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Biomedical subjects

J M Ford

Publications and source records attributed to J M Ford.

At least 19 recordsLinked to original sources
PubMed1992

Pharmacokinetics of pamidronate in patients with bone metastases.

BACKGROUND: Pamidronate is a second-generation bisphosphonate used in the treatment of tumor-induced hypercalcemia and in the management of bone metastases from breast cancer, myeloma, or prostate cancer. The pharmacokinetics of pamidronate is unknown in cancer patients. PURPOSE: To determine the influence of the rate of administration and of bone metabolism, we studied the pharmacokinetics of pamidronate at three different infusion rates in 37 patients with bone metastases. METHODS: Three groups of 11-14 patients were given 60 mg pamidronate as an intravenous infusion over a period of 1, 4, or 24 hours. Urine samples were collected in the three groups of patients. Plasma samples were obtained only in the 1-hour infusion group. The assay of pamidronate in plasma and urine was performed by high-performance liquid chromatography with fluorescence detection after the derivatization of pamidronate with fluorescamine. RESULTS: The body retention (BR) at 0-24 hours of pamidronate represented 60%-70% of the administered dose and was not significantly modified by the infusion rate. In particular, the BR at 0-24 hours was not reduced at the fastest infusion rate. Among patients, a threefold variability in BR at 0-24 hours occurred, which was related directly to the number of bone metastases and, to some extent, to creatinine clearance. At 60 mg/hour, the plasma kinetics followed a multiexponential course characterized by a short distribution phase. The mean (+/- SD) half-life of the distribution phase was 0.8 hour (+/- 0.3), the mean (+/- SD) of the area under the curve for drug concentration in plasma x time at 0-24 hours was 22.0 +/- 8.8 mumol/L x hours, and the mean (+/- SD) of the maximum plasma concentration was 9.7 mumol/L (+/- 3.2). Pharmacokinetic variables remained unchanged after repeated infusions applied to four patients. Clinically, the three infusion rates were equally well tolerated without significant toxicity. CONCLUSIONS: The 1-hour infusion rate could be proposed as kinetically appropriate for the administration of pamidronate to patients with metastatic bone diseases.

Aged↗
PubMed1991

Effect of buthionine sulfoximine on toxicity of verapamil and doxorubicin to multidrug resistant cells and to mice.

Resistance of tumor cells to chemotherapeutic drugs may be due to several mechanisms within a single cell line. Resistance to doxorubicin in the human multidrug resistant breast cancer cell line, MCF-7 AdrR, has been attributed to increased glutathione (GSH) S-transferase and GSH peroxidase activity, as well as to increased expression of the mdr1 gene product, P-glycoprotein. We studied the potentiation of doxorubicin activity in these cells by buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, and by verapamil and trans-flupenthixol, agents which interact with P-glycoprotein. Treatment with BSO enhanced the effect of doxorubicin by 1.5-fold, while verapamil or transflupenthixol caused a greater reversal of drug resistance. The combination of BSO with trans-flupenthixol produced no further potentiation of doxorubicin activity. However, the combination of BSO with verapamil and doxorubicin caused up to a 10-fold increment in antiproliferative effect. To explore the mechanism by which BSO interacted with this drug combination, we determined whether or not BSO might potentiate the effects of verapamil. These studies demonstrated that the effects of BSO were predominantly due to an increase in verapamil toxicity rather than to doxorubicin toxicity. In addition, when mice received concentrations of BSO in their drinking water sufficient to deplete GSH and were treated with verapamil, the calcium channel blocker was lethal to 9 of 12 mice receiving BSO compared to 1 of 10 control animals receiving verapamil alone. These studies demonstrate that BSO does not markedly increase the pharmacological effect of doxorubicin against MCF-7 AdrR cells and suggest that alterations in GSH and related enzymes are not a major factor in drug resistance in this cell line. Furthermore, BSO can increase the toxicity of verapamil, a finding which may have important implications for clinical trials.

Animals↗
PubMed1991

Event-related potentials and eyeblink responses in automatic and controlled processing: effects of age.

Seventeen young (mean age = 20.2 years old) and 16 elderly (mean age = 72.6 years old) women were tested with event-related potential (ERP) paradigms designed to elicit responses in reaction time tasks and to a startling noise burst. EEG was analyzed from 17 standard 10-20 electrode sites. Reaction time and performance data suggested that the elderly did not perform worse than the young. Nevertheless, the physiological responses of the elderly differed significantly from those of the young. While the task-dependent P3s at Pz were smaller in the elderly than in the young, the automatic P3 was smaller yet. The distribution of both types of P3 across the scalp was more uniform in the elderly than in the young. Single-trial analyses revealed that the P3 amplitude differences at Pz were not due to latency dispersal of single trials. Single-trial startle eye blink responses to intense noise bursts during the automatic paradigm were considerably less frequent in the elderly, although their individual startle blinks were actually larger. The data demonstrate that the electrophysiological responses of the elderly are different from the young both in tasks eliciting automatic responses and in tasks requiring controlled processing.

Adult↗
PubMed1991

Modulation of resistance to alkylating agents in cancer cell by gossypol enantiomers.

Several cell lines resistant to alkylating agents possess increased activity of glutathione-S-transferase (GST) drug detoxifying enzymes. Inhibition of certain enzymes of the glutathione redox system may affect cellular sensitivity to alkylators. We report that the (-.)enantiomer of gossypol is a potent and selective inhibitor of GST alpha and GST pi isozymes, and that in combination with buthionine sulfoximine (BSO), causes the enhanced modulation of alkylator resistance in two drug resistant cell lines with increased GST activity. The use of (-)gossypol alone had no effect on the 2-5-fold resistance of MCF-7 Adr and Walker resistant cells to chlorambucil, melphalan and BCNU. Cellular depletion of glutathione with BSO resulted in a 2-4-fold modulation of cell sensitivity to these alkylators. However, the combination of (-)gossypol with BSO resulted in a markedly greater modulation of alkylator sensitivity than with either inhibitor alone. Therefore, the complementary inhibition of glutathione and GST by BSO and (-)gossypol, respectively, produced a synergistic modulation of alkylator cytotoxicity in these drug resistant cell lines. The favorable clinical pharmacokinetics of (-)gossypol suggest its further evaluation for use in combination with BSO and alkylating agents in clinical trials.

Alkylating Agents↗
PubMed1991

Event-related potentials in alcoholic men: P3 amplitude reflects family history but not alcohol consumption.

Multilead event-related potentials (ERPs), elicited by auditory and visual stimuli requiring a button press response and by a startling noise requiring no response, were recorded from male alcoholics and age-matched male controls (26-60 years old). Single-trial analyses of blink responses to the startling stimuli indicated that alcoholics startle less frequently but with equivalent amplitude as the controls. In contrast, single-trial analyses of P3 indicated that alcoholics generate a P3 as often as controls, but that their individual P3s are smaller. Alcoholics who reported a positive family history of problem drinking had larger startle blink amplitudes and smaller auditory and visual P3s than did alcoholics who reported a negative family history. Hierarchical regression analysis was used to demonstrate that smaller P3s in family history positive alcoholics were independent of lifetime alcohol consumption.

Adult↗
PubMed1990

Cancer incidence in migrants to New South Wales.

Cancer incidence in migrants to New South Wales (NSW) from the British Isles, north-central, eastern and southern Europe, the Middle East and Asia has been compared with that in Australian-born residents using data from the NSW Central Cancer Registry for 1972-84. Indirectly standardized incidence ratios (SIRs) were low in migrants from all 6 regions for melanoma of skin and cancers of lip and, except in men from eastern Europe, colon. Oesophageal, rectal and prostatic cancers also tended to be relatively less common. Cancers which were more common than in the Australian-born were those of the stomach and, for men, bladder (except in the Asian-born). Migrants from different regions showed variations from the cancer pattern of the Australian-born population which, for the most part, were predictable from the known incidence of cancer in the countries within the region of origin. Exceptions were the high relative incidence of nasopharyngeal cancer in migrants from southern Europe and bladder cancer in men from all regions other than Asia.

Age Factors↗
PubMed1990

Cellular and biochemical characterization of thioxanthenes for reversal of multidrug resistance in human and murine cell lines.

We have previously shown that phenothiazines sensitize multidrug resistant (MDR) cells to chemotherapeutic drugs in a manner related to specific structural features, and have identified structurally related thioxanthenes with increased anti-MDR activity. We have now studied the structure-activity relationships of 16 thioxanthenes in the human breast cancer line MCF-7 AdrR. trans-Thioxanthene stereoisomers were 2- to 7-fold more potent than cis-thioxanthenes for antagonizing MDR. The most potent thioxanthenes possessed a halogenated tricyclic ring connected by a 3-carbon alkyl bridge to a piperazinyl or piperadinyl side group. The chemosensitizing effects of the lead compound, trans-flupenthixol, its stereoisomer cis-flupenthixol, its phenothiazine homologue fluphenazine, and the calcium channel blocker verapamil, were further studied in a series of sensitive and MDR cell lines. trans-Flupenthixol caused a greater reversal of cellular resistance to doxorubicin, vinblastine, vincristine, and colchicine in MCF-7 AdrR, KB-V1, and P388/DOX MDR cells than the other chemosensitizers. In particular, trans-flupenthixol was 2- to 3-fold more potent for reversing MDR than equimolar concentrations of verapamil. Furthermore, trans-flupenthixol fully reversed resistance to doxorubicin, vincristine, and colchicine in MDR MCF-7 and NIH 3T3 cells transfected with the mdr1 gene. None of these agents altered MDR in a non-P-glycoprotein expressing MCF-7 cell line selected with mitoxantrone, nor in any of the parental cell lines. The stereoselective antagonism of the flupenthixol isomers on several putative cellular targets was studied to explore the mechanism of their chemosensitizing activity. cis- and trans-flupenthixol were equally active inhibitors of protein kinase C and calmodulin. Both cis- and trans-flupenthixol were also potent inhibitors of [3H]azidopine binding to P-glycoprotein. The apparent lack of clinical toxicity of trans-flupenthixol makes it an attractive drug for possible use in the modulation of tumor resistance in vivo if appropriate tissue concentrations can be achieved.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Cancer incidence in New Zealand born residents of New South Wales.

Cancer incidence in New Zealand born residents of New South Wales (NSW) has been compared with that in the Australian born population using data from the NSW Central Cancer Registry for the period 1972-84. Indirectly age-standardised incidence ratios (SIR) showed that New Zealand born women living in NSW had higher rates of cancer at all sites combined (SIR = 112) and a significant excess of colorectal cancer (SIR = 126). Although overall cancer rates were similar in men born in New Zealand to those in the Australian born men, the New Zealanders had a significantly higher risk of colorectal (SIR = 124) and testicular cancer (SIR = 227), cancers which are more common in New Zealand than in Australia. While the SIRs for lung cancer in men and melanoma of skin in both sexes were low, no cancer was significantly less common in New Zealand born residents of NSW than in the Australian born.

Colonic Neoplasms↗
PubMed1990

Cancer incidence in migrants to New South Wales from England, Wales, Scotland and Ireland.

Cancer incidence in migrants to New South Wales (NSW) from individual countries within the British Isles has been compared with that in the Australian-born population using data from the NSW Central Cancer Registry for the period 1972-84. Indirectly age-standardised incidence ratios (SIR) showed that, for cancer at all sites combined, Scottish migrants had a significantly higher, and English migrants a lower, incidence than the native-born Australians. Melanoma of skin was less common in migrants from all four countries while lung cancer was more common. In all except the Irish migrants, stomach cancer was more frequent than in the Australian-born. Raised SIRs for bladder cancer were found in men from all the countries and for breast cancer in all except the Irish women but only in the English migrants were these ratios significant. English migrants differed from those from Wales, Scotland and Ireland in that, compared with the Australian-born, they had significantly lower SIRs for cancer of the colon (both sexes), head and neck, larynx and prostate (men), gallbladder and kidney (women), and a higher SIR for ovarian cancer. Bone cancer was relatively more common in men born in Wales. 'Other genital' cancers (penis and scrotum; vulva and vagina) tended to be more frequent in migrants from each country than in the Australian-born.

England↗
PubMed1990

Cancer incidence in European migrants to New South Wales.

The incidence of cancer in migrants to New South Wales (NSW) from Italy, Greece, Yugoslavia, Germany, the Netherlands, Poland and USSR has been compared with that in the Australian-born population using data from the NSW Central Cancer Registry for 1972-84. The indirectly age-standardized incidence ratios (SIR) in all seven countries were low for melanoma of skin and high for gastric cancer. Cancers of the colon, oesophagus and lip also tended to have low SIRs. Migrants from Italy, Greece and Yugoslavia had significantly less cancer at all sites than the native-born Australians mainly due to low SIRs for cancers of colon, lung (except Yugoslavian-born men), prostate and, in men, 'head and neck' (excluding nasopharynx). Cancers of breast and testis were relatively less common in migrants from Italy and Yugoslavia. SIRs were high for cancers of bladder (in Italian-born men), liver (in Greek- and Yugoslavian-born men) and nasopharynx (in Greek-born men and Italian-born men and women). Amongst migrants from the four more northerly European countries, ovarian cancer was relatively more common in women from Germany and Poland as was bladder cancer in men, but not women, from Germany and the Netherlands. Cancers which had significantly increased SIRs in one migrant group only were lung (Dutch-born men), cervix uteri and body of uterus (German-born women), gallbladder and bile ducts (Polish-born women), thyroid (Italian-born women), connective and other soft tissue (Russian-born men) and brain (Greek-born men and women computed together). Lymphomas were relatively less common in men born in Yugoslavia.

Emigration and Immigration↗
PubMed1990

The effect of propranolol on paracetamol metabolism in man.

Ten healthy volunteers were treated for 4 days with 160 mg propranolol HCl and placebo in random order. At the end of each treatment salivary antipyrine kinetics and the plasma kinetics and urinary excretion of paracetamol and its major metabolites were measured following a 1500 mg oral dose. Propranolol prolonged the half-life of antipyrine by 11 +/- 5% (mean +/- s.e. mean) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol increased the half-life of paracetamol by 25 +/- 12% (P less than 0.05) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol decreased the partial clearance of paracetamol to its cysteine and mercapturate derivatives by 16 +/- 3% (P less than 0.05) and 32 +/- 7% (P less than 0.05), respectively. The partial clearance to the glucuronide conjugate was decreased by 27 +/- 6% (P less than 0.05), whereas that to sulphate was not changed significantly. Propranolol inhibits paracetamol metabolism predominantly through inhibition of the oxidation and glucuronidation pathways.

Acetaminophen↗
PubMed1990

Geographical distribution of cancers of the kidney and urinary tract and analgesic nephropathy in Australia and New Zealand.

Age-standardised incidence rates for cancers of the renal parenchyma, renal pelvis and bladder and for end-stage renal failure due to analgesic nephropathy for the years 1982-83 were compared between the Australian states and New Zealand, and within New South Wales (NSW), to determine whether these rates paralleled the previous prevalence of consumption of phenacetin-containing analgesics. Whereas little variation was seen within Australasia in respect of the incidence of cancer of the renal parenchyma and bladder, both cancer of the renal pelvis and end-stage renal failure due to analgesic nephropathy had higher incidence rates amongst women in NSW and Queensland than in the other states or New Zealand. Within NSW, the average annual incidence rates during 1973-82 for renal pelvic cancer in the Hunter region of 1.3 (m) and 1.6 (f) per 100,000 were the highest in the state. These high incidence rates coincided with areas known to have had a high prevalence of consumption of compound analgesics containing phenacetin. In an international comparison with populations which had published incidence rates for each of the periods 1973-77 and 1978-82, the rate for cancer of the renal pelvis in women was highest in both time periods in NSW and had increased absolutely at a faster rate.

Adolescent↗
PubMed1990

Biochemical correlates of the antitumor and antimitochondrial properties of gossypol enantiomers.

Racemic gossypol has been shown to have antitumor properties that may be due to its ability to uncouple tumor mitochondria or to its inhibitory effects on a variety of nonmitochondrial enzymes. We have studied the antimitochondrial and enzyme-inhibiting properties of gossypol in human carcinoma cell lines of breast (MCF-7, T47-D), ovarian (OVCAR-3) colon (HCT-8), and pancreatic (MiaPaCa) origin by comparing the effects of its purified (+)- and (-)-enantiomers. (-)-Gossypol shows up to 10-fold greater antiproliferative activity than (+)-gossypol in the cancer cell lines and in normal hematopoietic stem cells grown in vitro, with IC50 values ranging from 1.5 to 4.0 microM for the cancer cells and from 10 to 20 microM for the human marrow stem cells. As well, multidrug-resistant MCF/Adr cells appear more resistant to (-)-gossypol than their parental cell line. Electron microscopy indicates that the earliest ultrastructural change in tumor cells exposed to a cytotoxic (10 microM) concentration of (-)-gossypol is the selective destruction of their mitochondria. Consistent with this observation, 31P magnetic resonance spectroscopy detects pronounced changes in tumor cell high energy phosphate metabolism within 24 hr of (-)-gossypol treatment, manifest by 1.6- to greater than 50-fold differential reductions in the intracellular ratios of ATP/Pi, relative to (+)-gossypol-treated cell lines; the magnitude of these antimitochondrial effects correlates with the antiproliferative activity of (-)-gossypol. Northern blot RNA analyses suggest that treatment with a 5-10 microM dose of (-)-gossypol induces a transient increase in the expression of heat shock gene products, particularly hsp-70 transcripts. The mean 5-fold increase in (-)-gossypol-induced hsp-70 mRNA appears coincident with a comparable heat-stimulated increase in transcript levels, as compared with control or (+)-gossypol-treated cells. The enzyme-inhibiting properties of gossypol enantiomers were compared in cell-free assays measuring glutathione-S-transferase-alpha, -mu, and pi activities, calmodulin stimulation of cyclic nucleotide phosphodiesterase, and protein kinase C activity. Both enantiomers are near equivalent antagonists of calmodulin stimulation and protein kinase C activity, exceeding the potency of known inhibitors such as phenothiazines by as much as 50-fold. In contrast, (-)-gossypol is a 3-fold more potent inhibitor of glutathione-S-transferase-alpha and -pi isozyme activity, resulting in IC50 values of 1.6 and 7.0 microM, respectively, for these two isozymes.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗