Acute cardiovascular effects of tranylcypromine: correlation with plasma drug, metabolite, norepinephrine, and MHPG levels

BACKGROUND: Recent case reports, small series, and uncontrolled, unblinded studies have suggested that tranylcypromine may produce pressor reactions in some patients. However, the physiologic mechanism underlying this cardiovascular change is unknown. METHOD: The authors studied the acute cardiovascular effects of tranylcypromine in 13 patients and attempted to correlate these changes with plasma measures of parent drug, possible pressor metabolites, norepinephrine, and 3-methoxy-4-hydroxyphenylglycol. RESULTS: Significant elevations in supine blood pressure occurred after administration of tranylcypromine and correlated with tranylcypromine dose. Similar changes were not observed in standing blood pressure measurements. In fact, an orthostatic decrease in blood pressure and increase in heart rate were observed. Amphetamine-like metabolites were not found. CONCLUSIONS: The authors speculate on possible mechanisms underlying these opposite cardiovascular effects.     

Development of a high performance zinc-62/copper-62 radionuclide generator for positron emission tomography.

Clinical utilisation of positron emission tomography could be enhanced by the availability of short-lived radionuclides derived from generator systems. The zinc-62/copper-62 combination is one such system which could be used as a source for a number of copper-62 radiopharmaceuticals. We have developed and optimised a high activity (5.6 GBq, 150 mCi) zinc-62/copper-62 generator to provide 62Cu in a form that is suitable for direct labelling of pyruvaldehyde-bis-(N4-methylthiosemicarbazone)-copper(II), Cu(PTSM). The distribution coefficients of Zn(II) and Cu(II) between anion-exchange resin and various hydrochloric acid/organic solvent mixtures were measured. Based on these measurements a generator eluent of 0.3 M HCl/40% ethanol provided 62Cu in greater than 90% yield in a 3-ml volume. A very low 62Zn breakthrough of less than 3 x 10(-7)% was achieved. Copper-PTSM was successfully labelled with the no-carrier-added 62Cu eluent directly from the generator with 94% radiochemical yield.     

A system for assaying homologous recombination at the endogenous human thymidine kinase gene.

A system for assaying human interchromosomal recombination in vitro was developed, using a cell line containing two different mutant thymidine kinase genes (TK) on chromosomes 17. Heteroalleles were generated in the TK+/+ parent B-lymphoblast cell line WIL-2 by repeated exposure to the alkylating nitrogen mustard ICR-191, which preferentially causes +1 or -1 frameshifts. Resulting TK-/- mutants were selected in medium containing the toxic thymidine analog trifluorothymidine. Mutations were characterized by exon-specific polymerase chain reaction amplification and direct sequencing. In two lines, heterozygous frameshifts were located in exons 4 and 7 of the TK gene separated by approximately 8 kilobases. These lines undergo spontaneous reversion to TK+ at a frequency of less than 10(-7), and revertants can be selected in cytidine/hypoxanthine/aminopterin/thymidine medium. The nature and location of these heteroallelic mutations make large deletions, rearrangements, nondisjunction, and reduplication unlikely mechanisms for reversion to TK+. The mode of reversion to TK+ was specifically assessed by DNA sequencing, use of single-strand conformation polymorphisms, and analysis of various restriction fragment length polymorphisms (RFLPs) linked to the TK gene on chromosome 17. Our data suggest that a proportion of revertants has undergone recombination and gene conversion at the TK locus, with concomitant loss of frameshifts and allele loss at linked RFLPs. Models are presented for the origin of two recombinants.     

Liver transplantation for erythropoietic protoporphyria liver disease.

In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this heme precursor. Some patients will develop progressive liver disease that may ultimately require liver transplantation. However, excessive production of protoporphyrin by the bone marrow continues after transplantation, which may cause recurrent disease in the allograft. This study was performed to define post-transplant survival, the risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease. The patients studied consisted of twelve males and eight females, with an average age of 31 (range, 13-56) years at the time of transplantation. The estimated maximum MELD score prior to transplant was 21 (range, 15-29). Unique complications in the perioperative period were light induced tissue damage in four patients and neuropathy in six, requiring prolonged mechanical ventilation in four. Patient and graft survival rates were 85% at 1 year, 69% at 5 years, and 47% at 10 years. Recurrent EPP liver disease occurred in 11 of 17 patients (65%) who survived more than 2 months. Three patients were retransplanted at 1.8, 12.6, and 14.5 years after the initial transplant for recurrent EPP liver disease. In conclusion, the 5-year patient survival rate in patients transplanted for EPP liver disease is good, but the recurrence of EPP liver disease appears to diminish long term graft and patient survival.     

A quick, sensitive high-performance liquid chromatography assay for monoethylglycinexylidide and lignocaine in serum/plasma using solid-phase extraction.

Recent advances in the investigation of liver disease and transplantation have seen the introduction of lignocaine as a probe of liver function. For this purpose, an assay that is sensitive and rapid is required for the major metabolite of lignocaine, monoethylglycinexylidide (MEGX). We have developed an accurate, low-cost high-performance liquid chromatography (HPLC) method using Bond-Elut phenyl (1 cc) cartridges for sample preparation. The total preparation time for five samples is less than 10 min and the run time is approximately 10 min/sample. Each cartridge can be used at least four times. Simultaneous measurement of another metabolite of lignocaine, glycinexylidide (GX), can be achieved by adjustment of the mobile phase and flow rate. The chromatogram is monitored with an UV detector at 210 nm. The inter- and intra-assay coefficients of variation for MEGX (10-250 micrograms/L) and lignocaine (100-2,000 micrograms/L) are less than 9.5 and less than 2%, respectively, with recoveries for MEGX, trimethoprim (internal standard), and lignocaine all greater than 85%. This method offers a rapid, sensitive assay that is clinically useful in the new role for lignocaine/MEGX in dynamic liver function testing.     

The abnormal anatomy of cleft lip and its correction

Summary The importance of the premaxillary position, size and shape in the development of the face and nose is discussed. The anthropological development of the premaxilla is studied. These factors are to be considered when cleft lip repairs are being planned and developed. Several cases are presented and discussed.     

Pharmacogenetic screening and therapeutic drugs.

BACKGROUND: Pharmacogenetics is the science of the influence of heredity on pharmacological response. ISSUES: The cost of severe adverse drug reactions in individuals has been estimated in the US alone to be in excess of US$4 billion. It has been argued that in a significant proportion of cases, the efficacy and toxicity profiles of drug therapy would be substantially improved in individuals if characteristics due to genetic variation were taken into account. Methods are now available, which make screening for susceptibility feasible. CONCLUSIONS: There are several therapeutic areas in which screening may give rise to significant improvements in outcome with cost-benefits to both the individual and the community. However, there is currently a lack of data on which cost-benefit analysis can be based. The challenge is to provide this information for new drugs, and for drugs with established therapeutic roles.