PubMed Health⌕ Search

Biomedical subjects

A Boddy

Publications and source records attributed to A Boddy.

At least 19 recordsLinked to original sources
PubMed2006

Systematic review: Cyclo-oxygenase-2 in human oesophageal adenocarcinogenesis.

BACKGROUND: Published in vitro and animal in vivo studies have demonstrated that cyclo-oxygenase-2 plays an important role during oesophageal adenocarcinogenesis. However, the extent to which these studies are directly relevant to events in the human lower oesophagus is questionable. AIM: To perform a systematic review of all available human studies that have evaluated levels of cyclo-oxygenase-2 expression during the progression from Barrett's metaplasia to oesophageal adenocarcinoma. METHODS: A literature search was performed to identify all studies which qualitatively or quantitatively assessed cyclo-oxygenase-2 protein or gene expression in either Barrett's, dysplastic or adenocarcinoma tissue in humans. RESULTS: A total of 27 studies met the inclusion criteria. There was general agreement that cyclo-oxygenase-2 was either absent or very weakly expressed in normal oesophageal squamous mucosa, but considerable disagreement regarding the presence of cyclo-oxygenase-2 in Barrett's and low-grade dysplasia. All studies agreed that high-grade dysplasia and adenocarcinoma expressed cyclo-oxygenase-2 to some extent although levels varied considerably between tissue samples. CONCLUSIONS: There is conflicting evidence in the literature for cyclo-oxygenase-2 playing an important role in early oesophageal adenocarcinogenesis. Other non-cyclo-oxygenase-2 targets may account for the epidemiological data supporting the use of non-steroidal anti-inflammatory drugs in the chemoprevention of oesophageal adenocarcinoma.

Adenocarcinoma↗
PubMed1999

Is the prognosis of heart failure improving?

UNLABELLED: BACKGROUND AND METHODS": Heart failure is common and effective therapy exists but as yet there is little evidence that the overall prognosis is improving in clinical practice. We sought to determine if mortality, re-admission with heart failure and re-admission for any cause, had changed between cohorts of first-time admissions for heart failure identified in 1984, 1988 and 1992 using linked hospital discharge and mortality data from Scotland (population approximately 5 million). FINDINGS: The number of first-time admissions for heart failure increased by 30% between 1984 and 1992, from 9716 to 12640. Their mean age was 74 years and 54% were women. Over the same period 3-year mortality declined in patients < 65 years from 53 to 41% (reduction in risk 12% (95% confidence interval 9-15%. Log-rank 70.0; P<0.001) and for patients > or =65 years from 71% to 66% (reduction in risk 5% (95% confidence interval 3-6%. Log-rank 74.5; P<0.0001). Time to death or first re-admission with heart failure also improved but not time to death or first re-admission for any cause. The total number of re-admissions increased between 1984 and 1992 but bed-days occupancy for heart failure and for any cause, adjusted for days alive, declined due to a reduction in length of stay. INTERPRETATION: These data suggest that the prognosis of patients with a first admission for heart failure is improving. The timing of improvement coincides with the gradual increase in the use of angiotensin converting enzyme inhibitors for heart failure although a causal link cannot be proved from these data.

Adult↗
PubMed1999

A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration.

2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered nolatrexed is active clinically. As oral bioavailability is high (70-100%), nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m(-2) day(-1) in 23 patients. Common toxicity criteria (CTC) grade 3 toxicities included nausea, vomiting, stomatitis and liver function test (LFT) abnormalities. Thrombocytopenia (grade 1 or 2) occurred at doses > or = 318 mg m(-2) day(-1) and neutropenia (grade 2) at 429 and 572 mg m(-2) day(-1). An erythematous maculopapular rash occurred at dosages > or = 318 mg m(-2) day(-1) (7 out of 19 patients). LFT abnormalities occurred in two out of six patients (grade 3 or 4 bilirubin and grade 3 alanine transaminase) at 572 mg m(-2) day(-1). Nolatrexed plasma concentrations 1 h after dosing were 6-16 microg ml(-1), and trough 3-8 microg ml(-1), at 572 mg m(-2) day(-1). Inhibition of thymidylate synthase was demonstrated by elevation of plasma deoxyuridine. Six-hourly oral nolatrexed for 10 days was associated with antiproliferative effects, but nausea and vomiting was dose limiting at 572 mg m(-2) day(-1). Nine patients were treated at 429 mg m(-2) day(-1); three out of nine experienced grade 3 nausea, but 17 out of 22 treatment courses were completed (with the co-administration of prophylactic antiemetics) and this dose level could be considered for phase II testing.

Administration, Oral↗
PubMed1999

Carboplatin and paclitaxel, alone and in combination: dose escalation, measurement of renal function, and role of the p53 tumor suppressor gene.

In this pharmacokinetic and dose-escalation study of the carboplatin/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combination, patients were randomly assigned to receive paclitaxel either as a 1-hour or a 3-hour infusion. The 1-hour infusion was feasible, with maximum tolerated doses similar to those previously reported for a 3-hour infusion. Using patients' age, height, plasma creatinine, and plasma creatine kinase provided an improved estimate of the glomerular filtration rate compared with the more traditional creatinine-based formulas according to population analysis of data derived from glomerular filtration rate estimates performed by an isotope method. Studies of the p53 gene sequence of ovarian tumors at diagnosis suggest that p53 mutations are a potent predictor of response to subsequent treatment with carboplatin.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee.

PURPOSE: D-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. METHODS: A group of 32 patients with refractory solid tumors completed 99 courses of D-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of D-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. RESULTS: The MTD was 8 g/m2 per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (Cmax) for D-limonene ranged from 10.8+/-6.7 to 20.5+/-11.2 microM. Predominant circulating metabolites were perillic acid (Cmax 20.7+/-13.2 to 71+/-29.3 microM), dihydroperillic acid (Cmax 16.6+/-7.9 to 28.1+/-3.1 microM), limonene-1,2-diol (Cmax 10.1+/-8 to 20.7+/-8.6 microM), uroterpenol (Cmax 14.3+/-1.5 to 45.1+/-1.8 microM), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of D-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. CONCLUSIONS: D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.

Adult↗
PubMed1998

High-dose cyclosporin with etoposide--toxicity and pharmacokinetic interaction in children with solid tumours.

The tolerability, anti-tumour activity and pharmacokinetic interaction of high-dose intravenous cyclosporin combined with intravenous etoposide was evaluated in children. Eighteen patients with recurrent or refractory tumours, all of whom had previously received etoposide, were treated with a combination of high-dose cyclosporin and etoposide. In 13, cyclosporin was given as a continuous infusion (15 mg kg(-1) per 24 h for 60 h) and in five a short 3-hour infusion of 30 mg kg(-1) day(-1) on three consecutive days. Pharmacokinetic profiles of etoposide were determined with and without cyclosporin. Cyclosporin levels ranged from 1359 to 4835 ng ml(-1) and cyclosporin increased the median area under the concentration time for etoposide curve from 7.2 to 12.5 mg ml(-1) min. The major toxicity was acute with varying forms of hypersensitivity reactions. In four cases this was severe. Hyperbilirubinaemia was present in 25 of 32 courses but was of short duration. In 14 courses, creatinine and/or urea was elevated, but was also transient. Significant hypertension was seen in six courses. Four of 17 patients evaluable for response obtained a partial response and one showed stable disease. It is concluded that in children given the combination of high-dose cyclosporin and etoposide, the etoposide dose should be halved in order to achieve an area under the drug concentration-time curve similar to that with etoposide alone. A continuous infusion schedule of cyclosporin is better tolerated during the period of administration but is associated with similar hepatic and renal dysfunction to a short schedule. The 24% response rate in children who had previously received etoposide suggests that this may be an effective method of enhancing drug sensitivity and further phase II evaluation is justified.

Adolescent↗
PubMed1996

Effects of pegorgotein on neurologic outcome of patients with severe head injury. A multicenter, randomized controlled trial.

OBJECTIVE: To evaluate outcome of patients with severe closed head injury treated with pegorgotein, a scavenger of oxygen-derived free radicals. DESIGN: Randomized, parallel, placebo-controlled, third-party-blind, multicenter trial, with a blinded, multicenter follow-up protocol. SETTING: Twenty-nine centers in the United States. PATIENTS: A total of 463 patients with severe closed head injury and a Glasgow Coma Scale score of 8 or less after resuscitation and stabilization. INTERVENTIONS: Patients received a single intravenous dose of placebo, 10 000 U/kg of pegorgotein, or 20 000 U/kg of pegorgotein within 8 hours after injury. OUTCOME MEASURES: The primary endpoint was the Glasgow Outcome Scale (GOS) score at 3 months after brain injury with GOS data trichotomized into good, fair, or poor outcome. Secondary efficacy endpoints included the Disability Rating Scale (DRS) and mortality. A secondary analysis was performed using GOS scores dichotomized into favorable and unfavorable outcomes. In a follow-up protocol at 6 months, GOS and DRS scores were again determined. RESULTS: Of 463 patients randomized, 162 received placebo; 149, pegorgotein 10 000 U/kg; and 152, pegorgotein 20 000 U/kg. Treatment groups were comparable with respect to demographic characteristics, mechanism of injury, and time to treatment. Pegorgotein was well tolerated at both dose levels. At month 3, the trichotomized analysis found no significant statistical difference in neurologic outcome between the pegorgotein and the placebo groups. Although differences were not statistically significant, there were more favorable outcomes and no increase in the number of deaths or vegetative states among the patients given pegorgotein, more subjects had good or favorable outcomes with the 10 000-U/kg dose than with the 20 000-U/kg dose or placebo, and less disability was observed with the 10 000-U/kg dose than with either the 20 000-U/kg dose or placebo. No differences in mortality rate or cause of death were found between the 10 000-U/kg and placebo groups at either month 3 or month 6. The only statistically significant difference between the groups was a decreased incidence of adult respiratory distress syndrome in the 10 000-U/kg group as compared with the placebo group (P<.015). CONCLUSIONS: In this clinical trial of 463 patients with severe head injury, no statistically significant difference in neurologic outcome or mortality was observed between patients treated with pegorgotein and those receiving placebo.

Adolescent↗
PubMed1996

Pharmacokinetically guided dosing of carboplatin and etoposide during peritoneal dialysis and haemodialysis.

Two patients with relapsed Wilms' tumour and renal failure requiring dialysis were given carboplatin and etoposide by pharmacokinetically guided dosing. The target area under the drug plasma concentration vs time curve (AUC) was 6 mg ml-1 min for carboplatin and 18 and 21 mg ml-1 min for etoposide. On course 1 measured AUCs of carboplatin and etoposide were 6 and 20 mg ml-1 min for patient 1 and 6 and 21 mg ml-1 min for patient 2 respectively. Peritoneal dialysis did not remove carboplatin or etoposide from the plasma, however carboplatin but not etoposide was cleared by haemodialysis. Therapy with carboplatin and etoposide is possible in children and adults with renal failure who require dialysis, but in this situation pharmacokinetic monitoring is essential.

Adolescent↗
PubMed1996

Etoposide phosphate infusion with therapeutic drug monitoring in combination with carboplatin dosed by area under the curve: a cancer research campaign phase I/II committee study.

The area under the plasma concentration-time curve (AUC) following an intravenous dose of etoposide varies considerably among patients, which in part contributes to the unpredictability of toxicity and response seen in individual patients. This study evaluated the utility of therapeutic drug monitoring of etoposide in reducing the interpatient variability of etoposide steady-state concentrations during prolonged infusion. The etoposide prodrug etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ) was administered by infusion using an adaptive dosing strategy. It was given in combination with carboplatin, which was dosed on an AUC basis. Patients with histologically or cytologically proven small cell lung cancer were treated with etoposide phosphate by continuous 120-hour infusion and carboplatin at a dose calculated by the Calvert formula to give an AUC of 5 mg/ mL.min. Blood samples were taken on days 2 through 5 of each treatment cycle, and high-performance liquid chromatography was used to measure the plasma etoposide concentration. The resultant concentrations were compared with target concentrations of 1 or 2 micrograms/mL and these data were used to calculate the rate of infusion for the following 24 hours. In the first cohort, the target etoposide concentration was 1 microgram/mL, and this was achieved (mean +/- SD = 1.05 +/- 0.24 micrograms/mL) by infusing etoposide phosphate doses of 21 to 109 mg (15 to 68 mg/m2) per day. In the second cohort, the target concentration of 2.0 micrograms/mL was achieved (mean +/- SD = 2.05 +/- 0.31 micrograms/mL) with infused etoposide phosphate doses of 69 to 193 mg (41 to 114 mg/m2) per day. This technique reduced the variation in plasma levels and resulted in predictable hematologic toxicity. Cumulative hematologic toxicity necessitated an extension of the treatment cycle from 3 to 4 weeks, however. Of six evaluable patients, two had a complete response and one had a partial response. Therapeutic drug monitoring was shown to reduce the interpatient variation in the plasma etoposide concentration by half and shows promise for individualizing treatment with combination chemotherapy. Exploiting the known relationships between the pharmacokinetics and pharmacodynamics of these two drugs by using therapeutic drug monitoring may lead to better therapeutic safety and efficacy.

Adult↗
PubMed1995

Carboplatin in combination with paclitaxel in advanced ovarian cancer: dose determination and pharmacokinetic and pharmacodynamic interactions.

Data from various phase I/II studies of carboplatin in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have suggested that the degree of thrombocytopenia seen is less than that expected when carboplatin is given alone. However, some studies also have suggested that the area under the plasma concentration-time curve (AUC) of carboplatin is lower than that expected, raising the possibility of a pharmacokinetic interaction. Patients with advanced epithelial ovarian cancer were treated with first-line carboplatin (AUC = 7, using the 51Cr EDTA [edetic acid] clearance method) and escalating doses of paclitaxel. Thrombocytopenia was mild and was significantly less when the paclitaxel dose was 175 mg/m2 versus 150 mg/m2. Paclitaxel kinetics were nonlinear, as previously reported. The achieved carboplatin AUC was 7 +/- 1 mg/mL.min, indicating that the pharmacokinetics of carboplatin are not affected by paclitaxel. Glomerular filtration rates measured in 184 patients using the 51Cr EDTA clearance method were compared with rates estimated from the plasma creatinine level using the Cockcroft-Gault or Jeliffe formulas and showed a significant bias of these two formulas. Clearances above 50 mL/min were underestimated by an amount that became greater as the clearance increased and was approximately 25% to 35% for patients with clearances in the normal range. Since creatinine-based methods have been used in many previous studies, care is needed in interpreting the predicted AUC values from these studies. Carboplatin and paclitaxel may be given safely in combination at full doses, and the thrombocytopenia seen is significantly less than that observed with single-agent carboplatin. No evidence exists of a pharmacokinetic interaction, and the observation in some studies that the carboplatin AUC was lower than expected was probably due to the methodology used to estimate the glomerular filtration rate.

Adult↗
PubMed1995

The effect of zanoterone, a steroidal androgen receptor antagonist, in men with benign prostatic hyperplasia. The Zanoterone Study Group.

PURPOSE: Zanoterone (100 to 800 mg.) versus placebo was studied in 463 patients with benign prostatic hyperplasia. MATERIALS AND METHODS: Study end points were maximum urinary flow rate, American Urological Association symptom index, prostate volume, prostate specific antigen and sex steroid concentrations after 6 months of treatment. RESULTS: Mean increases in maximum urinary flow rate were 2 to 3-fold over placebo, although only the 200 mg. group had significant results (1.7 ml. per second, p = 0.026). There were no statistically significant differences between the zanoterone and placebo groups in symptom index or prostate volume. Estradiol and testosterone concentrations, and the incidence of breast pain and gynecomastia increased significantly with zanoterone compared with placebo. Prostate specific antigen levels decreased significantly. CONCLUSION: Zanoterone did not demonstrate a favorable risk-to-benefit profile for the treatment of benign prostatic hyperplasia.

Aged↗
PubMed1995

Clinical pharmacokinetics of the antipurine antifolate (6R)-5,10- dideaza-5,6,7,8-tetrahydrofolic acid (Lometrexol) administered with an oral folic acid supplement.

(6R)-5,10-Dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) is an antipurine antifolate which selectively inhibits glycinamide ribonucleotide formyltransferase. Lometrexol pharmacokinetics were evaluated in 17 patients (32 courses) as part of a Phase I study in which folic acid supplementation was used to improve tolerance to the drug, its clinical utility being previously limited by severe cumulative toxicity. Lometrexol was administered as an i.v. bolus every 4 weeks at a starting dose of 12 mg/m2, with subsequent interpatient dose escalation to 16, 30, and 45 mg/m2. p.o. folic acid (5 mg/day) was given for 7 days before and 7 days after lometrexol administration. The disposition of total lometrexol in plasma was best described by a biexponential model for data acquired up to 12 h after drug administration, although triexponential plasma pharmacokinetics were often found to give a more adequate description when data were available at later time intervals (24 h and greater). Mean plasma half-lives (+ SD) for model-dependent analysis were t1/2alpha 19 +/- 7 min, t1/2beta 256 +/- 96 min, and t1/2gamma (where measurable) 1170 +/- 435 min. Lometrexol area under plasma concentration versus time curve was proportional to the dose administered. Moderate plasma protein binding of lometrexol was evident (78 +/- 3%) with an inverse linear relationship between fraction of unbound lometrexol and the concentration of serum albumin. The volume of distribution of lometrexol at steady state was between 4.7 and 15.8 l/m2. Renal elimination of lometrexol, studied in 19 patients (21 courses), was considerable, accounting for 56 +/- 17% of the total dose administered within 6 h of treatment, and 85 +/- 16% within 24 h of treatment. These recoveries of unchanged lometrexol indicate that the drug does not appear to undergo appreciable systemic metabolism at the range of concentrations studied. Lometrexol pharmacokinetics were also examined in seven patients who received 45 or 60 mg/m2 lometrexol as part of a separate study of the drug given with folinic acid rescue 5-7 days after treatment. No marked differences were evident in lometrexol plasma half-lives, plasma clearance, or the extent of plasma protein binding, indicating that there is not a pronounced pharmacokinetic interaction between lometrexol and folic acid.

Adult↗
PubMed1993

The association of age and frailty with the pharmacokinetics and pharmacodynamics of metoclopramide.

We have investigated the association of age and frailty with the pharmacokinetics and pharmacodynamics of the conjugated drug, metoclopramide. Six healthy young, six healthy elderly (> 65 years), and six frail elderly (> 65 years) subjects were studied on two occasions, receiving 10 mg metoclopramide by intravenous bolus and orally, in random order. Blood and urine were collected for measurement of pharmacokinetic parameters. Liver volume was measured by ultrasound. Sedation and contentment were self-recorded on visual analogue scales. Liver volume was not significantly different in the three groups, nor was bio-availability of metoclopramide. Clearance was similar in the young and fit elderly but reduced in the frail elderly subjects when compared with the young (p < 0.05), both when expressed in absolute terms and per unit liver volume. There were no differences in percentages cleared as the free drug or as the sulphate or glucuronide metabolite within or between groups, suggesting that frailty can produce a general impairment of conjugation pathways. The frail elderly subjects reported more sedation after intravenous dosage than the other subjects, whilst only young subjects reported akathisia. This did not relate to pharmacokinetic differences and seemed therefore to reflect associated pharmacodynamic changes in specific receptor or target sites.

Administration, Oral↗
PubMed1989

Binding of sulfonamides to carbonic anhydrase: influence on distribution within blood and on pharmacokinetics.

Four new aromatic sulfonamides were synthesized and purified by standard techniques. Two were unsubstituted, primary sulfonamides and two possessed substituents on the sulfonamide nitrogen. The affinity of the inhibitors for the enzyme carbonic anhydrase was determined in terms of the inhibitory potency, which was found to be dependent on the presence of an unsubstituted sulfonamide group. Binding studies were performed in erythrocyte suspensions using a range of concentrations and the unbound, extracellular concentrations were determined by high-performance liquid chromatographic (HPLC) assay. The dissociation constant of binding and the total binding capacity of the erythrocytes were estimated by nonlinear regression using a two-site binding model. The affinity of the compounds for erythrocytes reflected their inhibitory potency against the enzyme. Binding to plasma proteins was more dependent on lipophilicity and pKa and was stronger for the substituted sulfonamides. Pharmacokinetic studies in rats showed that the unsubstituted sulfonamides with a high affinity for carbonic anhydrase in erythrocytes have longer half-lives and lower clearance values than the substituted sulfonamides which were more strongly bound to plasma proteins. However, comparison of unbound clearance values showed that the variations in molecular structure, which produced differences in carbonic anhydrase binding and in distribution, also produced variations in susceptibility to elimination processes.

Animals↗
PubMed1989

Efficiency of drug targeting: steady-state considerations using a three-compartment model.

Physiological models have often been used to investigate the processes involved in drug targeting. Such a model is used to investigate some aspects of drug targeting, including the pharmacodynamics of therapeutic and toxic effects. A simple pharmacodynamic model is incorporated in a three-compartment pharmacokinetic model. Conventional administration and drug targeting are compared at steady state for the same degree of therapeutic effect. The efficiency of drug targeting is quantified as the ratio (TA) of the rates of administration of free drug or of a drug-carrier complex required to achieve this effect. Also, the ratios of drug concentrations in the toxicity compartment (DTI) or of the consequent degree of toxic effects (TI) are used to compare conventional administration with drug targeting. The kinetic characteristics of the drug-carrier complex, rate of elimination, and rate of free drug release, influence TA but not DTI or TI. The importance of these characteristics depends on the cost and toxicity of the drug-carrier complex or of the carrier alone. The pharmacodynamics of the free drug in both the target and the toxicity compartments have an important influence on TI but not on TA or DTI. As the pharmacological selectivity of the drug increases, so does TI. However, a drug with good pharmacological selectivity may not be suitable for drug targeting. TI is also very dependent on the shape of the effect-concentration curves, particularly that for toxicity. While TA increases as the rate of elimination of free drug from either central or target compartments increases, TI may actually be reduced if release of free drug is not confined to the target compartment.

Chemistry, Pharmaceutical↗