PubMed Health⌕ Search

Biomedical subjects

G Forrest

Publications and source records attributed to G Forrest.

At least 37 records · Page 2Linked to original sources
PubMed1994

A double-blind, placebo-controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients.

1. The effect of carbamazepine (CBZ), sodium valproate (VPA) and phenytoin (PHT) on the pharmacokinetics of oxcarbazepine (OXC) was explored in three groups of 12 epileptic patients taking one of these drug as monotherapy. 2. Each patient took a single 600 mg dose of OXC followed 7 days later by 3 weeks' treatment with OXC 300 mg thrice daily and matched placebo in random order. 3. Seven untreated patients, acting as controls, were prescribed the single OXC dose and 3 weeks' active treatment only. 4. In those patients completing the study, the area under the concentration-time curve (AUC) at steady-state for hydroxycarbazepine (OHCZ), the active metabolite of OXC, was significantly lower in the CBZ-treated group than in controls (P < 0.05). 5. No other differences in AUCs or elimination half-lives for OHCZ were found between treated and untreated patients following single or multiple OXC dosing. 6. Median AUCs of CBZ, VPA and PHT during a dosage interval did not differ significantly after treatment with OXC and placebo. 7. Ten patients completing the study complained of side-effects during treatment with OXC compared with one taking placebo (P < 0.01). 8. There were no important changes in cognitive function testing during administration of OXC compared with placebo. 9. Standard doses of OXC can be given as add-on therapy in epileptic patients receiving CBZ, VPA or PHT without producing a clinically relevant pharmacokinetic interaction.

Adult↗
PubMed1994

Vigabatrin and lamotrigine in refractory epilepsy.

Epilepsy arises from an imbalance of inhibitory and excitatory influences in the brain. Vigabatrin (VIG) decreases the breakdown of the inhibitory neurotransmitter gamma-aminobutyric acid, whereas lamotrigine (LTG) reduces presynaptic excitatory amino acid release. 22 patients with refractory epilepsy, treated with an anticonvulsant regimen containing VIG, entered a balanced, double blind, placebo controlled, crossover trial of additional LTG. Treatment periods of 12 weeks (25 mg, 50 mg, 100 mg LTG twice daily for four weeks at each dose, and matched placebo) were followed by wash out intervals of four weeks. 14 of the 20 patients completing the study improved, resulting in a significant fall in seizure days and numbers. Analysis of seizure type confirmed a beneficial effect on partial and secondary generalised tonic-clonic seizures. At the highest LTG dose (200 mg daily) there was a median fall of 37% in seizure count with nine (45%) patients reporting > 50% reduction. Three of these patients were seizure free during this month of treatment. Side effects were minimal throughout the study. Concentrations of other antiepileptic drugs, including those of carbamazepine 10,11-epoxide, were not modified by LTG. This study suggests a substantial efficacy for a regimen containing VIG and LTG. Combinations of drugs with complementary modes of action may provide a rational pharmacological approach to the management of refractory epilepsy.

Anticonvulsants↗
PubMed1994

Exercise for rheumatoid arthritis.

The approach to treating rheumatoid arthritis is changing. Greater emphasis on the exercise component of physical therapy can improve patients' muscle strength, endurance, and emotional well-being, and may even result in decreased joint inflammation.

Arthritis, Rheumatoid↗
PubMed1993

A comparison of the potassium and magnesium-sparing properties of amiloride and spironolactone in diuretic-treated normal subjects.

1. The relative potencies of amiloride (5 and 20 mg) and spironolactone (25 and 100 mg) for plasma and erythrocyte electrolytes were investigated in a double-blind, randomised, balanced, crossover study in 12 normal men treated concomitantly with hydrochlorothiazide 100 mg daily for 1 week. 2. Participants satisfied an a priori requirement for a fall in plasma potassium concentration of at least 0.5 mmol l-1 after 7 days of treatment with hydrochlorothiazide alone. 3. After hydrochlorothiazide alone, plasma potassium and sodium concentrations fell (P < 0.001). There were associated reductions in erythrocyte sodium (P < 0.01). Plasma magnesium concentration did not change, although erythrocyte magnesium decreased (P < 0.001). 4. Both amiloride and spironolactone attenuated the thiazide-induced fall in plasma potassium (relative potency, amiloride:spironolactone 10:1, 95% confidence interval 6.3-16.2:1). Amiloride but not spironolactone was associated with a dose-related increase in plasma magnesium; a relative potency estimation was precluded. There was little evidence of influences of amiloride or spironolactone on erythrocyte electrolytes. 5. On a weight basis, amiloride is ten times more potent than spironolactone as a potassium-sparing agent in diuretic-treated subjects but neither agent had major effects on erythrocyte potassium. The drugs may have divergent actions on magnesium handling; hydrochlorothiazide alone had no influence on plasma magnesium.

Adult↗
PubMed1991

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

1. Oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2. Serum concentrations of OXC and its active metabolite 10-OH-carbazepine (10-OH-CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3. Antipyrine metabolism, urinary 6-beta-hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4. Elimination half-lives (mean +/- s.e. mean) of 10-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 +/- 1.1 h; after 13.9 +/- 3 h). Trough plasma concentrations of 10-OH-CZ at steady-state (31 +/- 2.2 mumol l-1) were higher than predicted (16.5 +/- 4 mumol l-1). 5. Antipyrine metabolism, urinary 6-beta-hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6. OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose-concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.

Adult↗
PubMed1990

Antioxidant and xenobiotic-metabolizing enzyme gene expression in doxorubicin-resistant MCF-7 breast cancer cells.

We investigated the expression of the genes for several antioxidant and xenobiotic-detoxifying enzymes in the multidrug-resistant variant of the human breast cancer cell line MCF-7, MCF-7/Dox. MCF-7/Dox is greater than 500-fold resistant to doxorubicin by clonogenic assay. Enzyme activity determinations in the cytoplasmic compartment of MCF-7/Dox revealed a 25-fold increase in glutathione peroxidase level compared to the parent line (mean +/- SD, 10 +/- 2.8 versus 0.4 +/- 0.24 nmol/min/mg; P less than 0.005). The activity of the other major hydrogen peroxide-detoxifying enzyme, catalase, was diminished in MCF-7/Dox (2.0 +/- 0.4 versus 4.8 +/- 1.4 mumol/min/mg; P less than 0.025 compared to MCF-7). Superoxide dismutase activity did not differ between the two cell lines. The specific activity of the xenobiotic-detoxifying enzyme DT-diaphorase was 4-fold lower in MCF-7/Dox compared to MCF-7 (DT-diaphorase, 117 +/- 45 versus 509 +/- 123 nmol/min/mg; P less than 0.005). Daunorubicinol-producing carbonyl reductase activity was equal in the two lines. Northern blot analysis demonstrated a 0.9-kilobase band of glutathione peroxidase mRNA in MCF-7/Dox; no glutathione peroxidase mRNA was detected in MCF-7. A 2.4-kilobase catalase and 0.7- and 1.4-kilobase superoxide dismutase mRNAs were detectable in MCF-7/Dox and MCF-7. When normalized to 28S RNA, no difference in the mRNA levels of catalase and superoxide dismutase in MCF-7/Dox and MCF-7 could be determined. DT-diaphorase mRNAs of 1.4 and 2.7 kilobases were found in both MCF-7/Dox and MCF-7 cells. A 1.2-kilobase mRNA homologous to the putative carbonyl reductase cDNA was also easily detectable in both MCF-7 and MCF-7/Dox. The amount of mRNA for both xenobiotic-detoxifying enzymes was decreased 2- to 4-fold in the doxorubicin-resistant cells. Southern blot analysis of PstI- and MspI-restricted genomic DNA revealed no evidence for amplification or rearrangement of the glutathione peroxidase gene. These results indicate that, in addition to the previously described overexpression of anionic glutathione S-transferase in MCF-7/Dox cells, an augmented glutathione peroxidase mRNA level is the major alteration in antioxidant and xenobiotic-detoxifying enzyme expression that could contribute to doxorubicin insensitivity in these multidrug-resistant breast cancer cells.

Alcohol Oxidoreductases↗
PubMed1989

Resistance to hydrogen peroxide associated with altered catalase mRNA stability in MCF7 breast cancer cells.

We have established a variant of the human breast cancer cell line MCF7, designated MCF7/H2O2, which is 5-fold resistant to H2O2 by clonogenic assay. The specific activity of the H2O2 disposal enzyme catalase was elevated 3-fold in MCF7/H2O2; activities of other antioxidant enzymes, including glutathione peroxidase and superoxide dismutase, were not increased. The steady-state level of catalase mRNA was only slightly elevated (approx. 1.6-fold) in MCF7/H2O2 cells; however, degradation of catalase mRNA was markedly retarded in MCF-7/H2O2 compared to MCF-7 (82% of catalase mRNA remained 24 h after inhibition of RNA synthesis by actinomycin D in MCF-7/H2O2 vs. 32% in MCF7). The degradation rates of superoxide dismutase mRNA and 28 S ribosomal RNA were not reduced in MCF-7/H2O2; however, the rate of degradation of another mRNA species, beta-actin, was also significantly decreased. These data suggest that resistance to H2O2 in MCF7/H2O2 cells is mediated by elevated catalase activity which can be explained by stabilization of certain mRNA species, including catalase mRNA.

Actins↗
PubMed1989

Ultrasound: effectiveness of treatments given under water.

The purpose of this study was to determine whether ultrasound treatments given with a limb immersed in tap water are as effective in heating the tendons overlying a superficial bony prominence as ultrasound treatments given with the applicator and coupling agent in direct contact with the limb. The lateral epicondyle of a pig was treated with the applicator in contact with the limb and with the limb immersed in a water bath with the applicator held 2cm from the skin surface. With a thermocouple inserted into a 20-gauge needle, the temperature elevations in the tendon of the extensor muscles originating at the lateral epicondyle were measured. It was found that the temperatures of the tendons rose into the therapeutic range when the ultrasound was applied directly to the skin surface, but not when treatment was given under water. It is therefore preferable to give ultrasound treatments with the applicator in direct contact with the subject rather than in an immersion bath with tap water as the coupling agent.

Animals↗
PubMed1988

Simple high-performance liquid chromatographic method for the measurement of amiloride in body fluids.

A simplified rapid high-performance liquid chromatographic (HPLC) procedure has been developed for the measurement of amiloride in plasma or urine. Solid-phase extraction columns provide quick, clean and simple sample preparation, allowing ten samples to be processed in less than 5 min. The HPLC system uses a standard reversed-phase (C18) column with detection by ultraviolet absorption at 365 nm. The assay has been used to define plasma amiloride concentration-time profiles and to quantitate urine amiloride recovery in healthy men after repeated administration at two doses.

Adult↗
PubMed1988

Flavone acetic acid: a nonlinear pharmacokinetic model.

Flavone acetic acid pharmacokinetics were studied in 31 patients in a phase I clinical trial. The drug was given by i.v. infusions over 1, 1.5, 3, and 6 h at doses ranging from 0.5 to 6.4 g/m2. The pharmacokinetic parameters were determined according to a nonlinear model including Michaelis-Menten-type kinetics. The mean elimination half-life is 4.8 h and the mean volume of distribution of the central compartment, 7.61. Our model predicted a maximal tolerated dose (MTD) of 11.1 g/m2 on the basis of the "therapeutic window" concept, very close to the clinically observed MTD of 10 g/m2. This model is also operational when different protocols of inoculation are considered, such as a divided-dose schedule vs a unique infusion, and indicates that, at the MTD, injections should be made every 72 h to avoid drug accumulation.

Algorithms↗
PubMed1987

Phase I and pharmacokinetic study of flavone acetic acid.

Flavone acetic acid is the second in a series of compounds based on the flavonoid aglycone ring structure to be clinically evaluated in malignant disease. Preclinical studies have indicated that a minimum plasma level of 150 micrograms/ml is required before therapeutic efficacy (in a wide range of experimental tumors) is seen in mice; both in vitro and in vivo studies also suggest that the duration of drug exposure is crucial in determining activity. Thus a Phase I trial has been performed in a total of 54 patients using 3 schedules, i.e., a 1-, 3-, and 6-h infusion. In each case, treatment was given once weekly for a minimum of 3 weeks. The maximum tolerated doses were 6.4, 6.4, and 10.0 g/m2, respectively. Dose limiting toxicity was denoted by an intense feeling of warmth and flushing with a 1-h infusion, hypotension with a 3-h infusion, and hypotension and diarrhea with a 6-h infusion. No objective responses were seen in this Phase I trial. The recommended doses for Phase II trials of flavone acetic acid in Europe are 4.8 g/m2 over 1 h or 8.6 g/m2 over 6 h. At these doses the peak plasma concentrations obtained are 650 and 388 micrograms/ml, respectively. Total drug exposure (assessed by an area under the curve greater than 100 micrograms/ml) was approximately 50% greater for the 6-h schedule. This Phase I trial indicates that peak plasma concentrations associated with experimental activity are achievable in humans, although optimal drug exposure times have not yet been defined.

Adult↗
PubMed1986

Phase I and pharmacokinetic study of LM985 (flavone acetic acid ester).

We have conducted a Phase I and initial clinical pharmacological evaluation of LM985, the first of a series of compounds based on the flavone ring structure to be considered for clinical trial in malignant disease. The drug was administered i.v. to 26 patients with advanced cancer on an every-21-day schedule. Patients were treated at 14 dosage levels ranging from 10 to 1500 mg/m2. Dose limiting toxicity was identified as acute reversible hypotension occurring during drug infusion; no leukopenia, alopecia, hepatic toxicity, or renal toxicity was observed, but at the higher dose range, mild sedation was apparent. Twenty patients had measurable disease and were evaluable for response. One patient with colorectal carcinoma had stable disease after three courses of LM985; however, no other responses were seen. Pharmacokinetic and in vitro drug degradation studies imply that the ester LM985 is hydrolyzed to LM975 (flavone acetic acid) rapidly in vivo. LM975 is active in a variety of animal tumor models, but it does not have the cardiovascular side effects seen with LM985 (hypotension and bradycardia) in pithed or anesthetized rats. We would recommend that LM975 be considered for clinical trial, because it seems likely that substantially higher doses of LM975 than of LM985 can be given without dose limiting cardiovascular toxicity.

Adult↗
PubMed1985

Increased peritoneal permeability in patients with peritonitis undergoing continuous ambulatory peritoneal dialysis.

The distribution of cefuroxime (250 mg) was studied in patients with renal failure undergoing continuous ambulatory peritoneal dialysis (CAPD). 10 uninfected patients received the drug intravenously and intraperitoneally, while 9 patients with peritonitis were randomly allocated to intravenous or intraperitoneal administration. Samples were taken over the first 6 hour dialysis period. In the infected patients, more drug (p less than 0.01) crossed into the peritoneal cavity following intravenous injection and reached the systemic circulation following intraperitoneal administration than in the uninfected group. This increased permeability of the peritoneal membrane during infection may result in unexpected systemic toxicity in patients treated with intraperitoneal antibiotics.

Adult↗
PubMed1983

Carbamazepine 10, 11 epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants.

Steady state carbamazepine (CBZ) plasma concentrations were similar in 15 epileptics receiving monotherapy and in 24 patients taking CBZ in combination with one other anticonvulsant. The ratio of CBZ 10, 11-epoxide (CBZ-E) to the parent drug was significantly higher (P less than 0.01) in those patients taking concomitant phenytoin (n = 9), phenobarbitone or primidone (n = 9), and valproic acid (n = 6) than in the patients receiving CBZ alone. In the monotherapy group, there was a significant correlation between CBZ-E/CBZ ratio and the concentration of the parent drug (P less than 0.05). If CBZ-E has equipotent anticonvulsant properties to CBZ in man as is the case in animal models, routine CBZ-E concentrations may provide further refinement in the therapeutic drug monitoring of CBZ.

Anticonvulsants↗
PubMed1983

Hepatic enzyme induction and leucocyte delta-aminolaevulinic acid synthase activity: studies with carbamazepine.

Antipyrine metabolism, daily urinary 6-beta-hydroxycortisol excretion, carbamazepine (CBZ) half-lives and leucocyte delta-aminolaevulinic acid synthase (ALA.S) activities were measured following 2 weeks' treatment with CBZ 400 mg and 600 mg once daily in eight healthy male volunteers. Dose-dependent induction of antipyrine metabolism was demonstrated but cortisol hydroxylation appeared maximally induced by the 400 mg dose. CBZ half-lives fell significantly in both studies (P less than 0.01 in each case) but a greater fall was seen with the higher dose (P less than 0.01). Plasma CBZ concentrations were higher following the eighth doses (P less than 0.01) in both studies. Leucocyte ALA.S activity increased by a mean of 657% following 1 week's treatment with 400 mg CBZ and 1145% on the 600 mg dose. In both studies ALA.S activities fell towards baseline during the second week of treatment. CBZ possesses potent dose-dependent hetero- and auto-inducing properties. Leucocyte ALA.S activity may represent a novel in vivo index of extrahepatic enzyme induction in man.

5-Aminolevulinate Synthetase↗