Biomedical subjects
I Lenox-Smith
Publications and source records attributed to I Lenox-Smith.
Nebulized pentamidine as prophylaxis for Pneumocystis carinii pneumonia.
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Alveolitis associated with sulphamethoxypyridazine.
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Failure to demonstrate synergy between interferon-alpha and a synthetic antiviral, enviroxime, in rhinovirus infections in volunteers.
Marked synergy between the antirhinoviral effect of rHuIFN alpha and enviroxime has been observed in vitro but an attempt to demonstrate it in volunteers was unsuccessful. The sub-optimal intranasal dose of rHuIFN alpha (0.18 Mu four times daily for 4 1/4 days) used prophylactically in the trial did reduce the severity of colds induced by RV9 and 14, but the difference did not reach statistical significance and was not enhanced by the administration of enviroxime (0.28 mg six times daily for six days). The main reason for failure is thought to be the rapid removal of enviroxime from the nose when given intranasally.
Fatal Stevens-Johnson syndrome associated with Fansidar and chloroquine.
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Intranasal chalcone, Ro 09-0410, as prophylaxis against rhinovirus infection in human volunteers.
The antirhinovirus agent chalcone Ro 09-0410 was tested in double-blind place-controlled volunteer trials for its protective efficacy against experimental rhinovirus infection. Fifty volunteers received either drug (26 volunteers) or placebo (24 volunteers) both before and after challenge with 20-40 tissue culture infecting dose (TCID50) of human rhinovirus 2 (RV2). There was no evidence that medication significantly reduced the incidence of infection or illness, indeed there was some increase in the nasal secretion produced.
A comparative study of Ro 03-8799: racemic mixture and enantiomers.
The maximum single dose of the 2-nitroimidazole hypoxic cell radiosensitiser Ro 03-8799 is limited to 1 g/m2 by the occurrence of a well characterised acute syndrome of sweating, nausea and mental changes. In an attempt to increase the tolerable dose, the clinical toxicity of the racemic mixture was compared with that of the R- and S-enantiomers of Ro 03-8799. Twelve patients received escalating alternate doses of racemic mixture and R- or S-enantiomer, the dose levels being 0.25 g/m2, 0.5 g/m2, 0.75 g/m2 and 1.0 g/m2. Careful monitoring of the acute syndrome failed to demonstrate any consistent differences between racemic mixture and either enantiomer. This would suggest that the toxicity is not mediated via any specific central nervous system receptor. It is concluded that separation of Ro 03-8799 into its enantiomers will not enable a clinically useful increase in dosage.
The pharmacokinetics of a new radiosensitiser, Ro 03-8799 in humans.
A new hypoxic cell radiosensitiser, Ro 03-8799 has been administered intravenously to human volunteers and its kinetic parameters derived from plasma and urine data. Good penetration of drug into tumour tissue is found, consistent with its large volume of distribution. The plasma clearance of this compound is rapid due to high metabolic and renal clearances. These parameters combine to produce an elimination half-life of 5.6 h, approximately half that of misonidazole, a well studied radiosensitiser. It is hoped that this decrease in total body exposure will also reduce the cumulative toxicity seen when misonidazole is administered repeatedly.
Evaluation of the antirhinovirus chalcone Ro 09-0415 given orally to volunteers.
Ro 09-0415, a phosphorylated 'pro-drug' of the potent antirhinovirus compound, 4' ethoxy-2'-hydroxy-4, 6' dimethoxy-chalcone (Ro 09-0410) was tested in a double-blind placebo-controlled trial for its protective effect against experimental rhinovirus infection. The maximum dose, 1200 mg bd, based on considerations of practicality and tolerance was given orally both before and after challenge with a sensitive rhinovirus, type 9. Plasma concentrations of active compound in excess of those required for the inhibition of rhinovirus type 9 in vitro were achieved, but there was no evidence to suggest that treatment with Ro 09-0415 had a beneficial effect. It is concluded that Ro 09-0415 given orally is unlikely to be of value in the prophylaxis or therapy of human rhinovirus infection.
The radiosensitizer Ro 03-8799 and the concentrations which may be achieved in human tumours: a preliminary study.
A new hypoxic cell radiosensitizer, Ro 03-8799, has been administered i.v. to 2 normal and 6 patient volunteers. Generally in non-necrotic tumours the concentrations obtained were 3 times greater than in plasma sampled at the same time. These observations added to the reports concerning toxicology in monkeys and rats and radiosensitizing efficiency in the laboratory, suggest that Ro 03-8799 may prove to be much more effective sensitizer than misonidazole in man.
Phosphonopeptides as antibacterial agents: metabolism and pharmacokinetics of alafosfalin in animals and humans.
The metabolism and pharmacokinetics of a synthetic antibacterial phosphonodipeptide, alafosfalin, have been studied in rats, baboons, and human volunteers. The compound was rapidly absorbed from the injection site after subcutaneous and intramuscular administration and gave peak plasma concentrations at 15 to 20 min after dosing. Distribution studies showed that high drug concentrations were produced in inflammatory exudates and most tissues except brain. Alafosfalin was rapidly cleared from the general circulation, mainly by the kidney. Plasma half-lives were 20 min in rats and approximately 1 h in baboons and humans. Alafosfalin was well absorbed after oral administration, but was extensively hydrolyzed to alanine and L-1-aminoethylphosphonic acid before it reached the general circulation. This first-pass metabolism was less marked in humans than in animals. Administration of 200-mg intramuscular and 500-mg oral doses produced concentrations of intact phosphonodipeptide in human plasma and urine which were in excess of the in vitro minimal inhibitory concentrations for many pathogenic organisms. The rate of absorption and elimination of alafosfalin in humans were also very similar to published data on beta-lactam antibiotics. This suggests that the pharmacokinetics can be matched to provide synergistic combinations for clinical use.
Serum concentration measurements in man of the radiosensitizer Ro-07-0582: some preliminary results.
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The management of purulent exacerbations of chronic bronchitis. A comparison of co-trimoxazole and tetracycline.
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Skin rashes associated with the administration of the 2-nitroimidazole, misonidazole.
Misonidazole, a 2-nitroimidazole, is receiving extensive trial as a radiosensitizing drug in the treatment of patients with malignant disease. Drug sensitivity rashes have been observed and the collected cases from three centers are reported. Of a total of 380 patients there were five (1.3%) instances of definite rash and ten (2.6%) instances of observed rash. These figures are compared with the incidence of sensitivity rashes with other drugs in the nitroimidazole group.