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Biomedical subjects

M Simmonds

Publications and source records attributed to M Simmonds.

33 records · Page 2Linked to original sources
PubMed1998

Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain.

PURPOSE: Supplemental, "as-needed," administration of an opioid is a common approach to the problem of breakthrough pain in cancer patients. Oral transmucosal fentanyl citrate (OTFC) is undergoing investigation as a new treatment for breakthrough pain. The primary purpose of the study was to demonstrate that a single-unit dose of OTFC can safely and effectively treat breakthrough pain. A secondary goal was to determine appropriate dosing guidelines. PATIENTS AND METHODS: This was a multicenter, randomized, double-blind, dose-titration study in 62 adult cancer patients using transdermal fentanyl for persistent pain. Consenting patients provided 2 days of baseline data to evaluate the performance of their usual breakthrough pain medication. Patients then randomly received 200 microg or 400 microg OTFC in double-blind fashion. (Patients were always assigned, rather than randomized, to 200 microg if 400 microg represented > 20% of around-the-clock medication.) Pain intensity (PI), pain relief (PR), and global satisfaction scores were recorded. OTFC was then titrated until the patient received adequate PR for each episode using one OTFC unit. Orders to titrate up were ignored one third of the time to improve the blind. Two days of baseline data were compared with 2 days of OTFC data after titration identified an effective dose of OTFC. RESULTS: Most patients (76%) found a safe and effective dose of OTFC. There was no meaningful relationship between the around-the-clock opioid regimen and the effective dose of OTFC. In open-label comparisons, OTFC produced a faster onset of relief and a greater degree of PR than patients' usual breakthrough medication. Somnolence, nausea, and dizziness were the most common side effects associated with OTFC. CONCLUSION: Most patients find a single OTFC dosage that adequately treats breakthrough pain. The optimal dose is found by titration and is not predicted by around-the-clock dose of opioids.

Administration, Buccal↗
PubMed1994

Reversible renal failure in renal transplant patients receiving oral acyclovir prophylaxis.

Two children who developed acute renal failure in the immediate post-renal transplantation period are presented. Each was immunosuppressed with cyclosporin and was also receiving oral acyclovir for prophylaxis against cytomegalovirus infection. Renal biopsy findings suggested drug toxicity. Discontinuation of acyclovir coincided with reversal of renal impairment. As cyclosporin levels were at the lower end of the therapeutic range, we believe acyclovir to be the likely causative agent.

Acute Kidney Injury↗
PubMed1994

The accuracy of magnitude production of submaximal precision and power grips and gross motor efforts.

The objective of the study was to measure maximal and subjectively graded submaximal efforts in a pinch grip, power grip, and stoop life activity, subsequently to study the relationship of these efforts across activities and time, and furthermore to determine the reliability of effort perception of activities in different grades of operation. Ten normal male university students with mean age of 22.2 years, mean height of 175.3 cm, and mean weight of 71.4 kg volunteered for the study. All subjects were required to exert their maximal efforts, 80%, 60%, 40%, and 20% (of the maximal) effort in pinching, gripping and stoop lifting for three trials in a random order on four different days. The subjects were tested at the same time of the day on a Monday, Wednesday, Friday of one week, and Friday of the next week. While the activity and perception had significant main effects (p < 0.001) the trial was significant only for average strength (p < 0.04). There was a significant two-way interaction between activity and perception; all other interactions were not significant. There was a systematic bias in perception at all graded contractions except at 40% level of effort. The perceived 60% and 80% of maximal voluntary contractions (MVC) were lower and 20% was higher than their respective objective values based on MVC (p < 0.01). At 40% effort there was no statistical difference between perceived and objective strength effort in all three activities. The reliability of perception was similar for precision, power, or gross activity.

Adult↗
PubMed1989

Alphaxalone reveals GABAA receptor-mediated inhibition in guinea-pig ileum.

Contractions of the transmurally stimulated guinea-pig ileum were not affected by 10 microM bicuculline, a competitive GABAA receptor antagonist. The GABAA potentiator alphaxalone depressed the responses to 2 and 20 Hz stimulation by 20% and 40%, respectively, but had no effect on 0.2 Hz responses. The depressions were prevented by 10 microM bicuculline. This suggests that endogenous activation of GABAA receptors during transmural stimulation was normally subthreshold but, when pharmacologically potentiated, inhibitory effects were seen.

Anesthetics↗
PubMed1988

Marked heterogeneity of aromatase activity in human malignant melanoma tissue.

The prognosis from human malignant melanoma varies according to sex and to multiple histologic, biologic and cell kinetic parameters. Thus melanomas exhibit a major degree of heterogeneity in their biologic properties and further characterization of their biochemical heterogeneity should yield important information. The present study sought to demonstrate the activity of a biochemical marker of estrogen synthesis, the aromatase enzyme, in melanoma tissue and to determine its range of activity. Initially, we validated a highly sensitive radiometric assay for aromatase by comparing it with a direct product isolation method. We detected production of 417 pmol/g protein/h of estrone and 37.3 pmol/g protein/h of estradiol by direct product isolation in a human melanoma and 398 pmol estrone/g protein/h by the radiometric assay. The activity present was blocked by similar amounts of the aromatase inhibitor, aminoglutethimide, as were necessary to block placental, breast cancer, and rat brain aromatase activity. We then assayed aromatase radiometrically in 19 human melanomas and found measurable activity ranging from 9 to 398 pmol estrone/g protein/h in 15 tissues. No relationship with the patient's age or sex was demonstrated. The activity exceeded by 2-fold that previously detected in 49/61 human breast cancers. This study identified a marker enzyme in melanoma tissue which varied by 40-fold among human tumors. Correlation of aromatase activity with prognosis and response to various types of therapy is now necessary to establish the biologic relevance of this finding.

Adult↗
PubMed1988

Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome.

We conducted a randomized clinical trial in men with stage D2 prostate cancer to test whether androgen priming potentiates the efficacy of cytotoxic chemotherapy. Eighty-five men with progressive prostate cancer refractory to orchiectomy were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal androgen secretion and were administered cyclic intravenous (IV) chemotherapy. The patients were randomized to receive either androgen priming or no additional treatment for three days before and on the day of chemotherapy. Median duration of follow-up was 43 months. Response rate (remission plus disease stabilization) was not significantly different between the stimulation and control arm when the analysis was restricted to evaluable patients (79% v 73%, respectively) or when it was extended to all patients (46% v 61%). Median duration of response was similar for the stimulation and control arm (9 and 10 months, respectively). Median survival was 10 months in the stimulation and 15 months in the control group (P = .0047). The androgen sensitivity of the tumors was supported by the greater toxicity in the stimulation arm associated with androgen administration. Factors found to be independently associated with improved clinical outcome included a high Karnofsky score and hematocrit, long duration of response to the initial castration, and normalization of an elevated serum acid phosphatase on treatment. We conclude that in this group of patients with advanced disease, androgen priming does not potentiate the efficacy of chemotherapy and is actually associated with a worse outcome. Furthermore, our data emphasize the heterogeneity of biologic behavior of prostate cancer.

Acid Phosphatase↗
PubMed1987

Androgen depletion and repletion as a means of potentiating the effect of cytotoxic chemotherapy in advanced prostate cancer.

Seventy-five patients with stage D-2 prostate cancer refractory to orchiectomy have been entered in a controlled trial to test whether androgen priming enhances the efficacy of chemotherapy. All patients are treated with aminoglutethimide and hydrocortisone as a means of achieving medical adrenalectomy and are given cyclic i.v. chemotherapy with cytoxan, adriamycin and 5-fluorouracil. Patients in the stimulation arm (N = 39) receive, in addition, fluoxymesterone (5 mg p.o. b.i.d.) for 3 days before and on the day of chemotherapy. A similar response rate was observed in the stimulation and control arm (83% vs 74% respectively) when the analysis was restricted to evaluable patients. When all patients were included, a significantly higher response rate was observed in the control arm (64% vs 49%, P less than 0.05) as a result of the larger fraction of unevaluable patients in the stimulation arm (41% vs 14%). Median duration of response is 9 months in the stimulation and 10 months in the control arm. Median overall survival in the stimulation and control group is 12 months and 16 months respectively. Significant toxicity consisting of exacerbation of bone pain and, in two patients, development of reversible spinal cord compression was observed following androgen priming. Our results suggest that combined medical adrenalectomy and chemotherapy are highly effective in the treatment of advanced prostate cancer. Thus far, no additional benefit has been observed with androgen priming.

Aminoglutethimide↗
PubMed1987

Dietary lipids: an additional regulator of plasma levels of sex hormone binding globulin.

The effect of dietary lipid consumption on plasma levels of sex-hormone binding globulin (SHBG), free testosterone and cholesterol was studied in 6 normal men. After consuming a diet with a high fat content (greater than 100 g fat/day) for two weeks, the mean plasma cholesterol level increased (p less than 0.02) while the mean SHBG level decreased (p less than 0.02). Changing the diet from one with a high fat to low fat content (less than 20 g fat/day) for a further two week period resulted in a significant reduction in mean plasma cholesterol level (p less than 0.001) while the mean SHBG level increased (p less than 0.01). The increase in plasma SHBG was associated with a significant decrease in the free testosterone fraction and free testosterone concentration. No significant changes were detected in plasma samples obtained from the same men during a control period. The results from this study demonstrate that dietary lipid intake is an additional factor involved in the regulation of plasma levels of SHBG.

Adult↗
PubMed1986

Androgen priming and response to chemotherapy in advanced prostatic cancer.

A total of 67 patients with progressive stage D2 prostatic cancer refractory to orchiectomy was entered in a controlled clinical trial to test whether androgen priming enhances the efficacy of cytotoxic drugs. All patients were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal androgen secretion and were given cyclic intravenous chemotherapy. In addition, the 34 patients randomized to the stimulation arm received fluoxymesterone for 3 days before and on the day of chemotherapy. There was 33 controls. The median duration of followup was 24 months. A modestly higher response rate (objective remission plus disease stabilization) was observed in the stimulation arm (85 versus 72 per cent, p less than 0.05) when the analysis was restricted to the evaluable patients. However, a larger fraction of unevaluable patients was present in the stimulation group (41 versus 16 per cent), mostly as a result of toxicity from fluoxymesterone, which prompted early discontinuation of treatment. Thus, when data analysis included all patients the response rate actually was slightly higher in the control than in the stimulation arm (60 versus 50 per cent, p not significant). No difference was observed in median duration of response (9 months in both groups) or over-all survival. Our data suggest that at least in those patients with advanced disease androgen priming does not seem to enhance significantly the antitumor effect of the combination of amino-glutethimide and chemotherapy, and is associated with significant toxicity. These largely negative results may be explained by the large number of hormone-resistant cells present in tumors that have become refractory to orchiectomy.

Aged↗
PubMedDate not supplied

Hormone stimulation and chemotherapy in advanced prostate cancer: interim analysis of an ongoing randomized trial.

We report here in the interim analysis of an ongoing randomized clinical trial designed to test whether androgen priming enhances tumor chemosensitivity in men with stage D prostate cancer refractory to orchiectomy. All patients are continuously treated with aminoglutethimide and hydrocortisone, to lower adrenal androgen secretion, and are given cyclic chemotherapy. Patients in the stimulation arm receive also the synthetic androgen, fluoxymesterone, for 3 days before and on the day of chemotherapy. Of 57 patients entered to date, 41 have received adequate treatment to be evaluable. Response to therapy (objective remissions + stabilizations of disease) occurred in 17 of 18 evaluable patients (94%) randomized to the stimulation arm, and in 16 of 23 evaluable patients (70%) in the control group (p less than 0.025). Duration of response was not significantly different in the two groups (median: 9 months in the stimulation and 12 months in the control arm). With 30% of the total of 57 patients still alive, survival is not significantly different in the stimulation (median: 13 months) and control arm (median: 16 months). As expected, patients who responded to treatment lived significantly longer than those who failed to benefit. Two episodes of reversible spinal cord compression occurred during androgen administration. (The risk of this serious side effect may be reduced by performing a screening myelogram to rule out subclinical spinal metastasis). Our preliminary data suggest that androgen priming may enhance the tumoricidal effect of cytotoxic drugs in advanced prostate cancer. The lack of improvement in duration of response and survival may be explained by the large fraction of hormone-independent cells probably present in patients with tumors refractory to orchiectomy.

Aged↗
PubMedDate not supplied

Hormone stimulation and chemotherapy in advanced prostate cancer: preliminary results of a prospective controlled clinical trial.

Preliminary evidence suggests that the sensitivity of endocrine-dependent neoplasms to chemotherapy may be enhanced by transient hormonal stimulation of tumor growth. To test this concept, we are conducting a prospective controlled trial in men with stage D2 prostate cancer who have relapsed following orchiectomy. All patients are continuously treated with aminoglutethimide and hydrocortisone to lower adrenal androgen secretion plus cyclic chemotherapy. Patients in the stimulation arm receive, in addition, the synthetic androgen fluoxymesterone for 3 days before and on the day of chemotherapy. Of 41 patients entered to date, 26 are evaluable. Twenty-one (81%) obtained either an objective remission or stabilization of disease with a mean duration of 9+ months and 10 patients still responding. Thus far, the response rate is similar in the control and stimulation groups. Androgen administration was associated with a rise in acid phosphatase and usually a modest flare of symptoms except for 2 patients who developed spinal cord compression. These preliminary data indicate that the combination of aminoglutethimide and chemotherapy has a potent antitumor effect on advanced prostate cancer refractory to orchiectomy. A large number of patients and a longer follow up are needed to assess whether transient androgen administration potentiates the effect of chemotherapy.

Acid Phosphatase↗