitters in the fluorescence microscopy of chromosomes treated with quinacrine derivatives.

Fluorescence-determined preferential binding of quinacrine to DNA.

Quinacrine complexes with native DNA (Calf thymus, Micrococcus lysodeikticus, Escherichia coli, Bacillus subtilis, and Colstridium perfringens) and synthetic polynucleotides (poly(dA) . poly(dT), poly[d(A-T)] . poly[d(A-T)], poly(dG) . poly(dC) and poly[d(G-C)] . poly[d(G-C)]) has been investigated in solution at 0.1 M NaCl, 0.05 M Tris HCl, 0.001 M EDTA, pH 7.5, at 20 degrees C. Fluorescence excitation spectra of complexes with dye concentration D = 5-30 microM and DNA phosphate concentration P = 400 microM have been examined from 300 to 500 nm, while collecting the emission above 520 nm. The amounts of free and bound quinacrine in the dye-DNA complexes have been determined by means of equilibrium dialysis experiments. Different affinities have been found for the various DNAs and their values have been examined with a model that assumes that the binding constants associated with alternating purine and pyrimidine sequences are larger than those relative to nonalternating ones. Among the alternating nearest neighbor base sequences, the Pyr(3'-5')Pur sequences, i.e., C-G, T-G, C-A and T-A seem to bind quinacrine stronger than the remaining sequences. In particular the three sites, where a G . C base pair is involved, are found to display higher affinities. Good agreement is found with recent calculations on the energetics of intercalation sites in DNA. The analysis of the equilibrium shows also that the strength of the excitation spectrum of bound dye depends strongly upon the ratio of bound quinacrine to DNA. This effect can be attributed to dye-dye energy transfer along DNA.

Mepacrine pigmentation in systemic lupus erythematosus. New data from an ultrastructural, biochemical and analytical electron microscopic investigation.

A case of mepacrine pigmentation occurring in a patient with systemic lupus erythematosus has been investigated by fluorescent light microscopy, gas--liquid chromatography and analytical electron microscopy. There is strong evidence for the presence of mepacrine itself within the typical granules, which have been shown by electron microscopy to be membrane bound and intracellular. Analytical electron microscopy also showed that the granules contain large quantities of iron and smaller quantities of sulphur.

Tautomerism of singly protonated chloroquine and quinacrine.

Differential absorptiometric pH titrations of the antimalarials chloroquine and quinacrine, employing the respective uncharged species at pH 12.5 in the reference cell, show that protolytic dissociation from the heterocyclic ring nitrogen atoms occurs over pH 6--12. This finding indicates that the singly charged cations of the drugs exist measurably in two tautomeric forms. The tautomeric equilibrium constants were calculated from the titration data. The existence of these tautomeric equilibria may have significance in the pharmacodynamics of chloroquine and quinacrine.

Granulomatous pneumonitis. A result of intrapleural instillation of quinacrine and talcum powder.

A 73-year-old man with bilateral recurrent pleural effusions had relief of symptoms with intrapleural instillation of quinacrine hydrochloride and talcum powder. At postmortem, examination of the lungs showed granulomatous consolidation of a portion of the lower lobe of the left lung. The granulomatous reaction was in response to large numbers of talc and quinacrine crystals within the pulmonary parenchyma. A review of the literature disclosed no reports of pulmonary damage following the intrapleural administration of these two agents. This unusual complication of therapy may have resulted from the aspiration of crystals through a small, undetected bronchopleural fistula.