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Biomedical subjects

Robert A Parker

Publications and source records attributed to Robert A Parker.

At least 19 recordsLinked to original sources
PubMed2007

Effects of metformin and rosiglitazone in HIV-infected patients with hyperinsulinemia and elevated waist/hip ratio.

OBJECTIVE: To evaluate the effects of metformin and rosiglitazone, alone or in combination, on fat distribution, insulin sensitivity, and lipids in HIV-infected patients with insulin resistance and changes in fat distribution. METHODS: A total of 105 subjects were randomly assigned to receive metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks) with rosiglitazone placebo (Met/P, N = 26); rosiglitazone (4 mg/day) with metformin placebo (Rosi/P, N = 27); rosiglitazone (4 mg/day) plus metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks; Met/Rosi, N = 25); or dual placebo (P/P, N = 27) for 16 weeks. Efficacy assessments included oral glucose tolerance testing, abdominal computed tomography, whole-body dual-energy X-ray absorptiometry, and the measurement of fasting lipids and other biochemical indices. Safety was monitored throughout. Intent-to-treat analyses were performed using non-parametric methods. RESULTS: The median insulin area under the curve (AUC) decreased significantly compared with baseline in both groups randomly assigned to rosiglitazone (Rosi/P -25.7 microIU/ml, P = 0.012; Met/Rosi -17.7 microIU/ml, P = 0.002); and tended to decrease in the Met/P group (-11.1 microIU/ml, P = 0.058). The change in AUC with combination therapy was significant compared with placebo (P = 0.032). No treatment was associated with significant changes in visceral or subcutaneous abdominal fat. Leg fat increased in subjects on Rosi/P compared with placebo (+4.8 versus -8.3%, P = 0.034). Rosiglitazone, but not metformin, increased adiponectin but also increased LDL-cholesterol and decreased HDL-cholesterol. Gastrointestinal effects occurred frequently in subjects on metformin. CONCLUSION: Both treatments improved insulin sensitivity, but neither reduced visceral fat. Rosiglitazone may increase subcutaneous fat in some individuals.

Adult↗
PubMed2006

Effects of testosterone supplementation on whole body and regional fat mass and distribution in human immunodeficiency virus-infected men with abdominal obesity.

BACKGROUND: Whole body and abdominal obesity are associated with increased risk of diabetes mellitus and heart disease. The effects of testosterone therapy on whole body and visceral fat mass in HIV-infected men with abdominal obesity are unknown. OBJECTIVE: The objective of this study was to determine the effects of testosterone therapy on intraabdominal fat mass and whole body fat distribution in HIV-infected men with abdominal obesity. METHODS: IN this multicenter, randomized, placebo-controlled, double-blind trial, 88 HIV-positive men with abdominal obesity (waist-to-hip ratio > 0.95 or mid-waist circumference > 100 cm) and total testosterone 125-400 ng/dl, or bioavailable testosterone less than 115 ng/dl, or free testosterone less than 50 pg/ml on stable antiretroviral regimen, and HIV RNA less than 10,000 copies per milliliter were randomized to receive 10 g testosterone gel or placebo daily for 24 wk. Fat mass and distribution were determined by abdominal computerized tomography and dual energy x-ray absorptiometry during wk 0, 12, and 24. We used an intention-to-treat approach and nonparametric statistical methods. RESULTS: Baseline characteristics were balanced between groups. In 75 subjects evaluated, median percent change from baseline to wk 24 in visceral fat did not differ significantly between groups (testosterone 0.3%, placebo 3.1%, P = 0.75). Total (testosterone -1.5%, placebo 4.3%, P = 0.04) and sc (testosterone-7.2%, placebo 8.1%, P < 0.001) abdominal fat mass decreased in testosterone-treated men, but increased in placebo group. Testosterone therapy was associated with significant decrease in whole body, trunk, and appendicular fat mass by dual energy x-ray absorptiometry (all P < 0.001), whereas whole body and trunk fat increased significantly in the placebo group. The percent of individuals reporting a decrease in abdomen (P = 0.01), neck (P = 0.08), and breast size (P = 0.01) at wk 24 was significantly greater in testosterone-treated than placebo-treated men. Testosterone-treated men had greater increase in lean body mass than placebo (testosterone 1.3%, placebo -0.3, P = 0.02). Plasma insulin, fasting glucose, and total high-density lipoprotein and low-density lipoprotein cholesterol levels did not change significantly. Testosterone therapy was well tolerated. CONCLUSIONS: Testosterone therapy in HIV-positive men with abdominal obesity and low testosterone was associated with greater decrease in whole body, total, and sc abdominal fat mass and a greater increase in lean mass compared to placebo. However, changes in visceral fat mass were not significantly different between groups. Further studies are needed to determine testosterone effects on insulin sensitivity and cardiovascular risk.

Abdominal Fat↗
PubMed2006

Mixed patterns of changes in central and peripheral fat following initiation of antiretroviral therapy in a randomized trial.

INTRODUCTION: Although peripheral fat loss is a consistent feature of HIV-associated lipodystrophy, less is known about whether changes in central and peripheral fat occur in tandem or independently over time. We examined intraindividual changes in dual-energy x-ray absorptiometry (DEXA) and anthropometry data over 64 weeks after initiation of antiretroviral therapy (ART). METHODS: In ACTG 384, ART-naive subjects were randomized to receive didanosine and stavudine or zidovudine and lamivudine plus efavirenz, nelfinavir, or both. In the metabolic substudy A5005S (N= 329), waist, hip, thigh, and arm circumferences were measured in triplicate. DEXA scanning was performed in 157 subjects. RESULTS: Individual changes in limb and trunk fat at week 64 correlated positively (R =.72, P <.001). Most subjects had directionally concordant changes in limb and trunk fat (36% gained and 32% lost in both regions). In 26%, trunk fat increased while limb fat decreased, whereas the reverse occurred in only 6% (P <.001). Changes in waist and hip circumferences also correlated positively (R =.62, P <.001). The proportion of subjects with waist/hip ratio more than .95 (men) or .90 (women) was 34% at baseline and 47% at week 64 (P =.003). In those who developed increased waist/hip ratio, 76% had increased waist circumference. CONCLUSIONS: Individual results obtained by both anthropometry and DEXA show diverse patterns of fat gain and loss over 64 weeks after initiation of ART, but changes tended to occur in the same direction. Increased waist/hip ratio was predominantly associated with increased waist circumference. There was no evidence that central fat accumulation and peripheral fat loss are linked in most subjects.

Absorptiometry, Photon↗
PubMed2006

Age- and gender-related differences in ischemia/reperfusion injury and cardioprotection: effects of diazoxide.

BACKGROUND: Recent studies have demonstrated that aging is associated with reduced tolerance to ischemia and that the aged (not senescent) female heart has greater susceptibility to ischemia as compared with the aged male heart. Previously, we have shown that ischemia can be modulated with cardioplegia in the male heart; however, efficacy in the female heart was unknown. METHODS: In this study, male and female mature (15 to 20 weeks) aged (>32 months) rabbit hearts (n = 134) were subjected to Langendorff perfusion. Control hearts were perfused for 180 minutes. Global ischemia hearts received 30 minutes of equilibrium, 30 minutes of global ischemia, and 120 minutes of reperfusion. Cardioplegia +/- diazoxide was infused separately, 5 minutes before global ischemia. RESULTS: Global ischemia significantly decreased postischemic functional recovery and significantly increased infarct size in the mature and aged male and female heart (p < 0.05 versus control). The effects of global ischemia were significantly exacerbated (p < 0.05) in the aged heart as compared with the mature heart. Cardioplegia +/- diazoxide significantly increased postischemic functional recovery and significantly decreased infarct size in mature male and female hearts, but these effects were significantly decreased in the aged heart (p < 0.05) and in the aged female as compared with the aged male heart. CONCLUSIONS: Postischemic functional recovery and infarct size are affected by age but not by gender. The cardioprotection afforded by cardioplegia is affected by age and gender with a strong age-by-gender interaction for end-diastolic pressure and infarct size. Our results indicate that currently optimized cardioplegia protocols effective in the male heart are not as efficacious in the aged female heart.

Aging↗
PubMed2006

Coordinated response to SARS, Vancouver, Canada.

Two Canadian urban areas received travelers with severe acute respiratory syndrome (SARS) before the World Health Organization issued its alert. By July 2003, Vancouver had identified 5 cases (4 imported); Toronto reported 247 cases (3 imported) and 43 deaths. Baseline preparedness for pandemic threats may account for the absence of sustained transmission and fewer cases of SARS in Vancouver.

Adult↗
PubMed2005

Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides.

OBJECTIVE: To determine if particular components of antiretroviral drug regimens are associated with greater insulin resistance, dyslipidemia, and peripheral lipoatrophy. METHODS: Metabolic and body composition variables were measured prospectively over 64 weeks in 334 antiretroviral-naive, HIV-infected subjects who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine/lamivudine or didanosine/stavudine in a factorial design, multicenter trial. Subjects assigned to efavirenz (n = 110) were compared with those assigned to nelfinavir (n = 99); subjects assigned to zidovudine/lamivudine (n = 154) were compared with those assigned to didanosine/stavudine (n = 180). A subset of 157 subjects had serial dual-energy X-ray absorptiometry (DEXA) scans. RESULTS: Lipid measures increased in all groups. Greater increases in high density lipoprotein (HDL) cholesterol occurred with efavirenz than with nelfinavir. Greater increases in total cholesterol, non-HDL cholesterol and HDL cholesterol occurred with stavudine and didanosine than with zidovudine/lamivudine. There were no differences in insulin resistance in the comparisons. After initial increases in the first 16 weeks, median limb fat decreased. Greater changes in percentage changes in limb fat occurred with didanosine/stavudine (-16.8%) than with zidovudine/lamivudine (+4.0%; P < 0.001 for overall change from baseline) and with nelfinavir (-13.1%) compared with efavirenz (+1.8%; P = 0.003). CONCLUSIONS: Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.

Absorptiometry, Photon↗
PubMed2005

The effects of highly active antiretroviral therapy on albuminuria in HIV-infected persons: results from a randomized trial.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) regimens, especially those containing protease inhibitors (PIs), are at increased risk for cardiovascular events. Albuminuria is a known independent predictor for the development of cardiovascular disease and may potentially increase in patients receiving PIs. Alternatively, albuminuria may improve with HAART as a result of treating renal parenchymal HIV infection. Longitudinal studies have not been performed previously addressing the effects of HAART on albuminuria. METHODS: We evaluated the effects of HAART on albumin to creatinine ratios (ACRs) during the initial 64 weeks of therapy in 68 previously untreated HIV-infected subjects, without pre-existing diagnosed diabetes or hypertension, enrolled in a randomized trial comparing PI-based (n = 32) with non-PI-based (n = 36) HAART regimens. We also estimated the prevalence of albuminuria, defined as an ACR > or =3.4 mg/mmol, in these subjects prior to initiation of HAART. RESULTS: The changes in ACR over the initial 64 weeks of therapy in those receiving PIs [0.0 mg/mmol (-0.4, 0.3)] and in those not receiving PIs [0.0 mg/mmol (-0.5, 0.3)] were not significantly different. There was also no significant difference in the change in the ACR in the group as a whole. However, albuminuria at baseline was found in seven (10%) subjects. Five of these seven subjects had substantial improvements in ACR, ranging from 45 to 95%, with HAART use; three subjects had resolution of albuminuria. ACR at baseline significantly correlated with the baseline HIV-1 RNA level (r = 0.25; P = 0.04) and negatively with CD4 cell count (r = -0.25; P = 0.04). CONCLUSION: Albuminuria in HIV-infected, treatment-naïve patients was found more frequently than expected and may be influenced by baseline immune status. Although we did not observe an effect of HAART on ACR during the first 64 weeks of therapy, we cannot exclude the possibility that HAART may be beneficial in those patients with significant albuminuria prior to treatment. Research in larger cohorts is required to investigate more definitively the associations between immune status, antiretroviral therapies and renal function in HIV-infected patients.

Adult↗
PubMed2005

Incidence of pancreatitis in HIV-1-infected individuals enrolled in 20 adult AIDS clinical trials group studies: lessons learned.

OBJECTIVE: To report on the incidence of clinical- and laboratory-defined pancreatitis in HIV-1-infected individuals treated with antiretrovirals (ARVs). METHODS: Pancreatitis incidence rates were calculated based on a Poisson distribution for subjects enrolled in 1 or more of 20 Adult AIDS Clinical Trials Group studies from October 1989 through July 1999. RESULTS: A total of 8451 subjects were enrolled. The overall pancreatitis rates were 0.61 per 100 person-years (PYs) clinical and 2.23 per 100 PYs clinical/laboratory. Pancreatitis rates for single, dual, and triple nucleoside reverse transcriptase inhibitors (NRTIs) were similar. Rates of pancreatitis in didanosine (ddI) arms seemed to be dose dependent. Pancreatitis rates in ddI/hydroxyurea (HU) arms were not significantly different from the rates for ddI alone. Overall pancreatitis rates for ddI/stavudine (d4T) trials were high at 4.16 per 100 PYs clinical and 6.25 per 100 PYs clinical/laboratory. The highest rates were seen with the combination of indinavir (IDV)/ddI/d4T with or without HU. CONCLUSIONS: The combination of NRTIs and definition has an impact on the incidence of pancreatitis. Standardization of definition and more comprehensive evaluations are needed to determine how much of this pancreatitis is directly caused by ARVs and how much is attributable to preexisting comorbidities and other known risk factors.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Effect of hormone replacement, alendronate, or combination therapy on hip structural geometry: a 3-year, double-blind, placebo-controlled clinical trial.

UNLABELLED: This study examined the effect of hormone replacement, alendronate, or combination therapy on hip structural geometry in 373 postmenopausal women over 3 years. We found that antiresorptive agents alone or in combination result in improvement in parameters of hip structural geometry and BMD. These data provide additional information regarding potential mechanisms for fracture reduction with antiresorptive therapy. INTRODUCTION: Fracture reduction is only partially explained by increased BMD. The aim of this study was to examine changes in structural geometry of the hip, derived from DXA in postmenopausal women after treatment with antiresorptive agents. MATERIALS AND METHODS: This was a double-blind, placebo-controlled, randomized clinical trial of 373 women over the age of 65 years, who were randomized to hormone replacement therapy, alendronate, combination therapy, or placebo for 3 years. The outcomes included the DXA-derived hip structure analysis program by Beck, which is an engineering interpretation of the DXA data. The indices included cross-sectional area, section modulus (a measure of bending strength), outer diameter, cortical thickness, and buckling ratio (an index of cortical bone stability). Properties were measured in cross-sectional regions traversing the femur at the narrowest point on the femoral neck, the intertrochanteric region, and the proximal shaft. RESULTS: In the femoral neck, improvement in the hip structure analysis indices were generally significantly greater with combination therapy than either monotherapy; increases were also greater at the intertrochanter compared with hormone replacement therapy. For example, the section modulus at the intertrochanter and narrow neck increased 10.6% and 10.3%, respectively, with combination therapy, 9.1% and 7.3% with alendronate, 5.8% and 6.9% with hormone replacement therapy, and 3.4% and 3.2% with placebo (p < 0.01 across the four groups). Buckling ratio increased, suggesting decreased stability in the placebo group, whereas there was either no change or significant improvements (p < 0.05) in each active treatment group. CONCLUSIONS: We conclude that changes in the distribution of bone mass underlying the improvements in density with antiresorptive agents in combination or alone have positive effects on structural strength and stability at the proximal femur. This study provides additional information on the potential mechanisms for fracture reduction with antiresorptive agents.

Aged↗
PubMed2005

Early changes in biochemical markers of bone turnover are associated with long-term changes in bone mineral density in elderly women on alendronate, hormone replacement therapy, or combination therapy: a three-year, double-blind, placebo-controlled, randomized clinical trial.

Elderly women on combination therapy with alendronate and hormone replacement for osteoporosis have greater gains in bone mass than those on monotherapy. It is not known whether early changes in markers can predict the long-term changes in bone density with therapy. We assessed bone density and biochemical markers of bone turnover [urine N-telopeptide cross-linked collagen type 1 (NTx), serum bone-specific alkaline phosphatase, and osteocalcin] every 6 months for 3 yr in a double-blind, placebo-controlled, randomized clinical trial. After a 3-month run-in phase, 373 community-dwelling, elderly women were randomized to 1) alendronate, 2) hormone replacement therapy, 3) combination therapy with alendronate and hormone replacement therapy, or 4) placebo. Women on active treatment with the greatest decrease in markers of bone turnover at 6 months had the greatest increases in spine and hip bone density at 3 yr. The response to alendronate was generally associated with greater reductions in markers than the response to hormone replacement and was associated with greater increases in bone density at the spine and hip. Those in the tertile with the greatest decrease in urinary NTx had a 10.1% increase in spine bone density and a 6.1% increase in hip bone density compared with those in the lowest tertile, who had a 5.9% increase in spine bone density and a 2.1% increase in hip bone density. In women on active treatment, the area under the receiver operator curve for a 6-month change in markers to predict a response in bone mineral density at 3 yr was highest for urine NTx (range, 75-78%) and lowest for osteocalcin (range, 60-66%). We conclude that short-term changes in biochemical markers of bone turnover at 6 months predict bone density changes at the spine and hip at 3 yr in elderly women on alendronate, hormone replacement therapy, or combination therapy.

Aged↗
PubMed2005

The effect of hormone replacement on physical performance in community-dwelling elderly women.

PURPOSE: Our aim was to determine the effect of hormone replacement on physical performance measures, functional ability, physical activity, falls, and cognitive function in elderly women. SUBJECTS AND METHODS: Following a 3-month, open-label, run-in phase, we randomized 373 community-dwelling women aged 65 years and older to receive conjugated equine estrogen 0.625 mg/day plus or minus medroxyprogesterone 2.5 mg/day vs placebo for 3 years in a double-blind fashion. We assessed time to rise from a chair, timed walking, balance, Instrumental Activities of Daily Living, Physical Activity Scale of the Elderly, Folstein Mini-Mental State Examination, and falls. RESULTS: Over 3 years, except for balance scores, performance measures declined significantly (all P<.05). There were no significant mean differences between women on hormone replacement versus placebo for rising time (0.1, -0.5 to 0.7 seconds [mean, 95% confidence interval]), walking normal (0.0, -0.4 to 0.4 seconds), and walking fast (0.2, -0.1 to 0.6 seconds). There were no significant mean differences between the two groups for the Instrumental Activities of Daily Living (0.1, -0.1 to 0.3 points), Physical Activity Scale of the Elderly (-3, -15 to 8 points), Folstein Mini-Mental State Examination (-0.1, -0.3 to 0.3 points), or the proportion of participants reporting falls (-1, -11 to 9%). CONCLUSION: In elderly women, hormone replacement had no statistically significant effect on cognition or balance, nor did it prevent the age-related decline in physical measures of mobility, ability to rise from a chair, self-reported activities of daily living, physical activity scores, or falls.

Accidental Falls↗
PubMed2005

Vitamin D supplementation in older women.

BACKGROUND: The purpose of this study was to determine if vitamin D supplementation, 400-800 IU daily, could effectively treat vitamin D deficiency and insufficiency over 3 months. METHODS: To test this hypothesis, we conducted a cross-sectional survey followed by a 3-month, open-label run-in phase prior to a randomized clinical trial. We enrolled 573 community-dwelling women age 65 or older, 373 of whom completed the run-in phase. All women received a daily multivitamin containing 400 IU of vitamin D and one to two calcium supplements containing 200 IU of vitamin D. We assessed bone mineral metabolism (including 25-hydroxyvitamin D and parathyroid hormone), markers of bone turnover, and bone mineral density. RESULTS: Of the 553 screened participants who had baseline vitamin D levels available, 16% had vitamin D deficiency (serum vitamin D < 10 ng/ml) and 48% had vitamin D insufficiency (serum vitamin D between 10 and 20 ng/ml). Only 36% of participants had normal vitamin D levels (serum vitamin D > or = 20 ng/ml). Baseline vitamin D intake was negatively associated with serum parathyroid hormone (r = -0.29, p <.0001), and not associated with bone mineral density or bone resorption. Vitamin D deficiency was associated with decreased physical activity and slower gait. Of the 373 women who completed the run-in phase and received treatment with a multivitamin and vitamin D-containing calcium supplement, vitamin D deficiency decreased from 16% at baseline to 0% at 3 months, and vitamin D insufficiency decreased from 48% at baseline to 20% at 3 months (p <.001). CONCLUSIONS: We conclude that vitamin D deficiency and insufficiency, which are common among ambulatory, community-dwelling elderly women, can be normalized in 80% of patients over 3 months with vitamin D supplementation of 400-800 IU/d.

Aged↗
PubMed2005

Pathogenicity of simian-human immunodeficiency virus SHIV-89.6P and SIVmac is attenuated in cynomolgus macaques and associated with early T-lymphocyte responses.

Because most studies of AIDS pathogenesis in nonhuman primates have been performed in Indian-origin rhesus macaques (Macaca mulatta), little is known about lentiviral pathogenicity and control of virus replication following infection of alternative macaque species. Here, we report the consequences of simian-human immunodeficiency virus SHIV-89.6P and SIVmac251 infection in cynomolgus (Macaca fascicularis) and rhesus macaques of Chinese origin. Compared to the pathogenicity of the same viruses in Indian rhesus macaques, both cynomolgus and Chinese rhesus macaques showed lower levels of plasma virus. By 9 to 10 months after infection, both viruses became undetectable in plasma more frequently in cynomolgus than in either Chinese or Indian rhesus macaques. Furthermore, after SHIV-89.6P infection, CD4+ T-cell numbers declined less and survival was longer in cynomolgus and Chinese rhesus macaques than in Indian rhesus macaques. This attenuated pathogenicity was associated with gamma interferon ELISPOT responses to Gag and Env that were generated earlier and of higher frequency in cynomolgus than in Indian rhesus macaques. Cynomolgus macaques also developed higher titer neutralizing antibodies against SHIV-89.6 at 10 and 20 weeks postinoculation than Indian rhesus macaques. These studies demonstrate that the pathogenicity of nonhuman primate lentiviruses varies markedly based on the species or geographic origin of the macaques infected and suggest that the cellular immune responses may contribute to the control of pathogenicity in cynomolgus macaques. While cynomolgus and Chinese rhesus macaques provide alternative animal models of lentiviral infection, the lower levels of viremia in cynomolgus macaques limit the usefulness of infection of this species for vaccine trials that utilize viral load as an experimental endpoint.

Animals↗
PubMed2005

The effect of long-term storage on measured plasma lactate concentrations and prospective lactate results from a multicenter trial of antiretroviral therapy.

Plasma lactate measurements are typically performed in real time, limiting their usefulness in multicenter or longitudinal studies. To determine the stability of lactate specimens, blood was drawn in sodium fluoride/potassium oxalate tubes from 13 volunteers before and after 5 min of handgrip exercise to intentionally increase lactate concentrations. Plasma was stored at -70 degrees C. Aliquots were assayed in real time and after 1, 3, 6, 9, 12, 18, and 24 months. Real-time lactate concentrations measured at baseline ranged from 0.52 to 2.23 mmol/L before and from 2.91 to 11.04 mmol/L after handgrip exercise. Using a linear mixed model, the estimated change from baseline at month 24 was 1.67% (95% confidence interval, -0.70% to 4.03%) for pre-exercise samples and 0.39% (95% CI, -1.13% to 1.91%) for post-exercise samples. Stored serial specimens from 232 HIV-infected subjects in a multicenter trial of antiretroviral therapy were also assayed centrally. Among those, median plasma lactate increased from baseline to 64 weeks by 0.4 mmol/L with zidovudine+lamivudine treatment and by 0.6 mmol/L with didanosine+stavudine (each p<0.001 from baseline; p=0.04 for difference between groups over time). When performed as in this study, frozen storage with central batch lactate analysis is appropriate for prospectively collected samples in multicenter trials.

Acidosis, Lactic↗
PubMed2003

Phase I trial of concurrent twice-weekly recombinant human interleukin-12 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma.

PURPOSE: To maintain interferon gamma (IFNgamma) induction by recombinant human interleukin-12 (rhIL-12) and enhance its activity against melanoma and renal cell cancer, a regimen of twice-weekly intravenous (IV) rhIL-12 was modified to include concurrent low-dose subcutaneous (SC) IL-2 in a phase I dose escalation study. PATIENTS AND METHODS: Patients received 6-week cycles of twice-weekly IV rhIL-12 at doses of 300 to 500 ng/kg. Midway through cycle 1, low-dose SC IL-2 was added. The IL-2 was escalated from 0.5 to 6.0 MU/m2. Grade 3 elevations of hepatic ALT, AST, or alkaline phosphatase were not considered dose-limiting unless values were more than 10 times normal. During cycle 1, patients underwent immune monitoring to assess the effect of IL-2 on lymphocyte activation and cytokine production induced by rhIL-12. RESULTS: Twenty-eight patients were enrolled onto the study. The maximum-tolerated dose (MTD) was 500 ng/kg rhIL-12 plus 3 MU/m2 IL-2. Toxicities related to the addition of IL-2 at the MTD included fever or chills, anemia, fatigue, nausea or vomiting, and orthostatic hypotension. At the MTD, IL-2 significantly augmented IFNgamma and IFNgamma-inducible protein-10 production by rhIL-12 and led to a three-fold expansion of natural killer cells. There was one major clinical response (partial response) as well as two pathologic responses; all occurred in melanoma patients. Stable disease for three to six cycles was only observed at or above the MTD in melanoma and renal cell cancer patients. CONCLUSION: The addition of concurrent low-dose IL-2 to rhIL-12 is well tolerated, restores and maintains immune activation by rhIL-12, and has clinical activity. This regimen should be further investigated in phase II studies in untreated patients with melanoma or renal cell cancer and in other rhIL-12-responsive malignancies.

Adult↗
PubMed2003

Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial.

CONTEXT: Therapy with individual antiresorptive agents has been shown to be effective for prevention and treatment of postmenopausal osteoporosis, but whether combination antiresorptive therapy with hormones and bisphosphonates is safe or efficacious or how these agents compare in elderly women is unknown. OBJECTIVE: To determine whether hormone replacement and the bisphosphonate alendronate sodium in combination are efficacious and safe, and how they compare with monotherapy in community-dwelling elderly women. DESIGN: Randomized, double-blind, placebo-controlled, clinical trial. SETTING AND PARTICIPANTS: Five hundred seventy-three community-dwelling women age 65 years or older were screened: 485 completed screening and 373 (aged 65 to 90 years) were randomized following a 3-month, open-label, run-in phase with hormone replacement and alendronate placebo. The trial was conducted at a single academic US medical center from January 1996 to May 2001. INTERVENTIONS: Participants were randomly assigned in a 2 x 2 factorial design to receive hormone replacement (conjugated equine estrogen, 0.625 mg/d, with or without medroxyprogesterone, 2.5 mg/d) and alendronate, 10 mg daily, both agents, or neither. All participants received calcium and vitamin D supplements. MAIN OUTCOME MEASURES: Annualized change in bone mineral density of the hip and spine and occurrence of adverse events. RESULTS: Bone mineral density at 3 years was significantly greater at all femoral and vertebral sites in women treated with combination therapy than with monotherapy, with mean (SD) increases of 5.9% (3.8) at the total hip, 10.4% (5.4) at the posteroanterior lumbar spine, and 11.8% (6.8) at the lateral lumbar spine. Mean (SD) increases in bone mass at the hip in women treated with alendronate alone were significantly greater than in those treated with hormone replacement therapy alone (4.2% [3.8] vs 3.0% [4.9]; P<.05, respectively), and alendronate resulted in more responders to therapy. All therapies were well tolerated and participant retention was 90% at 3 years. CONCLUSIONS: Combination therapy with hormone replacement and alendronate was efficacious and well tolerated in this cohort. Alendronate was superior to hormone replacement, and combination therapy was superior to either therapy alone. Combination therapy may represent an option for women with more severe disease or for those who have failed to achieve an adequate response to monotherapy.

Aged↗
PubMed2003

Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease.

In normoglycemic offspring of two type 2 diabetic parents, low insulin sensitivity (S(I)) and low insulin-independent glucose effectiveness (S(G)) predict the development of diabetes one to two decades later. To determine whether low S(I), low S(G,) or low acute insulin response to glucose are predictive of diabetes in a population at low genetic risk for disease, 181 normoglycemic individuals with no family history of diabetes (FH-) and 150 normoglycemic offspring of two type 2 diabetic parents (FH+) underwent i.v. glucose tolerance testing (IVGTT) between the years 1964-82. During 25 +/- 6 years follow-up, comprising 2,758 person years, the FH- cohort (54 +/- 9 years) had an age-adjusted incidence rate of type 2 diabetes of 1.8 per 1,000 person years, similar to that in other population-based studies, but significantly lower than 16.7 for the FH+ cohort. Even when the two study populations were subdivided by initial values of S(I) and S(G) derived from IVGTT's performed at study entry, there was a 10- to 20-fold difference in age-adjusted incidence rates for diabetes in the FH- vs. FH+ individuals with low S(I) and low S(G). The acute insulin response to glucose was not predictive of the development of diabetes when considered independently or when assessed as a function of S(I), i.e., the glucose disposition index. These data demonstrate that low glucose disposal rates are robustly associated with the development of diabetes in the FH+ individuals, but insulin resistance per se is not sufficient for the development of diabetes in individuals without family history of disease and strongly suggest a familial factor, not detectable in our current measures of the dynamic responses of glucose or insulin to an IVGTT is an important risk factor for type 2 diabetes. Low S(I) and low S(G), both measures of glucose disposal, interact with this putative familial factor to result in a high risk of type 2 diabetes in the FH+ individuals, but not in the FH- individuals.

Adult↗