Biomedical subjects

J Cooper

Publications and source records attributed to J Cooper.

At least 163 records · Page 9Linked to original sources

PubMed1997

When exemplification fails: hypocrisy and the motive for self-integrity.

Two experiments investigated how the dissonance that follows a hypocritical behavior is reduced when 2 alternatives are available; a direct strategy (changing behavior to make it less hypocritical) or an indirect strategy (the affirmation of an unrelated positive aspect of the self). In Experiment 1, after dissonance was aroused by hypocrisy, significantly more participants chose to reduce dissonance directly, despite the clear availability of a self-affirmation strategy. In Experiment 2, participants again chose direct resolution of their hypocritical discrepancy, even when the opportunity to affirm the self held more importance for their global self-worth. The discussion focuses on the mechanisms that influence how people select among readily available strategies for dissonance reduction.

Adult↗

PubMed1997

An endogenous A2B adenosine receptor coupled to cyclic AMP generation in human embryonic kidney (HEK 293) cells.

1. Cyclic AMP generation by adenosine analogues was examined in human embryonic kidney (HEK 293) cells by use of a [3H]-adenine pre-labelling methodology. 2. Adenosine analogues showed the following rank order of potency (pD2 value): 5'-N-ethylcarboxamidoadenosine (NECA, 5.24)>2-chloroadenosine (4.41) > or = adenosine (4.19)= N6-(2-(4-aminophenyl)-ethylamino)adenosine (APNEA, 4.11). The A2A-selective agonist CGS21680 failed to elicit a significant stimulation of cyclic AMP generation at concentrations below 30 microM. 3. Of these agents, NECA was observed to exhibit the greatest intrinsic activity, while in comparison maximal responses to adenosine (76+/-8% NECA response), 2-chloroadenosine (70+/-6%) and APNEA (40+/-3%) were significantly reduced. 4. Antagonists of the NECA-evoked cyclic AMP generation showed the rank order of apparent affinity (apparent pA2 value): CGS 15943 (7.79)=XAC (7.74)>DPCPX (7.01)=PD115199 (6.93) 8FB-PTP (6.80)>KF 17837 (5.98)>3-propylxanthine (5.13). 5. Agarose gel electrophoresis of the products of the polymerase chain reaction, with cDNA generated from HEK 293 cell total RNA showed virtually identical patterns and nucleotide sizes in comparison with the vector for the full length human brain A2B adenosine receptor. 6. We concluded that HEK 293 cells express an endogenous adenosine receptor coupled to cyclic AMP generation which is of the A2B subtype.

2-Chloroadenosine↗

PubMed1997

Argyrophilic nucleolar organizer regions in auditory meatal skin and middle ear cholesteatoma.

Comparative silver-staining of argyrophilic nuclear organizer regions (AgNORs) was performed to study the proliferative activity of auditory meatal skin and middle ear cholesteatoma. AgNOR expression patterns were counted by standardized methods in two centres, Bochum and London, and mean numbers of dots per nucleus were calculated. Specimens of normal auditory meatal skin showed 1.54 dots/nucleus (n = 12) in the Bochum study, whereas cholesteatoma had 3.71 dots/nucleus (n = 21). In the London study normal meatal skin showed two dots/nucleus (n = 4), whereas acquired cholesteatoma (n = 8) gave a mean of 4.90 dots/nucleus and congenital cholesteatoma a mean of 4.70 dots/nucleus (n = 2). Our findings confirm the hyperproliferative state of middle ear cholesteatoma, suggest that the congenital variety of cholesteatoma may have a similar activity and indicate that AgNOR staining is a useful technique for assessing cellular proliferation in cholesteatoma and objectifying and quantifying its aggressive behaviour.

Cell Division↗

PubMed1997

Synovial cysts of the lumbar spine: a review.

Four cases of synovial cyst (ganglion) arising from the facet joints of the lumbar spine are reported. A typical presenting feature was exacerbation of pain on standing or walking, mimicking vascular claudication. MRI proved in all four cases to be the definitive investigation and surgery the treatment of choice, producing excellent results.

Aged↗

PubMed1997

Relationship between acetylator status, smoking, and diet and colorectal cancer risk in the north-east of England.

Some previous studies have suggested that the fast phenotype of the N-acetyltransferase NAT2 may confer susceptibility to colorectal cancer because of greater activation of dietary heterocyclic amines, particularly in individuals who also consume well-done red meat, but other studies have not supported this. We describe a large case-control study examining the interaction between dietary, smoking and drinking habits, and acetylation genotype in relation to susceptibility to colorectal cancer. One-hundred-and-seventy-four incident cases and 174 matched controls were recruited. Genotyping for polymorphisms in NAT2 was performed using a method that detects >95% of slow alleles and data on personal habits were collected using a standardized questionnaire. We found no difference in the frequency of the fast acetylator genotype between cases and controls [odds ratio = 0.95 (95% CI 0.61-1.49)], and analysis by sex, age and site also revealed no difference in acetylator genotype. There was, however, considerable heterogeneity in dietary risk factors between fast and slow acetylators. Analysis by acetylator type shows that recent smoking was more frequent in slow acetylator cases than matched controls [OR = 2.31 (1.16-4.6)] and that heavy alcohol consumption was also more frequent in the slow acetylator cases than controls [OR = 2.5 (1.02-7.29)]. In contrast, frequent fried meat intake was seen more frequently in fast acetylator cases than matched controls [OR = 6.0 (1.34-55)]. The odds ratio for the combination of fast acetylator status and frequent fried meat consumption in cases was 6.04 (1.6-26). Our study suggests that there may be different risk factors for colorectal cancer in slow and fast acetylators, and reveals a new observation that slow acetylators may be at risk of colon cancer from smoking. In our community, the overall effect of acetylator status on colorectal cancer risk is neutral.

Acetylation↗

PubMed1997

Mapping the minimal murine T cell and B cell epitopes within a peptide vaccine candidate from the conserved region of the M protein of group A streptococcus.

The highly conserved C-terminus of the M protein of group A streptococcus (GAS) is a promising vaccine candidate. An epitope within the conserved C-terminus of the M protein, peptide 145 (a 20-mer with the sequence: LRRDLDASREAKKQVEKALE), has been defined which is the target of opsonic antibodies in both humans and mice, and is recognized by the sera of most adults living in areas of high streptococcal exposure. However, due to potential cross-reactivity between T cells stimulated by this region of the M protein and host cardiac myosin, it is critical to define precisely the minimal protective epitopes within p145. Studies have shown that the immunodominant epitope expressed by p145 is conformational, occurring as an alpha-helical coiled-coil. To enable us to map the murine minimal B cell and T cell epitopes within p145, we have used a novel strategy that allowed us to present shorter sequences of p145 in a native-like conformation. The minimal B cell epitope was found to be contained within residues 7-20 of the p145 sequence, and we have shown that mice immunized with this region are able to generate antibodies that bind to and also opsonize the organism GAS. The T cell epitope is located at the N-terminal region of the p145 sequence, residues 3-14. We have managed, therefore, to define a vaccine candidate--a minimal opsonic B cell epitope within the p145 sequence--that does not incorporate a potentially deleterious T cell epitope.

Amino Acid Sequence↗

PubMed1997

Intravenous regional analgesia using morphine. The effect on postoperative pain following total knee arthroplasty.

BACKGROUND: We hypothesised that any peripheral action of morphine may contribute to improved postoperative analgesia. The aim of this study was to evaluate the analgesic efficacy of morphine administered preoperatively into an exsanguinated limb prior to total knee arthroplasty. METHODS: A randomised, double-blind, controlled study was performed in 50 patients having total knee arthroplasty surgery. Patients were divided into two groups. In the study group, 0.125 mg/kg morphine in 60 ml of saline was administered intravenously (iv) into the exsanguinated operative limb via a cannula in the foot. A saline intramuscular (im) injection was administered into the opposite leg. The control group received 60 ml saline iv into the operative leg and 0.125 mg/kg morphine im into the opposite leg. Pain was assessed postoperatively using a 10-point visual analogue scale and by comparing morphine requirements and demand:delivery ratios from a patient-controlled analgesic pump. RESULTS: We found no statistically significant difference between the groups in relation to any of the analgesic measures employed. CONCLUSIONS: Intravenous regional analgesia using morphine provides no analgesic advantage over the intramuscular route from 6-24 h postoperatively.

Analgesia, Patient-Controlled↗

PubMed1997

Collection and short-term preservation of semen from free-ranging eastern grey kangaroos (Macropus giganteus: Macropodidae).

OBJECTIVES: To evaluate electro-ejaculation of free-range eastern grey kangaroos in the field and assess the efficacy of four diluents to preserve sperm motility over a 48-h period at 5 degrees C. PROCEDURE AND DESIGN: Under gaseous anaesthesia, 25 free-range kangaroos were electro-ejaculated and characteristics of the ejaculate noted. Spermatozoa obtained from eight ejaculates were diluted in phosphate buffered saline containing various combinations of egg yolk and glucose and refrigerated at 5 degrees C for 48 h. RESULTS: Spermatozoa were recovered from 24 of 28 ejaculates. Mean (+/- SEM) semen volume (mL) and pH were 25.0 +/- 1.9 and 7.1 +/- 0.1 respectively. The forward motility (%), rate of movement of sperm (0 to 5) and sperm concentration (x 10(6)/mL) were 77.4 +/- 1.5, 3.8 +/- 0.9 and 31.2 +/- 7.3 respectively. There was no significant difference between the four diluents in their ability to maintain forward motility of spermatozoa over 48 h. However, rate of movement over the same period was significantly (P < 0.01) improved when sperm were diluted in phosphate buffered saline containing 10% egg yolk. CONCLUSIONS: Electro-ejaculation is a safe and reliable method for collecting semen from free-ranging eastern grey kangaroos. Preliminary attempts at short-term preservation showed that the motility of kangaroo spermatozoa could be adequately stored for 24 h and that the addition of egg yolk to the semen diluent was beneficial for improving the rate of sperm movement.

Animals↗

PubMed1997

Assessment of the humoral immune response against Plasmodium falciparum rhoptry-associated proteins 1 and 2.

Naturally occurring antibody responses to Plasmodium falciparum rhoptry-associated proteins 1 and 2 (RAP-1 and RAP-2) were measured with recombinant and parasite-derived forms of the antigens. For comparative purposes, responses to multiple forms of three other malarial antigens were also examined. The sera of 100 Papua New Guineans were screened for antibodies. Eighty-six and 82% of individuals over 30 years of age had antibodies that recognized parasite-derived RAP-1 and RAP-2, respectively. Importantly, we found that recombinant and native antigens share linear epitopes seen by the human immune system; thus, the recombinant proteins may be adequate human immunogens. However, antibodies affinity purified on recombinant RAP-1 reacted with other antigens in addition to parasite-derived RAP-1. Thus, the antigenicity of RAP-1 may have been overestimated previously. The recognition of RAP-1 and RAP-2 correlated with age and with the recognition of recombinant forms of the ring-infected erythrocyte surface antigen, merozoite surface protein 1, and merozoite surface antigen 2 (MSA2) antigens. Antibodies to these antigens appear to be generated in response to the total exposure to malaria of the host. Antibodies to conserved regions of MSA2 had stronger correlations with both age and the recognition of other antigens than did the full-length recombinant MSA2 molecule. In contrast to results with the other antigens, there was no significant difference in the ages of individuals with a certain antibody titer to the full-length recombinant or parasite-derived MSA2 molecule, but antibodies to these two antigens did correlate with parasitemia. For all antigens tested, antibody levels after two infections can approach the peak levels of antibodies obtained in immune individuals.

Adolescent↗

PubMed1997

Reproducibility of the signal averaged P wave: time and frequency domain analysis.

OBJECTIVE: To assess the reproducibility of time and frequency domain variables derived from the signal averaged P wave. DESIGN: Longitudinal within patient study. SETTING: Regional cardiothoracic centre. PATIENTS: 20 patients (10 with documented paroxysmal atrial fibrillation and 10 normal controls) were studied on three occasions to assess the reproducibility of repeated signal averaged P wave recordings. Digital P wave recordings were made on a further 10 patients on a single occasion and the recordings signal averaged twice in order to assess the reproducibility of the averaging system itself in the absence of biological variation. MAIN OUTCOME MEASURES: P wave duration, spatial velocity, and energies contained in frequency bands from 20, 30, and 60-150 Hz of the P wave spectrum were measured after P wave specific signal averaging. Coefficients of reproducibility were calculated for paired signal averaged P waves derived by signal averaging the same digital recordings on two separate occasions, for recordings performed in the same patients immediately after each other ("back to back") and those performed one week apart. RESULTS: System reproducibility when the same digital P wave recordings were signal averaged on two separate occasions was high (< 11% for all variables). For P wave duration the coefficient of reproducibility was 11.4% for back to back recordings and 13.1% for those one week apart. The reproducibility of spatial velocity and P wave energy was low. Variation in P wave morphology was noted when successive P waves from the same subject were examined. If recordings with the same P wave morphology were analysed the reproducibility of spatial velocity and P wave energy improved but remained significantly poorer than that for P wave duration. CONCLUSIONS: P wave duration is reproducible within subjects in the short and medium term. Frequency domain and spatial velocity analysis are poorly reproducible, due more to spontaneous variation in P wave morphology than to instability of the signal averaging process. This may limit the utility of signal averaged P wave variables other than duration for the prediction of atrial arrhythmia.

Adult↗

PubMed1997

Signal averaged P wave compared with standard electrocardiography or echocardiography for prediction of atrial fibrillation after coronary bypass grafting.

OBJECTIVE: To define the clinical value of the signal averaged P wave (SAPW) and to compare it with the standard electrocardiogram (ECG), echocardiogram, and clinical assessment for the prediction of atrial fibrillation after coronary bypass grafting (CABG). DESIGN: Prospective validation cohort study. SETTING: Regional cardiothoracic centre. PATIENTS: 201 unselected patients undergoing first elective CABG were recruited over six months. Patients requiring concomitant valve surgery were excluded. MAIN OUTCOME MEASURES: Age, sex, cardiothoracic ratio, and cardioactive drugs were noted. P wave specific SAPW recordings, ECG, and M mode echocardiograms from which left atrial diameter was measured were performed within 24 hours of surgery. Filtered P wave duration (SAPWD), spatial velocity, and energy were calculated from the SAPW. From the ECG, lead II P wave duration, P terminal force in lead V1, total P wave duration, and isoelectric interval were measured. Patients had Holter monitoring for 48 hours postoperatively and daily ECGs until discharge. RESULTS: Two patients died (1%) and 10 were unsuitable for analysis (5%). Of the remaining 189, 51 (27%) had atrial fibrillation (AF) lasting > 1 hour at a mean of 2 (0.5 to 7) days after CABG. Of the variables examined, only SAPWD (AF group 148 (SD 12), v 142 (14) ms, P = 0.008) and male sex (AF group 96%, v 78%, P < 0.01) were significantly different. A prospectively defined SAPWD of > 141 ms predicted atrial fibrillation with positive and negative predictive accuracies of 34% and 83%. Logistic regression analysis identified both male sex and SAPWD as significant independent predictors of postoperative atrial fibrillation. CONCLUSIONS: Signal averaged P wave duration was a better predictor of atrial fibrillation after coronary bypass grafting than standard electrocardiographic or echocardiographic criteria. The predictive value of this test is such that it is likely to be useful in the design of prospective trials of prophylactic antiarrhythmic treatment but is of limited use using current techniques in the clinical management of individual patients.

Atrial Fibrillation↗

PubMed1997

Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study.

PURPOSE: The present intergroup phase III randomized study compared combined chemotherapy (CT) plus radiotherapy (RT) treatment versus RT only in patients with locally advanced esophageal cancer. MATERIALS AND METHODS: Two courses of chemotherapy during 50 Gy RT followed by additional two courses of the same CT, versus 64 Gy RT alone were investigated. CT consisted of cisplatin 75 mg/m2 on day 1 [corrected] and fluorouracil (5FU) 1,000 mg/m2/d on days 1 to 4 every 4 weeks with RT and every 3 weeks post-RT. The main objective of the study was to compare overall survival between the two randomized treatment groups. Patients were stratified by tumor size, histology, and degree of weight loss. RESULTS: Sixty-two assessable patients were randomized to receive RT alone, and 61 to the combined arm. Patients characteristics were as follows: squamous cell cancer, 90% versus 85%; weight loss greater than 10 lb, 61% versus 69%; and tumor size, > or = 5 cm, 82% versus 80% on the RT and CT-RT arms, respectively. Systemic side effects, which consisted of nausea, vomiting, and renal and myelosuppression, occurred more frequently on the combined arm, while local side effects were similar in both groups. With a minimum follow-up time of 5 years for all patients, the median survival duration was 14.1 months and the 5-year survival rate was 27% in the combined treatment group, while the median survival duration was 9.3 months with no patients alive at 5 years in the RT-alone group (P < .0001). Additional patients (69) were treated with the same combined therapy and were analyzed. The results of the last group confirmed all of the results obtained with combined CT-RT in the randomized trial, with a median survival duration of 17.2 months and 3-year survival rate of 30%. CONCLUSION: We conclude that cisplatin and 5FU infusion given during and post-RT of 50 Gy is statistically superior to standard 64-Gy RT alone in patients with locally advanced esophageal cancer.

Adult↗

PubMed1997

Clinical use of aromatase inhibitors in the treatment of advanced breast cancer.

The aim of endocrine therapy is to reduce the estrogenic stimulus for tumour growth. After failure of tamoxifen--the standard "first-line" hormonotherapy for advanced breast cancer (ABC)--the most frequently prescribed endocrine therapies are progestins and aromatase inhibitors (AIs) ("second-line" hormonotherapy). Estrogen deprivation through AIs provides effective treatment of hormone-dependent ABC in postmenopausal (PMP) women. Over the past few years, the goals of our research programme were to develop more potent, more selective and better tolerated AIs than our first AI, aminoglutethimide (AG). Lentaron (4-hydroxyandrostenedione, formestane), a highly selective steroidal compound was the first of the new AIs to be used in clinical trials. It is a substrate analogue, administered as an i.m. injection every 2 weeks. It is effective in the treatment of ABC with an objective response rate (ORR) similar to tamoxifen and megestrol acetate (MA) and is generally well tolerated; rare instances of injection site reactions have been reported. Afema (fadrozole HCl), a non-steroidal AI is active orally, and effectively suppresses estrogen levels in PMP women, but it is not completely selective for aromatase when administered at higher than therapeutic doses. At the therapeutic dose of 1 mg twice a day it has an anti-tumour efficacy similar to MA, a good tolerability and no clinically relevant effects on other hormones of the endocrine system. Letrozole is the fourth of our AIs in clinical development. It is a non-steroidal, achiral, orally active, potent and highly selective competitive AI. Clinical endocrine studies have shown that the dose of 0.5 mg a day is the lowest dose achieving maximum estrogen suppression. Over a wide dose range, a lack of clinically relevant effects on other hormones of the endocrine system has confirmed its high selectivity. In four phase Ib/IIa studies in PMP patients with ABC who failed previous therapy, letrozole produced ORRs of 9, 31, 33 and 36%. One phase IIb/III study has been completed and two others are ongoing, comparing two doses of letrozole with MA or AG to confirm the anti-tumour efficacy of letrozole in the treatment of ABC in PMP women after treatment with anti-estrogens. Preliminary results from the completed trial show that letrozole 2.5 mg is superior to 0.5 mg in terms of ORR, time to progression and time to treatment failure, and is superior to the standard dose of MA in terms of ORR and tolerability. Therefore letrozole 2.5 mg can be recommended as a first choice for the treatment of PMP patients with hormone receptor-positive or unknown ABC after anti-estrogen therapy.

Aromatase Inhibitors↗

PubMed1997

Increased concentration of soluble human leukocyte antigen class I levels in the bronchoalveolar lavage of human pulmonary allografts.

BACKGROUND: Human leukocyte antigen (HLA) class I antigens, are glycoproteins expressed on the cell surface and are also secreted (sHLA) into the surrounding fluids. This study investigates whether pulmonary allograft rejection is associated with an increased amount of sHLA class I in the bronchoalveolar lavage (BAL) fluid. METHODS: Enzyme-linked immunosorbant assays were used to measure sHLA class I levels in BAL samples from 66 lung transplant recipients. RESULTS: Analysis of pulmonary allograft recipients revealed that the mean concentration of sHLA class I was significantly higher in samples from recipients with acute rejection than in recipients with no evidence of rejection. Seventy-two percent of the patients with rejection had sHLA levels above the normal range for patients with infection or rejection. Conversely, sHLA levels were within normal limits in 94% of the control population. Time kinetic analysis revealed that in subjects with rejection, sHLA class I levels peaked in the first 2 weeks after transplantation and decreased thereafter. Increased levels of sHLA were found in patients with acute rejection but not in those with chronic rejection. Fifty-nine percent (n = 10) of the patients with infection had sHLA levels within the normal (no infection or rejection) range. The remaining 41% (n = 7) with infection had sHLA above the normal range. Fifty-seven percent (n = 4) of the latter group had cytomegalovirus infection. These results were confirmed in a prospective study carried out by analyzing paired samples obtained during and after rejection. Eight of the nine patients had high BAL sHLA class I during acute rejection, and low BAL sHLA class I levels after resolution of the acute rejection. CONCLUSION: Our data demonstrate that measurement of sHLA class I levels in BAL samples is a sensitive indicator of acute rejection.

Acute Disease↗

PubMed1997

A phase II trial of paclitaxel and cisplatin in patients with locally advanced metastatic esophageal cancer: a preliminary report.

We demonstrated in an earlier trial that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has substantial antineoplastic activity, with acceptable toxicity, in patients with advanced metastatic esophageal cancer. Preclinical and clinical data from studies in other tumors indicate substantial additive or even synergistic activity for paclitaxel/cisplatin combination chemotherapy. We encountered substantial toxicity with a cisplatin/paclitaxel/5-fluorouracil combination. To maximize paclitaxel dose, we initiated a phase II trial using cisplatin and paclitaxel alone. This report summarizes preliminary data from that trial. Paclitaxel 200 mg/m2 is given as a continuous, 24-hour infusion on day 1. On day 2, cisplatin 75 mg/m2 is given. Courses are repeated every 21 days. Dose adjustments are based on myelosuppression, neurotoxicity, and (for cisplatin) renal or auditory toxicity. All patients receive recombinant human granulocyte colony-stimulating factor to minimize the risk of neutropenic fever. The primary end point of the study is tumor regression. Secondary end points include duration of response and toxicity. Two groups of patients are being studied. Those with advanced metastatic disease receive chemotherapy alone as palliative treatment. The second group has locoregional disease that is potentially resectable. These patients receive combined-modality therapy involving induction paclitaxel/cisplatin chemotherapy followed by surgery. To date, 37 evaluable patients have been treated. Twenty had advanced metastatic disease and 17 were treated before planned surgery. Twenty-seven patients had adenocarcinoma and 10 had epidermoid carcinoma. Major objective responses were seen in 49% of all patients, with similar response rates for patients with metastatic and locoregional disease. The median duration of response for patients with metastases is 4+ months. Among 14 patients treated before surgery, one experienced a complete pathologic response, and the neoplasms of 43% were downstaged. Primary toxicity was neutropenia, which was tolerable. Surgical morbidity or mortality did not increase. Cisplatin plus paclitaxel is an active combination in the treatment of patients with advanced or locoregional esophageal cancer. Further studies with this combination both in metastatic and locally advanced disease are indicated.

Adult↗

PubMed1996

[Quality development in family practice--development and use of health indicators].

In 1995 the Norwegian general practitioners' associations embarked upon a three-year project to assess a new model for improving the quality of primary health care. Indicators are proposed for assessing quality and setting standards in local practice. Software has been developed to simplify collection of data and production of reports from computerized medical records. Peer groups of 5-10 practitioners discuss results, agree on local standards and plan improvements. General practitioners who participate in a cycle of quality improvement will be awarded credits for recertification as specialists in general practice. The initial topics are: care of diabetics, use of laboratory tests, management of sore throat, and management of migraine. This national project will be evaluated both in terms of improvement in the quality of care, and of the views of the participating practitioners.

Family Practice↗

PubMed1996

Fadrozole hydrochloride in postmenopausal patients with metastatic breast carcinoma.

BACKGROUND: Fadrozole hydrochloride (CGS-16949A) belongs to the class of aromatase inhibitors that lowers circulating estrogen levels by inhibiting the conversion of androgens to estrogens, thereby causing tumor regression in patients with breast carcinoma. METHODS: This was a prospective, randomized, Phase II study of fadrozole hydrochloride in postmenopausal patients with metastatic breast carcinoma. The three treatment groups received, respectively, fadrozole hydrochloride 0.6 mg three times daily, 1 mg twice daily, and 2 mg twice daily orally. RESULTS: Fifty-six patients were entered on protocol and 54 were eligible (2 patients were perimenopausal). Eight patients had received no prior therapy, 15 patients had received prior hormonal therapy, 5 patients had received prior chemotherapy, and 28 patients had received both. After 12 weeks of treatment, 2 complete and 3 partial responses were observed. Forty patients continued treatment beyond 12 weeks, and 3 additional responses were achieved. Thus, 8 of 56 patients responded (14% overall response rate). Responses did not appear to be dose-related. The median duration of response was 36 months (range, 8-45 months). Subjective toxicity was mild to moderate and appeared more frequent on the 2 mg twice daily dosing schedule. No objective toxicity in laboratory parameters was observed. No patient had severe or life-threatening toxicity. Fadrozole hydrochloride plasma concentrations (obtained every 2 weeks for 12 weeks) appeared to be dose-dependent and noncumulative. CONCLUSIONS: This study confirms modest activity of fadrozole hydrochloride in a heterogeneous group of patients with breast carcinoma treated at three different dose levels.

Adolescent↗

PubMed1996

Fadrozole HCL (CGS-16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: results of two randomized double blind controlled multiinstitutional trials.

BACKGROUND: Breast cancer patients with prior response to endocrine therapy achieve subsequent benefit from additional endocrine therapies. The efficacy and safety of an aromatase inhibitor, fadrozole HCL, were compared with megestrol acetate in post menopausal patients who had disease progression after receiving antiestrogen therapy either for metastatic disease or as adjuvant therapy. METHODS: In 2 multiinstitutional prospective trials, 683 postmenopausal patients were randomized to receive either fadrozole HCL, 1 mg twice daily, or megestrol acetate, 40 mg 4 times daily, in a double blind fashion after progression on first-line hormonal therapy. Objective response rates, time to progression, survival and safety of the two regimens were compared. RESULTS: Results of intent-to-treat analyses are presented in this study. No significant differences were detected between the two treatment groups in time to progression, objective response rates, duration of response, and survival in either trial. There were no clinically meaningful differences between the treatment groups in the incidence and severity of adverse experiences, except that weight gain, fluid retention, and dyspnea were observed in more patients in the megestrol acetate group compared with those receiving fadrozole HCL, whereas nausea and vomiting were observed in more patients in the fadrozole HCL group compared with those receiving megestrol acetate. CONCLUSIONS: Fadrozole HCL was as efficacious as megestrol acetate in postmenopausal patients with metastatic breast carcinoma after one hormonal therapy. Adverse experiences were mild with both therapies, but megestrol acetate was associated wiht a higher frequency of weight gain, fluid retention and dyspnea, whereas fadrozole HCL was associated with a higher frequency of nausea and vomiting.

Adult↗