Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature.

Terbinafine is an allylamine antifungal agent widely used to treat dermatophyte onychomycosis and dermatomycoses. We report 10 severe cutaneous adverse reactions associated with terbinafine therapy which required discontinuation of the antifungal agent: erythema multiforme (five patients), erythroderma (one), severe urticaria (one), pityriasis rosea (one) and worsening of pre-existing psoriasis (two patients). The spectrum of cutaneous adverse effects associated with terbinafine therapy is reviewed. Patients should be counselled about discontinuing terbinafine at the onset of a cutaneous eruption and about seeking medical advice about further management.

Characterization of gp39, a B-lymphocyte associated differentiation antigen which is also present on granulocytes and macrophages.

The biosynthesis and biochemical characteristics of the 39,000 cell surface glycoprotein detected by Mab 41H.16 were investigated. Experiments utilizing tunicamycin, endoglycosidase H, endoglycosidase F and N-glycosidase F indicate that the mature molecule expressed at the cell surface is composed largely of N-linked oligosaccharides of both the complex and high mannose types. When synthesized in the presence of tunicamycin, the molecule appeared on the cell surface with a Mr of 32,000. Digestion with both endoglycosidase H and endoglycosidase F yielded a single band of Mr 37,000. Parallel experiments with N-glycosidase F revealed species of approx. 35,000 and 32,000. Synthesis in the presence of monensin yielded a 37,500 product. [3H]Glucosamine and [3H]mannose were incorporated into the molecule but no evidence for fucose incorporation could be found. Microheterogeneity of gp39 with respect to Mr and oligosaccharide structure was demonstrated by biosynthetic labelling and lectin chromatography. Biosynthetic pulse-chase labelling showed that the de novo synthesis of the 39,000 molecule occurs without detectable precursor formation. Results of temperature-dependent phase separation experiments were consistent with gp39 being an integral membrane protein. Two-dimensional electrophoresis showed heterogeneity of the isoelectric points associated with the N-linked oligosaccharides. Galactose oxidase/NaB[3H]4 labelling showed that a terminal sialic acid protects a galactose residue. All results are consistent with the conclusion that the gp39 molecule is an integral membrane glycoprotein composed of heterogeneous N-linked oligosaccharides of both the complex and high mannose types.

Clinical and laboratory characteristics of acute leukemia with the 4;11 translocation.

This report describes the clinical and laboratory features of seven cases of acute leukemia associated with the 4;11 chromosomal translocation. All seven children had acute lymphoblastic leukemia by standard morphologic and cytochemical criteria. Leukemic blasts from six of seven patients were terminal deoxynucleotidyl transferase-positive. Immunologic phenotyping suggested the leukemias were of B cell origin; blasts from five patients expressed HLA-DR and p24 (CD-9 antibody), blasts from three patients expressed B4 (CD-19), and blasts from two patients expressed the common acute lymphoblastic leukemia antigen (CD-10). One patient's leukemic blasts contained cytoplasmic immunoglobulin. Analysis of DNA from four of five patients demonstrated additional evidence of B cell differentiation with heavy-chain immunoglobulin gene rearrangement. When DNA from the four patients with heavy-chain immunoglobulin gene rearrangement was analyzed, one patient's DNA demonstrated light-chain immunoglobulin gene rearrangement. However, flow cytometric analysis of blasts from three patients showed the simultaneous expression of the lymphoid-associated antigen B4 (CD-19) and the myeloid-associated antigen My-1 (X-Hapten). Electron microscopic examination of blasts from one patient that expressed both lymphoid- and myeloid-associated antigens demonstrated ultrastructural characteristics of both lineages. These findings suggest that acute leukemia with the t(4;11) abnormality has mixed lineage characteristics as a result of leukemogenesis in a multipotential progenitor cell or aberrant gene expression later in differentiation. Furthermore, serial analysis of karyotype, immunophenotype, and heavy-chain immunoglobulin genes revealed changes in these biologic markers over time, suggesting continued chromosome rearrangement and gene modulation after the leukemogenic event in cells with the t(4;11).

A monoclonal antibody detecting a 39,000 m.w. molecule that is present on B lymphocytes and chronic lymphocytic leukemia cells but is rare on acute lymphocytic leukemia blasts.

Monoclonal antibody 41H.16 was produced by using the hybridoma methodology in the mouse system with cells from a patient with hairy cell leukemia as the immunogen. This antibody reacts with the majority of Slg+ cells in the peripheral blood and with all B lymphoblastoid cell lines. Reactivity with conventional Ig determinants, Fc or C3 receptors, has been excluded. The antibody reacted with cells from 68 patients with CLL but showed no reactivity with cells in 69 specimens from patients with non-T, non-B ALL. The apparent m.w. of the antigen detected by this antibody is approximately 39,000.

Drug sequence-dependent toxicity and small bowel mucosal injury in mice treated with low doses of 3-deazauridine and 1-beta-D-arabinofuranosylcytosine.

The toxicity to mice of combinations of 1-beta-D-arabinofuranosylcytosine and 3-deazauridine was investigated. The drugs were administered daily i.p. on Days 1 to 5, each drug at 10 mg/kg body weight; these dosages are small fractions of the dosages at which 10% of the treated animals died when either drug was administered alone on the foregoing schedule. This drug combination was severely toxic when 3-deazauridine was administered 2 to 8 hr prior to 1-beta-D-arabinofuranosylcytosine; most mice treated in this way died within 3 days of the last treatment. Histological examination showed that severe damage to the small bowel mucosa resulted from treatment with the drugs in the above, lethal sequence. In contrast, treatments with this drug combination at the same dosages were tolerated when the two agents were administered simultaneously or when 1-beta-D-arabinofuranosylcytosine preceded 3-deazauridine. Under the latter conditions, small bowel mucosal injury was much less severe. Female mice were more sensitive to the toxic treatment regimen than were male mice and were protected against the latter when either the 3-deazauridine or the 1-beta-D-arabinofuranosylcytosine component was preceded by treatment with nitrobenzylthioinosine (100 mg/kg), a potent inhibitor of nucleoside transport.

Formation of 1-beta-D-arabinofuranosylcytosine diphosphate choline in cultured human leukemic RPMI 6410 cells.

When incubated with 1-beta-D-arabinofuranosylcytosine (ara-C), RPMI 6410 cells formed a hitherto unrecognized ara-C metabolite, 1-beta-D-arabinofuranosylcytosine diphosphate choline. This compound was characterized by (a) chromatographic behavior, (b) chemical and enzymatic hydrolysis, (c) phosphorus content, and (d) incorporation of [5-3H]ara-C and [methyl-14C]choline. Formation of 1-beta-D-arabinofuranosylcytosine diphosphate choline by RPMI 6410 cells was enhanced in the presence of 3-deazauridine (DU) and was preceded by that of 1-beta-D-arabinofuranosylcytosine triphosphate. The antiproliferative effects of ara-C and DU toward RPMI 6410 cells were potentiated when the agents were present together. The anabolism of ara-C during a 24-hr interval of culture was markedly enhanced by the presence of DU; cellular concentrations of 1-beta-D-arabinofuranosylcytosine triphosphate and 1-beta-D-arabinofuranosylcytosine diphosphate choline were 5- and 15-fold higher than those in the absence of DU. This enhancement appears to be the basis of the potentiation of cytotoxicity resulting from combination of the agents. Pretreatment of RPMI 6410 cells with DU resulted in enhanced rates of cellular uptake of ara-C. ara-C uptake under these circumstances was blocked by the inhibitor of nucleoside transport, nitrobenzylthioinosine.

Formation of 1-beta-D-arabinofuranosylcytosine diphosphate choline in neoplastic and normal cells.

1-beta-D-Arabinofuranosylcytosine diphosphate choline was formed from 1-beta-D-arabinofuranosylcytosine (ara-C) during incubation in vitro of peripheral myeloblasts from patients with acute myelogenous leukemia and cultured cells (nonleukemic human lymphocytes, mouse lymphoma L5178Y, and HeLa); as well, 1-beta-D-arabinofuranosylcytosine diphosphate choline was formed in vivo in mouse leukemia L1210 cells and mouse liver. 3-Deazauridine enhanced the anabolism of ara-C in nonleukemic lymphocytes in vitro and leukemia L1210 cells in vivo but did not influence ara-C anabolism in the other cell types. In acute myelogenous leukemia myeloblasts incubated in vitro with ara-C, concentrations of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate were maximal after 8 hr of incubation and formation of the latter preceded that of 1-beta-D-arabinofuranosylcytosine diphosphate choline.

On the accumulation of adenosine 3':5'-monophosphate in Ehrlich cells and adenylate cyclase desensitization in response to epinephrine.

The time course of the action of epinephrine on cAMP levels in isolated mouse Ehrlich ascites cells was studied. Following the addition of hormone (10(-7) to 10(-4) M), cAMP levels reached a maximum within 1 min and declined to about 2 fold basal levels within 10-20 min. The decline phase was not due to the metabolism of epinephrine or accumulation of an inhibitor in the medium. Experiments involving timed additions of theophylline to epinephrine-treated cells suggested that the rate of cAMP synthesis declined progressively with time. Cells treated with epinephrine and then washed free of hormone were shown to be refractory to hormonal stimulation of cAMP levels. Adenylate cyclase prepared from epinephrine-treated cells was shown to exhibit decreased sensitivity to the hormone in in vitro incubations. Resensitization of the enzyme could be achieved by washing pretreated cells free of epinephrine and reincubating them for 1/2 to 2 h. Neither desensitization nor resensitization were prevented by cycloheximide or actinomycin D. Desensitization could not be induced by incubating cels with dibutyryl-cAMP. The desensitization phenomenon is considered to be a mechanism whereby cells protect themselves against the possible harmful effects of high levels of cAMP maintained over a long period of time.