Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in pr... more Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in preclinical testing was found to be less nephrotoxic and emetogenic than cis-diamminedichloroplatinum (CDDP), while retaining a broad spectrum of antitumor activity. We have conducted a Phase I trial of CBDCA in 38 patients with advanced carcinoma. The drug was given without hydration as a 24-hr constant i.v. infusion on Day 1 of a 28-day cycle. Seventy-five cycles of CBDCA were administered in eight dose levels ranging from 20 to 320 mg/sq m. Dose-limiting toxicity was myelosuppression, primarily thrombocytopenia, occurring between Days 14 and 28 of the cycle. Myelosuppression was first observed at a dose of 240 mg/sq m and became dose-limiting at 320 mg/sq m, which is the recommended dose for Phase II trial. Other toxicities included nausea and vomiting and reversible renal failure seen in two patients with low normal pretreatment creatinine clearances. No consistent changes were seen on serial audiograms. Plasma concentrations of total and ultrafilterable platinum were measured by flameless atomic absorption spectrophotometry. Following cessation of the infusion, a half-life of 170 +/- 34 min (S.D.) was found for CBDCA-derived ultrafilterable platinum. In vitro clonogenic assay of a CDDP-sensitive human ovarian cancer cell line using clinically achievable drug concentrations suggests that prolonged infusions of CBDCA may be more cytotoxic than bolus administration. In this study, minimal responses were seen in two patients with ovarian carcinoma who had failed previous combination chemotherapy including CDDP. In addition, three patients with refractory metastatic breast cancer responded to CBDCA (two minimal responses and one partial response) with remission durations averaging 3 months. CBDCA behaves as predicted by preclinical studies with different toxicities from CDDP and apparent activity in breast cancer.
20022 Background: MRP4 is an ATP-binding cassette transporter and amphipathic anion efflux pump w... more 20022 Background: MRP4 is an ATP-binding cassette transporter and amphipathic anion efflux pump which transports prostaglandins, nucleoside analogues, glutamate and phosphate analogues. High MRP4 expression is prognostic of poor outcome in neuroblastoma and also correlates with MYCN amplification, suggesting regulation by this oncogene. Although MRP4 is known to be expressed in normal prostate epithelium, its expression in prostate cancer (PC) is undefined. This study aimed to define the pattern of expression of MRP4 in normal and malignant prostate tissue and assess the association with androgen exposure. Methods: 84 radical prostatectomy specimens from patients with clinically localized PC (22 neoadjuvant androgen ablation therapy, 62 no neoadjuvant treatment), 42 specimens of hyperplasia adjacent to PC and 16 cases of advanced PC were assessed for MRP4 expression using in situ hybridisation and immunohistochemistry. PC cell lines were assessed by immunoblotting. Results: There were significantly higher levels of MRP4 mRNA and protein expression in localized PC compared to hyperplasia (p=0.006). Conversely, MRP4 protein levels were significantly decreased in PCs treated with neoadjuvant androgen ablation therapy compared to cancers exposed to normal testosterone levels (p < 0.0001). There was also a trend towards decreased MRP4 expression in advanced PCs. Furthermore, immunoblotting revealed that MRP4 protein was more highly expressed in androgen-dependent (LNCaP) compared to androgen-independent (PC3/DU145) cell lines. In addition, in a panel of 14 normal human tissues only kidney and prostate tissue expressed MRP4 protein suggesting limited expression of MRP4 in human tissues. Discussion: Elevated MRP4 expression is found in malignant compared to benign prostate tissue while lower MRP4 expression is seen after androgen ablation suggesting that MRP4 may be an androgen-regulated gene. In addition, there is relatively little expression of MRP4 in normal tissues. These data suggest that MRP4 is important in the progression to PC and that it may be a potential therapeutic target. No significant financial relationships to disclose.
Journal of Chromatography B: Biomedical Sciences and Applications, Dec 1, 1992
An assay using reversed-phase high-performance liquid chromatography with electrochemical detecti... more An assay using reversed-phase high-performance liquid chromatography with electrochemical detection was developed to measure hydroxyurea in plasma at concentrations suitable for pharmacokinetic studies. The sample preparation is simple, the analysis rapid and assays can be batched. The between-run precision is excellent (coefficient of variation = 2.8-4.5%) and the limit of detection is 0.02 mmol/l. Preliminary studies have shown that the method is suitable for pharmacokinetic studies.
In patients with hepatocellular carcinoma, surgical resection may offer a chance of cure. However... more In patients with hepatocellular carcinoma, surgical resection may offer a chance of cure. However, tumor recurrence is not infrequent after resection. To identify the pathologic factors that are of prognostic significance and predictive value in tumor recurrence, the authors studied 278 patients (243 men, 35 women) who had hepatectomy for hepatocellular carcinoma. Disease free and actuarial survival were correlated with 20 pathologic parameters of the resected specimens using multivariate analysis. The median follow-up period was 23.6 months. The overall disease free survival rates at 1, 3 and 5 years were 42%, 23%, and 17%, respectively, and the overall actuarial survival rates for the corresponding time periods were 70%, 39%, and 28%, respectively. The results indicated that tumor encapsulation (P = 0.004) and heavy intratumor inflammatory infiltrates (P = 0.003) were independent favorable factors related to tumor recurrence. Negative resection margins (P = 0.001) and heavy intratumor inflammatory infiltrates (P = 0.003) were independent favorable factors correlated with survival. From this analysis, it was determined that detailed histologic examination of resected specimens of hepatocellular carcinoma is important in assessing long term prognosis and stratification of patients for treatment.
9570 Background: Beta-catenin, in its role as a nuclear signaling molecule, has been implicated i... more 9570 Background: Beta-catenin, in its role as a nuclear signaling molecule, has been implicated in prostate carcinogenesis through modulation of androgen receptor activity. Mice in whom beta-catenin is overexpressed in the nuclei of prostatic epithelium develop hyperplastic and dysplastic lesions. Hence this study focused on nuclear beta-catenin expression and aimed to define the pattern of beta-catenin protein expression in the nuclei of normal, hyperplastic and malignant human prostate tissue and to determine whether changes in expression were associated with disease progression and/or prognosis. METHODS Five normal prostates, 26 benign prostatic hypertrophy specimens, 232 radical prostatectomy specimens from patients with clinically localized prostate cancer (PC), 186 specimens of hyperplasia adjacent to PC and 20 cases of advanced PC were assessed for beta-catenin expression using immunohistochemistry. RESULTS There were significantly lower levels of nuclear beta-catenin expression in localized PC compared to benign prostate tissue (p<0.001). Nuclear beta-catenin expression was also lower in advanced compared to localized PC (p<0.001). In addition, lower levels of nuclear beta-catenin expression (immunoreactivity in <10% of malignant cells) predicted for a shorter biochemical relapse-free survival in patients with localized PC (HR 1.9, 95%CI 1.2-3.0; p=0.008) and were inversely correlated with pre-operative prostate-specific antigen (PSA) levels (p=0.01). Analysis of a low-risk subgroup of patients with pre-operative PSA levels <10 ng/ml (n=114), demonstrated that lower levels of nuclear beta-catenin (<10% of malignant cells) again predicted for a poorer prognosis (HR 3.2, 95%CI 1.4-7.3; p=0.006). CONCLUSIONS Lower levels of nuclear beta-catenin expression are found in malignant compared to benign prostate tissue. Lower nuclear beta-catenin expression is also associated with a poorer prognosis in localized PC, in particular in the low-risk subgroup of patients with pre-operative PSA levels <10 ng/ml. Consequently, nuclear beta-catenin expression may be of clinical utility as a pre-operative prognostic marker in patients with low-risk PC. No significant financial relationships to disclose.
TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous... more TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
The effect of pretreatment with intravenous metoclopramide (10 mg) and atropine (0 6 mg), both se... more The effect of pretreatment with intravenous metoclopramide (10 mg) and atropine (0 6 mg), both separately and combined, on the absorption rate and relative oral bioavailability of the antiarrhythmic drug, mexiletine (400mg) was studied in eight fasting healthy males using a Latin Square design for order of pretreatment administration. 2 The time (Tmax) of the maximum mexiletine plasma concentration (Cpmax) was reduced by metoclopramide (P < 0-001) and was increased by atropine (P < 0-01) compared with saline control. Tmax was not significantly altered by combined metoclopramide and atropine pretreatment. 3 Atropine pretreatment was associated with a significant reduction of Cpmax (P < 0-05) and of elimination half-life (P< 0 05). 4 The area under the mexiletine plasma concentration-time curve was not affected by any of the pretreatments. 5 The results suggested that metoclopramide enhanced and atropine decreased the rate of mexiletine absorption without altering the relative oral bioavailability. When the pretreatments were administered in combination, metoclopramide reversed the delay in mexiletine absorption produced by atropine.
The influence of liver volume and body weight on plasma theophylline clearance was investigated i... more The influence of liver volume and body weight on plasma theophylline clearance was investigated in asthmatic children and adults. A linear relationship (r = +0.99) was demonstrated between ideal body weight and liver volume estimated by an ultrasonic scanning technique. Age-related changes in liver volume-to-body weight ratio could account for only 30% of differences in plasma theophylline clearance (1/h/kg) between children and adults. It is summized that increased hepatic mixed function oxidase activity is the major contributor to the higher plasma theophylline clearance in children.
In June 1998, a 50-year-old woman presented to hospital with vomiting, dehydration, serum calcium... more In June 1998, a 50-year-old woman presented to hospital with vomiting, dehydration, serum calcium of 4.7 mmol/l and deranged liver function tests. Prior to her presentation she had been unwell for 6 weeks with polyuria and anorexia. She was rehydrated and her calcium was corrected with intravenous pamidronate. Investigations revealed undetectable parathyroid hormone (PTH) and multiple liver lesions, the largest measuring 6 cm. Biopsy of the liver lesions confirmed metastatic adenocarcinoma (? site of origen). There was insufficient tissue to assess for hormone receptors. A breast mass measuring 3 cm was identified in the left breast in retrospect, consistent with a diagnosis of metastatic breast cancer.
Summary Thirty patients with hormone‐refractory prostate cancer were treated with cycles of oral ... more Summary Thirty patients with hormone‐refractory prostate cancer were treated with cycles of oral cyclophosphamide (100 mg/m2/dayfor 14 days, with a 14‐day gap). Eighteen patients had a significant improvement in symptoms of advanced disease, 6 had objective partial remissions and 13 had stabilisation of disease (criteria of National Prostatic Cancer Project). The median survival from the time of diagnosis was 33.3 months, and from the commencement of cyclophosphamide 12.7 months. The treatment was well tolerated. Oral cyclophosphamide is active in the treatment of advanced hormone‐refractory prostate cancer and yields symptomatic and objective remissions without undue side effects. This observation requires validation, with further testing of its impact on survival in randomised clinical trials.
The effect of pretreatment with intravenous metoclopramide (10 mg) and atropine (0.6 mg), both se... more The effect of pretreatment with intravenous metoclopramide (10 mg) and atropine (0.6 mg), both separately and combined, on the absorption rate and relative oral bioavailability of the antiarrhythmic drug, mexiletinee (400 mg) was studied in eight fasting healthy males using a Latin Square design for order of pretreatment administration. The time (Tmax) of the maximum mexiletin plasma concentration (Cpmax) was reduced by metoclopramide (P < 0.001) and was increased by atropine (P < 0.01) compared with saline control. Tmax was not significantly altered by combined metoclopramide and atropine pretreatment. Atropine pretreatment was associated with a significant reduction of Cpmax (P < 0.05) and of elimination half-life (P < 0.05). The area under the mexiletine plasma concentration-time curve was not affected by any of the pretreatments. The results suggested that metoclopramide enhanced and atropine decreased the rate of mexiletine absorption without altering the relative oral bioavailability. When the pretreatments were administered in combination, metoclopramide reversed the delay in mexiletine absorption produced by atropine.
Forty-three patients with disseminated prostate cancer, resistant to orchidectomy or hormone ther... more Forty-three patients with disseminated prostate cancer, resistant to orchidectomy or hormone therapy with estramustine were treated. Of the 33 evaluable patients, three patients had stable disease and two had a partial tumour response according to National Prostatic Cancer Project criteria. Twenty-five patients (58%) showed improvement in pain and urinary symptoms. Ten patients (23%) had side effects requiring cessation of therapy. These results show that estramustine has a limited role in the treatment of advanced prostate cancer and that therapy is frequently associated with intolerable side effects.
Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in pr... more Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in preclinical testing was found to be less nephrotoxic and emetogenic than cis-diamminedichloroplatinum (CDDP), while retaining a broad spectrum of antitumor activity. We have conducted a Phase I trial of CBDCA in 38 patients with advanced carcinoma. The drug was given without hydration as a 24-hr constant i.v. infusion on Day 1 of a 28-day cycle. Seventy-five cycles of CBDCA were administered in eight dose levels ranging from 20 to 320 mg/sq m. Dose-limiting toxicity was myelosuppression, primarily thrombocytopenia, occurring between Days 14 and 28 of the cycle. Myelosuppression was first observed at a dose of 240 mg/sq m and became dose-limiting at 320 mg/sq m, which is the recommended dose for Phase II trial. Other toxicities included nausea and vomiting and reversible renal failure seen in two patients with low normal pretreatment creatinine clearances. No consistent changes were seen on serial audiograms. Plasma concentrations of total and ultrafilterable platinum were measured by flameless atomic absorption spectrophotometry. Following cessation of the infusion, a half-life of 170 +/- 34 min (S.D.) was found for CBDCA-derived ultrafilterable platinum. In vitro clonogenic assay of a CDDP-sensitive human ovarian cancer cell line using clinically achievable drug concentrations suggests that prolonged infusions of CBDCA may be more cytotoxic than bolus administration. In this study, minimal responses were seen in two patients with ovarian carcinoma who had failed previous combination chemotherapy including CDDP. In addition, three patients with refractory metastatic breast cancer responded to CBDCA (two minimal responses and one partial response) with remission durations averaging 3 months. CBDCA behaves as predicted by preclinical studies with different toxicities from CDDP and apparent activity in breast cancer.
20022 Background: MRP4 is an ATP-binding cassette transporter and amphipathic anion efflux pump w... more 20022 Background: MRP4 is an ATP-binding cassette transporter and amphipathic anion efflux pump which transports prostaglandins, nucleoside analogues, glutamate and phosphate analogues. High MRP4 expression is prognostic of poor outcome in neuroblastoma and also correlates with MYCN amplification, suggesting regulation by this oncogene. Although MRP4 is known to be expressed in normal prostate epithelium, its expression in prostate cancer (PC) is undefined. This study aimed to define the pattern of expression of MRP4 in normal and malignant prostate tissue and assess the association with androgen exposure. Methods: 84 radical prostatectomy specimens from patients with clinically localized PC (22 neoadjuvant androgen ablation therapy, 62 no neoadjuvant treatment), 42 specimens of hyperplasia adjacent to PC and 16 cases of advanced PC were assessed for MRP4 expression using in situ hybridisation and immunohistochemistry. PC cell lines were assessed by immunoblotting. Results: There were significantly higher levels of MRP4 mRNA and protein expression in localized PC compared to hyperplasia (p=0.006). Conversely, MRP4 protein levels were significantly decreased in PCs treated with neoadjuvant androgen ablation therapy compared to cancers exposed to normal testosterone levels (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). There was also a trend towards decreased MRP4 expression in advanced PCs. Furthermore, immunoblotting revealed that MRP4 protein was more highly expressed in androgen-dependent (LNCaP) compared to androgen-independent (PC3/DU145) cell lines. In addition, in a panel of 14 normal human tissues only kidney and prostate tissue expressed MRP4 protein suggesting limited expression of MRP4 in human tissues. Discussion: Elevated MRP4 expression is found in malignant compared to benign prostate tissue while lower MRP4 expression is seen after androgen ablation suggesting that MRP4 may be an androgen-regulated gene. In addition, there is relatively little expression of MRP4 in normal tissues. These data suggest that MRP4 is important in the progression to PC and that it may be a potential therapeutic target. No significant financial relationships to disclose.
Journal of Chromatography B: Biomedical Sciences and Applications, Dec 1, 1992
An assay using reversed-phase high-performance liquid chromatography with electrochemical detecti... more An assay using reversed-phase high-performance liquid chromatography with electrochemical detection was developed to measure hydroxyurea in plasma at concentrations suitable for pharmacokinetic studies. The sample preparation is simple, the analysis rapid and assays can be batched. The between-run precision is excellent (coefficient of variation = 2.8-4.5%) and the limit of detection is 0.02 mmol/l. Preliminary studies have shown that the method is suitable for pharmacokinetic studies.
In patients with hepatocellular carcinoma, surgical resection may offer a chance of cure. However... more In patients with hepatocellular carcinoma, surgical resection may offer a chance of cure. However, tumor recurrence is not infrequent after resection. To identify the pathologic factors that are of prognostic significance and predictive value in tumor recurrence, the authors studied 278 patients (243 men, 35 women) who had hepatectomy for hepatocellular carcinoma. Disease free and actuarial survival were correlated with 20 pathologic parameters of the resected specimens using multivariate analysis. The median follow-up period was 23.6 months. The overall disease free survival rates at 1, 3 and 5 years were 42%, 23%, and 17%, respectively, and the overall actuarial survival rates for the corresponding time periods were 70%, 39%, and 28%, respectively. The results indicated that tumor encapsulation (P = 0.004) and heavy intratumor inflammatory infiltrates (P = 0.003) were independent favorable factors related to tumor recurrence. Negative resection margins (P = 0.001) and heavy intratumor inflammatory infiltrates (P = 0.003) were independent favorable factors correlated with survival. From this analysis, it was determined that detailed histologic examination of resected specimens of hepatocellular carcinoma is important in assessing long term prognosis and stratification of patients for treatment.
9570 Background: Beta-catenin, in its role as a nuclear signaling molecule, has been implicated i... more 9570 Background: Beta-catenin, in its role as a nuclear signaling molecule, has been implicated in prostate carcinogenesis through modulation of androgen receptor activity. Mice in whom beta-catenin is overexpressed in the nuclei of prostatic epithelium develop hyperplastic and dysplastic lesions. Hence this study focused on nuclear beta-catenin expression and aimed to define the pattern of beta-catenin protein expression in the nuclei of normal, hyperplastic and malignant human prostate tissue and to determine whether changes in expression were associated with disease progression and/or prognosis. METHODS Five normal prostates, 26 benign prostatic hypertrophy specimens, 232 radical prostatectomy specimens from patients with clinically localized prostate cancer (PC), 186 specimens of hyperplasia adjacent to PC and 20 cases of advanced PC were assessed for beta-catenin expression using immunohistochemistry. RESULTS There were significantly lower levels of nuclear beta-catenin expression in localized PC compared to benign prostate tissue (p<0.001). Nuclear beta-catenin expression was also lower in advanced compared to localized PC (p<0.001). In addition, lower levels of nuclear beta-catenin expression (immunoreactivity in <10% of malignant cells) predicted for a shorter biochemical relapse-free survival in patients with localized PC (HR 1.9, 95%CI 1.2-3.0; p=0.008) and were inversely correlated with pre-operative prostate-specific antigen (PSA) levels (p=0.01). Analysis of a low-risk subgroup of patients with pre-operative PSA levels <10 ng/ml (n=114), demonstrated that lower levels of nuclear beta-catenin (<10% of malignant cells) again predicted for a poorer prognosis (HR 3.2, 95%CI 1.4-7.3; p=0.006). CONCLUSIONS Lower levels of nuclear beta-catenin expression are found in malignant compared to benign prostate tissue. Lower nuclear beta-catenin expression is also associated with a poorer prognosis in localized PC, in particular in the low-risk subgroup of patients with pre-operative PSA levels <10 ng/ml. Consequently, nuclear beta-catenin expression may be of clinical utility as a pre-operative prognostic marker in patients with low-risk PC. No significant financial relationships to disclose.
TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous... more TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
The effect of pretreatment with intravenous metoclopramide (10 mg) and atropine (0 6 mg), both se... more The effect of pretreatment with intravenous metoclopramide (10 mg) and atropine (0 6 mg), both separately and combined, on the absorption rate and relative oral bioavailability of the antiarrhythmic drug, mexiletine (400mg) was studied in eight fasting healthy males using a Latin Square design for order of pretreatment administration. 2 The time (Tmax) of the maximum mexiletine plasma concentration (Cpmax) was reduced by metoclopramide (P < 0-001) and was increased by atropine (P < 0-01) compared with saline control. Tmax was not significantly altered by combined metoclopramide and atropine pretreatment. 3 Atropine pretreatment was associated with a significant reduction of Cpmax (P < 0-05) and of elimination half-life (P< 0 05). 4 The area under the mexiletine plasma concentration-time curve was not affected by any of the pretreatments. 5 The results suggested that metoclopramide enhanced and atropine decreased the rate of mexiletine absorption without altering the relative oral bioavailability. When the pretreatments were administered in combination, metoclopramide reversed the delay in mexiletine absorption produced by atropine.
The influence of liver volume and body weight on plasma theophylline clearance was investigated i... more The influence of liver volume and body weight on plasma theophylline clearance was investigated in asthmatic children and adults. A linear relationship (r = +0.99) was demonstrated between ideal body weight and liver volume estimated by an ultrasonic scanning technique. Age-related changes in liver volume-to-body weight ratio could account for only 30% of differences in plasma theophylline clearance (1/h/kg) between children and adults. It is summized that increased hepatic mixed function oxidase activity is the major contributor to the higher plasma theophylline clearance in children.
In June 1998, a 50-year-old woman presented to hospital with vomiting, dehydration, serum calcium... more In June 1998, a 50-year-old woman presented to hospital with vomiting, dehydration, serum calcium of 4.7 mmol/l and deranged liver function tests. Prior to her presentation she had been unwell for 6 weeks with polyuria and anorexia. She was rehydrated and her calcium was corrected with intravenous pamidronate. Investigations revealed undetectable parathyroid hormone (PTH) and multiple liver lesions, the largest measuring 6 cm. Biopsy of the liver lesions confirmed metastatic adenocarcinoma (? site of origen). There was insufficient tissue to assess for hormone receptors. A breast mass measuring 3 cm was identified in the left breast in retrospect, consistent with a diagnosis of metastatic breast cancer.
Summary Thirty patients with hormone‐refractory prostate cancer were treated with cycles of oral ... more Summary Thirty patients with hormone‐refractory prostate cancer were treated with cycles of oral cyclophosphamide (100 mg/m2/dayfor 14 days, with a 14‐day gap). Eighteen patients had a significant improvement in symptoms of advanced disease, 6 had objective partial remissions and 13 had stabilisation of disease (criteria of National Prostatic Cancer Project). The median survival from the time of diagnosis was 33.3 months, and from the commencement of cyclophosphamide 12.7 months. The treatment was well tolerated. Oral cyclophosphamide is active in the treatment of advanced hormone‐refractory prostate cancer and yields symptomatic and objective remissions without undue side effects. This observation requires validation, with further testing of its impact on survival in randomised clinical trials.
The effect of pretreatment with intravenous metoclopramide (10 mg) and atropine (0.6 mg), both se... more The effect of pretreatment with intravenous metoclopramide (10 mg) and atropine (0.6 mg), both separately and combined, on the absorption rate and relative oral bioavailability of the antiarrhythmic drug, mexiletinee (400 mg) was studied in eight fasting healthy males using a Latin Square design for order of pretreatment administration. The time (Tmax) of the maximum mexiletin plasma concentration (Cpmax) was reduced by metoclopramide (P < 0.001) and was increased by atropine (P < 0.01) compared with saline control. Tmax was not significantly altered by combined metoclopramide and atropine pretreatment. Atropine pretreatment was associated with a significant reduction of Cpmax (P < 0.05) and of elimination half-life (P < 0.05). The area under the mexiletine plasma concentration-time curve was not affected by any of the pretreatments. The results suggested that metoclopramide enhanced and atropine decreased the rate of mexiletine absorption without altering the relative oral bioavailability. When the pretreatments were administered in combination, metoclopramide reversed the delay in mexiletine absorption produced by atropine.
Forty-three patients with disseminated prostate cancer, resistant to orchidectomy or hormone ther... more Forty-three patients with disseminated prostate cancer, resistant to orchidectomy or hormone therapy with estramustine were treated. Of the 33 evaluable patients, three patients had stable disease and two had a partial tumour response according to National Prostatic Cancer Project criteria. Twenty-five patients (58%) showed improvement in pain and urinary symptoms. Ten patients (23%) had side effects requiring cessation of therapy. These results show that estramustine has a limited role in the treatment of advanced prostate cancer and that therapy is frequently associated with intolerable side effects.
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