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D C Smith

Publications and source records attributed to D C Smith.

At least 73 records · Page 4Linked to original sources
PubMed1998

All-trans-retinoic acid modulation of drug-metabolizing enzyme activities: investigation with selective metabolic drug probes.

PURPOSE: All-trans-retinoic acid (ATRA) is a retinoid analogue that has been shown to be effective in acute promyelocytic leukemia. It is currently being investigated for efficacy in the treatment and prevention of various types of cancer. One of the factors limiting its use is the observed increase in ATRA clearance and elimination which occurs shortly after treatment is started, leading to reduced levels of drug in the body and loss of effectiveness. ATRA efficacy may be enhanced if this autoinduction of metabolism can be overcome, for example through the inhibition of the activity of the induced specific metabolizing enzyme(s). This requires the identification of this induced enzyme(s) and development of approaches to selectively inhibit its activity. METHODS: In the course of a phase II evaluation of ATRA in prostate cancer, we investigated the activities of five specific cytochrome P450 (CYP) (CYPs 1A2, 2C19, 2D6, 2E1 and 3A4) and N-acetyltransferase enzymes using a newly developed five-drug cocktail involving caffeine, mephenytoin, debrisoquine, chlorzoxazone and dapsone respectively. Enzyme activities were assessed in 17 patients with hormone-refractory prostate cancer before the initiation of ATRA therapy, after 14 days of continuous ATRA administration and 7 days after cessation of drug therapy. RESULTS: After 14 days of ATRA therapy, the activities of CYP2E1 (chlorzoxazone hydroxylase) and N-acetyltransferase (in fast acetylators only) were increased by 83% and 29% (P < 0.05), respectively. Both activities returned to baseline by 7 days after cessation of therapy and the profiles were similar to the changes seen in the clearance of ATRA itself. There were no changes in the activities of any of the other enzymes investigated. CONCLUSION: This study shows that ATRA selectively modulates the activities of specific metabolizing enzymes and that this approach may be useful in identifying enzymes that can be explored in an attempt to mitigate ATRA autoinduction through selective modulation of enzyme activities. Further investigations are required to determine whether the elevated enzymes are also responsible for the increased clearance and elimination of ATRA.

Adenocarcinoma↗
PubMed1998

A phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer.

OBJECTIVES: To test the use of 1 mg/day of oral diethylstilbesterol (DES) as a treatment for patients with advanced prostate cancer who had failed primary hormonal therapy. Approximately 40,000 men this year will experience first-line hormonal therapy failure for their metastatic prostate cancer. At this time there is no standard therapy for men whose first-line hormonal manipulation has failed. This clinical problem has been exacerbated by the use of prostate-specific antigen (PSA) as a proved biomarker to follow disease progression. Patients who are experiencing hormonal therapy failure now present with a rising PSA, and virtually all are asymptomatic. The dilemma of how to treat these patients represents a new clinical problem for the medical oncologist and urologist that needs to be answered. METHODS: We conducted a Phase II trial of oral DES in 21 patients. Patients were followed for response by PSA criteria and toxicity. A decrease in two serial measurements of PSA of greater than 50% from baseline was judged to be a partial response. RESULTS: Nine of 21 patients achieved a PSA response (43% response rate with 95% confidence intervals of 22% to 64%) leading to early cessation of this Phase II trial. Eight of 13 patients (62%) who had only one prior hormone manipulation that failed demonstrated a PSA response, whereas only 1 of 8 patients (13%) who had received two or more hormone treatments responded (P = 0.07). The median follow-up is 82 weeks (range 8 to 122) among 16 surviving patients. The survival rate at 2 years is 63% (95% confidence interval 41% to 99%). CONCLUSIONS: DES appears to be an active agent for second-line hormone therapy for metastatic prostate cancer. Because it has been taken off the market for economic reasons, DES should be considered for development under the orphan drug strategy.

Administration, Oral↗
PubMed1998

Development of glass-ionomer cement systems.

In the 1960s the idea of positive physico-chemical adhesion with tooth substance resulted in the invention of polyacrylic acid-based cements, first the zinc polycarboxylate and, subsequently, the glass-ionomer cements. These materials were shown to undergo specific adhesion with hydroxyapatite and proved to have properties satisfactory for a variety of clinical applications. The key properties of the glass-ionomer cements--fluoride release over a prolonged period and specific adhesion to enamel and dentine coupled with aesthetic qualities are related to their characteristics as aqueous polyelectrolyte systems. In order to improve toughness, speed of setting and resistance to dehydration, hybrid materials in which some of the water content of the glass-ionomer system was replaced by water-soluble polymers or monomer systems capable of ambient polymerization were formulated in the late 1980s. These materials, which have been termed resin-modified glass-ionomer cements, involve, ideally, the formation of an interpenetrating polymer network combining the acid-base cross-linking reaction of the metal ion-polyacid with the cross-linking polymerization of the monomer system or additive action of the polymers. In the predominantly resin materials there is little polyelectrolyte character and it is controversial whether such materials should be categorized as glass-ionomer cement systems. The specific advantages of these materials over traditional glass-ionomer systems and over composite restorative systems remain to be fully documented. Studies of adsorption to hydroxyapatite of typical monomers using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF SIMS) indicate that resistance to water displacement decreases as hydrophobicity increases.

Biocompatible Materials↗
PubMed1998

Cerebral oxygenation during paediatric cardiac surgery: identification of vulnerable periods using near infrared spectroscopy.

OBJECTIVE: Neurologic sequelae remain a well recognised complication of paediatric cardiac surgery. Monitoring of cerebral oxygenation may be a useful technique for identifying vulnerable periods for the development of neurologic injury. We sought to measure regional cerebral oxygenation in children undergoing cardiac surgery using near infrared spectroscopy to ascertain such vulnerable periods. METHODS: Observational study of 18 children (median age 1.3 years) undergoing cardiac surgery (17 with cardiopulmonary bypass, 8 with circulatory arrest). Regional cerebral oxygenation was monitored using the INVOS 3100 cerebral oximeter and related to haemodynamic parameters at each stage of the procedure. RESULTS: Prior to the onset of bypass, 10 patients had a decrease in regional cerebral oxygenation of > or = 15% points, reaching an absolute haemoglobin saturation less than 35% in 5 cases. The most common cause was handling and dissection around the heart prior to and during caval cannulation. With institution of bypass, regional cerebral oxygenation increased by a mean 18% points to a mean maximum of 75%. During circulatory arrest regional cerebral oxygenation decreased with rate of decay influenced by temperature at onset of arrest (0.25%/min at < 20 degrees C; 2%/min at > 20 degrees C). Reperfusion caused an immediate increase in regional cerebral oxygenation followed by a decrease during rewarming. Discontinuation of bypass caused a precipitous decrease in regional cerebral oxygenation in 5 patients, reaching less than 50% in 3 patients. CONCLUSIONS: These observations suggest that the pre- and early post-bypass periods are vulnerable times for provision of adequate cerebral oxygenation. Near infrared spectroscopy is a promising tool for monitoring O2 supply/demand relationships especially during circulatory arrest.

Brain↗
PubMed1998

Are changes in the evoked electromyogram during anaesthesia without neuromuscular blocking agents caused by failure of supramaximal nerve stimulation?

The evoked electromyogram often decreases during anaesthesia in the absence of neuromuscular block. We have measured the electromyogram of the first dorsal interosseous muscle evoked by train-of-four stimulation of the ulnar nerve in 63 patients undergoing anaesthesia for minor surgery. We used Medicotest P-00-S electrodes, a Datex Relaxograph and a current sink in the stimulating leads in parallel with the current path through the patient. The current sink was used to shunt some of the maximum available output current from the Relaxograph while maintaining the supramaximal stimulus current passing through the patient. After 30 min of anaesthesia, when the muscle response to train-of-four was stable, the ulnar nerve stimulus current was increased by reducing the proportion shunted through the current sink. The electromyographic response did not change during the study in 13 patients. In the remaining 50 patients, the response decreased to 78.4% (SD 27.1%, range 7.5-95.0%) of baseline values over the first 20 min of anaesthesia. In 22 of these patients, the electromyographic response increased from 71.4 (SD 22.6)% to 92.3 (9.5)% of baseline responses when the stimulus current was increased by 12.3 (2.4) mA, while in the remaining 28 patients the response decreased to 83.7 (10.6)% and did not increase with increasing stimulus current. These results suggest that loss of supramaximal stimulation is partly responsible for the observed changes in the evoked electromyogram during anaesthesia.

Adult↗
PubMed1998

Trauma to the aorta and aortic arch branches.

Deceleration and crushing injuries of the chest may traumatize the thoracic aorta or its branches. Traumatic aortic rupture has received significant attention over the past 40 years, whereas the aortic arch branch injuries remain under-recognized. Despite the development of new imaging modalities, angiography remains the gold standard for evaluation of a patient with suspected thoracic arterial injury. Recently, computed tomography and transesophageal echocardiography have been used for serial examination of minimal aortic injuries that are treated conservatively. Medical treatment of the ruptured aorta, delayed surgical repair, and endoluminal deployment of stent-grafts are new developments that provide new options and pose new questions in the management of thoracic arterial injuries.

Adult↗
PubMed1998

Breast milk contamination and silicone implants: preliminary results using silicon as a proxy measurement for silicone.

In response to concerns about contamination of human breast milk from silicone gel-filled breast implants, and because silicon levels are assumed to be a proxy measurement for silicone, we compared silicon levels in milk from lactating women with and without implants. Two other sources of infant nutrition, cow's milk and infant formulas, were also analyzed for silicon. The survey took place at the Breast-feeding Clinic at Women's College Hospital in Toronto. A convenience sample of lactating women, 15 with bilateral silicone gel-filled implants and 34 with no implants, was selected. Women with foam-covered or saline implants or with medically related silicone exposures were ineligible. Collection of samples was scrupulously controlled to avoid contamination. Samples were prepared in a class 100 "ultraclean" laboratory and analyzed using graphite furnace atomic absorption spectrophotometry. Silicon levels were analyzed in breast milk, whole blood, cow's milk, and 26 brands of infant formulas. Comparing implanted women to controls, mean silicon levels were not significantly different in breast milk (55.45 +/- 35 and 51.05 +/- 31 ng/ml, respectively) or in blood (79.29 +/- 87 and 103.76 +/- 112 ng/ml, respectively). Mean silicon level measured in store-bought cow's milk was 708.94 ng/ml, and that for 26 brands of commercially available infant formula was 4402.5 ng/ml (ng/ml = parts per billion). We concluded that lactating women with silicone implants are similar to control women with respect to levels of silicon in their breast milk and blood. Silicon levels are 10 times higher in cow's milk and even higher in infant formulas.

Adult↗
PubMed1998

Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation.

PURPOSE: Although vagus nerve stimulation (VNS) is now marketed throughout most of the world as a treatment for drug-resistant epilepsy, the therapeutic mechanism of action of VNS-induced seizure suppression has not yet been established. Elucidation of this mechanism is an important first step in the development of strategies to improve VNS efficacy. Because the locus coeruleus (LC) has been implicated in the antinociceptive effects of VNS, we chemically lesioned the LC in the present study to determine if it is a critical structure involved in the anticonvulsant mechanisms of VNS. METHODS: Rats were chronically depleted of norepinephrine (NE) by a bilateral infusion of 6-hydroxydopamine (6-OHDA) into the LC. Two weeks later, they were tested with maximal electroshock (MES) to assess VNS-induced seizure suppression. In another experiment, the LC was acutely inactivated with lidocaine, and seizure suppression was tested in a similar fashion. RESULTS: VNS significantly reduced seizure severities of control rats. However, in animals with chronic or acute LC lesions, VNS-induced seizure suppression was attenuated. CONCLUSIONS: Our data indicate that the LC is involved in the circuitry necessary for the anticonvulsant effects of VNS. Seizure suppression by VNS may therefore depend on the release of NE, a neuromodulator that has anticonvulsant effects. These data suggest that noradrenergic agonists might enhance VNS-induced seizure suppression.

Animals↗
PubMed1998

Change in serum prostate-specific antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer.

PURPOSE: Prostate-specific antigen (PSA) has been used as a marker of advanced prostate cancer but remains controversial. To evaluate PSA as a predictor of survival, we analyzed data from sequential phase II trials of estramustine and etoposide. METHODS: A landmark analysis that used data from 62 men with PSA levels at baseline and 8 weeks was conducted. The best PSA measure (of six evaluated) was incorporated into a multiple regression model with performance status (PS); relative change in PSA level; and pretreatment PSA, alkaline phosphatase, and hemoglobin values. RESULTS: A decrease in PSA of 50% or greater at 8 weeks was associated with a significantly increased survival (P=.0005, two-sided log-rank test). Median survival from the landmark was 91 weeks in patients with a 50% or greater decrease at 8 weeks versus 38 weeks in those without this decrease. Modeling showed that PS, pretreatment hemoglobin level, and relative change in PSA level were significant prognostic factors, with a significant interaction between PS and pretreatment hemoglobin level. In the final model, a relative change in PSA level at 8 weeks of less than 50% had an adjusted relative risk of 2.20 (95% confidence interval, 1.21 to 4.00). A decrease in PSA level of 50% or greater at any time during therapy was associated with a response in measurable disease (P=.0369, two-sided Fisher's exact test). CONCLUSION: The PSA value after 8 weeks of this cytotoxic regimen does predict survival. A decrease in PSA level is associated with both survival and response in soft tissue lesions and should be incorporated into the response criteria and reporting of trials of cytotoxic agents in prostate cancer.

Aged↗
PubMed1998

Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma.

PURPOSE: Both paclitaxel and carboplatin have single-agent activity against carcinoma of the urothelium. We evaluated the combination of paclitaxel and carboplatin in the treatment of advanced cancers of the urothelium. PATIENTS AND METHODS: Patients with cancers of the urothelium who had no prior chemotherapy (prior adjuvant chemotherapy > 6 months allowed) were eligible for treatment. Eligibility requirements were performance status of 2 or less, creatinine level less than 2.0 mg/dL, granulocyte count (AGC) 1,500/microL or greater, platelet count 100,000/microL or greater, and total bilirubin level less than 1.5 mg/dL. Paclitaxel 200 mg/m2 followed by carboplatin (area under the curve [AUC] 5, Calvert formula) were administered every 21 days. Patients were evaluated for toxicity weekly and assessed for response every 6 weeks. RESULTS: Thirty-six patients were entered onto the study and 35 patients were assessable for response. A total of 184 cycles were administered (median, six cycles per patient). Nine patients required one dose reduction, and seven patients required two dose reductions for a nadir AGC less than 500/microL, with only one episode of febrile neutropenia and sepsis. Myalgias and arthralgias of grades 1 to 2 occurred in 16 patients and usually lasted 2 to 3 days after treatment. There were no treatment delays because of toxicity. There were 18 responses; seven complete responses (CRs) and 11 partial responses (PRs) (response rate 51.5%; 95% confidence interval, 35 to 68). Median response durations for CR and PR were 6 and 4 months, respectively. Overall median survival was 9.5 months. CONCLUSION: The combination of paclitaxel and carboplatin is an active and well-tolerated regimen for the treatment of advanced urothelial carcinoma. Because of the modest toxicity of this combination, paclitaxel and carboplatin should be considered for addition to other agents with activity in urothelial carcinomas.

Adult↗
PubMed1997

Diadenosine polyphosphate-stimulated gluconeogenesis in isolated rat proximal tubules.

Diadenosine polyphosphates released into the extracellular environment influence a variety of metabolic and other cellular activities in a wide range of target tissues. Here we have studied the impact of these novel nucleotides on gluconeogenesis in isolated rat proximal tubules. Gluconeogenesis was stimulated following exposure of isolated proximal tubules to a range of adenine-containing nucleotides including ADP, ATP, Ap3A, Ap4A, Ap5A and Ap6A. The concentration-dependence of ATP-, Ap3A- and Ap4A-mediated stimulation of gluconeogenesis was similar and was consistent with a role for these agents in the physiological control of renal metabolism. Nucleotide-stimulated gluconeogenesis was diminished in the presence of agents that interfere with phospholipase C activation or intracellular Ca2+ metabolism, indicative of a role for polyphosphoinositide-mediated Ca2+ mobilization in the mechanism of action of ATP, Ap3A and Ap4A. The characteristics of binding of [2-3H]Ap4A to renal plasma-membrane preparations suggest that Ap4A mediates its effects on proximal tubule gluconeogenesis via interaction with P2y-like purinoceptor(s) also recognized by extracellular ATP.

Adenine Nucleotides↗
PubMed1997

A phase II trial of all-trans-retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis.

Retinoids have been shown to have substantial anticancer activity in a number of preclinical and clinical situations. There are considerable epidemiologic, in vitro and in vivo data which indicate that retinoids may have a role in the prevention and therapy of human prostate cancer. Based on anecdotal evidence of response in one patient with hormone-refractory prostate cancer (HRPC), we conducted a phase II trial in HRPC during which we also examined changes in pharmacokinetics of all-trans-retinoic acid (ATRA) which occurred during therapy. Enrolled in the study were 17 patients with HRPC who received 50 mg/m2 ATRA three times daily orally on days 1-14, repeated every 22 days. The pharmacokinetics of ATRA were assessed with the first dose on day 1, again on day 14 and after a 7-day interruption in ATRA therapy on day 22. Patients were evaluable for response if they completed two 14-day courses of ATRA; among 13 such patients no responses were seen. Four patients were considered unevaluable for response owing to rapid disease progression in three and intercurrent illness in one. Apparent clearance of ATRA changed substantially during therapy: day 1 3779 +/- 4215 ml/min, day 14 7179 +/- 3197 ml/min, day 22 3213 +/- 2357 ml/min. Area under the curve was proportionately diminished on day 14 compared with day 1 and had returned to baseline by day 22. We conclude that ATRA is not active in HRPC. Failure of this agent in HRPC may be related to failure of drug delivery associated with enhanced mechanisms of ATRA clearance which occur within a few days of beginning ATRA treatment.

Adult↗
PubMed1997

Infection of a chronically implanted iliac artery stent.

Pseudoaneurysm formation and infection at the site of iliac artery stenting are uncommon complications that occur soon after stent placement. We describe a case in which an infected pseudoaneurysm developed 22 months following stent implantation. Stent infection, although rare, has potentially disastrous implications, as made evident by a review of the literature. Prophylactic antibiotic therapy at the time of stent placement is recommended.

Aneurysm, False↗
PubMed1997

Assessment of an ovine antivenom raised against venom from the desert black cobra (Walterinnesia aegyptia).

The desert black cobra (Walterinnesia aegyptia) is an elapid widely distributed throughout the deserts of Saudi Arabia and currently available antivenoms are ineffective in the treatment of its envenoming. Walterinnesia aegyptia venom was assessed for several of its physicochemical, enzymatic and biological characteristics. An antivenom was raised in sheep using a low-dose immunization schedule and digested with papain to provide Fab fragments. The antivenom neutralized all of the above enzymatic and biological activities and provided good protection in mice (ED50 0.25 g/kg), whereas the commercial polyspecific products showed only partial neutralization and did not protect mice.

Animals↗
PubMed1997

A phase II trial of oral estramustine and oral etoposide in hormone refractory prostate cancer.

OBJECTIVES: We previously demonstrated that the combination of oral estramustine (15 mg/kg/day) and oral etoposide (50 mg/m2/day) is effective first-line therapy for the treatment of hormone refractory prostate cancer. We initiated a new Phase II trial utilizing a lower dose of estramustine (10 mg/kg/day) and allowing previous chemotherapy treatment. METHODS: Estramustine (10 mg/kg/day) and etoposide (50 mg/m2/day) were administered orally for 21 of 28 days. Sixty-two patients were enrolled with a minimum of 26 weeks of follow-up. RESULTS: Of 15 patients with measurable soft tissue disease, 8 (53%) had a partial response (PR). Seven of these 8 patients also demonstrated a decrease in baseline prostate-specific antigen (PSA) of more than 50%. The median survival of all patients was 56 weeks. Of 47 patients with disease limited to the bone, 16 (34%) had a PR to therapy based on decrease in pretreatment PSA of more than 50%. Overall, 24 (39%) of 62 patients demonstrated a decrease in pretreatment PSA levels of at least 50% from baseline. Twenty-two patients received previous chemotherapy. There were no differences in survival or disease response in patients treated with previous chemotherapy compared with untreated patients. Pretreatment hemoglobin, PSA, alkaline phosphatase and lactate dehydrogenase levels were not significant prognostic factors, but performance status was an important predictor of survival. CONCLUSIONS: We conclude that the combination of oral estramustine (10 mg/kg/day) and oral etoposide (50 mg/m2/day) is an active regimen for hormone refractory prostate cancer.

Administration, Oral↗
PubMed1997

The use of prostate-specific antigen as a surrogate end point in the treatment of patients with hormone refractory prostate cancer.

Prostate-specific antigen increasingly is being used as a surrogate end point in trials of new agents in patients with hormone refractory prostate cancer. This article reviews data that support this marker as a surrogate end point and the contradictory data reported recently for trials of suramin. These contrasting views may originate in the different mechanisms of actions of the agents studied. These data suggest that a decline in prostate-specific antigen of at least 50% from baseline may be an important predictor of survival for patients receiving cytotoxic therapy.

Antineoplastic Agents, Hormonal↗
PubMed1997

A short- and long-term shear bond strength study using acids of varying dilutions on bovine dentine.

OBJECTIVES: The purpose of this study was to evaluate the short-(24 h) and long-(180 day) term shear bond strengths of resin to bovine dentine etched with varying dilutions of aqueous solutions of phosphoric and maleic acids. METHODS: Bovine dentine surfaces were prepared using water irrigated #600 grit SiC paper. The dentine surfaces were etched in groups of 10 teeth using various dilutions of phosphoric or maleic acid. Using the Scotchbond Multipurpose System (SBMP; 3M Co., MN, USA) and a wet technique the etched surfaces were primed and unfilled bonding resin (UBR) was applied to the dentine surface within the confines of a gelatin cylinder. A cylinder of filled resin (Z 100; 3M Co., MN, USA) was then photocured and the specimens were then stored in water for 24 h or 180 days prior to shear bond testing to failure. RESULTS: The results showed that high bond strengths were recorded using acids which were more dilute than those commercially available. There were also indications that phosphoric acid is not the etching acid of choice for the SBMP system. CONCLUSIONS: The results of this study showed that high bond strengths can be achieved in dentine using etching acids which are more dilute than those commercially available. Maleic acid appears to be the etchant of choice for the SBMP system.

Acid Etching, Dental↗