Microsomal catalyzed N-hydroxylation of guanabenz and reduction of the N-hydroxylated metabolite: characterization of the two reactions and genotoxic potential of guanoxabenz.

The N-reduction of the centrally acting alpha 2-adrenoreceptor agonist guanoxabenz (Benzérial), an N-hydroxyamidinohydrazone, to the amidinohydrazone guanabenz (Wytensin, Hipten, Rexitene) by microsomal fractions from rabbits, pigs and humans has been detected in vitro. The conversion rates with rabbit microsomal fractions were markedly slower than those in the cases of fractions from humans and pigs. It was also possible to demonstrate the N-oxidation of guanabenz to guanoxabenz by the use of microsomal fractions from rabbits, pigs, and humans. Furthermore, the oxidation was also observed in reconstituted systems in the presence of enriched cytochrome P450 fractions, purified isoenzyme P450 2C3, and heterologously expressed P450 2C3 of the subforms 6 beta H and 6 beta L. The analyses were performed with a newly developed HPLC technique and were confirmed by LC-MS methods. The kinetic parameters determined for the metabolic cycle (bioreversible reactions) are indicative of a predominance of the reduction of guanoxabenz to guanabenz in vivo. Accordingly, guanoxabenz in part constitutes a prodrug of guanabenz. Examination of guanabenz and guanoxabenz for mutagenicity by means of the Ames test revealed that guanoxabenz has pronounced mutagenic effects in the strains TA 98 and TA 1537. Guanabenz did not exhibit mutagenicity so that the N-reduction of guanoxabenz has significance in terms of detoxification.

[Fatal course of a sequestration crisis in hemoglobin SC disease]. / Letal verlaufende Sequestrationskrise bei Hämoglobin-SC-Krankheit.

A 14 year-old patient developed severe anemia and splenomegaly 2 days after the onset of a febrile upper airway infection. The hemoglobin concentration had dropped to 1.1 g/dl. Death occurred as consequence of the acute anemia and peripheral circulatory failure. The crisis was caused by an acute splenic sequestration. Hemoglobin SC disease could be identified as the underlying disorder. Hemoglobin SC disease usually has a milder course than sickle cell disease. However the patients may develop the same crisis-like symptoms. Splenic sequestration is caused by the occlusion of the splenic sinuses due to sickled and aggregated erythrocytes with subsequent trapping of large blood volumes and circulatory failure. Regular transfusions and/or splenectomy are recommended to prevent splenic sequestration crisis.

Acquisition of coccidioidomycosis at necropsy by inhalation of coccidioidal endospores.

Coccidioidomycosis is accepted as being noncontagious because the infectious arthroconidial form of Coccidioides immitis is not produced in humans and other mammalian hosts. However, disseminated coccidioidomycosis developed in a veterinarian who autopsied a horse with disseminated disease but without draining lesions or productive cough. We postulate transmission occurred by inhalation of tissue-phase endospores aerosolized in the course of dissection.

Erythrocyte pyruvate kinase deficiency: a kinetic method for differentiation between heterozygosity and compound-heterozygosity.

The goal of the present study was to search for criteria that allow one to distinguish between normal individuals and heterozygotes as well as compound heterozygotes for pyruvate kinase (PK) deficiency. As the residual activity of PK with heterozygotes was between 35% and 110% of the normal activity, it was necessary to find other methods to prove heterozygosity. The PK in the hemolysates of 23 patients suffering from PK deficiency, 36 paternal and maternal enzymes as well as the enzymes of five heterozygous and four normal siblings together with those of 20 normal individuals, were studied according to the recommendations of the International Committee for Standardization in Haematology. The following hematological and enzyme kinetic parameters can serve to identify heterozygotes for PK deficiency: 1) a slight reticulocytosis, 2) an up-to-twofold increase of the intracellular concentrations of glucose-6-phosphate in the erythrocyte, 3) a mixed cooperativity of the phosphoenolpyruvate (PEP)-binding process of PK, 4) a decreased nucleotide specificity with guanosine diphosphate and uridine diphosphate, and 5) a lowered affinity for adenosine diphosphate. The most significant criterium found with all heterozygotes was a mixed cooperativity of the PEP-binding process caused by the presence of a mixture of normal and mutant PK.

Miconazole for treatment of disseminated coccidioidomycosis. Unfavorable experience.

Miconazole at dosages up to 30 mg/kg/day was given intravenously to seven patients with complicated courses of disseminated coccidioidomycosis. Six had received treatment with amphotericin B previously and five of these patients could be evaluated for the efficacy of the treatment. In three patients the condition failed to respond to therapy, another patient required intratracheal administration of amphotericin B later, and the fifth patient had an equivocal response to treatment. Severe phlebitis, pruritus, nausea, vomiting, hyperlipidemia, and thrombocytosis were frequent side effects. These limited unfavorable results indicate that until controlled studies demonstrate its safety and efficacy, therapy with miconazole should be reserved for highly selected patients with disseminated coccidioidomycosis who cannot receive amphotericin B.

Disseminated Trichosporon capitatum infection in an immunosuppressed host.

Trichosporon is a frequent cause of superficial mycotic infections but has rarely been associated with invasive disease. A patient undergoing bone marrow transplantation who died from disseminated Trichosporon capitatum infection with endocarditis is reported, and the clinical spectrum of human infection caused by fungi of this genus is reviewed. To our knowledge, this is the first reported case of clearly invasive disease caused by this specific organism and emphasizes the expanding spectrum of unusual infections in the severely immunosuppressed patient.