Biomedical subjects

D J Stewart

Publications and source records attributed to D J Stewart.

At least 91 records · Page 5Linked to original sources

PubMed1998

Expression of endothelial factors after arterial injury in the rat.

Endothelin-1 (ET-1) and nitric oxide (NO) are potent vasoactive factors known to play a role in vascular remodeling. This study assessed the temporal expression of endothelial NO synthase (eNOS), preproET-1, and ETA and ETB receptor mRNAs in the rat carotid artery after balloon injury using quantitative competitive reverse transcription-polymerase chain reaction (qcRT-PCR) and the ribonuclease protection assay (RPA). Levels of ET-1 increased sharply after arterial injury, peaking (5.1-fold) at 2 days. This was associated with a dramatic increase in the expression of ETB (63-fold) and ETA (158-fold) receptor mRNA, peaking at days 1 and 2, respectively. Expression of eNOS was not detectable immediately after balloon injury, consistent with complete denudation, but reappeared after day 2 and increased to preinjury levels by day 14. The recovery of eNOS expression mirrored the return of ET-1 and ET receptor expression to baseline levels. The results confirm profound upregulation of the ET system in this model of arterial injury and suggest a critical role for eNOS expression and re-endothelialization in the normalization of ET-1 and ET receptor expression during the recovery phase, events that may be important in long-term arterial patency.

Animals↗

PubMed1998

Increased cardiac and pulmonary endothelin-1 mRNA expression in canine pacing-induced heart failure.

The canine model of pacing-induced heart failure (HF) simulates human dilated cardiomyopathy and is characterized by severe hemodynamic perturbations. We have previously demonstrated increased plasma endothelin-1 (ET-1) and left ventricular (LV) tissue peptide levels in this model. However, the gene expression of ET-1 has not been studied. Accordingly, we compared preproET-1 mRNA in the lungs and LV in control normal dogs, dogs with severe HF after 3 weeks of rapid pacing (pHF), and pHF dogs chronically treated with an ETA antagonist, LU135252 (pHF-LU). PreproET-1 mRNA expression was determined by ribonuclease protection assay and quantified by densitometry. In paced dogs, mean pulmonary artery pressure (PA) and LV end-diastolic pressure (LVEDP) increased markedly from 16 +/- 4 and 8 +/- 3 mm Hg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mm Hg, respectively, at 3 weeks (both p < 0.001). Treatment with LU135252 attenuated the increase in PA and LVEDP by 30% and 19%, respectively (p < 0.05 for both). Compared to controls, preproET-1 mRNA expression in the LV and lungs was markedly increased in pHF. This was not changed in the LV but was reduced in the lungs by treatment with the ETA antagonist. Increased pulmonary and LV expression of preproET-1 suggests that ET-1 plays a role in mediating the pulmonary hypertension and LV dysfunction characteristic of this model.

Animals↗

PubMed1997

Risk stratification after myocardial infarction using signal-averaged electrocardiographic criteria adjusted for sex, age, and myocardial infarction location.

BACKGROUND: The objectives were to investigate the factors influencing signal-averaged ECGs (SAECGs) recorded in patients after myocardial infarction (MI) and to develop criteria for predicting arrhythmic events (AEs) that account for these factors. METHODS AND RESULTS: SAECGs were recorded 5 to 15 days after MI in 2461 patients without bundle-branch block. The duration (QRSd), terminal potential (VRMS), and terminal duration (LAS) of the filtered QRS were measured. During follow-up (17 +/- 8 months), AEs (arrhythmic death; ventricular tachycardia, VT; ventricular fibrillation, VF) occurred in 80 patients (3.3%). Receiver operating characteristic curves showed that QRSd discriminated patients with all types of AEs, but VRMS and LAS discriminated only VT patients; QRSd minus LAS also discriminated AE patients. Sex, age, and MI location significantly affected the SAECG; survivors without VT or VF were divided into subgroups (2 sex x 4 age x 2 MI), and QRSd values exceeding the 70th percentile in each subgroup predicted AEs with a sensitivity of 65.4%. An unadjusted QRSd criterion showed the same overall sensitivity and specificity but with less uniform values for each subgroup. A Cox model was constructed by use of multiple prognostic indicators, and in rank order, QRSd, previous MI, and Killip class were predictive of AEs. CONCLUSIONS: SAECG adjustments for sex, age, and MI location did not improve sensitivity and specificity but produced a more uniform predictive performance. The proposed criteria are based only on QRSd, because late potentials (VRMS and LAS) did not discriminate patients with sudden death. Duration of high-level activity during QRS (QRSd-LAS) can predict AEs, suggesting that the arrhythmogenic substate involves a large mass of myocardium.

Age Factors↗

PubMed1997

Arterial occlusion in patients with peripheral vascular disease treated with platinum-based regimens for lung cancer.

BACKGROUND: Patients with cancer may be hypercoagulable, and smoking can cause both lung cancer and peripheral vascular disease. Cisplatin-based chemotherapy has been reported to cause a variety of vascular side effects. CASE REPORTS: Five patients with bronchogenic carcinoma and peripheral vascular disease developed acute arterial occlusion soon after receiving a combination of cisplatin or carboplatin plus etoposide. All these patients had risk factors for atherosclerosis and three of them had preexisting known peripheral vascular disease. CONCLUSIONS: The occurrence of acute arterial occlusion soon after initiation of chemotherapy suggests that it might have been a complication of this therapy. Hence, caution should be exercised when using platinum-based (and other?) chemotherapy in patients with known moderate or severe peripheral vascular disease.

Aged↗

PubMed1997

Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods.

OBJECTIVE: To assess factors that affect cisplatin nephrotoxicity. METHODS: In 425 patients treated with cisplatin, we assessed the effect of pretreatment factors and treatment conditions on the rise in serum creatinine with the first course of cisplatin, on the maximum rise in serum creatinine over the entire course of the cisplatin therapy, and on residual nephrotoxicity after the last cisplatin treatment ended. (Because of the nature of the relationship between serum creatinine and creatinine clearance, rise in serum creatinine was divided by pretreatment creatinine squared.) Patients were dichotomized into the upper quartile versus the lower three quartiles of degree of nephrotoxicity. Multivariate analyses were based on logistic regression, controlling for cisplatin dose per course. RESULTS: Controlling for cisplatin dose per course, factors most closely associated with nephrotoxicity during the first course of cisplatin were: serum albumin and potassium, body surface area, and administration of cisplatin over 2-5 days per course vs 1 day (negative associations). Controlling for cisplatin dose per course, the single factor most closely associated with maximum life-time cisplatin nephrotoxicity was concurrent use of a vinca alkaloid (negative association). Controlling for cisplatin dose per course, factors most closely associated with residual nephrotoxicity after the end of cisplatin therapy were cumulative dose of cisplatin, concurrent use of metoclopramide (positive associations), uric acid and concurrent use of phenytoin and a vinca alkaloid (negative associations). The association of nephrotoxicity with uric acid and with body surface area was felt to be an artifact resulting from its positive association with pretreatment serum creatinine. Nephrotoxicity during the first course of cisplatin also correlated significantly with autopsy kidney cortex platinum concentrations in 77 evaluable patients. CONCLUSIONS: (1) While several factors correlated with cisplatin nephrotoxicity, most of the observed nephrotoxicity was not explained by the variables identified. (2) While most patients received intravenous hydration, patients receiving high hydration volumes did not have significantly less nephrotoxicity than patients receiving lower hydration volumes: (3) Of the variables identified, serum albumin, metoclopramide and phenytoin may have affected nephrotoxicity by altering cisplatin uptake into or distribution within the kidney.

Antineoplastic Agents↗

PubMed1997

Pilot study of multiple chemotherapy resistance modulators plus epirubicin in the treatment of resistant malignancies.

We studied the toxicity and efficacy of adding to epirubicin five resistance modulators in the treatment of resistant solid tumors. Additional drugs were added in successive cohorts of patients, such that cohort 1 patients received two drugs along with their epirubicin, while cohort 4 patients received five modulators along with their epirubicin. Metronidazole, tamoxifen (cohort 1), dipyridamole (cohort 2), ketoconazole (cohort 3) and cyclosporin (cohort 4) were administered with epirubicin. A total of 22 patients were treated. Nausea and vomiting was usually mild to moderate. There was an unexpectedly high incidence of possible cardiac toxicity associated with treatment, although in some patients it was uncertain whether or not observed cardiac events were related to treatment. Granulocytopenia was significant in all four cohorts, but it was unclear whether it was increased by the modulators. There were two febrile neutropenic events in cohorts 1 and 2 successfully treated with antibiotics, and three septic deaths (one in each of cohorts 1, 2 and 4). It was elected to discontinue enrollment on the study prematurely in light of cardiac and other toxicity seen in the first two patients accrued in cohort 4. A single response was observed. While this approach is feasible, the observed toxicity and the difficulty patients experienced in ingesting the large number of prescribed pills will make further exploration of this approach difficult.

Adjuvants, Pharmaceutic↗

PubMed1997

Rat natriuretic peptide receptor genes are regulated by glucocorticoids in vitro.

The effects of glucocorticoids on NPR-A and NPR-B mRNA transcription and natriuretic peptides ANP and CNP mediated cGMP production by intact vascular smooth muscle cells (VSMC) were studied in rat. Cultured VSMC were prepared from rat mesenteric arteries of 12-week-old Sprague-Dawley rats by enzymatic digestion. Dexamethasone-induced NPR-A mRNA increase was detectable early in the incubation periods and reached a plateau after 48 hours of glucocorticoid administration. This mRNA increase was mimicked by cortisol and inhibited by the glucocorticoid receptors antagonist RU 38,486. The levels of NPR-B mRNA remained unchanged during all the periods of stimulation. However, cGMP generated by both receptors in dexamethasone treated cells was higher than in control cells and this production was mimicked by cortisol and also blocked by RU 38,486. Desoxycorticosterone acetate (DOCA) had no effect on the levels of cGMP production. The results suggest that glucocorticoids have transcriptional and posttranscriptional effects on rat mesenteric arteries cells through glucocorticoid receptors.

Animals↗

PubMed1997

Antiandrogen withdrawal syndrome with nilutamide.

Antiandrogens are combined with medical or surgical castration to achieve total androgen blockade in metastatic prostate cancer. Discontinuation of antiandrogens at disease progression has been associated with prostate-specific antigen (PSA) decrease, symptom improvement, and occasionally objective tumor regression. Two cases of metastatic prostate cancer demonstrating decrease in PSA of 92% and 56% on discontinuation of nilutamide therapy are reported. Improvement in urinary symptoms, bone pain and, in one, disappearance of para-aortic lymphadenopathy paralleled the PSA decrease. The duration of the withdrawal response of 6 months was comparable to those reported with discontinuation of flutamide.

Aged↗

PubMed1997

Phase II study of a one hour paclitaxel infusion in combination with carboplatin for advanced non-small cell lung cancer.

PURPOSE: To determine the activity, toxicity, and optimal dose of paclitaxel when given by one hour infusion combined with carboplatin in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-seven previously untreated patients with stage IIIB or IV NSCLC were enrolled. Paclitaxel was administered by one hour infusion at a dose of 175 mg/m2 for the first cycle, and was escalated up to 255 mg/m2 over successive cycles if tolerated. In the absence of toxicity, the carboplatin dose was kept constant at an area under the concentration-time curve (AUC) of 6. Cycles were repeated at 3-week intervals until progression or intolerable toxicity occurred. RESULTS: Thirty-six patients were evaluable for toxicity and survival, and thirty-five for responses. The partial response rate was 10 of 35 (29%) and there were no complete responses. The median duration of response was 4.8 months (range 0.5-11.7 months). The median survival duration was 6.5 months, and 1 year survival was 31%. The mean paclitaxel dose was 188 mg/m2. Treatment was generally well tolerated. Four patients (11%) had febrile neutropenia. Five patients (14%) had grade 3 neuropathy, and 4 (11%) had grade 3 nausea and vomiting. Minor toxicities included alopecia, myalgias, arthralgias and stomatitis. CONCLUSIONS: Paclitaxel and carboplatin is a well-tolerated regimen that can safely be given by a one hour paclitaxel infusion. The modest response rate observed in this study may be due to either the low dose-intensity of paclitaxel or the short infusion duration. Further trials to optimize the relative doses of paclitaxel and carboplatin are needed.

Adult↗

PubMed1997

HIV protease inhibitors, saquinavir, indinavir and ritonavir: inhibition of CYP3A4-mediated metabolism of testosterone and benzoxazinorifamycin, KRM-1648, in human liver microsomes.

The protease inhibitors, ritonavir, indinavir and saquinavir, the most potent anti-HIV drugs developed to date, interact with many drugs by competing for CYP3A4, an enzyme central to the metabolism of a wide variety of compounds. Human liver microsomes were used to compare inhibition by these three protease inhibitors. The inhibition was the greatest with ritonavir and indinavir and less potent with saquinavir.

Antibiotics, Antitubercular↗

PubMed1997

Cranial radiation and concomitant cisplatin and mitomycin-C plus resistance modulators for malignant gliomas.

We studied the toxicity and efficacy of adding in sequence 4 resistance modulators to combination chemotherapy and radiotherapy in the treatment of glioblastoma multiforme and poor prognosis anaplastic astrocytomas. Patients received cisplatin plus mitomycin-C concurrently with and following 60 Gy of radiotherapy administered over 6 weeks. Resistance modulators were added in sequence to chemotherapy in each cohort of 6 patients as follows: metronidazole + pentoxifylline (cohort 1); + dipyridamole (cohort 2), + beta carotene (cohort 3). Central nervous system toxicity (which ranged from drowsiness to seizures and loss of consciousness) was frequent. The incidence of gastrointestinal symptoms was substantial, but was usually mild to moderate in severity. Three of 11 patients evaluable for response achieved a partial remission with treatment. The median survival duration for all patients was 26 weeks from initial diagnosis. The study was terminated prematurely because of significant toxicity (in this study as well as in parallel concurrent studies of similar design in other tumor types) and apparent lack of benefit.

Adult↗

PubMed1997

Multiple resistance modulators combined with carboplatin for resistant malignancies: a pilot study.

BACKGROUND: Chemotherapy resistance is probably multifactorial; hence, we assessed the feasibility of adding to carboplatin 6 concurrent resistance modulators in 53 patients with resistant cancers. METHODS: Pentoxifylline and dipyridamole were added to carboplatin 400 mg/m2 in cohort 1, and metronidazole was also given in cohort 2. Mannitol and saline were administered in each cohort with the theoretical objective of improving carboplatin delivery to tumors by reducing blood viscosity. Because of excessive toxicity in cohort 2, cohort 3 received the same modulators as in cohort 2 but with a reduced dose of carboplatin (200 mg/m2). Subsequent patients had the following drugs added to those in the previous cohort: novobiocin (cohort 4), tamoxifen (cohort 5), ketoconazole (cohort 6). Cohort 7 patients received the 6 cohort 6 modulators along with carboplatin 300 mg/m2. RESULTS: Thrombocytopenia was excessive in early cohorts with a carboplatin dose of 400 mg/m2, but was minimal at lower doses. Other toxicity was generally tolerable and reversible, particularly at carboplatin doses < or = 300 mg/m2, although gastrointestinal and neurological toxicity tended to worsen as additional modulators were added. No major responses (but 4 minor responses) were seen in this patient population with heavily pretreated or primarily resistant cancers. CONCLUSIONS: Acceptable doses for phase II studies are carboplatin 300 mg/m2, 20% mannitol 250 ml plus normal saline 500 ml over 1 hr prior to carboplatin, pentoxifylline 700 mg/m2/day p.o. from 3 days before carboplatin to cessation of therapy, dipyridamole 100 mg/m2 p.o. q6h x 6 days starting 24 hr before carboplatin, metronidazole (750 mg/m2 p.o. 12 hr and immediately before, and 24 hr after carboplatin; 250 mg/m2 suppository p.r. 12 hr and immediately before, and 6 and 24 hr after carboplatin; and 500 mg/m2 i.v. right after carboplatin), novobiocin 600 mg/m2 p.o. q12h x 6 days starting 24 hr before carboplatin, and tamoxifen 100 mg/m2/day plus ketoconazole 700 mg/m2/day x 3 days starting the day before carboplatin, with oral dexamethasone and ondansetron as antimetics.

Adult↗

PubMed1997

Age- and gender-related changes in endothelin and catecholamine release, and in autonomic balance in response to head-up tilt.

1. There is an increase in circulating levels of vasoconstrictive hormones and an alteration in baroreceptor responsiveness with aging. The role of changes in endothelium-dependent and -independent vasoconstrictive hormones in relation to age and gender, with simultaneous assessment of autonomic balance in response to head-up tilt, has been incompletely studied. 2. Sixteen young [25 +/- 3 years (mean +/- SEM)] and 16 older normal volunteers (68 +/- 7 years) underwent a 30 min head-up tilt test at 60 degrees. Haemodynamics were measured every 5 min and blood samples for neurohormone measurement were drawn at baseline, 5, 10, 15 and 30 min into the test. Heart rate variability was analysed in 5 min segments at the baseline, and during the test. The younger subjects exhibited a greater increase in heart rate and diastolic blood pressure, despite lower absolute levels of noradrenaline (norepinephrine) and endothelin-1. Analysis of heart rate variability yielded a decrease in both high- and low-frequency bands in the aged; power at low-frequency decreased only in the young subjects. The age-related differences in blood pressure and noradrenaline levels were markedly attenuated in the female subjects. In addition, endothelin-1 levels and power spectral measurements at low frequency were the lowest in younger females throughout the tilt. 3. Despite attenuated cardiovascular response to tilt, both systemic adrenergic 'drive' and endothelin-1 levels increase in parallel with aging. Thus, endothelium-dependent and -independent vasoconstrictive hormone levels increase with age in the resting state and in response to neurohumoral stimulation in humans.

Adult↗

PubMed1997

Mitoxantrone in the treatment of metastatic transitional cell carcinoma of the prostate. A case report.

A 61-year-old man with pulmonary and bone metastases from a primary transitional cell carcinoma of the prostate (TCCP) refractory to MVAC was treated with mitoxantrone 16 mg/m2 i.v. at 3-week intervals. With this, he experienced an objective partial remission lasting 5 months and a significant decrease in cancer-related symptoms. Mitoxantrone deserves further evaluation in this rare disease.

Antibiotics, Antineoplastic↗

PubMed1997

L-arginine infusion increases basal but not activated cerebral blood flow in humans.

Nitric oxide is a potent vasodilator. Infusion of its precursor, L-arginine, results in increased cerebral blood flow (CBF) in experimental animals. We examined the effects of L-arginine infusion on CBF in humans using positron emission tomography and the quantitative H2(15)O method. Six subjects received 500 ml of 0.9% NaCl solution, and six subjects received an infusion of L-arginine (16.7 mg/kg/min; 500 mg/kg). Before and after the i.v. infusion, paired CBF measurements were performed at baseline and with vibrotactile stimulation of the right hand. In scans performed without vibrotactile stimulation, mean whole-brain CBF increased from 34.9 +/- 3.7 ml 100 g-1 min-1 to 38.2 +/- 4.4 ml 100 g-1 min-1. (9.5%; p < 0.005) after L-arginine infusion. The temporal pattern of CBF changes differed from that of plasma growth hormone and insulin levels and of arterial pH. In contrast, in the saline group, mean whole-brain CBF did not change significantly (35.8 +/- 5.9 ml 100 g-1 min-1 to 35.9 +/- 6.4 ml 100 g-1 min-1; 0.3%). Vibrotactile stimulation produced significant focal increases in CBF, which were unaffected by L-arginine infusion. L-arginine infusion was associated with an increase in plasma L-citrulline, a byproduct of nitric oxide synthesis.

Adult↗

PubMed1997

African urbanization: dependent linkages in a global economy.

"The colonial experience drastically altered the indigenous urban system in Africa, replacing it with a European-driven urban system designed to facilitate the extraction of resources. The urban system and the nature of ties with the colonial power allowed African integration into the world economy only in a dependent fashion. These dependent ties were deepened as the world economy became more globalized in the post-colonial period. The continent rapidly urbanized, with much of the population concentrating in primate cities. This urbanization was not accompanied by economic growth; as a result Africa will soon become a continent of large cities--with urban population they cannot physically and economically support."

Africa↗

PubMed1997

Gene expression of natriuretic peptide receptors in rats with DOCA-salt hypertension.

In our previous studies, we found that the atrial natriuretic peptide (ANP) binding and guanylyl cyclase activity of A-type natriuretic peptide receptors (NPR-A) were upregulated in renal papillae but downregulated in vascular tissues and glomeruli of rats with deoxycorticosterone acetate (DOCA)-salt hypertension [E. Nuglozeh, G. Gauquelin, R. Garcia, J. Tremblay, and E. L. Schiffrin. Am. J. Physiol. 259 (Renal Fluid Electrolyte Physiol. 28): F130-F137, 1990]. To further understand the molecular significance of these regulations, we measured the relative abundance of the transcripts of NPR-A and NPR-B by Northern blot in the aorta, mesenteric arteries, adrenal cortex, renal papillae, and lungs in DOCA-salt hypertensive and control rats. In renal papillae we also examined the translation and transcription of NPR-A by ribosome loading and run-on assay. Compared with controls, the steady-state levels of mRNA for NPR-A were increased in the aorta and mesenteric arteries but were decreased in the adrenal cortex and renal papillae in DOCA-salt-treated rats. NPR-B mRNA was decreased in the aorta, mesenteric arteries, and adrenal cortex in hypertensive rats. In lungs the mRNA for both receptors was unchanged. Translation of NPR-A mRNA, as assessed by ribosome loading, was reduced in renal papillae. Transcriptional activity of its gene was not detectable in these tissues. Guanosine 3',5'-cyclic monophosphate levels generated by NPR-A in renal papillae and by NPR-A and NPR-B in the adrenal cortex, aorta, and mesenteric arteries of DOCA-salt-treated rats remained increased in hypertension. The higher NPR-A activity in the presence of a lower level of its mRNA in renal papillae and the higher NPR-B activity in the presence of a lower level of its mRNA in the vasculature, adrenal cortex, and lungs can alternatively be explained by receptor stabilization or increased receptor recycling.

Adrenal Cortex↗

PubMed1997

Endothelin-1 myocardial clearance, production, and effect on capillary permeability in vivo.

Myocardial metabolism of endothelin-1 (ET-1) and its effect on coronary microcirculatory exchanges were obtained in anesthetized dogs by combining the indicator-dilution technique with immunoreactive ET-1 measurements. The myocardium extracted 17.7 +/- 4.6% of tracer ET-1 (n = 12). Simultaneously measured ET-1 levels in the aorta (0.97 +/- 0.46 pg/ml) and coronary sinus (0.96 +/- 0.53 pg/ml) were not different, supporting a production of ET-1 by the heart that balances the amount extracted. Intracoronary infusion of ET-1 (5 ng.kg-1.min-1) increased coronary sinus ET-1 levels approximately 50-fold, decreased coronary blood flow per unit of interstitial space by approximately 30% (P = 0.006), and increased myocardial microcirculatory transit times (n = 6). Permeability to albumin was unaffected by ET-1, whereas the permeability-surface area product for sucrose decreased following derecruitment of myocardial capillaries. We conclude that there is a normal myocardial metabolic balance of ET-1 and that the heart marginally contributes to circulating ET-1. Pharmacological doses of ET-1 may adversely affect myocardial metabolism by reducing blood flow and the permeability-surface area product for small circulating substances.

Animals↗