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J Higgins

Publications and source records attributed to J Higgins.

At least 19 recordsLinked to original sources
PubMed1995

Cloning, expression and characterization of biologically active feline tumour necrosis factor-alpha.

We report the cloning, expression and characterization of biologically active feline tumour necrosis factor-alpha (fTNF-alpha). Messenger RNA was extracted from feline peritoneal macrophage cultures and used to synthesize cDNA for polymerase chain reaction (PCR) amplification. The PCR products were cloned into the plasmid vector pCRII and sequenced, showing 99.3% homology with a published fTNF-alpha gene sequence. Subcloning into the vector pGEX-2T and subsequent expression resulted in a 43 kDa fusion protein of fTNF-alpha and glutathione S-transferase (GST). Thrombin cleavage of the fusion protein yielded a 17 kDa protein. This protein cross-reacted with a monoclonal anti-human TNF-alpha antibody in Western blotting, but not with a polyclonal anti-murine TNF-alpha serum. Recombinant fTNF-alpha (rfTNF-alpha) and rfTNF-alpha-GST had a CD50 of 15 ng ml-1 and 230 ng ml-1, respectively, in the L929 cytotoxicity assay. Cats given rfTNF-alpha-GST intravenously manifested the typical biological effects of TNF-alpha, including fever, depression, and piloerection. The rfTNF-alpha-GST upregulated IL-2 receptor and MHC-II antigen expression on peripheral blood mononuclear cells stimulated in vitro, but had no effect on TNF-alpha receptor and MHC-I antigen expression.

Animals↗
PubMed1995

Alveolar macrophage cytokine and growth factor production in a rat model of crocidolite-induced pulmonary inflammation and fibrosis.

The present study was undertaken to further define the role of alveolar macrophages (AM) in the pulmonary response to crocidolite fibers. Briefly, groups of 4 male F344 rats were intratracheally instilled with saline or saline suspensions of crocidolite at 2 or 20 mg/kg body weight. Animals were sacrificed 3, 7, 14, and 28 d after exposure and the lung response was characterized by analysis of bronchoalveolar lavage fluid (BALF) for markers of lung injury and inflammation. AM obtained in BALF were cultured and their production of the pro-inflammatory cytokines, tumor necrosis factor alpha (TNF alpha), and interleukin-1 (IL-1) were characterized along with fibronectin, a protein known to stimulate fibroblast migration and proliferation. Lung hydroxyproline content was determined 28 d after exposure and lung histopathology was characterized on d 28 and 90 after exposure. Crocidolite instillation resulted in transient dose-related pulmonary inflammation as evidenced by increased numbers of BALF neutrophils at the low dose and neutrophils, macrophages, and lymphocytes at the high dose. Cytotoxicity and increased permeability were demonstrated by increased levels of BALF lactate dehydrogenase (LDH) and total protein, respectively. AM TNF alpha and IL-1 production were increased only at the high crocidolite dose. This cytokine response was greatest at d 3 and decreased thereafter. AM TNF alpha and IL-1 release were positively correlated with the increased BALF neutrophils. In contrast to TNF alpha and IL-1, AM fibronectin release was increased at both the low and high doses, with the magnitude of response increasing over time. Consistent with previous acute asbestos inhalation studies, histopathology revealed inflammation localized at the level of the terminal bronchioles and alveolar ducts. Fibrosis was demonstrated at both doses by increased trichrome staining of lung tissue sections. Only the high dose resulted in a detectable increase in lung hydroxyproline. Given the bioactivities of TNF alpha, IL-1, and fibronectin, their increased production after crocidolite exposure indicates they contribute to the pulmonary inflammation and fibrosis occurring with this mineral fiber. In addition, the correlation of increased AM TNF alpha and IL-1 production with increased BALF neutrophils supports a role for these cytokines in crocidolite-induced inflammatory cell recruitment. Lastly, association of a persistent increase in AM fibronectin production with an eventual increase in lung collagen deposition extends the growing database indicating this response is a predictive marker of pulmonary fibrosis.

Analysis of Variance↗
PubMed1994

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up.

The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations > 3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.

Alanine Transaminase↗
PubMed1994

Infection of cats with molecularly cloned and biological isolates of the feline immunodeficiency virus.

Molecularly cloned viruses are considered essential reagents for characterizing viral domains responsible for infectivity and disease pathogenesis in the host. The infectivity and hematological alterations associated with two molecularly cloned isolates of feline immunodeficiency virus (FIV-pPPR and FIV-pF34) and an uncloned isolate (FIV-PPR) were assessed by inoculation of cats. Inoculated cats were tested for viral antibody, viremia, and clinical pathological disease. Peripheral blood mononuclear cells isolated from inoculated cats were assayed for virus infection by virus isolation, amplification of proviral DNA (by polymerase chain reaction), and in situ hybridization for viral RNA. Over 50% of the cats inoculated with cloned virus FIV-pF34 failed to seroconvert even when coinfected with feline leukemia virus; these cats were consistently virus positive only by amplification of proviral DNA. All cats inoculated with cloned virus FIV-pPPR seroconverted and were found virus positive by at least two of three virus detection assays. Both cloned viruses were less capable of suppressing CD4:CD8 ratios when compared to the biological isolates from which they were cloned. Isolates which replicate efficiently in feline peripheral blood mononuclear cells (PBMC), i.e., FIV-pPPR or biological FIV-PPR, caused greater virus load and lower CD4:CD8 ratios when compared to cloned FIV-pF34, which replicates efficiently in feline adherent cell lines and macrophages but poorly in primary feline PBMC. Molecular clones FIV-pF34 and FIV-pPPR will be useful reagents for characterization of viral determinants of virus load and possibly, cell tropism in vivo.

Animals↗
PubMed1994

An experimental study of primary feline immunodeficiency virus infection in cats and a historical comparison to acute simian and human immunodeficiency virus diseases.

Sixteen adolescent specific pathogen free cats were inoculated with the Petaluma strain of feline immunodeficiency virus (FIV) and two cats were then necropsied at each of 5, 10, 21, 28, 42, 56, 70, and 84 day time points following infection. Lymphadenopathy gradually increased starting at Day 10 and persisted for the duration. Gross clinical signs of fever, mild to severe malaise, anorexia, diarrhea, dehydration, and generalized soreness appeared around Day 42, peaked at Day 56, and disappeared by Days 70-84 post-infection. Leukopenia, associated initially with a mild lymphopenia and later by both a mild lymphopenia and a severe neutropenia, appeared 14-28 days following infection, troughed at Day 56, and persisted thereafter. The CD4+:CD8+ T cell ratio started to decrease around Day 28, reaching a nadir at Days 56-70. This decrease was due to a decline in the absolute numbers and percentage of CD4+ T cells and an increase in the percentage of CD8+ T cells. Significant histopathologic lesions included myeloid hyperplasia between Days 56-70 post-infection; thymitis with cortical involution and follicular hyperplasia starting at Day 42; lymphoid hyperplasia of peripheral and mesenteric nodes, spleen and tonsils beginning around Day 42; typhlitis most evident from Day 56 onward, and an interstitial nephritis and pneumonitis that was most intense after Day 42. Virus was isolated from peripheral blood mononuclear cells (PBMC) beginning 2 weeks post-infection, and plasma viremia appeared 1 week later. Plasma and PBMC-associated viremia peaked at 42-56 days following infection and decreased abruptly thereafter. Proviral DNA was detectable as early as 5 days after infection in blood leukocytes and after 10 days in other organs. The central nervous system, lungs, thymus, tonsils and mesenteric lymph nodes were the earliest sites of virus localization. Antibodies to the FIV capsid protein appeared 14 days following infection and reached peak levels by Days 42-56. Abnormalities occurring during the primary stage of FIV infection were consistent with those described for acute simian and human immunodeficiency virus-induced disease.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Bepridil improves left ventricular performance in patients with angina pectoris.

Patients with coronary artery disease and angina pectoris have abnormalities of left ventricular (LV) diastolic performance. These abnormalities, which exist when the patients are at rest and not experiencing angina, are presumably secondary to abnormalities of intracellular calcium metabolism. Twenty-three patients with chronic exertional angina pectoris participated in a placebo-controlled, randomized, cross-over trial of bepridil hydrochloride. Angina frequency, nitroglycerin (NTG) consumption, and treadmill exercise capacity were assessed, and each patient underwent first-pass radionuclide cineangiography while receiving placebo or bepridil to assess LV performance. Bepridil decreased angina frequency from 8.5 +/- 0.6 to 4.4 +/- 1.5 episodes per week (p < 0.01) and NTG consumption from 7.2 +/- 2.4 to 3.6 +/- 1.5 tablets per week (p < 0.01). Total treadmill exercise time, time to onset of angina, and time to 1-mm ST segment depression increased significantly during bepridil therapy. Cardiac output (CO), stroke volume (SV), and ejection fraction (EF) increased at rest and during peak upright bicycle exercise. Peak ejection rate and peak filling rate increased, and time to peak ejection rate and time to peak filling rate decreased at rest and at peak exercise during bepridil therapy. In addition, early diastolic filling fraction increased and atrial filling volume decreased during bepridil treatment. Bepridil is effective as monotherapy for treatment of patients with exertional angina; its use is associated with increased exercise capacity and decreased angina frequency and NTG consumption as well as improved LV systolic and diastolic performance at rest and during peak exercise.

Adult↗
PubMed1992

Effects of antianginal therapy on left ventricular systolic and diastolic performance: comparison of the response to bepridil, propranolol, and diltiazem.

Abnormalities of left ventricular (LV) systolic performance develop during exercise in patients with coronary artery disease (CAD) as a result of ischemia-induced regional wall motion abnormalities. Like patients with hypertension and those with hypertrophic cardiomyopathy, patients with CAD display abnormalities of LV diastolic performance under basal conditions in the absence of ischemia. The purpose of these studies was to compare the effects of bepridil versus those of propranolol or diltiazem in patients with exertional angina pectoris. LV systolic and diastolic performance were assessed at rest and during peak upright bicycle exercise by first-pass radionuclide ventriculography. Compared with propranolol, bepridil increased exercise capacity, cardiac output, and stroke volume and decreased systemic vascular resistance. Compared with diltiazem, bepridil increased exercise capacity, peak filling rate, and early diastolic filling fraction and decreased systemic vascular resistance, heart rate, time to peak filling rate, and atrial filling volume. Bepridil therapy is associated with improved exercise capacity and decreased anginal frequency and nitroglycerin consumption. In addition, its use is accompanied by favorable changes in LV systolic and diastolic function at rest and during exercise. These changes are consistent with benefits resulting from resolution of myocardial ischemia as well as from positive lusitropic effects of bepridil on the ventricular myocardium.

Angina Pectoris↗
PubMed1992

Menopausal bone loss is partially regulated by dietary intake of vitamin D.

Five years ago we reported results from a cross-sectional study of the effect of nutritional factors on calcium-regulating hormones and bone loss in perimenopausal women. We found an inverse correlation between serum 25-hydroxyvitamin D (25OHD) and immunoreactive parathyroid hormone (PTH), and we postulated that over time, women with lower 25OHD would lose more bone because of increased bone remodeling induced by secondary hyperparathyroidism. We have followed 38 of these women for 5 years. Twenty-two have gone through menopause and we are reporting observations on these 22 subjects. Bone mineral analysis was performed twice a year at the distal and mid-radius using single-photon absorptiometry. The slope of the bone mineral content curve was calculated by least squares. Bone loss increased within 6 months of the rise in serum follicle stimulating hormone (FSH) to greater than 40 mIU/ml. We continued to see a negative correlation between 25OHD and PTH (r = -0.450, P = 0.03). Premenopause, PTH was negatively correlated with the proximal bone mineral content (PBMC) slope (-0.604, P = 0.002). The distal bone mineral content (DBMC) 5-year slope was correlated with dietary vitamin D (r = 0.509, P = 0.02), the higher the intake, the less negative the slope. The 5-year PBMC slope was negatively correlated with serum osteocalcin (OC) levels (r = -0.382, P = 0.08). Before menopause, the change in PBMC was positively correlated with OC (r = 0.450, P = 0.03). Postmenopause, the correlation with DBMC slope was negative (r = -0.506, P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

25-Hydroxyvitamin D 2↗
PubMed1992

Stimulation of rat alveolar macrophage fibronectin release in a cadmium chloride model of lung injury and fibrosis.

Rats were exposed to saline or cadmium chloride (CdCl2) at 25, 100, or 400 micrograms/kg body weight by intratracheal instillation. At 3, 7, 14, and 28 days after exposure five animals/treatment were euthanized, the lungs were lavaged, and bronchoalveolar lavage fluid (BALF) was analyzed for lactate dehydrogenase (LDH), total protein, N-acetylglucosamindase (NAG), and cell number, type, and viability. Lung hydroxyproline concentration was characterized as a marker of lung collagen. Alveolar macrophages (AM) obtained in BALF were cultured and the release of fibronectin and TNF was determined. Lung tissue was examined microscopically at 28 and 90 days after exposure. Exposure to CdCl2 resulted in lung injury and inflammation demonstrated by increases in BALF LDH, total protein, NAG, and inflammatory cells. AM TNF release was not significantly changed by CdCl2 treatment. All doses of CdCl2 stimulated AM fibronectin secretion, a response which persisted throughout the 28-day postexposure period examined. Pulmonary fibrosis was demonstrated biochemically and/or histologically (trichrome staining tissue) at all CdCl2 dose levels. The association of CdCl2-induced AM fibronectin release with lung fibrosis confirms and extends previous observations relating AM-derived fibronectin to the development of interstitial lung disease and provides further evidence that the persistent increase in AM fibronectin release represents an early indicator of fibrosis.

Animals↗
PubMed1992

Interaction of acute feline herpesvirus-1 and chronic feline immunodeficiency virus infections in experimentally infected specific pathogen free cats.

Cats with or without chronic feline immunodeficiency virus (FIV) infection were exposed to feline herpesvirus, type 1 (FHV-1). FIV infected cats became sicker than non-FIV infected cats and required more supportive treatment. However, there were no differences in the length of their illness or in the levels and duration of FHV-1 shedding. FHV-1 infection caused a transient neutrophilia at Day 7 with a rapid return to preinfection levels. The neutrophilia coincided with a transient lymphopenia that was accompanied by a decline in both CD4+ and CD8+ T-lymphocytes. A brief decrease in the CD4+/CD8+ T-lymphocyte ratio occurred at Day 14 in both FIV infected and non-infected cats. This decrease was mainly the result of an absolute and transient increase in CD8+ T-lymphocytes. CD4+ and CD8+ T-lymphocyte numbers and CD4+/CD8+ T-lymphocyte ratios returned to baseline within 4-8 weeks in both FIV infected and non-infected cats. FIV infected cats produced less FHV-1 neutralizing antibodies during the first 3 weeks of infection than non-FIV infected animals. The IgM FHV-1 antibody response was depressed in FIV infected cats whereas the IgG antibody response was unaffected. FHV-1 infection evoked a comparable transient loss of lymphocyte blastogenic responses to concanavalin A and pokeweed mitogen in both FIV infected and non-infected cats. However, response to pokeweed mitogen took longer to return to normal in FIV infected animals. Lymphocytes from FIV infected cats had a greater and more sustained proliferative response to FHV-1 antigen than non-FIV infected cats. The ongoing IgG antibody response to FIV was not affected by FHV-1 infection.

Acute Disease↗
PubMed1992

Effects of fosinopril on cardiac function in patients with hypertension. Radionuclide assessment of left ventricular systolic and diastolic performance.

Numerous pharmacologic agents are capable of lowering the blood pressure of hypertensive patients; however, each drug has a characteristic side effect profile and effect on cardiac performance. In this study, the hemodynamic effects of the angiotensin converting enzyme inhibitor fosinopril were assessed at rest and at peak upright bicycle exercise by first-pass radionuclide cineangiography in 12 patients with essential hypertension. Fosinopril reduced blood pressure at rest in the seated position from 152/101 to 131/85 mm Hg (P less than .01) and at peak exercise from 206/103 to 184/91 mm Hg (P less than .01). Fosinopril therapy was associated with an increase in stroke volume and cardiac output and a decrease in systemic vascular resistance at rest and during peak exercise. Both peak ejection rate and peak filling rate increased significantly at rest during fosinopril therapy. The unique cardiotropic response to fosinopril may reflect its effects on the myocardial renin-angiotensin system, and suggests that this agent may offer a therapeutic advantage compared with other angiotensin converting enzyme inhibitors.

Adolescent↗
PubMed1992

Comparison of the cardiac and hemodynamic effects of lisinopril and atenolol in patients with hypertension: therapeutic implications.

The antihypertensive and hemodynamic effects of lisinopril and atenolol were evaluated in 21 patients with mild-to-moderate essential hypertension. Left ventricular systolic and diastolic performances were assessed prior to and following treatment by first-pass radionuclide cineangiography at rest and during peak upright bicycle exercise. Both lisinopril and atenolol treatment significantly reduced the blood pressure. Lisinopril therapy was associated with a reduction in systemic vascular resistance and left ventricular end-diastolic and end-systolic volumes but no change in stroke volume, cardiac output, peak ejection rate, peak filling rate, time to peak ejection rate, or time to peak filling rate. In contrast, atenolol therapy was associated with an increase in end-diastolic volume and stroke volume but no change in cardiac output; the left ventricular peak ejection and peak filling rates were decreased by atenolol treatment. Although both lisinopril and atenolol each significantly reduced the blood pressure, lisinopril had no effect on left ventricular systolic or diastolic performance; in contrast, atenolol decreased both systolic and diastolic parameters of ventricular performance. Left ventricular function may be affected in significantly different ways despite apparent similarities in blood pressure control in patients who respond to angiotensin converting enzyme inhibition or beta-adrenergic receptor blockade. Differences in hemodynamic response to an antihypertensive agent may be important in the selection of a drug for the treatment of subsets of patients with cardiac function abnormalities.

Adult↗
PubMed1992

Colonic epithelial cell proliferation in a rat model of nongenotoxin-induced colonic neoplasia.

BACKGROUND: The effect on colonic cell proliferation of poligeenan, a nongenotoxic polysaccharide that induces colon tumors in rats, was compared with guar gum and carrageenan. EXPERIMENTAL DESIGN: Fischer 344 rats were fed a basal diet supplemented with carrageenan and poligeenan fibers for up to 91 days. The quantitative levels of proliferation, location of the proliferating cells, and the ability of the mucosa to readapt by removing the experimental fibers from the diet were tested. RESULTS: The mucosal epithelium exhibited a 5-fold increase in thymidine kinase activity in both the carrageenan and poligeenan groups. Proliferating cells appeared at the luminal surface only in the poligeenan-treated rats, and the number of proliferating cells in the upper third of the crypt increased 35-fold. A second and third set of animals were fed one of the three test diets for either 28 or 64 days, followed by a 28-day recovery period. Proliferation in the guar- and carrageenan-treated groups returned to basal levels. In poligeenan-treated rats, thymidine kinase levels, and proliferating cells in the upper third of the crypt remained 2- and 11-fold, respectively, above controls. CONCLUSIONS: The difference in recovery time between the poligeenan group and the others, and the luminal location of proliferating cells may prove useful as markers in understanding early events in the carcinogenic process induced by a nongenotoxin.

Administration, Oral↗
PubMed1992

Study of patients who chose private health care for treatment.

A questionnaire survey was carried out in 1991 in Wessex regional health authority of a sample of private patients having inpatient treatment in eight independent hospitals, and in pay beds in three National Health Service hospitals. A total of 649 patients replied (response rate 60.7%). Sixty respondents to the questionnaire were also interviewed. The aim of the study was to discover which groups of people chose private care rather than using the NHS, and why. In view of the current emphasis on consumerism in health care, the study also aimed to examine how patients exercised choice in a market situation and how well informed they were when they did so. The questionnaire asked about the role and influence of the general practitioner in patients' decisions to use private health care for treatment. The largest group of respondents were in the 36-50 years age group (34.2%). Of the respondents 59.9% were women, 54.1% were in social class 2 and 77.3% were married or cohabiting. The most common reason for using private health care for treatment was to avoid NHS waiting lists (61.5% of respondents) although they did not necessarily know how long that wait would have been. Patients sought their general practitioner's opinion about whether to use private health care in 187 cases (28.8%). The majority of the 649 patients (71.2%) had decided to use private health care before consulting the general practitioner. However, patients were influenced by their general practitioner's advice on the choice of consultant and choice of hospital.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Private patients' perceptions of nursing practice in the National Health Service.

A study of private patients (n = 649) was carried out in Wessex Region in January 1991 to discover why patients decide to go private rather than use the NHS for in-patient treatment. Relatively few patients complained of the attitudes of nurses in the NHS, but just over one third mentioned nursing as a significant problem in the NHS and, of this group, over half were critical of nurses' attitudes. Further analysis revealed that these perceptions were not based on direct experience (of those who said that nursing was a problem, only 5 per cent had been NHS in-patients since 1985), but alarm about the public image of nursing remains.

Adult↗
PubMed1991

Expanded clinical evaluation of lovastatin (EXCEL) study results: IV. Additional perspectives on the tolerability of lovastatin.

This randomized, double-blind, multicenter, diet-and-placebo-controlled study was designed to clarify the dose-response relationship of lovastatin therapy to lipid-modifying efficacy and drug-related adverse events. Exclusion criteria were minimized so that study patients were representative of the majority of patients with moderate hypercholesterolemia seen in medical practice. After 6 weeks on the American Heart Association Step 1 Diet, a total of 8,245 patients were randomly assigned to 48 weeks of treatment with diet and placebo or lovastatin at dosages of 20 or 40 mg once a day or 20 or 40 mg twice a day. All adverse events were monitored, with particular attention to evaluation of liver and muscle. Liver transaminase elevations suggestive of possible hepatotoxicity, defined as successive elevations in either aspartate transaminase or alanine aminotransferase greater than 3 times the upper limit of normal, occurred in equal numbers of placebo and lovastatin 20 mg/day treated patients (0.1%). The frequencies were higher in lovastatin 40 mg/day and 80 mg/day patient groups (0.9 and 1.5%, respectively). No patient was diagnosed as having clinically symptomatic hepatic dysfunction. Creatinine kinase (CK) elevations above the upper limit of normal occurred frequently in placebo- (29%), as well as lovastatin-treated patients (29-35%), and muscle symptoms were reported with similar frequency in all groups (7-9%). The combination of muscle symptoms with marked CK elevations (greater than 10 times the upper limit of normal) was seen in only five patients: one in a 40 mg/day dose group and four in the 80 mg/day dose group. No patient developed rhabdomyolysis. The incidence of clinical and laboratory adverse events requiring discontinuation was 6% for the placebo group and from 7% (20 mg/day) to 9% (80 mg/day) for lovastatin treatment groups. No new types of adverse experiences related to lovastatin treatment were reported. Lovastatin, as an adjunct to diet for the reduction of elevated LDL cholesterol, was generally very well tolerated.

Alanine Transaminase↗
PubMed1991

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia.

In the Expanded Clinical Evaluation of Lovastatin (EXCEL) Study, a multicenter, double-blind, diet- and placebo-controlled trial, we evaluated the efficacy and safety of lovastatin in 8245 patients with moderate hypercholesterolemia. Patients were randomly assigned to receive placebo or lovastatin at a dosage of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Lovastatin produced sustained, dose-related (P less than .001) changes as follows (for dosages of 20 to 80 mg/d): decreased low-density lipoprotein-cholesterol level (24% to 40%), increased high-density lipoprotein-cholesterol level (6.6% to 9.5%), decreased total cholesterol level (17% to 29%), and decreased triglyceride level (10% to 19%). The National Cholesterol Education Program's low-density lipoprotein-cholesterol level goal of less than 4.14 mmol/L (160 mg/dL) was achieved by 80% to 96% of patients, while the less than 3.36 mmol/L (130 mg/dL) goal was achieved by 38% to 83% of patients. The difference between lovastatin and placebo in the incidence of clinical adverse experiences requiring discontinuation was small, ranging from 1.2% at 20 mg twice daily to 1.9% at 80 mg/d. Successive transaminase level elevations greater than three times the upper limit of normal were observed in 0.1% of patients receiving placebo and 20 mg/d of lovastatin, increasing to 0.9% in those receiving 40 mg/d and 1.5% in those receiving 80 mg/d of lovastatin (P less than .001 for trend). Myopathy, defined as muscle symptoms with a creatine kinase elevation greater than 10 times the upper limit of normal, was found in only one patient (0.1%) receiving 40 mg once daily and four patients (0.2%) receiving 80 mg/d of lovastatin. Thus, lovastatin, when added after an adequate trial of a prudent diet, is a highly effective and generally well-tolerated treatment for patients with moderate hypercholesterolemia.

Adult↗