Human Aldehyde Dehydrogenase: Kinetic Identification of the Isozyme for Which Biogenic Aldehydes and Acetaldehyde Compete

Michaelis constants and maximal velocities for phenylacetaldehyde (a metabolite of phenylethylamine), 3,4-dihydroxyphenylacetaldehyde (a metabolite of dopamine), 5-hydroxyindole acetaldehyde (a metabolite of serotonin), and 3,4-dihydroxyphenylglycolaldehyde (a metabolite of epinephrine and norepinephrine) have been determined for both cytoplasmic (E1) and mitochondrial (E2) isozymes of human liver aldehyde dehydrogenase (EC 1.2.1.3). Kinetic constants with biogenic aldehydes have never been previously determined for individual homogeneous isozymes of aldehyde dehydrogenase from any species. Mathematical treatment of these constants suggests that competition with acetaldehyde during alcohol metabolism would severely inhibit dehydrogenation of biogenic aldehydes with the mitochondrial and not the cytoplasmic isozyme of human liver aldehyde dehydrogenase.     

Dose-Additive Inhibition of Intake of Ethanol by Cholecystokinin and Bombesin

Cholecystokinin (CCK) and bombesin (BBS) are neuropeptides of the brain and gut which have been shown to inhibit intake of ethanol. CCK octapeptide and BBS tetradecapeptide were injected intraperitoneally in both single doses and combinations of doses to determine interactions of the two peptides in the control of consumption of ethanol. Water-deprived rats were given access to 5% w/v ethanol for 30 min, followed by a 30-min access to water, daily. One minute before presentation of ethanol, rats were injected with either saline or one of ten peptide solutions (three of CCK alone, three of BBS alone, and four combinations of both). Results from the injections of single peptides were used to determine predicted inhibitions of the peptide combinations, assuming perfect additivity of doses. None of the actual values of inhibition of intake of ethanol by peptide combinations differed significantly from its predicted additive value. Endogenous CCK-like and BBS-like peptides may suppress intake of ethanol by an additive mechanism of inhibition.     

Effect of hemodilution on brain tissue during global ischemia

This study evaluates the effect of blood volume and hematocrit changes on brain tissue during temporary global ischemia. Normal saline was administered intravenously to 55 gerbils to achieve hypo-, normo-, and hypervolemic hemodilution and uniform 30% hematocrit reduction. Each group had unilateral carotid artery ligation and temporary (20 minute) contralateral carotid occlusion. After ten days or death, brains were harvested, preserved in formalin, sectioned in a manner which provided adequate samples of both cortex and hippocampus, and stained with H&E and luxol fast blue. They were then examined and staged microscopically for white and gray matter infarction, edema, and neuronal injury and loss. Histologic studies were performed in a randomized and blinded manner and were classified by one of four categories: normal, minimal, moderate, and severe changes. Three of ten (30%) controls survived ten days but had severe neuronal loss, minimal cerebral edema and a minimal to moderate number of white matter strokes. Survival was best in animals treated with hypovolemic hemodilution (43%). Other rates were: normovolemic (33%), controls (30%), and hypervolemic (8.3%). The degree of brain tissue damage was markedly less in the normovolemic group. In this model, normovolemic hemodilution followed by hypovolemic hemodilution offered the best overall cerebral protection during global ischemia.     

Effects of new fish oil derivative on fatty acid phospholipid-membrane pattern in a group of Crohn's disease patients

Fish oil has been recently proposed as a possible effective treatment in inflammatory bowel disease (IBD); however, a lot of annoying side effects (ie, belching, halitosis, diarrhea, etc) affect patient compliance. We carried out a study of patient tolerance in a group of Crohn's disease (CD) patients with a new fish oil derivative consisting of 500-mg capsules of eicosapentaenoic-docosahexaenoic (EPA 40%-DHA 20%), a free fatty acid mixture (Purepa), and we also evaluated its incorporation into phospholipids, both in plasma and in red cell membranes. Five groups of 10 CD patients in remission received nine Purepa capsules daily in four different preparations (A: uncoated, B: coated, pH 5.5; C: coated, pH 5.5, 60 min time release; D: coated, pH 6.9) and 12 × 1-g capsules daily of a triglyceride preparation (Max-EPA, EPA 18%-DHA 10%), respectively. We coated three of the four Purepa preparations in order to delay the release of contents in an attempt to minimize the side effects. After six weeks of treatment, the group taking Purepa capsules, coated, pH 5.5, 60 min time release (group C) showed the best incorporation of EPA and DHA in red blood cell phospholipid membranes (EPA from 0.2 to 4.4%, DHA from 3.7 to 6.3%), and no side effects were registered, whereas in all other groups side effects were experienced in 50% or more of subjects. This new preparation will make it possible to treat patients for long periods.     

Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: A phase I study

Background: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin. Methods: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m², three patients were treated at 90 mg/m², and five patients received 120 mg/m². A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation. Results: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p<0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m². Conclusions: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC. The results of this study were presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

Shelf-lives and factors affecting the stability of morphine sulphate and meperidine (pethidine) hydrochloride in plastic syringes for use in patient-controlled analgesic devices

Published reports regarding the stability of morphine are at variance, especially in syringes used in patient-controlled analgesia (PCA) devices. In addition to the effects of container type and vehicle, reasons for this variation include the effect of excipients temperature and light during storage. Furthermore, the literature varies regarding the mechanisms of decomposition for morphine. To our knowledge, the stability of meperidine (pethidine) stored in plastic syringes has not been reported. The purposes of this study were to investigate the stability of morphine sulphate (1 and 5 mg/ml) and meperidine hydrochloride (5 and 10 mg/ml) in plastic syringes for use in PCA devices for a duration of 12 weeks, and evaluate the influence of light (240 foot-candies), temperature (-20, 4 and 23d?C), diluent (5% dextrose or normal saline), and drug concentration on the stability of these narcotic analgesics. Samples were taken bi-weekly for solutions protected from light and weekly for solutions exposed to light. Morphine sulphate and meperidine hydrochloride concentrations were quantified using independent, stability-indicating, high performance liquid chromatographic assays. The within-day and between-day coefficients of variation for these assays were 4% over each of the concentration ranges studied. Under the conditions of this study, it is proposed that although decomposition of morphine to its main product, pseudomorphine, can be interpreted using first-order kinetics, consecutive (to form the N-oxide) and parallel mechanisms (to form apomorphine) exist. Morphine solutions were more stable in normal saline than in 5% dextrose. SheIf-life data indicate that morphine is stable for at least 6 weeks when protected from light. Exposure to light accelerates morphine decomposition two to six-fold depending on the concentration, and the shelf-life is reduced to about 1 week in some instances. Meperidine solutions in both vehicles under all conditions had shelf-lives of at least 12 weeks. No effects of light were detected and no changes in solution colour were observed. This study illustrates that patients using PCA devices must be advised about shelf-lives as well as correct storage conditions to protect solutions of these drugs from environmental factors that may alter shelf-lives. Pharmacists should also note that other formulation factors such as: antioxidants, preservations, buffers, impurities, and the source and quality of containers, may significantly alter the shelf-lives of these drugs.