All-trans retinoic acid in hematological malignancies, an update. GER (Gruppo Ematologico Retinoidi).

BACKGROUND AND OBJECTIVE: During the past ten years, the study of retinoids has undergone a total transformation. The Italian Society of Experimental Hematology decided to discuss these advances at a meeting in Florence on April 18, 1996. INFORMATION SOURCES: The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. In addition, all the authors of the present article have been actively working in the field of retinoids and have contributed several papers. Summaries of their oral presentations at the Florence meeting are reported in the Appendix to this review article. STATE OF ART AND PERSPECTIVES: One of the most important advances has been the elucidation of new molecular mechanisms of control of gene expression by retinoids. A number of new retinoids have been synthesized by chemists, some of which are being screened for potential clinical use, and a few have already had a tremendous impact on clinical practice. The most important achievements have been obtained in acute promyelocytic leukemia. In 1988 a Chinese group working in Shanghai showed that using all-trans retinoic acid (ATRA) alone 94% of acute promyelocytic leukemic patients obtained complete remission through differentiation of the leukemic clone. This result transformed a dream into reality and allowed researchers to move from laboratory experience to clinical applications of this differentiating therapy. Expanding the spectrum of hematological malignancies that may respond to ATRA remains a challenge; however, several results show some activity of retinoids alone or in combination with other drugs in juvenile chronic myeloid leukemia (CML), myelodysplastic syndrome, cutaneous T-cell lymphoma and CML. Particularly interesting are the studies that explored the potential clinical synergism of ATRA-based combination therapies with growth factors, other differentiating agents such as vitamin D3, immunomodulators like interferons, or chemotherapeutic agents, in particular Ara-C, all of which show promising in vitro effects when used in combination with retinoids.

Neonatal B lymphocyte subpopulations and method of delivery.

We studied four groups of healthy term newborn infants: (1) 11 infants born by vaginal delivery; (2) 11 infants born by elective cesarean section; (3) 10 infants born by emergency cesarean section with labor, and (4) 10 infants born by complicated vaginal delivery. Total and differential leukocyte counts, cortisol blood level, and B lymphocyte subpopulations (SmIg, sIgD, sIgM, CD19, CD20, CD21, CD23) were evaluated in cord blood samples from the four infant groups. Furthermore, the Pentothal blood level was measured in infants born by elective cesarean section and in their mothers at delivery. Higher total and differential leukocyte counts and cortisol blood levels were observed in group 1 and 4 infants as compared with group 2 and 3 infants. A significant correlation was observed between cortisol blood level and leukocyte counts. The percentages of positivity to cell surface markers of B lymphocyte subpopulations were significantly higher in infants born by elective cesarean section. A negative significant correlation of thiopentone with sIgM and CD21 was observed. These data indicate a significant influence of method of delivery and of thiopentone on B lymphocyte subpopulations.

Clinical pharmacokinetics: the pharmacological monitoring of plasmatic levels in therapy.

Recent developments of clinical pharmacology show that in particular circumstances the determination of the plasmatic levels of drugs seems to be the best way to insure the best dosage schedules for each patient. For this and other reasons, at the Hospital Pharmacological Service a clinical pharmacokinetic laboratory was set up about two years ago. It is involved both in pharmacokinetic research with the aim of pointing out the reasons of a quantitatively or qualitatively unusual response to the drug (generally lack of therapeutic effect or untoward effects) and in finding the best practical administration route for each patient of those drugs which show a high incidence of undesirable side effects. At the moment, salicylates, quinidine, phenobarbital, phenytoin, theophylline, digoxin and gentamicin are routinely monitored. Other drugs under examination are valporic acid, methotrexate, etc. In the present paper the first results obtained are reported.

Determination of quinidine and metabolites in urine by reverse-phase high-pressure liquid chromatography.

A new reverse-phase high-pressure liquid chromatography assay allowing simultaneous but separate quantitation of urinary levels of quinidine and its major metabolites, 2'-quinidinone, 3-OH-quinidine and a newly detected N-oxide, is described. The compounds were separated on a alkyl phenyl column using 0.05 M phosphate buffer pH 4.5/acetonitrile/tetrahydrofuran (80 : 15 : 5, v/v) as mobile phase and were detected by UV at lambda = 230 nm. The assay procedure includes extraction of the compounds from urine samples into a mixture of dichloromethane/isopropanol (4 : 1, v/v), evaporation of the organic extracts to dryness and reconstitution of the residue in acetonitrile. The new assay was compared to a modification of the Cramer and Isaksson fluorescence assay which has recently been recommended for analysis of quinidine in urine. The consistently higher quinidine levels observed in the fluorescence assay could be accounted for by the quinidine levels and metabolite carry-over as determined by HPLC.

Preliminary study of pharmacokinetics and metabolism of sodium 2-n-propylpentanoate in pig and human.

The pharmacokinetics of sodium 2-n-propyl-pentanoate have been studied in pig and human. The drug is excreted in the human urine as a mixture of glucuronide and other unidentified conjugates. It appears that no other conjugates can be found in pig's urine. Treatment with sulfatase does not identify sulfate-conjugates in human urine. Coadministration of acetyl salicylic acid (ASA) increases the fraction of glucuronide and other conjugates in human urine. The rate of renal excretion of the drug appears to be increased during concomitant administration of ASA.