Biomedical subjects

D J Stewart

Publications and source records attributed to D J Stewart.

At least 127 records · Page 7Linked to original sources

PubMed1995

Alterations in bronchoalveolar lavage and plasma endothelin-1 levels early after lung transplantation.

A temporary increase in pulmonary vascular resistance is observed during the first 24 hr following lung allotransplantation. We hypothesized that such early vascular changes are secondary to endothelial injury by ischemia-reperfusion, and that this may be mediated by an increased pulmonary endothelin-1 production/release. To test this hypothesis, radioimmunoassay was used to analyze endothelin-1 levels in bronchoalveolar lavage and plasma taken before surgery and at 1 hr, 4 hr, 24 hr, and 1 week after transplantation. The study was carried out on 2 groups of mongrel dogs. One group was subjected to left single-lung allotransplantation and the other to autotransplantation. Endothelin-1 levels in the bronchoalveolar lavage samples from the lung allografts were significantly increased at 1 (0.70 +/- 0.18 pg/ml) and 4 (1.84 +/- 0.65 pg/ml) hr after transplantation compared with the preoperative value (0.14 +/- 0.05 pg/ml), and declined at 24 (0.85 +/- 0.84 pg/ml) hr after transplantation. Similarly, plasma endothelin-1 levels in the allografts were significantly increased at 1 (2.0 +/- 0.80 pg/ml) and 4 (2.0 +/- 0.71 pg/ml) hr after transplant when compared with preoperative levels (0.54 +/- 0.09 pg/ml). Plasma endothelin-1 levels, however, remained significantly high after 24 hr (1.4 +/- 0.4 pg/ml; P < 0.007) and decreased after 1 week after transplant (0.89 +/- 0.32 pg/ml). On the other hand, endothelin-1 levels in bronchoalveolar lavage from the autograft group remained relatively unchanged; however, plasma levels showed a significant increase at 4 hr (6.6 +/- 1.8 pg/ml) after transplantation compared with preoperative levels (2.8 +/- 0.38 pg/ml). Elevation of endothelin-1 levels early after lung transplantation may play an important role in early high pulmonary vascular resistance and temporary graft dysfunction.

Airway Resistance↗

PubMed1995

Clinical relevance of endothelial dysfunction in cardiovascular disorders.

The potential role of endothelial dysfunction, defined by an imbalance in the production of endothelium-derived vasodilator and constrictor factors is discussed. Evidence is presented that increased endothelin-1 production plays an important role in the clinical and morphological manifestations of pulmonary hypertension, particularly in primary disease. As well, the potential contribution of a relative decrease in nitric oxide production to inappropriately elevated pulmonary vascular resistance in patients with secondary causes of pulmonary hypertension, particularly those with congestive heart failure is discussed.

Cardiovascular Diseases↗

PubMed1995

Response of brain metastases from breast cancer to megestrol acetate: a case report.

A 56 year old women was treated with megestrol acetate (Megace) 40 mg p.o. q.i.d. for her cerebellar metastasis of primary adenocarcinoma of the breast. She had previously undergone two surgical resections of her brain metastasis, and a course of radiotherapy. After failing to tolerate tamoxifen therapy, she received Megace, with marked improvement in her cerebellar tumor on CT scans. Despite good control of her brain tumor with Megace, she developed progressive neurological symptoms thought to be due to meningeal carcinomatosis, and died two years after initiating Megace therapy. We conclude that Megace could potentially be beneficial in some patients with brain metastases from adenocarcinoma of the breast.

Adenocarcinoma↗

PubMed1995

A phase II study of 5-fluorouracil plus folinic acid in malignant gliomas in adults.

Fourteen patients with malignant gliomas were entered on a phase II study of 5-fluorouracil 300-370 mg/m2 plus folinic acid 200 mg/m2 x 5 days q4 weeks. To be eligible, patients could not have received more than 1 prior chemotherapy regimen. A single patient with a recurrent oligodendroglioma responded. Toxicity (predominantly stomatitis, diarrhea, and granulocytopenia) was tolerable and was similar to that seen in studies of 5-fluorouracil plus folinic acid in other tumor types. This regimen has minimal activity in recurrent malignant gliomas.

Adult↗

PubMed1995

Intraarterial cisplatin plus intravenous doxorubicin for inoperable recurrent meningiomas.

The majority of meningiomas are cured by surgical resection. There is little information in the literature on the use of chemotherapy in meningiomas. We report 2 patients with inoperable recurrences of meningiomas that responded (1 patient) or stabilized (1 patient) when treated with the combination of intracarotid cisplatin plus intravenous doxorubicin.

Adolescent↗

PubMed1995

Pharmacology, relative bioavailability, and toxicity of three different oral cyclophosphamide preparations in a randomized, cross-over study.

Thirty-six patients were entered on this study to determine the pharmacology, bioavailability, and toxicity of three different oral formulations of cyclophosphamide (Cytoxan, Endoxan, and an investigational direct compression tablet). Patients were randomized with respect to the order in which they received the different oral cyclophosphamide preparations, and received each one for two weeks followed by a two week washout period. Concurrent chemotherapy was allowed provided it remained constant across all 3 courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and phosphoramide mustard were measured by gas chromatography with electron capture detection. Peak plasma cyclophosphamide concentrations and times to peak plasma cyclophosphamide and phosphoramide mustard preparations were significantly greater for Endoxan than for Cytoxan and the investigational direct compression tablet. Drug area under the concentration-time curve (AUC), bioavailability, and plasma elimination half-life could not be reliably calculated for Endoxan but were similar for Cytoxan and the investigational formulation. Based on AUC comparisons, bioavailability of parent compound (relative to an oral cyclophosphamide solution) was 85% for Cytoxan and 69% for the investigational formulation. This difference was not significant. There were no significant differences between the 3 formulations with respect to any individual type of toxicity, although the investigational formulation tended to be associated with somewhat less overall toxicity (p = 0.08).

Administration, Oral↗

PubMed1995

Immunological parameters associated with antigenic competition in a multivalent footrot vaccine.

A murine model for antigenic competition with multivalent D. nodosus pili vaccine has been established that parallels the phenomenon observed in sheep where levels of antibody, specific for any particular serogroup of pili, are significantly lower following vaccination in the presence of multiple serogroups of pili than with that serogroup alone. This competition was observed in both high and low responder strains of mice and was not dependent on the multiplicity of the antigens in the multivalent vaccine but could be observed with a large excess of a single heterologous serogroup. Competition was manifest by a reduction in the number of serogroup-specific antibody secreting cells elicited in response to vaccination. The antibody response to a single serogroup of pili reached a plateau at high doses and it was at these doses that antigenic competition was most pronounced, under conditions where both B- and T-cell responses were limiting. The limit in T-cell responsiveness was not imposed at the level of presentation of antigen. Pili-specific T cells were largely cross-reactive for different serogroups, and under conditions of limiting T-cell stimulation within a lymph node the available T cells would have to be shared between B cells specific for each serogroup of pili, which may in turn result in the decrease of serogroup-specific antibody induced following inoculation with the multivalent vaccine.

Animals↗

PubMed1995

Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin.

We assessed factors which affect cisplatin concentrations in human surgical tumour specimens. Cisplatin 10 mg m-2 was given i.v. to 45 consenting patients undergoing surgical resection of neoplasms, and platinum was assayed in resected tumour and in deproteinated plasma by flameless atomic absorption spectrophotometry. By multiple stepwise regression analysis of normalised data, patient characteristics that emerged as being most closely associated (P < 0.05) with tumour platinum concentrations (after correcting for associations with other variables) were tumour 'source' [primary brain lymphomas, medulloblastomas and meningiomas ('type LMM') > 'others' > lung cancer > head/neck cancer > gliomas) or tumour 'type' (LMM > brain metastases > extracerebral tumours > gliomas), serum calcium and chloride (positive correlations) and bilirubin (negative). Tumour location (intracranial vs extracranial) did not correlate with platinum concentrations. If values for a single outlier were omitted, high-grade gliomas had significantly higher platinum concentrations (P < 0.003) than low-grade gliomas. For intracranial tumours, the computerised tomographic scan feature that correlated most closely with platinum concentrations in multivariate analysis was the darkness of peritumoral oedema. Tumour source or type is a much more important correlate of human tumour cisplatin concentrations than is intracranial vs extracranial location. Serum calcium, chloride and bilirubin levels may affect tumour cisplatin uptake or retention. CT scan characteristics may help predict cisplatin concentrations in intracranial tumours.

Blood-Brain Barrier↗

PubMed1995

Pressure tuning infrared spectroscopic study of cisplatin-induced structural changes in a phosphatidylserine model membrane.

The dynamic effect of cis-diamminedichloroplatinum(II) (DPP) and its aquated metabolite (DDP-OH) on a dimyristoylphosphatidylserine (DMPS) model membrane was investigated by pressure tuning vibrational spectroscopy. The native species (DDP-Cl) and the aquated species (DPP-OH) were both observed to bind to the carboxylate group of the serine as evidenced by a frequency shift of 1622-1620 cm-1. However, only DDP-OH was observed to bind to the phosphate group (PO(-)2). The binding of either drug to DMPS resulted in an increased pressure required to halt the reorientational fluctuations of the acyl chains, indicating that the distance between the chains were increased. The two drugs did not partition into the matrix of the hydrophobic section in the model membrane. Collectively, these data suggest that DDP-Cl and DDP-OH are capable of binding to the polar head group of DMPS, resulting in an enlargement of the area of the head and a subsequent increase in the intermolecular distance between the acyl chains.

Antineoplastic Agents↗

PubMed1995

A phase II study of 5-fluorouracil and high dose folinic acid in cisplatin-refractory metastatic bladder cancer.

BACKGROUND: Bladder cancer is a chemosensitive tumour, however, there is no effective therapy for patients with metastatic disease who failed to respond or relapsed after prior treatment with cisplatin-based chemotherapy. Single agent 5-fluorouracil has modest activity in bladder cancer. The combination of 5-fluorouracil with folinic acid results in stabilization of the ternary complex of 5-fluorodeoxyuridine monophosphate-thymidylate synthetase-5,10 methylene tetrahydrofolate leading to increased DNA inhibition and increased cytotoxicity of 5-fluorouracil. PATIENTS AND METHODS: Fourteen evaluable patients with metastatic bladder cancer were treated with 5-fluorouracil at 300 mg/m2 and folinic acid at 200 mg/m2 daily for five days. RESULTS: There were no complete or partial responses. One patient had a minor response and three patients had stable disease. Diarrhea and mucositis occurred in 25% of patients. There was one treatment-related death. CONCLUSION: High dose folinic acid did not increase the cytotoxicity of 5-fluorouracil in metastatic bladder cancer after cisplatin failure.

Adult↗

PubMed1995

A phase II study of 5-fluorouracil plus high-dose folinic acid in the treatment of recurrent small cell lung cancer.

Fourteen patients with small cell lung cancer (SCLC) previously treated with one or two chemotherapy regimens were entered in this study. 5-Fluorouracil 370 mg/m2 or 300 mg/m2 was given with folinic acid 200 mg/m2 by i.v. rapid infusion on days 1 through 5. Cycles were repeated every 28 days. There were no objective responses. One patient had stable disease for 47 weeks. The overall median survival duration was 23 weeks. Toxicity was comparable to that seen in other studies of 5-fluorouracil plus folinic acid.

Aged↗

PubMed1995

Prolonged disease-free survival following surgical debulking and high-dose cisplatin/doxorubicin in a patient with bulky metastases from giant cell tumor of bone refractory to "standard" chemotherapy.

A 32-year-old man developed multiple pulmonary metastases from a giant cell tumor of bone. His metastases failed to respond to several chemotherapy regimens (high-dose methotrexate with folinic acid plus doxorubicin 90 mg/m2; cyclophosphamide + bleomycin + actinomycin D; mitoxantrone + dacarbazine; and cisplatin 110 mg/m2). He underwent surgical resection (incomplete) of > 1 kg of tumor from his right lung in March 1985, followed by chemotherapy with menogaril (to which he did not respond). In August 1985, he underwent surgical resection (again, incomplete) of > 1 kg of tumor from his left lung. At the time of surgery, the left and right lung tumors differed histopathologically, with giant cell tumor present in the right lung and sarcoma in his left lung. He received carmustine in October 1985 and mitomycin C in December 1985 without response. His multiple bilateral lung metastases had again become quite large by September 1986. At that time, he received doxorubicin 90 mg/m2 plus cisplatin 120 mg/m2, and for the first time experienced tumor reduction (minor response). He underwent a subtotal resection of right lung and chest wall metastases in December 1986, and underwent subtotal resection of left lung metastases in January 1987. Grossly visible residual tumor was left behind on both sides at the time of surgery, although none was apparent on chest radiograph. He received a final chemotherapy treatment with doxorubicin 90 mg/m2 plus cisplatin 120 mg/m2 on February 2, 1987. He remained free of evidence of residual or recurrent tumor at the time of last followup in February, 1994.

Adult↗

PubMed1995

Lack of role for nitric oxide (NO) in the selective destabilization of endothelial NO synthase mRNA by tumor necrosis factor-alpha.

The constitutive expression of endothelial nitric oxide (NO) synthase (cNOS) is essential for the physiological regulation of vascular tone and structure. The mechanism of downregulation of steady state cNOS mRNA in human umbilical vein endothelial cells exposed to tumor necrosis factor-alpha (TNF-alpha) was investigated by using Northern blot analysis of total cellular RNA. TNF-alpha produced a dose- and time-dependent decrease in cNOS mRNA expression that was near maximal at 10 U/mL and 6 hours of exposure, respectively. In contrast, steady state expression of endothelin-1 and plasminogen activator inhibitor-1 (PAI-1) mRNA was upregulated by TNF-alpha. The pharmacological generation of NO using sodium nitroprusside (10 mumol/L) and S-nitroso-acetylpenicillamine (100 to 400 mumol/L) had no effect on cNOS mRNA levels, and TNF-alpha-induced downregulation of cNOS was not prevented by coincubation with the inhibitors of NO synthesis N omega-nitro-L-arginine methyl ester (1 mmol/L) and NG-monomethyl L-arginine (10 mmol/L). Under control conditions, cNOS and PAI-1 mRNA were stable after treatment with actinomycin D for periods greater than 24 hours, whereas endothelin-1 message was rapidly degraded (half-life, < 1 hour). Pretreatment with TNF-alpha (30 U/mL) selectively reduced that half-life of cNOS mRNA to less than 12 hours without altering the stability of PAI-1 message. TNF-alpha-induced destabilization of cNOS mRNA could be partially prevented by coincubation with cycloheximide (1 mumol/L) but was not reproduced by addition of sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗

PubMed1995

Pharmacokinetics and bioequivalence of etoposide following intravenous administration of etoposide phosphate and etoposide in patients with solid tumors.

PURPOSE: To assess the pharmacokinetics and bioequivalence of etoposide following intravenous (i.v.) administration of etoposide phosphate (Etopophos; Bristol-Myers Squibb, Princeton, NJ), a prodrug of etoposide, and VePesid (Bristol-Myers Squibb). PATIENTS AND METHODS: Forty-nine solid tumor patients were randomized to receive Etopophos or VePesid on day 1 of a day-1,3,5 schedule of treatment. The alternate drug was given on day 3 and repeated on day 5. The dose, 150 mg/m2 of etoposide equivalent, was administered by constant rate infusion over 3.5 hours. The plasma concentrations of etoposide phosphate and etoposide were determined using validated high-performance liquid chromatography (HPLC) assays. Pharmacokinetic parameters were calculated by a noncompartmental method. Etopophos was considered to be bioequivalent to VePesid if the 90% confidence limits for the differences in mean maximum concentration (Cmax) and AUCinf of etoposide were contained within 80% to 125% for the long-transformed data. RESULTS: Forty-one patients were assessable for pharmacokinetics and bioequivalence assessment. Following i.v. administration, etoposide phosphate was rapidly and extensively converted to etoposide in systemic circulation, resulting in insufficient data to estimate its pharmacokinetics. The mean bioavailability of etoposide from Etopophos, relative to VePesid, was 103% (90% confidence interval, 99% to 106%) based on Cmax, and 107% (90 confidence interval, 105% to 110%) based on area under the concentration versus time curve from zero to infinity (AUCinf) values. Mean terminal elimination half-life (t1/2), steady-state volume of distribution (Vss), and total systemic clearance (CL) values of etoposide were approximately 7 hours, 7 L/m2, and 17 mL/min/m2 after Etopophos and VePesid treatments, respectively. The main toxicity observed was myelosuppression, characterized by leukopenia and neutropenia. CONCLUSION: With respect to plasma levels of etoposide, i.v. Etopophos is bioequivalent to i.v. VePesid.

Adult↗

PubMed1995

Oral etoposide and carboplatin. Effective therapy for elderly patients with small cell lung cancer.

PURPOSE: Elderly patients with small cell lung cancer (SCLC) and/or those with comorbid conditions are frequently not considered candidates for standard combination chemotherapy. An active, but less toxic regimen is needed for this group of patients. PATIENTS AND METHODS: Forty-seven elderly (> 65 years) or medically unfit patients with SCLC were treated with oral etoposide 100 mg/m2 x 7 days and carboplatin 150 mg/m2 day 1. Treatment was given every 3-4 weeks for six cycles in responding patients. Patients responding to the chemotherapy regimen were also treated with prophylactic cranial irradiation, and limited-stage patients received thoracic radiotherapy. The study population included 36 extensive-stage patients and 11 limited-disease patients with renal or cardiac disease that precluded standard chemotherapy. The median age of the study population was 69 years (range: 47-84). RESULTS: Nine of 47 patients were inevaluable for response, including four patients who succumbed to sepsis. Of the 38 patients evaluable for response, 71% responded (95% CI: 56-86%) (88% LD; 67% ED) with a complete response in 29% of patients (50% LD; 23% ED). Based on an analysis of intent to treat, the overall response rate was 60% and the median survival time of the whole group was 46 weeks (LD, 59 weeks; ED, 45 weeks). Treatment was generally well tolerated. Neutropenia was the dose-limiting toxicity; the median nadir granulocyte count was 1.04 x 10(9)/L (range: 0-8.2). CONCLUSION: We conclude that this regimen can provide palliation to SCLC patients who might not otherwise be considered for systemic chemotherapy.

Aged↗

PubMed1995

Nucleotide and deduced protein sequence of the extracellular, serine basic protease gene (bprB) from Dichelobacter nodosus strain 305: comparison with the basic protease gene (bprV) from virulent strain 198.

In earlier studies, it appeared that benign strains of the Gram-negative, obligate anaerobe, Dichelobacter nodosus, were devoid of the extracellular, serine basic protease (pI approximately 9.5) of virulent strains. However, Southern and PCR analysis have shown a homologous gene (bprB) in the representative benign strain 305. The deduced amino acid sequence of the prepro- and mature protease regions of bprB confirmed this homology and showed 97% sequence identity with the bprV precursor from virulent strain 198. Identity in the carboxy-terminal extension region was 90%. Expression studies in Escherichia coli transformed with bprB, showed that the gene was capable of the production of an active protease. A protease, albeit with a lower iso-electric point (approximately 8.6), was isolated from D. nodosus culture supernatants and shown to cross-react with antibodies raised against the more basic protease from strain 198. The amino acid sequence encoded by the strain 305 gene revealed two additional acidic residues consistent with a lowered iso-electric point and supported the conclusion that bprB and bprV produce equivalent basic proteases.

Amino Acid Sequence↗

PubMed1995

Plasma endothelin-1 levels in human lung transplant recipients.

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells and is believed to play an important role in the pathophysiology of the pulmonary vasculature. We have investigated the early changes in ET-1 plasma levels in lung transplant recipients at various intervals before and after isolated lung transplantation. The mean plasma ET-1 level immediately before transplantation was 0.8 +/- 0.1 pg/ml. This was significantly increased to 2.6 +/- 0.5 pg/ml shortly after unclamping and vascular reperfusion of the allograft, and remained high 4 h (2.3 +/- 0.5 pg/ml), 6 h (2.4 +/- 0.6 pg/ml), and 12 h (1.7 +/- 0.3 pg/ml) after transplantation. Thereafter, the level of ET-1 started to decline, reaching 1.3 +/- 0.3 pg/ml 24 h and 0.9 +/- 0.3 pg/ml 1 week after transplantation. This early increase in ET-1 plasma level is consistent with our observation of alterations in pulmonary vascular resistance, pulmonary artery pressure and cardiac output early after transplantation. These findings demonstrate that an increase in plasma ET-1 levels shortly after lung transplantation may have a detrimental effect during the postoperative course early after transplantation.

Blood Pressure↗

PubMed1994

Characterization of a basic serine proteinase (pI approximately 9.5) secreted by virulent strains of Dichelobacter nodosus and identification of a distinct, but closely related, proteinase secreted by benign strains.

An extracellular serine proteinase with a PI approximately 9.5 (referred to as 'basic proteinase') was purified to homogeneity, from strains of Dichelobacter nodosus that cause virulent foot-rot, by gel filtration of concentrated culture supernatant on Sephadex G-100 and chromatography on sulphopropyl-Sephadex C-25 at pH 8.6 D. nodosus strains that cause benign foot-rot do not secrete a corresponding basic proteinase with a pI of approximately 9.5. Benign strains secrete a closely related, but distinct, proteinase which has the same molecular mass and N-terminal sequences as the 'virulent' basic proteinase, but a lower pI of approximately 8.6. The basic proteinases from both strains appear to interact with other proteins present in the culture medium, which results in anomalous behavior on gel filtration. Pure D. nodosus 'virulent' basic proteinase has a molecular mass of 36 kDa and showed a low solubility at I < 0.05 precipitating quantitatively from solution as microcrystals. The proteinase shows optimal activity at pH 8.0 and is stable to heating to 55 degrees C for 30 min, but at higher temperatures activity is rapidly lost. Bivalent-metal ions (e.g. Ca2+) are required to maintain the structural integrity and stability of the proteinase; in the presence of EDTA or conditions that cause protein unfolding, the proteinase undergoes rapid and complete autolysis. Cleavage of oxidized insulin A- and B-chain showed that the basic proteinase has a broad specificity, including cleavage at lysine and arginine bonds.

Amino Acid Sequence↗