Low-molecular-weight heparins in ischemic heart disease

PURPOSE OF REVIEW: The objective of this review was to summarize the recent developments regarding the use of low-molecular-weight heparins in the management of acute coronary syndromes. RECENT FINDINGS: In the setting of unstable angina and non-ST-elevation myocardial infarction, enoxaparin is superior to unfractionated heparin in reducing death, myocardial infarction, and recurrent ischemia both in the short-term and to 1 year. However, this does not necessarily imply a class effect of low-molecular-weight heparins in general. When combined with glycoprotein IIb/IIIa inhibitors, enoxaparin appears to be effective and safe even for patients treated according to an early invasive strategy. In patients receiving fibrinolytics for ST-elevation myocardial infarction, low-molecular-weight heparins are as effective as unfractionated heparin in maintaining patency of the infarct-related artery and in reducing the composite endpoint of death and reinfarction. However, serious bleeding is more common, especially among the elderly, and the optimal dosing regimen in ST-elevation myocardial infarction remains to be defined. SUMMARY: Low-molecular-weight heparins are safe and effective in the management of unstable angina and non-ST-elevation myocardial infarction, with or without concurrent administration of glycoprotein IIb/IIIa inhibitors. Ongoing studies will clarify the role of low-molecular-weight heparins as adjunctive therapy for fibrinolysis.     

Recombinant human thrombopoietin (rhTPO) after autologous bone marrow transplantation: a phase I pharmacokinetic and pharmacodynamic study

Thrombocytopenia following myelotoxic therapy is a common problem and when severe (<20,000/microl) can lead to severe morbidity and mortality. Thrombopoietin (TPO) is a naturally occurring glycosylated peptide which stimulates the differentiation of bone marrow stem cells into megakaryocyte progenitor cells, induces the expression of megakaryocyte differentiation markers, promotes megakaryocyte proliferation, polyploidization and, ultimately, the formation of increased numbers of platelets in the circulation. TPO has now been produced by recombinant technology and has entered clinical trials. This open label phase I study was designed to determine the safety, tolerance and pharmacokinetics of recombinant thrombopoietin (rhTPO) when administered to patients after undergoing high-dose chemotherapy followed by autologous bone marrow transplantation. rhTPO was administered intravenously by bolus injection at doses ranging from 0.3 to 4.8 microg/kg/day every 3 days to 30 patients and 0.6 microg/kg daily to three patients. rhTPO was begun the day after marrow infusion and continued until platelet recovery to >20,000/microl. G-CSF was concomitantly administered to promote myeloid recovery. Serious adverse events or neutralizing antibodies to rhTPO were not observed during the study. Median platelet recovery after ABMT was 19 days (range, 11-41). Neither the dose nor the schedule of rhTPO appeared to have any impact upon the time course of platelet recovery. In this phase I study, rhTPO was found to be well tolerated without the development of neutralizing antibodies and without compromising neutrophil recovery. Platelet recovery was similar for all doses studied warranting further evaluation in phase II and III trials designed to test for platelet recovery efficacy.     

The place of HDL in cholesterol management. A perspective from the National Cholesterol Educational Program

The guidelines developed by the Adult Treatment Panel of the National Cholesterol Education Program identified low density lipoprotein (LDL) as the major atherogenic lipoprotein, and high levels of LDL-cholesterol as the primary target for cholesterol-lowering therapy. Low levels of high density lipoprotein (HDL)-cholesterol were recognized as a major risk factor for coronary heart disease. This report reexamines in depth the recommendations of the Adult Treatment Panel on HDL-cholesterol. Two major questions are discussed: (1) Should HDL-cholesterol levels be measured in all adults, as recommended for total cholesterol? (2) Should patients found to have a low serum HDL [corrected]-cholesterol level (less than 35 mg/dL [less than 0.91 mmol/L]) enter medical therapy to raise the level? The guidelines of the Adult Treatment Panel are reaffirmed as appropriate from the current perspective. These guidelines recommend that HDL-cholesterol levels be determined in patients deemed to be at high risk for coronary heart disease and suggest that HDL measurement is optional for individuals with borderline-high total levels. The guidelines of the Adult Treatment Panel recommend that low HDL-cholesterol levels be raised mainly by hygienic means (ie, smoking cessation, weight loss, aerobic exercise). When drug therapy is required for high LDL-cholesterol levels in the presence of low HDL levels, cholesterol-lowering drugs that concomitantly raise HDL should be given first priority.     

Gastric emptying characteristics of a novel (13)C-octanoate-labeled muffin meal

GOALS: Determine the gastric emptying characteristics of a novel, 350-kcal test meal consisting of two muffins, using scintigraphy and the 13C-octanoate breath test (OBT). STUDY: Healthy volunteers underwent three studies on separate days within a 1-week period. On day 1, we measured emptying of the 350-kcal muffin test meal labeled simultaneously with 99mTc sulfur colloid and 13C-octanoate. On day 2, reproducibility of the OBT using a single-labeled 350-kcal test meal was assessed. On day 3, the effect of erythromycin on the 350-kcal OBT was determined. RESULTS: The mean (+/-SD) half-emptying time (T1/2) as measured by scintigraphy was 104 +/- 24 minutes, versus 212 +/- 52 minutes by OBT. There was a strong correlation between T1/2 determined by scintigraphy and the breath test (r = 0.83). Multiple linear regression analysis identified a significant relationship between T1/2 determined by scintigraphy and the 90-and 180-minute breath samples. There was a strong correlation (r = 0.830, slope = 0.732 +/- 0.120 [SE], intercept = 26.4 +/- 12.7) between the T1/2 obtained using the regression equation and the actual T1/2 obtained by scintigraphy. The mean T1/2 (+/-SD) for replicate determinations using the OBT was 209 +/- 52 minutes, compared with 196 +/- 42 minutes on days 1 and 2, respectively (not significant, p = 0.28, paired Student t test). Treatment with erythromycin on day 3 produced a significant decrease in T1/2 (155 +/- 49 minutes, p = 0.002). CONCLUSIONS: The 350-kcal muffin meal OBT provides a convenient, nonscintigraphic way of measuring solid-phase gastric emptying. Multiple linear regression appears promising as a method of analyzing OBT data and may allow for an abbreviated breath test protocol.     

Presumptive diagnosis and treatment of pulmonary tuberculosis based on radiographic findings

We analyzed the outcome of therapy for 139 patients who were treated for a presumptive diagnosis of pulmonary tuberculosis based on radiographic abnormalities. Patients who had acid-fast bacilli seen on sputum smears and patients who had received adequate therapy for tuberculosis in the past were excluded from the analysis. Accuracy of the diagnosis was determined by comparison of clinical and radiographic findings after 3 months of isoniazid, rifampin, and ethambutol, as well as the results of sputum cultures. Of 139 patients started on therapy presumptively, 66 (48%) were determined to have current tuberculosis (16 had positive cultures, 43 because of improvement in their chest films, and 7 because of clinical improvement). Adverse reactions requiring change of therapy occurred in six of 72 (8.3%) patients determined to have inactive tuberculosis. One patient had both tuberculosis and carcinoma found at bronchoscopy after 3 months of therapy. For purposes of comparison, chest radiographs of 59 patients documented by culture to have current tuberculosis were reviewed. Of these, 45 (70%) were improved at 3 months. Presumptive therapy is of benefit in that it stops progression of the disease at an early stage and decreases the potential for spread of tuberculous infection. In addition, such therapy coupled with systematic reevaluation of patients substantiates the diagnosis or indicates that further evaluation is needed. These benefits must be weighed against the adverse reactions and costs of overtreating patients with inactive disease. Determining the appropriateness of presumptive therapy must be based on local factors including prevalence of tuberculosis and available resources.     

Is an "a la carte" combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group

Randomized trials have shown the enhancement of efficacy with interferon alfa-2b and ribavirin (IFN-R) in comparison with interferon monotherapy (IFN) as first line treatment of chronic hepatitis C. Further definition of response based on disease, patient, and treatment characteristics is needed to determine the degree of benefit for the various patient subgroups. The aim of this study was to answer this question by analyzing the data from 1,744 naive patients included in trials that compared 24- or 48-week IFN-R treatment. Response factors were identified by logistic regression and receiver operating characteristics curves. Five independent characteristics were associated with a sustained loss of hepatitis C virus (HCV) RNA (<100 copies/mL) 24 weeks after the end of treatment: genotype 2 or 3, baseline viral load less than 3.5 million copies/mL, no or portal fibrosis, female gender, and age younger than 40 years. There was a significant advantage for IFN-R in comparison with IFN alone whatever the combination of factors. The most efficient strategy is to treat all patients for 24 weeks. If the 24-week polymerase chain reaction (PCR) is positive, treatment can be stopped. If the 24-week PCR is negative, patients with fewer than 4 favorable factors should be treated for an additional 24 weeks. Conclusion: The combination of IFN-R is better as first line treatment than IFN monotherapy. For patients who are PCR negative after 24 weeks of treatment, genotyping and baseline viral load, fibrosis stage, gender, and age are useful predictive factors in determining whether to continue an additional 24 weeks of treatment.     

Deoxyribonucleotide pools, base pairing, and sequence configuration affecting bromodeoxyuridine- and 2-aminopurine-induced mutagenesis.

Despite recent experiments showing that BrdUrd-induced mutagenesis can be independent of the level of bromouracil (BrUra) substitution [Kaufman, E.R. & Davidson, R.L. (1978) Proc. Natl. Acad. Sci. USA 75, 4982-4986; Aebersold, P.M. (1976) Mutat. Res. 36, 357-362], BrUra.G base mispairs are a major determinant of mutagenesis. We propose that the experiments cited above are sensitive predominantly to G . C leads to A . T transitions driven by the immeasurably small but highly mutagenic substitution of BrUra for cytosine and not by the gross substitution of BrUra for thymine in DNA. More generally, we show how accumulated evidence suggests that both BrdUrd and 2-aminopurine have two mutagenic effects intracellularly: perturbation of normal deoxyribonucleoside triphosphate pools and analogue mispairs in DNA. We propose a molecular basis for various observations of normal exogenous deoxyribonucleosides as synergists and counteragents to base analogue mutagenesis. A model is proposed to explain the antipolarity of BrdUrd and 2-aminopurine mutagenesis--i.e., why mutants at hot spots for induction by one base analogue are usually hot spots for reversion by the other. It is concluded that the configuration of the neighboring nucleotides surrounding the base analogue mispair, and not the base analogue's preference for inducing A . T leads to G . C or G . C leads to A . T errors, is responsible for the antipolarity of BrdUrd and 2-aminopurine mutagenesis.