Search PubMed⌕ Search

Biomedical subjects

D C Smith

Publications and source records attributed to D C Smith.

At least 55 records · Page 3Linked to original sources
PubMed1999

Phase II trial of suramin in patients with metastatic renal cell carcinoma.

This study was conducted to assess the efficacy and toxicity of suramin administered using a fixed dose schedule in patients with advanced renal cell carcinoma. Fourteen eligible patients with advanced renal cell carcinoma were enrolled and treated on a fixed dose schedule of suramin administered over 12 weeks. Suramin was administered by intravenous infusions over 1 hour. None of the 13 evaluable patients demonstrated an objective response. Only 3 patients completed the 12-week therapy course, with the majority developing progressive disease on therapy. The fixed dosage schedule was well tolerated with minimal to moderate toxicity. Suramin in this fixed dose schedule is well tolerated but has no activity in advanced renal cell carcinoma.

Adult↗
PubMed1999

A systematic evaluation of conventional and novel transvenous pathways for defibrillation.

INTRODUCTION: Conventional implantable cardioverter defibrillators employ endocardial (shock) electrodes with a lead located in the right ventricular apex (RV) and a "hot-can" electrode located subcutaneously in the left pectoral region. In the event of a high defibrillation threshold (DFT) a third electrode is frequently employed in the superior vena cava (SVC). We report the comparison of conventional and novel locations of additional electrodes with the RV/Can configuration, in a porcine model. METHOD: In 12 anesthetized pigs (30-45 kg), endocardial defibrillation electrodes were randomized to the following locations: RV/Can, RV/Can + SVC, RV/Can + main pulmonary artery (MPA) and RV/Can + left pulmonary artery wedge position (PAW), RV/Can + high inferior vena cava (HIVC), RV/Can + Low inferior vena cava (LIVC). Ventricular fibrillation (VF) was induced using 60 Hz alternating current. After 10 seconds VF a rectangular biphasic shock was delivered by the ARD9000 (Angeion Corp). The DFT was determined for each configuration using a modified four-reversal binary search. All configurations were compared using a repeated measures analysis of variance (ANOVA) statistical test and the five 3-electrode configurations were compared to the RV/Can position using a Dunnett test. RESULTS: Mean DFTs: RV = 21.5 +/- 4.8 J, SVC = 16.8 +/- 4.7 J (p < 0.05 vs. RV), HIVC = 21.1 +/- 4.7 J (p <. 0.05), LIVC = 19.1 +/- 5.7 J (p <. 0.05 vs. RV), MPA = 16.0 +/- 5.8 J (p < 0.01), PAW = 17.5 +/- 4.6 J (p < 0.05 vs. RV). CONCLUSIONS: Relative to the RV/can configuration the addition of a third electrode in the PA, PAW or SVC significantly reduces the DFT in the pig. The addition of an electrode to the IVC did not significantly reduce the DFT in our model.

Animals↗
PubMed1999

Enhanced recognition memory following vagus nerve stimulation in human subjects.

Neuromodulators associated with arousal modulate learning and memory, but most of these substances do not freely enter the brain from the periphery. In rodents, these neuromodulators act in part by initiating neural messages that travel via the vagus nerve to the brain, and electrical stimulation of the vagus enhances memory. We now extend that finding to human verbal learning. We examined word-recognition memory in patients enrolled in a clinical study evaluating the capacity of vagus nerve stimulation to control epilepsy. Stimulation administered after learning significantly enhanced retention. These findings confirm in humans the hypothesis that vagus nerve activation modulates memory formation similarly to arousal.

Double-Blind Method↗
PubMed1999

Toxin entry: how bacterial proteins get into mammalian cells.

Certain bacteria secrete protein toxins that catalytically modify and disrupt essential processes in mammalian cells, often leading to cell death. As the substrates modified by these toxins are located in the mammalian cell cytosol, a catalytically active toxin polypeptide must reach this compartment in order to act. The toxins bind to receptors on the surface of susceptible cells and enter them by endocytic uptake. Endocytosed toxins initially accumulate in endosomes, where some of these proteins take advantage of the acidic environment within these organelles to form, or contribute to the formation of, protein-conducting channels through which the catalytic polypeptide is able to translocate into the cytosol. Other toxins are unable to respond to low pH in this way and must undergo intracellular vesicular transport to reach a compartment where pre-existing protein-conducting channels occur and can be exploited for membrane translocation--the endoplasmic reticulum. In this way, cell entry by this second group of toxins demonstrates that the secretory pathway of mammalian cells is completely reversible.

Animals↗
PubMed1999

Improved efficacy of anodal biphasic defibrillation shocks following a failed defibrillation attempt.

Although it is generally assumed that defibrillation becomes more difficult when the duration of VF is prolonged, after a failed defibrillation attempt, there is little information on the defibrillation efficacy of multiple shocks delivered at the same energy. The purpose of this study was to systematically examine the efficacy of a second shock delivered at the same or reversed polarity after a failed first shock. Defibrillation was attempted after 10 seconds of VF in 12 pigs (30-56 kg) using biphasic waveforms and a nonthoracotomy lead system. Shock energy was held constant for the first and second shocks at 50%-90% of the DFT. The second shock was delivered 10 seconds after a failed first shock. First and second shock polarity (first phase) was randomized to (+, +), (+, -), (-, -), (-, +). The incidence of successful defibrillation (for all polarities) was 12.3% for first and 49.1% for second shocks (P < 0.0001). Anodal first shocks had a 17.2% incidence of success as opposed to a 7.4% incidence of success with cathodal first shocks (P = 0.001). Anodal second shocks had a 55.5% incidence of success compared to a 42.7% incidence of success with cathodal second shocks (P = 0.008). There was no significant benefit from polarity reversal after a failed first shock (P = 0.29). In conclusion, less energy is required for successful defibrillation by a second shock after a failed first. The optimal configuration for first and second shocks is with the RV as anode. Polarity reversal of a second shock after a failed first does not affect the probability of second shock success.

Animals↗
PubMed1999

Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone-refractory prostate cancer.

PURPOSE: To evaluate the combination of intravenous (IV) paclitaxel, oral estramustine, and oral etoposide in patients with advanced hormone-refractory prostate cancer. PATIENTS AND METHODS: Forty patients with carcinoma of the prostate that was progressing despite hormonal therapy and who had undergone antiandrogen withdrawal (if previously treated with an antiandrogen) were enrolled onto this phase II trial. Patients were treated with oral estramustine 280 mg tid and oral etoposide 100 mg/d for 7 days, with paclitaxel 135 mg/m(2) IV over 1 hour on day 2 of each 21-day treatment cycle. Patients received a maximum of six cycles of therapy. RESULTS: Thirty-seven patients were assessable for response. Twenty-two had measurable disease at baseline; response was not assessable in six of these patients. Overall response was 45% (10 of 22 patients; 95% confidence interval [CI], 24% to 68%), and response was 63% (10 of 16) in assessable patients. Twenty-six patients had a > or = 50% decrease from their baseline prostate-specific antigen levels during therapy, for a response rate of 65% (95% CI, 48% to 79%) by this criterion. Median duration of response was 3.2 months, with an estimated median survival of 12.8 months. Major toxicities of therapy were leukopenia (eight patients had > or = grade 4 leukopenia) and anemia. Hematologic toxicity seemed to be associated with liver metastases. Serial measurements in 24 patients using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) showed no significant change in quality of life (QOL) as a result of therapy. CONCLUSION: The combination of IV paclitaxel, oral estramustine, and oral etoposide is active in patients with advanced prostate cancer. The regimen is tolerable and does not have a significant impact on QOL as measured by the FACT-P in a limited sample of patients.

Adenocarcinoma↗
PubMed1999

Oral chemotherapy in the treatment of hormone-refractory prostate cancer.

Oral chemotherapy has become a major component of the treatment of advanced prostate cancer. The recognition that prostate cancer grows very slowly and must be treated continuously with active agents has led to the development of several therapeutic regimens. These regimens employ oral agents such as estramustine, cyclophosphamide, and etoposide, as they can be taken on a daily basis at home by the patients. These regimens have demonstrated activity in patients with hormone-refractory prostate cancer; declines in both prostate specific antigen and soft tissue lesions have been demonstrated.

Administration, Oral↗
PubMed1999

Paclitaxel in the treatment of hormone-refractory prostate cancer.

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in men in the United States. In 1997 it was estimated that more than 41,000 men died of this disease. Treatment of metastatic disease remains palliative, with androgen ablation used as first-line therapy. After failure of androgen ablation, chemotherapy can now be used to induce a remission in many men. Treatment regimens that include paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have been particularly successful in treating hormone-refractory prostate cancer in the phase II setting. We have conducted a trial of estramustine 280 mg orally three times per day for 14 days combined with etoposide 50 mg/m2/d (in general, one 50-mg tablet twice a day) for 14 days, with paclitaxel 135 mg/m2 over 1 hour on day 2. This regimen is repeated every 21 days for a maximum of six cycles. Patients responding to therapy are then given a break and re-treated at physician discretion. On preliminary analysis, 24 of 38 patients demonstrated a decline in pretreatment prostate-specific antigen of more than 50% (63%). The regimen was well-tolerated and only seven patients demonstrated grade 3 or 4 neutropenia. Further analysis is ongoing.

Antineoplastic Agents, Phytogenic↗
PubMed1999

A Phase I trial of calcitriol (1,25-dihydroxycholecalciferol) in patients with advanced malignancy.

Vitamin D is a steroid hormone best known for its activity in regulating calcium and bone metabolism. Epidemiological evidence suggests that vitamin D may play a role in inhibiting the development of colon and prostate cancer. Vitamin D receptors are expressed in many types of malignant cells; in vitro and in vivo vitamin D and vitamin D analogues are active in suppressing the development and inhibiting the growth of numerous human and animal tumors. The major toxicity of the active form of vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), is the induction of hypercalcemia. There are no data indicating the maximum tolerated dose of calcitriol administered every other day (QOD) s.c. We hypothesized that this route and schedule would permit administration of higher doses of calcitriol, which might have anticancer activity. We conducted a Phase I trial of calcitriol given s.c. QOD in patients with advanced solid tumors. Thirty-six patients were entered at doses ranging from 2 to 10 microg QOD; dose-limiting toxicity (hypercalcemia) occurred in three of three patients entered at the 10-microg QOD dose. Hypercalciuria occurred at all dose levels examined. No other toxicity was seen. Assessment of serum calcitriol concentrations by a RIA revealed a decrease in concentration-time curves on day 7 compared to day 1 of therapy. A dose-dependent increase in peak serum level and estimated area under the concentration-time curve was seen. The maximum serum levels occurred at the 10-microg QOD dose: 288 +/- 74 and 321 +/- 36 pg/ml at days 1 and 7, respectively. The normal range of calcitriol serum concentration, determined using this assay, is 16-56 pg/ml. Serum calcitriol levels were maintained at near peak concentrations for at least 8 h following s.c. injection. This study indicates that substantial doses of calcitriol can be administered via this route with tolerable toxicity. Studies to explore approaches to ameliorate the hypercalcemia induced by calcitriol and to explore alternative schedules and interactions with other agents are warranted.

Adenocarcinoma↗
PubMed1998

Expression of mutant dynamin protects cells against diphtheria toxin but not against ricin.

Diphtheria toxin is believed to enter sensitive mammalian cells via receptor-mediated endocytosis from clathrin-coated pits, while ricin can enter via both clathrin-dependent and clathrin-independent endocytosis. The present study has confirmed this by determining the toxin sensitivity of COS-7y cells which were transiently overexpressing a trans dominant negative mutant of dynamin, a GTPase required for the budding of clathrin-coated vesicles from the plasma membrane. Cells overexpressing wild-type dynamin showed normal receptor-mediated endocytosis of transferrin and remained sensitive to both diphtheria toxin and ricin. Cells overexpressing a mutant dynamin defective in GTP binding and hydrolysis were unable to endocytose transferrin and were protected against diphtheria toxin, but they remained completely sensitive to ricin intoxication. Treating non-transfected cells or cells overexpressing mutant dynamin with nystatin caused a redistribution of the caveolae membrane marker protein VIP21-caveolin from the cell surface to intracellular locations, but did not affect their sensitivity to ricin. The redistribution of caveolin seen after nystatin treatment may reflect the disappearance of caveolae. If this is the case, caveolae are not responsible for the endocytosis of ricin. An alternative clathrin-independent route may operate for ricin, since cellular uptake, intracellular transport, and translocation into the cytosol remain unaffected when clathrin-dependent endocytosis is effectively blocked.

Animals↗
PubMed1998

Enhancement of 1,25-dihydroxyvitamin D3-mediated antitumor activity with dexamethasone.

BACKGROUND: The active metabolite of vitamin D, i.e., 1,25-dihydroxycholecalciferol (1,25-D3), inhibits the growth of murine SCCVII/SF squamous cell carcinoma cells, both in vitro and in vivo. However, in vivo use of 1,25-D3 is hampered as a result of hypercalcemia (i.e., elevated levels of calcium in the blood). Glucocorticoids, such as dexamethasone, affect calcium absorption and modulate vitamin D receptor binding and have been used to treat hypercalcemia. In this study, we examined the effect of dexamethasone on tumor growth inhibition by 1,25-D3. METHODS: The effects of 1,25-D3 and dexamethasone, alone and in combination, on the growth of SCCVII/SF cells in in vitro culture or in vivo in female C3H/HeJ mice were determined by clonogenic tumor cell assay and/or by actual changes in tumor volume. Vitamin D receptor-ligand-binding activities in whole-cell extracts from cells (in culture), tumors, and normal tissues were assayed by single-point saturation analysis and equilibrium binding. RESULTS: Treatment of cultured SCCVII/SF cells with 500 nM dexamethasone for 24 hours before addition of 1,25-D3 reduced their survival. The growth of SCCVII/SF tumors was inhibited in mice treated simultaneously with dexamethasone and 1,25-D3 (as compared with no treatment or single-agent treatment); hypercalcemia was also reduced. Total vitamin D receptor content in SCCVII/SF cells was increased after treatment with dexamethasone. Treatment of tumor-bearing animals with dexamethasone (9 microg/day) for 7 days led to increased vitamin D receptor-ligand-binding activities in whole-cell extracts from tumor or kidneys and decreased activity in intestinal mucosa. CONCLUSIONS: Dexamethasone may enhance the antitumor effect of 1,25-D3 by increasing vitamin D receptor-ligand-binding activity.

Animals↗
PubMed1998

Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat.

Peripherally administered or released substances that modulate memory storage, but do not freely enter the brain, may produce their effects on memory by activating peripheral receptors that send messages centrally through the vagus nerve. Indeed, vagus nerve stimulation enhances memory performance, although it is unclear whether this effect is due to the activation of vagal afferents or efferents. To eliminate the possible influence of descending fibers on memory storage processes, rats were implanted with cuff electrode/catheter systems along the left cervical vagus. Forty-eight hours following surgery, each animal received a 3. 0-microliter infusion (1.0 microliter/min) of either lidocaine hydrochloride (75.0 mM) or isotonic saline below the point of stimulation. Animals were then trained 10 min later on an inhibitory-avoidance task with a 0.75-mA, 1.0-s foot shock. Sham stimulation or vagus nerve stimulation (0.5-ms biphasic pulses; 20.0 Hz; 30 s; 0.2, 0.4, or 0.8 mA) was administered immediately after training. Memory, tested 24 h later, was enhanced by stimulation whether descending vagus nerve fibers were inactivated or not. Both lidocaine- and saline-infused groups showed an intensity-dependent, inverted-U-shaped pattern of retention performance, with the greatest effect observed for 0.4 mA (U = 9, p < .05, and U = 7, p < .01, respectively). Additionally, animals that received lidocaine infusions, but no vagus nerve stimulation, showed impaired memory compared to the performance of saline-infused control animals (U = 11, p < .05). Together, these findings suggest that vagal afferents carry messages about peripheral states that lead to the modulation of memory storage and that the memory-enhancing effect produced by vagus nerve stimulation is not mediated via the activation of vagal efferents.

Animals↗