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Biomedical subjects

L Smaldone

Publications and source records attributed to L Smaldone.

16 recordsLinked to original sources
PubMed1997

Meta-analysis of five randomized controlled trials comparing continuation of zidovudine versus switching to didanosine in HIV-infected individuals.

A meta-analysis of the original data from 2411 patients in the ACTG 116A, ACTG116B/117, ACTG175, BMS010 and CTN002 trials was conducted to improve the estimate of the effect of switching from zidovudine to didanosine on rates of clinical progression, to better quantify the rates of neurological events (including AIDS dementia and peripheral neuropathy) and to examine the effects of switching from zidovudine to didanosine among women and racial subgroups. In total, 1012 patients received zidovudine therapy, 557 received high-dose didanosine and 842 received didanosine. The median duration of follow-up was 15 months. Ninety-one percent of patients were male, 78% were white, mean age was 36.5 years. The median CD4 count was 195 cells/mm3 (range: 0-762) and the median duration of prior zidovudine therapy was 14 months (range: 0.1-94). There were 336 deaths and 686 new AIDS-defining illnesses (ADIs) or deaths. After stratification by study and adjusting for baseline CD4 count and presence of an AIDS diagnosis prior to baseline, the relative risks of death associated with switching from zidovudine to high-dose didanosine or to didanosine were 0.94 (P = 0.64) and 0.77 (P = 0.07), respectively. The relative risks of a new ADI or death associated with switching from zidovudine to high-dose didanosine and didanosine were 0.78 (P = 0.01) and 0.66 (P = 0.0001), respectively. There were 21 documented cases of AIDS dementia complex (ADC) during the entire follow-up period. The rates per 100 person years of follow-up were 0.70, 0.65 and 0.41 for the zidovudine, high-dose didanosine and didanosine arms, respectively. There were no significant differences in risks of ADC between treatment arms (zidovudine versus high-dose didanosine: P = 0.30, zidovudine versus didanosine: P = 0.97, didanosine versus high-dose didanosine: P = 0.41). Our data confirm a clinical benefit and CD4 increase associated with a switch from zidovudine to didanosine therapy. No statistical differences were detected between doses of didanosine with respect to survival or progression to a new ADI or death. Furthermore, there was no statistical difference in the frequency of ADC between treatment arms.

AIDS Dementia Complex↗
PubMed1995

Didanosine compared with continued zidovudine therapy for HIV-infected patients with 200 to 500 CD4 cells/mm3. A double-blind, randomized, controlled trial. Canadian HIV Trials Network Protocol 002 Study Group.

OBJECTIVE: To compare the safety and efficacy of didanosine with that of continued zidovudine therapy in persons with human immunodeficiency virus (HIV) infection who had received zidovudine for at least 6 months and had CD4 cell counts of 200 to 500 CD4 cells/mm3. DESIGN: Double-blind, randomized controlled trial. SETTING: 10 Canadian university-affiliated specialty clinics. PATIENTS: 246 patients were assigned to receive standard doses of either zidovudine or didanosine. OUTCOME MEASURES: The primary clinical end point was the occurrence of a new, previously undiagnosed acquired immunodeficiency syndrome (AIDS)-defining illness or death. RESULTS: 245 of 246 patients were eligible (118 receiving didanosine and 127 receiving zidovudine). Sixty-six percent were asymptomatic, 30% had AIDS-related complex, and 4% had AIDS. The median baseline CD4 count was 320 cells/mm3. The median previous duration of zidovudine therapy was 471 days. Nine new AIDS-defining illnesses developed during the study; all but one were in the zidovudine group (relative risk, 7.9 [95% CI, 1.0 to 63.3; P = 0.02]). A change to didanosine led to a statistically significant increase in CD4 counts by week 2 that persisted until the end of the study at week 48 (P < or = 0.01). Viral sensitivity studies (done in 102 patients) showed that 28% of the zidovudine group and 21% of the didanosine group had high-level in vitro resistance to zidovudine (50% inhibitory concentration greater than 0.8 microM) at baseline (P = 0.49). Only one patient in the didanosine group developed high-level resistance to zidovudine during the study. In the zidovudine group, the cumulative probability of developing high-level resistance to zidovudine was 59% at 1 year (P = 0.01). Abdominal pain, leukopenia, and neutropenia were more frequent in the zidovudine group, and hyperuricemia was more frequent in the didanosine group (P < 0.05). CONCLUSION: In clinically stable patients with 200 to 500 CD4 cells/mm3 who had tolerated zidovudine for at least 6 months, a change to didanosine led to a decrease in the rate of disease progression, a sustained increase in CD4 counts, and a decrease in the chances of developing high-level resistance to zidovudine. Both drugs were generally well tolerated.

Adult↗
PubMed1995

Design and implementation of the stavudine parallel-track program.

In a randomized, double-blind, large, simple trial, the safety and efficacy of two weight-adjusted dose levels of stavudine were evaluated in patients with advanced human immunodeficiency virus (HIV) infection. All patients were refractory to or intolerant of both zidovudine and didanosine. Patients weighing > or = 60 kg received 20 or 40 mg of stavudine twice daily. The dose was reduced to 15 or 30 mg for patients weighing 40-59 kg and to 10 or 20 mg for those weighing < 40 kg. The primary efficacy end points were survival and time to clinical progression of HIV disease. The primary safety end point was time to dose-limiting neuropathy. A total of 8127 patients were enrolled as of 31 July 1993. Although many patients who might have benefitted from stavudine were reached by the parallel-track program, a review of demographic data revealed disproportionate representation by white men from large metropolitan areas on both coasts.

Adult↗
PubMed1994

Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clinical deterioration while receiving zidovudine. A randomized, double-blind clinical trial. The Bristol-Myers Squibb AI454-010 Study Group.

OBJECTIVE: To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration. DESIGN: Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks. SETTING: Outpatient clinics at 19 tertiary care medical centers. PATIENTS: 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry. INTERVENTION: Peroral didanosine tablets (600 mg/d adjusted for weight, "high dose") or zidovudine capsules (600 mg/d). MEASUREMENTS: Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)--defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells. RESULTS: Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% Cl, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; Cl, 1.1 to 4.4). CONCLUSIONS: This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy.

AIDS-Related Complex↗
PubMed1994

Rates and risk factors for adverse events associated with didanosine in the expanded access program.

The didanosine Expanded Access Program was the largest AIDS treatment program to prospectively evaluate the safety of an antiretroviral agent among patients with advanced human immunodeficiency virus (HIV) disease in whom therapy with zidovudine was failing. A total of 21,198 patients who had infections refractory to zidovudine or who were intolerant of the drug received didanosine as a buffered powder for oral solution (sachet), with total daily doses of 6.6-10 mg/kg; the median CD4 lymphocyte count was 0.04 x 10(9)/L for this population. At the currently recommended dose (6.6-8.29 mg/[kg.d]), 6-month estimated rates of pancreatitis ranged from 1.2% for patients with AIDS-related complex (ARC) and CD4 lymphocyte counts of > or = 0.1 x 10(9)/L to 6.7% for patients with AIDS and CD4 lymphocyte counts of < 0.05 x 10(9)/L. Laboratory toxicities of World Health Organization grades 3 and 4 developed in fewer than 4% of patients entering the study with normal baseline values; the sole exception was leukopenia, which was documented in 8% of these patients. The results of this program demonstrated that patients with CD4 lymphocyte counts of < 0.10 x 10(9)/L or with a diagnosis of AIDS (defined by the 1987 classification system of the Centers for Disease Control and Prevention) were less tolerant of didanosine and significantly more likely to develop adverse clinical reactions and myelosuppression than other patients.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Safety profile of didanosine among patients with advanced HIV disease who are intolerant to or deteriorate despite zidovudine therapy: results of the Canadian Open ddI Treatment Program.

The aim of this study was to ascertain the safety profile of didanosine (Videx; ddI) within the Canadian Open Treatment Program. Symptomatic HIV+ subjects with AIDS or ARC or CD4 < 200/mm3 were eligible to receive didanosine if they were either (a) intolerant to zidovudine (Retrovir, ZDV) or (b) deteriorating despite ZDV therapy. The dose of didanosine (powder formulation) was based on body weight as follows: > or = 75 kg, 375 mg b.i.d.; 50-74 kg, 250 mg b.i.d.; 35-49 kg, 167 mg b.i.d. Participants were monitored with physical examinations and prespecified laboratory studies by their treating physicians on a monthly basis. Follow-up data were collected in a central database through five regional coordinators. A total of 168 physicians across Canada participated in the program, and 825 subjects who started didanosine after July 1, 1990, were included in the analysis. Of these, 97% were male, 88% homosexual, and 59% had a prior diagnosis of AIDS. Reasons for enrolling was ZDV intolerance in 39%, failure in 25%, both in 32%, and other in 4%. Data were prospectively collected until July 31, 1991. Total follow-up was 3,440 patient-months and median follow-up was 4.3 months. A total of 78 deaths were reported, 44 of which occurred within a month after the last dose of didanosine. Causes of death included AIDS-related unspecified causes (13 patients), MAC (11), wasting (7), AIDS-related CNS involvement other than OI's (7), Kaposi's sarcoma (7), Pneumocystis carinii pneumonia (6), sudden death, including suicides and accidents (6), lymphoma (5), toxoplasmosis (4), cryptococcosis (4), cytomegalovirus (3), unspecified causes (2), tuberculosis (1), PML (1), and disseminated histoplasmosis (1). Didanosine was discontinued in 140 (17%) subjects during the study period due to adverse events.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The disposition and protein binding of batanopride and its metabolites in subjects with renal impairment.

We have studied the disposition of batanopride and its three major metabolites (the erythro-alcohol, threo-alcohol, and N-desethyl metabolites) in 27 subjects with various degrees of renal function after intravenous infusion of a single dose of 3.6.mg.kg-1 of batanopride over 15 min. The subjects were assigned to one of three treatment groups: group 1, normal renal function (creatinine clearance > or = 75 ml.min-1 x 1.73 m-2; n = 13); group 2, moderate renal impairment (creatine clearance 30-60 ml.min-1 x 1.73 m-2; n = 8); group 3, severe renal impairment (creatinine clearance < or = 30 ml.min-1 x 1.73 m-2; n = 6). The terminal half-life of batanopride was significantly prolonged from 2.7 h in group 1 to 9.9 h in group 3. The renal clearance of batanopride was significantly lower in group 3 (25 ml.min-1) compared with group 1 (132 ml.min-1). There were no differences in plasma protein binding or steady-state volume of distribution of batanopride among the groups. There were significantly lower renal clearances for all three metabolites in groups 2 and 3 compared with group 1. The half-lives of all three metabolites were significantly prolonged in group 3 compared with group 1. The dose of batanopride may need to be reduced in patients with creatinine clearances less than 30 ml.min-1 x 1.73 m-2 to prevent drug accumulation and avoid possible dose-related adverse effects.

Adult↗
PubMed1992

Drug discovery and development in the pharmaceutical industry.

The discovery and development of new anticancer drugs is a complex and largely empirical process. New compounds can be discovered by screening, modification of existing compounds, rational drug design, and serendipitous basic research observations. Selection of compounds for clinical trials depends on assays of uncertain predictive value. In the pharmaceutical industry, priorities for development of potentially active entities are set and available resources allocated based on the availability and cost of supplies, patent status, potential spectrum of activity, ability to meet regulatory requirements, and market assessments. Competition for resources also occurs from noncancer drugs, eg, cardiovascular agents. Clinical development (testing and approval for commercial distribution) requires close attention to the requirements of national regulatory agencies such as the United States Food and Drug Administration. The arbitrary nature by which compounds with antitumor potential are chosen for development means that some that would be useful never reach clinical trial and others are never made generally available. This article reviews the decision making process in the pharmaceutical industry by which compounds are identified and selected for clinical trial, the regulations in the United States that govern such trials, and what is required to have the drug approved for commercial distribution.

Animals↗
PubMed1991

Double-blind, randomized crossover study of metoclopramide and batanopride for prevention of cisplatin-induced emesis.

We conducted a double-blind, randomized crossover study to compare the toxicity and antiemetic efficacy of the 5-hydroxytryptamine3 receptor antagonist batanopride with that of metoclopramide in 21 chemotherapy-naive patients receiving at least 70 mg/m2 cisplatin. The study was terminated when hypotension was observed following the infusion of batanopride at other institutions testing similar drug schedules. Although we observed no hypotension following treatment with batanopride in this trial, we did note asymptomatic prolongation of the corrected QT interval (QTc), PR interval, and QRS complex on the EKG in the batanopride arm. Of 15 evaluable patients, 8 experienced less than or equal to 2 episodes of emesis within 24 h of the first batanopride infusion, whereas 9/15 subjects experienced less than or equal to 2 emetic episodes following the administration of metoclopramide. Overall, the evidence suggests that this dosing schedule for batanopride may be too toxic for clinical use.

Antiemetics↗
PubMed1990

Overview of hormonal therapy in advanced breast cancer.

Hormonal therapy of breast cancer is widely used and effective. Although never curative in advanced disease, significant palliation and durable remissions can be obtained with a wide variety of hormonal manipulations. Historically, surgical ablation was used to reduce endogenous hormone levels, but this invasive procedure has been largely supplanted by drugs that reduce hormone secretion or block steroid hormone activity. A number of such antagonists are available, with tamoxifen probably the most widely used. Response can also be achieved with hormone agonists. Estrogens and androgens or their congeners have about the same level of activity as surgical ablation or drug antagonists (20% to 30% overall response rate). The progestins, another class of agonists, are also effective in the palliation of advanced breast cancer. Megestrol acetate, in part because of its oral formulation, is probably the most commonly used progestational drug for the treatment of breast cancer. Reports of 16 trials involving 1,342 patients show a response rate of 26% in patients with advanced breast cancer treated with megestrol acetate. The drug has proved active in a small number of male patients and, in randomized trials, it has been shown to be comparable with tamoxifen in efficacy (30% response for megestrol acetate v 35% for tamoxifen). Studies are currently under way to evaluate the possibility that high doses of megestrol acetate may increase response rates, and to determine whether weight gain, a well-described effect of this drug, may prove beneficial in cancer treatment.

Breast Neoplasms↗
PubMed1987

Clinical status of carboplatin.

Carboplatin, a cisplatin derivative, shows promise of being an effective weapon against ovarian, cervical, and small-cell lung cancer, as well as epidermoid cancer of the head and neck, with fewer toxic effects than cisplatin. It has successfully completed phase III investigation and clinical trials continue.

Animals↗
PubMed1985

Elevations in circulating 1,25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia.

Three patients with hypercalcemia associated with malignant lymphoma and elevations in plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] are described. In addition to the elevation of circulating 1,25-(OH)2D, these three patients were characterized by suppressed immunoreactive PTH levels and urinary cAMP excretion, elevated fasting urinary excretion of calcium, and absence of adenylate cyclase-stimulating activity in the tumor extracts. Bone marrow biopsy and skeletal radionuclide scans were negative for lymphoma in two patients. Surgical excision of a solitary splenic lymphoma in one patient and medical therapy in another patient resulted in rapid normalization of the serum calcium and plasma 1,25-(OH)2D levels. These findings confirm an earlier observation that elevated plasma levels of 1,25-(OH)2D may occur in certain patients with lymphoma and suggest that this vitamin D metabolite may act as a humoral or systemic mediator of hypercalcemia. Proof that this is the case and identification of the source of 1,25-(OH)2D production will require further study.

Aged↗
PubMedDate not supplied

Overview of phase I trials of 2',3'-dideoxyinosine (ddI) conducted on adult patients.

Ninety-two adult patients with AIDS or severe AIDS-related complex were treated with 2',3'-dideoxyinosine (didanosine; ddI) at dosages ranging from 0.8 to 66.0 mg/(kg.d) for at least 6 weeks in phase I trials. Potentially beneficial changes in weight (40% of patients), clinical signs or symptoms (40% of patients), CD4+ cell counts (25% of patients), and serum levels of HIV p24 antigen (50% of antigen-positive patients) were reported. Response rates tended to be higher among patients with AIDS-related complex and among those who had not received prior zidovudine therapy. A major response (improvement in at least one clinical parameter and in at least one laboratory marker) occurred in 29% of patients, and rates of major response tended to be higher in patients receiving higher dosages. The primary dose-limiting toxicity observed was peripheral neuropathy, which was observed with increasing frequency in patients receiving greater than 20 mg/(kg.d). Of the other adverse effects, pancreatitis was possibly dose-dependent and hyperuricemia (without clinical gout) occurred only at high doses. Dosages of 250 mg and 375 mg of ddI twice daily will be used in extended phase II/III studies.

AIDS-Related Complex↗