Ileal bypass for hyperlipidemia

Partial ileal bypass (PIB) is a safe, effective, and lasting therapy for the reduction of lipids and lipoproteins in patients with hyperlipidemia. Following PIB, circulating plasma and low-density lipoprotein (LDL) cholesterol fall markedly, while high-density lipoprotein (HDL) cholesterol rises. The average plasma cholesterol lowering is 25% after diet, with a 40% reduction in the LDL-cholesterol fraction; concurrently, the HDL-cholesterol rises about 8%. These effects have been demonstrated to be maintained for up to 20 years. Currently, PIB is being used in the Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized controlled clinical trial designed to assess the effects of lipid reduction on mortality and morbidity in a postmyocardial infarction population with arteriographically demonstrated coronary atherosclerosis.

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Resumen La derivación (bypass) ileal parcial (DIP) es una modalidad terapéutica segura, efectiva y durable para la reducción de los lípidos y lipoproteínas en pacientes con hiperlipidemia. Después de la DIP, los niveles de colesterol plasmático y de colesterol de baja densidad descienden en forma marcada, en tanto que los de colesterol de alta densidad ascienden. El promedio de reducción del colesterol plasmático es de 25% después de dieta, con una reducción de 40% de la fracción del colesterol de baja densidad; al mismo tiempo, el colesterol de alta densidad asciende alrededor de un 8%. Se ha demostrado que tales efectos perduran hasta por 20 años. Actualmente se utiliza la DIP en el Programa de Control QuirÚrgico de la Hiperlipidemia (POSCH), un ensayo interinstitucional prospectivo y aleatorizado diseñado para evaluar los efectos de la reducción de los niveles de lípidos sobre la mortalidad y la morbilidad en la población que ha sufrido infarto miocárdico con arteriosclerosis coronaria arteriograficamente demostrada.

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Résumé L'opération décrite par l'auteur en 1963, le courtcircuit partiel d l'iléon représente une méthode thérapeutique dénuée de danger, efficace et durable pour obtenir la réduction des lipides et des lipoprotéines chez les malades qui présentent une hyperlipidémie. A la suite de l'intervention la fraction du cholestérol lipoprotéique de haute densité s'élève. La chute moyenne du cholestérol plasmatique est de l'ordre de 25%: la réduction est de 40% en ce qui concerne la fraction LDL du cholestérol (la fraction athérogène) alors que la fraction HDL (la fraction protectrice) s'élève environ de 8%. Ces effets se maintiennent depuis plus de 20 ans. Actuellement, le court-circuit iléal partiel est soumis à un essai clinique randomisé de contrôle destiné à apprécier les effets de la réduction des lipides sur la morbidité et la mortalité chez des malades qui ont subi un infarctus et chez qui l'artériographie a démontré une athérosclérose coronarienne.

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Supported in part by National Heart, Lung, and Blood Institute, NIH, grant #R10 HL15265.     

Resolution of late-developing periprosthetic breast infections without prosthesis removal

Based on prior experience with implant exposure, an aggressive regimen to eradicate periprosthetic infections has proven successful in delayed gram-positive and gram-negative bacterial infections and in atypical microbacterial infections. The objective of the salvage procedure is to retain a prosthesis, to maintain breast contour, and to avoid psychological and physical consequences of prosthesis removal. The salvage procedure involves topical antisepsis, contracture release if needed, systemic and topical antibiotics with intermittent or continuous irrigation, and reinforcement of incision lines in selected cases using local tissue flaps.     

A Prospective Follow-Up Study of Cognitive Functions After Electroconvulsive Therapy

The authors studied primarily nonmemory cognitive functioning in a sample of 13 melancholic patients tested prior to electroconvulsive therapy (ECT) and at various intervals during a 1-2 year post-ECT follow-up period. Compared with 13 age-matched normal controls, the patients performed significantly worse at baseline and immediately after the sixth ECT, but were not significantly different at the 30-day, 6-month, and 1-2 year assessments. At 1-2 years post-ECT, cognitive impairment among patients was substantially and significantly less than observed pre-ECT.     

Factors affecting place of death in Washington State, 1968–1981

A study was carried out to determine factors affecting place of death (home, hospital, nursing home or other places) among all 426,115 resident deaths in Washington State during 1968–1981, using death certificate information. Sixteen percent of deaths occurred at home, 74% in institutions (51% in hospitals, 23% in nursing homes) and 9% at other places. Age, marital status and cause of death all strongly affect place of death. Further, the effect of each factor was strongly dependent on the others. Sex had no effect on place of death after controlling for other factors. Elderly people died relatively more frequently in nursing homes, infants and middle aged people in hospitals and young adults in other places. The frequency of deaths at home was quite constant by age. Hospitals were the most common place of death following both vascular disease (including heart attack) and neoplasms, and nursing homes were the most common place of death following cerebrovascular disease (including stroke). Race, socioeconomic status and urban or rural residents affected the place of death only slightly or not at all. The place of death pattern changed little during the time period 1968–1981, except for a slight increase in frequency of home deaths and a corresponding decrease in the frequency of deaths in other places.Among cancer patients, the likelihood of death at home was positively associated with longer periods of survival after diagnosis. Cancer patients of hospitals serving targeted populations, such as veterans, were relatively more likely to die in a hospital and less likely to die in a nursing home compared to other cancer patients, suggesting that the targeted hospitals are sometimes serving a nursing home function. There was a marked difference in the terminal cancer caseload by hospital. The number of cancer deaths per cancer diagnosis varied widely across hospitals (0.1 to 1.6) and was unrelated to size of the hospital or level of services offered.Intervention aimed at affecting place of death, such as increasing the number of deaths at home, will need to take account of the joint effect of age, marital status and disease.Lincoln Polissar, Ph.D., is Associate Member, Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA and Associate Professor, Department of Biostatistics, University of Washington in Seattle. Richard K. Severson, M.S., is the Project Coordinator, Fred Hutchinson Cancer Research Center. Norman K. Brown, M.D., is Clinical Professor of Medicine, School of Medicine, University of Washington.This research was supported by NCI Grant Nos. NCI-SR18, CA 29770–03 Requests for reprints should be sent to Lincoln Polissar, Ph.D., Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104     

Expressions of resistance and cross-resistance in teniposide-resistant L1210 cells

Summary Resistance to teniposide (VM-26) by VM-26 selected resistant L1210 cells in culture was attributed to alterations in the flux of VM-26 across the plasma membrane and to functions of homogeneously staining regions that appeared on one or more chromosomes. In the present study, electrophoresis of membrane-cytosol fractions of these resistant sublines demonstrated a protein band, M_r 22 kd, that was not evident in similar fractions of drugsensitive L1210 cells or three revertant sublines. The distribution of this protein among various cellular fractions could be altered by manipulation of the concentration of calcium ions. A representative subline, LIa5 M, was observed to have vesicles that reacted with Sudan black B stain, an indication of altered lipid metabolism. The LIa5 M subline was cross-resistant to etoposide, vincristine, doxorubicin, amsacrine, and actinomycin D. Concentrations of VM-26 that inhibited cell division to the same extent caused an accumulation of fewer cells in the G₂ stage of cell division in LIa5 M cultures than in L1210 cultures. These observations indicate that the LIa5 M subline expressed multiple drug resistance, as well as changes in the expression of cytotoxicity to VM-26.This investigation was supported by Research Project Grant CA 35319, by Cancer Center Support (CORE) Grant CA 21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities.Recipient of research support from a training grant, American Cancer Society Grant IN-85-06, to the University of Tennessee Center for the Health Sciences     

A Hypothesis to Explain Divergent Findings Among Studies Comparing the Efficacy of Unilateral and Bilateral ECT in Depression

This article explains divergent reports on the relative efficacy of unilateral and bilateral electroconvulsive therapy (ECT) by hypothesizing a therapeutic effect of both seizure and electrical stimulus, with the seizure's effect based on its intensity and generalization. The effect of the stimulus is normally obscured by the seizure but emerges with reduced electrical dosage or elevated threshold. These circumstances favor a therapeutic advantage for bilateral ECT, which introduces more electrical charge into a larger and differently distributed volume of brain and induces greater seizure generalization, more diencephalic stimulation, and a relative decrease in left relative to right hemisphere electroencephalographic (EEG) frequencies.     

Minimizing Therapeutic Differences Between Bilateral and Unilateral Nondominant ECT

Conflicting results continue to be reported for studies contrasting the therapeutic efficacy of bilateral and unilateral nondominant electroconvulsive therapy (ECT). At least in part, the therapeutic advantage for bilateral ECT observed by some investigators may be related to the use of nonoptimum unilateral ECT technique. Consideration of technique-related factors, such as stimulus electrode location, contact at the electrode-scalp interface, stimulus dosing, and seizure monitoring, will allow unilateral ECT to be carried out with maximal therapeutic potency.     

Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion

Summary A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m² per day for 5 days and repeated every 21–28 days. The patient population had a median age of 55 years (range 38–76) and a median Karnofsky performance status of 80 (range 60–100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/l (range 100–4800) in 8 heavily pretreated patients treated at 350 mg/m² per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m² and had WBC nadirs of 800/l and 600l. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m² per day, nadir 85000/l). Neither hyponatremia nor symptomatic hypoosmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m² per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09–6.79 g/ml. Steady state was achieved in 14.5±5.9 h (mean ±SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t^1/2 of 5.3±3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543±150 g/ml h and reflected a cyclophosphamide total-body clearance (CL_TB) of 103±31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6–4.3 g/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3%±7.6% and 15.1%±2.0% of the administered daily dose, respectively. The t^1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m² as an i.v. bolus. The AUC of alkylating activity associated with the 5-day continuous infusion of cyclophosphamide is about three times greater than the AUC of alkylating activity calculated after a 1500-mg/m² bolus dose of cyclophosphamide. Daily urinary excretions of cyclophosphamide and alkylating activity associated with the 5-day continuous infusion schedule are similar to those reported after bolus doses of cyclophosphamide.     

CB 1954 revisited

Summary Although it has been the subject of considerable interest for 15 years, originally as a cytotoxic agent and more recently as a radiosensitizer, there is very little pharmacokinetic information on CB 1954 (2,4-dinitro-5-aziridinylbenzamide). We have developed a rapid high-performance liquid chromatography assay for the drug and its metabolites and applied it to detailed examination of the pharmacokinetics of CB 1954 in mice and dogs. With IV administration a dose of 50 mg/kg gave peak blood concentrations of 100 g/ml in mice, while 25 mg/kg gave peak palsma concentrations of 27 g/ml in dogs. Peak concentrations were 3 to 5-fold lower for the IP route in mice and the oral route in dogs, and the bioavailabilities were 85% and 40%, respectively. Elimination t_1/2 values were 1.4–2 h in mice and 2.5–4 h in dogs and were independent of route of administration. Plasma protein binding was 57% but tissue penetration in mice was generally good. Tumour: plasma ratios were 50%–90%, while brain: plasma ratios were lower, at 37%–50%. The parent drug and several metabolites were identified and quantified in mouse urine, the total recovery being 24%–29%, of which 16%–25% was parent drug. The metabolites were also found in the circulation and in tissues. No changes in pharmacokinetics were seen with repeated dosing in mice or with administration of the protective agent phenyl AIC. Phenobarbitone pretreatment produced a small reduction in elimination t_1/2, mainly by accelerating aziridine ring removal. Allopurinol increased the blood levels of the 5-amino nitroreduction product. These studies provide a pharmacokinetic basis for interpreting the antitumour activity and toxicity of CB 1954, as well as for the development of new mixed-function sensitizers.