Minimum dose of fludarabine for the maximal modulation of 1-beta-D-arabinofuranosylcytosine triphosphate in human leukemia blasts during therapy.

1-beta-d-Arabinofuranosylcytosine (ara-C), an effective drug for acute leukemias, must be phosphorylated to its 5'-triphosphate, ara-CTP, for activity. Our previous studies during therapy of acute myelogenous leukemia (AML) patients demonstrated that the accumulation of ara-CTP in circulating leukemia blasts was increased by a median of 2-fold when fludarabine (30 mg/m2/day over 30 min) was infused 4 h prior to intermediate dose ara-C. The augmentation was dependent on the cellular concentration of fludarabine triphosphate (F-ara-ATP).

Pharmacological and biochemical strategies to increase the accumulation of arabinofuranosylguanine triphosphatein primary human leukemia cells.

Purine nucleoside phosphorylase deficiency leads to a dGTP-mediated T-lymphopenia, suggesting that an analogue of deoxyguanosine would be selectively effective in T-cell disease. 9-beta-D-Arabinofuranosylguanine (ara-G) is relatively resistant to hydrolysis by purine nucleoside phosphorylase and selectively toxic to T cells, but its low solubility has prevented its use in the clinic. 2-Amino-6-methoxy-arabinofuranosylpurine (GW506U) serves as the water-soluble prodrug for ara-G.

New access device for hemodialysis.

A new subcutaneous device (Dialock; Biolink Corp., Middleboro, MA) provides vascular access to patients who currently require hemodialysis (HD). The device consists of a port-like valve, implanted subcutaneously below the clavicle, which provides a linear flow passage to two catheters placed in the right atrium via the jugular vein.

Papillon - lefevre syndrome with mental retardation.

A 9-year old boy, born of consanguineous parents, presented with keratoderma of palms and soles associated with severe enamel hypoplasia and mental retardation. A clinical diagnosis of Papillon - Lefevre was supported by histopathology.

Eruptive mollusca contagiosa in an immunocompetent Indian adult.

A 35-year old Indian woman with eruptive onset of mollusca contagiosa with no underlying immunodeficiency who responded to etretinate therapy is reported.

Lymphangioma circumscriptum of scrotum of late onset.

Lymphangioma circumscriptum is the commonest type of lymphangioma which is characterised by small, grouped vesicles resembling frog spawn. An interesting case of thin walled lymphangioma circumscriptum is reported which started at a late age of 45 years and limited to scrotum in a 70-year old man.

Use of a phosphorus-enriched hemodialysate to prevent hypophosphatemia in a patient with renal failure-related pericarditis.

We describe a patient who suffered from renal failure-associated pericarditis and underwent daily 3.5-hour hemodialysis treatments for 17 days. The initially elevated serum phosphorus level gradually fell to below normal on days 11 and 12 as a result of the intensive dialytic therapy.

Accumulation of arabinosyluracil 5'-triphosphate during arabinosylcytosine therapy in circulating blasts of patients with acute myelogenous leukemia.

Arabinosylcytosine (ara-C) is the most effective nucleoside analogue for treatment of acute myelogenous leukemia. The cytotoxicity of ara-C depends on its conversion to the triphosphate ara-CTP. In plasma, a major metabolite of ara-C is its deamination product, arabinosyluracil (ara-U).

Cellular pharmacodynamics and plasma pharmacokinetics of parenterally infused hydroxyurea during a phase I clinical trial in chronic myelogenous leukemia.

Purpose: To determine the maximum-tolerated dose (MTD), toxicities, and antileukemic activity of hydroxyurea (HU) administered intravenously to patients with advanced-phase chronic myelogenous leukemia (CML). Further objectives were to analyze pharmacodynamic effect on deoxynucleotides (dNTPs) and to seek relationships between the decrease in dNTP pools and inhibition of DNA synthesis in CML blasts.

Patients And Methods: HU (8, 12, 18, 27, and 40 g/m2) was administered intravenously by a 24-hour continuous infusion to 19 adults with CML in blastic or accelerated phase.

Unilateral absent pulmonary perfusion due to bronchogenic carcinoma.

Ventilation-perfusion lung scans are commonly done in the diagnosis of pulmonary thromboembolic disease. We describe a patient in whom absent perfusion involving an entire lung was due to bronchogenic carcinoma. Echocardiography and chest computed tomography were essential tests in evaluating a nonembolic etiology.

Lichen nitidus of palms and soles.

Lichen nitidus occurs uncommonly on the palms and soles and has an unusual morphology at these sites. Two patients who presented with lesions on the palms and soles are reported. The first patient had rough papules with prominent keratotic plugs.

Incorporation of fludarabine and 1-beta-D-arabinofuranosylcytosine 5'-triphosphates by DNA polymerase alpha: affinity, interaction, and consequences.

Fludarabine and 1-beta-D-arabinofuranosylcytosine (ara-C) are effective nucleoside analogues for the treatment of leukemias when used as single agents or together. Recent trials of the fludarabine and ara-C therapy with or without growth factors suggested an improved clinical response by combining fludarabine and ara-C. The activity of these antimetabolites depends on their phosphorylation to the respective triphosphates, F-ara-ATP and ara-CTP.

Safety evaluation of wild apricot oil.

Wild apricot, a variety of Prunus armeniaca, grows in the hilly regions of India. The seeds yield 27% of kernels. The potential availability of the kernels is 40,000 tons/year and these yield 47% of oil.

Clinical experience with fludarabine in hemato-oncology.

Fludarabine monophosphate (Fludara) is a purine analogue which entered clinical trials in 1982. Although inactive in solid tumors, Fludara has marked activity in indolent lymphoproliferative disorders. The exact mechanism of action of Fludara is uncertain.

Pharmacology of purine nucleoside analogues.

Three new purine nucleoside analogues, pentostatin, cladribine and fludarabine, have demonstrated remarkable clinical activity in a variety of hematologic malignancies. Although they share structural similarities, their plasma pharmacology, metabolism, and mechanisms of action differ qualitatively and quantitatively. The plasma pharmacokinetics and the cellular pharmacodynamics are reviewed to provide a basis for dose schedules and rationales for combinations with other anticancer drugs.

Gemcitabine: preclinical pharmacology and mechanisms of action.

Gemcitabine is a nucleoside analog which exhibits metabolic characteristics that distinguish it from related compounds and may explain its activity in solid tumors. The active nucleotide forms are effectively accumulated to high concentrations in cells. This is due to both efficient phosphorylation and relatively slow elimination.

Clinical and laboratory studies of 2-chlorodeoxyadenosine +/- cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults.

Previous studies in pediatric patients with acute myelogenous leukemia (AML) have suggested that 2-chlorodeoxyadenosine (2CdA) is an effective therapeutic agent. Santana et al (J Clin Oncol 1992; 10: 364-370) reported a CR rate of 8/17 (95% Cl 23-72%) in children with relapsed AML and a median first CR of 21 months. The activity of 2CdA in adults with relapsed or refractory leukemia was therefore investigated in a phase I study.

Excision of 2',2'-difluorodeoxycytidine (gemcitabine) monophosphate residues from DNA.

The activity of gemcitabine (dFdC), an effective agent against solid tumors, depends on the incorporation of its triphosphate into DNA. In vitro investigations demonstrated that, depending on the sequence of template DNA, polymerases may pause after incorporation of gemcitabine nucleotide at either the 3'-terminal or 3'-penultimate position. Proofreading enzymes such as 3'-->5' exonucleases, which are associated with DNA polymerases, can excise mismatched deoxynucleotides from DNA.

Cutaneous focal mucinosis.

A 26-year-old male presented with asymptomatic, flesh coloured nodules on right elbow, forehead and right retroauricular region. A skin biopsy form the nodule stained with hematoxylin and eosin and special stain (mucicarmine) showed focal deposition of mucin in the dermis.

Influence of fludarabine on pharmacokinetics and pharmacodynamics of cytarabine: implications for a continuous infusion schedule.

Arabinosylcytosine (ara-C) is a cytotoxic agent with major activity against acute leukemias. To exert this effect, it must first be phosphorylated to its active 5'-triphosphate, ara-CTP, which is incorporated into DNA. Our previous studies demonstrated that preincubation with arabinosyl-2-fluoroadenine (F-ara-A) increased the rate of ara-CTP accumulation in leukemia cells when incubated with 10 microM ara-C.