Search PubMed⌕ Search

Biomedical subjects

I Smith

Publications and source records attributed to I Smith.

At least 145 records · Page 8Linked to original sources
PubMed1996

Phase I trial and tumour localisation of the anti-EGFR monoclonal antibody ICR62 in head and neck or lung cancer.

The purpose of this study was to determine the effect of the first rat monoclonal antibody (MAb ICR62) to the epidermal growth factor receptor (EGFR) in a phase I clinical trial in patients with unresectable squamous cell carcinomas. This antibody effectively blocks the binding of EGF, transforming growth factor (TGF)-alpha and HB-EGF to the EGFR, inhibits the growth in vitro of tumour cell lines which overexpress the EGFR and eradicates such tumours when grown as xenografts in athymic mice. Eleven patients with squamous cell carcinoma of the head and neck and nine patients with squamous cell carcinoma of the lung, whose tumours expressed EGFR, were recruited. Groups of three patients were treated with 2.5 mg, 10 mg, 20 mg or 40 mg of ICR62 and a further eight patients received 100 mg. All patients were evaluated for toxicity using WHO criteria. Patients' sera were tested for the clearance of MAb ICR62 and the development of human anti-rat antibodies (HARA). No serious (WHO Grade III-IV) toxicity was observed in patients treated with up to 100 mg of antibody ICR62. Antibody ICR62 could be detected at 4 h and 24 h in the sera of patients treated with 40 mg or 100 mg of ICR62. Only 4/20 patients showed HARA responses (one at 20 mg, one at 40 mg and two at 100 mg doses) and of these only the former two were anti-idiotypic responses. In four patients receiving doses of ICR62 at 40 mg or greater, biopsies were obtained from metastatic lesions 24 h later and examined for the localisation of ICR62 using anti-rat antibody reagent. In these patients we showed the localisation of MAb ICR62 to the membranes of tumour cells; this appeared to be more prominent at the higher dose of 100 mg. On the basis of these data we conclude that MAb ICR62 can be administered safely to patients with squamous cell carcinomas and that it can localise efficiently to metastases even at relatively low doses.

Adult↗
PubMed1996

Costs and benefits of cervical screening. I. The costs of the cervical screening programme.

In 1991, the average total Health Service cost of a cervical smear, including follow up at the colposcopy clinic, was almost 22.70 pounds in the Perth and Kinross district of Scotland. The average cost per colposcopy clinic visit was 30 pounds. The main cost elements were in general practice (55% of total) and the laboratory (33%), and most of the cost was for staff time.

Cost-Benefit Analysis↗
PubMed1996

An ideR mutant of Mycobacterium smegmatis has derepressed siderophore production and an altered oxidative-stress response.

The mycobacterial ideR protein is a homologue of the diphtheria-toxin repressor DtxR. We have previously demonstrated that Mycobacterium tuberculosis ideR, like DtxR, represses transcription of Corynebacterium diphtheriae iron-regulated promoters in vivo and binds to C. diphtheriae operators in a metal-dependent manner in vitro. We show here that ideR mutants of M. smegmatis, constructed by allelic replacement, were defective in their ability to repress siderophore biosynthesis in the presence of iron. They were also more sensitive to hydrogen peroxide and had decreased levels of catalase/peroxidase (KatG) and manganese superoxide dismutase (Mn-SOD). This indicates that ideR is a negative regulator of siderophore production and is required for the response to superoxide- and hydrogen peroxide stress. We propose that ideR is the mycobacterial counterpart of the Escherichia coli Fur protein, i.e. It is a pleiotropic regulator that couples iron metabolism to the oxidative-stress response.

Alleles↗
PubMed1996

Neurochemical effects following peripheral administration of tetrahydropterin derivatives to the hph-1 mouse.

The hph-1 mouse which displays tetrahydrobiopterin deficiency and impaired dopamine and serotonin turnover, has been used to study cofactor replacement therapy for disorders causing brain tetrahydrobiopterin deficiency. Subcutaneous administration of 100 mumol/kg (30 mg/kg) of tetrahydrobiopterin resulted in a twofold increase in brain cofactor concentration 1 h after administration. Concentrations remained above the endogenous level for at least 4 h but returned to normal by 24 h. The lipophilic tetrahydrobiopterin analogue 6-methyltetrahydropterin entered the brain five times more efficiently than tetrahydrobiopterin but was cleared at a faster rate. Tetrahydropterins linked to the lipoidal carrier N-benzyl-1, 4-dihydronicotinoyl did not result in a detectable increase in levels of brain pterins over the period of the study (1-4 h). Stimulation of monoamine turnover was not observed at any time point with either natural cofactor or the methyl analogue. Increasing the amount of tetrahydrobiopterin to 1,000 mumol/kg resulted in elevation of cofactor concentrations, a brief increase in the activity of tyrosine and tryptophan hydroxylase 1 h postadministration, and increased turnover of dopamine and serotonin metabolites lasting 24 h. However, 2 of 12 (17%) mice died following administration of this dose of cofactor. Our findings suggest that acute peripheral tetrahydrobiopterin administration is unlikely to stimulate brain monoamine turnover directly unless very large and potentially toxic doses of cofactor are used.

Animals↗
PubMed1996

'Tomudex' (ZD1694): a novel thymidylate synthase inhibitor with clinical antitumour activity in a range of solid tumours. 'Tomudex' International Study Group.

BACKGROUND: Anti-metabolites such as methotrexate (MTX) and 5-fluorouracil (5-FU) have been used clinically for many years. Although their effects are partly due to thymidylate synthase (TS) inhibition, they also have non-specific, non TS effects on RNA and purine synthesis. Direct and specific TS inhibitors therefore presented an attractive research target. Collaborative research between the Institute of Cancer Research and Zeneca Pharmaceuticals led to the design of specific folate based quinazoline TS inhibitors. ZD1694 ('Tomudex'), the first of these drugs reaching advanced clinical development, is currently completing phase III studies. DESIGN: Eight phase II trials were carried out using 'Tomudex', 3.0 mg/m2, given as a short 15-minute infusion 3-weekly. RESULTS: 'Tomudex' demonstrates activity in a range of tumour types, most notably advanced colorectal and breast cancer (objective response rate 26%) and has acceptable toxicity: the most common WHO grade 3 and 4 adverse events were self-limiting reversible increases in liver transaminases, transient leucopenia, diarrhoea, nausea and vomiting and tiredness or malaise. Mucositis/stomatitis, alopecia and skin toxicity were notable for their low incidence and mild intensity. CONCLUSIONS: 'Tomudex' represents the successful culmination of a rational drug design programme, and shows promise as a new cytotoxic for the treatment of colorectal cancer. Further studies in other tumour types are planned.

Adult↗
PubMed1996

Interactions between midazolam and remifentanil during monitored anesthesia care.

BACKGROUND: Remifentanil, an ultra-short-acting opioid analgesic, may be useful as an intravenous adjuvant to local anesthesia for treating patient discomfort and pain during monitored anesthesia care (MAC). However, the remifentanil dose requirements, interactions with other commonly used sedative drugs (such as midazolam), and recovery characteristics after ambulatory procedures have not been determined. Therefore, this study was designed to evaluate the safety and efficacy of remifentanil alone and in combination with different doses of midazolam during MAC. METHODS: Eighty-one healthy consenting women scheduled for elective breast biopsy procedures were randomly assigned to one of four treatment groups according to an institutional review board-approved, double-blind, placebo-controlled protocol. The study medication (containing either saline or 2 mg, 4 mg, or 8 mg of midazolam) was administered intravenously 5 min before starting an infusion of remifentanil at 0.1 microgram.kg-1.min-1. The remifentanil infusion was subsequently adjusted in 0.025- and 0.05-microgram.kg-1.min-1 increments to maintain patient comfort and adequate ventilation during the operation. The level of sedation was assessed at 1- to 10-min intervals during the procedure using the inverted observer's assessment of alertness/sedation (OAA/S) scale, with a score of 1 = awake, alert to 5 = asleep, unarousable. Discomfort and pain were assessed using numerical rating scales. Hemoglobin oxygen saturation, respiratory rate, blood pressure (systolic, diastolic, mean), and heart rate were monitored at 1- to 5-min intervals. Intraoperative amnesia was assessed by asking patients to recall a picture shown 5 min after the study medication was administered. Recovery was evaluated using the Aldrete score and the times to "home readiness" and actual discharge. Side effects and patient satisfaction were assessed in a follow-up telephone interview on the first postoperative day. RESULTS: Midazolam produced dose-dependent increases in the median level of sedation. Remifentanil produced a greater reduction in respiratory rate in the 4-mg and 8-mg midazolam groups. However, there were no significant differences in the hemodynamic variables or discharge times. Patients with OAA/S scores of 1 to 3 ("light" sedation) 5 min after the study medication experienced a greater incidence of intraoperative pruritus and postoperative nausea and vomiting (PONV) compared with those with OAA/S scores of 4 to 5 ("deep" sedation). Discharge times were prolonged for patients in the light sedation group in whom PONV developed. CONCLUSIONS: Use of remifentanil alone for MAC did not provide optimal sedation during local anesthesia. However, 0.05 to 0.1 microgram.kg-1.min-1 remifentanil in combination with 2 mg midazolam given intravenously, provided effective sedation and analgesia during MAC in healthy patients classified as American Society of Anesthesiologists status 1 to 2. Midazolam also produced dose-dependent potentiation of remifentanil's depressant effect on respiratory rate. In outpatients receiving a combination of midazolam and remifentanil during local anesthesia, the level of sedation appears to influence the incidence of both intraoperative pruritus and PONV.

Adjuvants, Anesthesia↗
PubMed1996

An animal model for human melanoma.

Experimental animal models that are directly relevant to human melanoma are lacking. We propose the Angora goat as a potentially useful field model with experimental potential and to this end have examined the prevalence and site distribution of all skin cancers in 28 Angora goat herds in Queensland, Australia. The prevalence of benign melanocytic lesions (lentigines) and their experimental induction by sunlight were also investigated. Among 1731 goats over 2 years of age, 139 malignant skin tumors were excised from 95 affected animals. The prevalence of squamous cell carcinoma (SCC) was 3.8% and of melanoma, 2.2%. Main site of occurrence of melanoma (83%) was the dorsal surface of the ear; in contrast SCC occurred mostly (84%) on the perineum. Lentigines were darker and more prevalent on the exposed compared with the unexposed surface of the ear in Angoras, analogous to the higher prevalence of nevi on the exposed compared with the less exposed inner surface of the arm in humans. Lentigines, which were also found on the perineum though lighter in color than on the dorsal ear, were absent in young animals under 3 months but were numerous in 1-3 year olds. Furthermore in an experimental substudy eight goats, having one flank repeatedly shorn and the contralateral flank left unshorn, revealed consistently more solar lentigines on the shorn flank (P < 0.05) when both sides were examined after 9 months. Histopathological examination of paired skin biopsies from five of these goats also showed more abundant pigmentation in skin from the exposed, as compared with the unexposed flank. These findings indicate that sunlight induces tumors and lentigines in goats in a highly site-specific manner. The Angora goat model may suggest paradigms for explaining the site differences observed for human melanoma and may also be useful in the future clarification of molecular changes following carcinogenic levels of sun exposure.

Animals↗
PubMed1996

Mild impairment of neuro-otological function in early treated congenital hypothyroidism.

Pure tone audiometry, tympanometry, acoustic stapedial reflex thresholds (ASRTs), and auditory evoked brain stem responses (AEBRs) were carried out in 38 children with early treated congenital hypothyroidism aged 10-12 years, together with tests of vestibular function (electronystagraphy, rotational, and caloric tests). Sensorineural hearing loss with thresholds of greater than 15 dB was detected in 18 children (10 at 8 kHz only); only two children had more than 40 dB hearing loss, each in one ear. Raised ASRTs were found in eight children and two children had abnormal AEBRs. Of the 29 children tested, 12 had an abnormality of vestibular function. Although not significant at the 5% level, there was a tendency for the abnormalities to be more prevalent and severe in the children with more severe hypothyroidism, as judged by pretreatment plasma thyroxine. It is concluded that (i) mild abnormality of hearing is still common in children with congenital hypothyroidism despite early treatment but this is much less severe than that found before neonatal screening and (ii) mild abnormalities of vestibular function may be common in early treated congenital hypothyroidism.

Acoustic Impedance Tests↗
PubMed1996

Pharmacokinetic study of oral and bolus intravenous 2-chlorodeoxyadenosine in patients with malignancy.

PURPOSE: This study was designed to evaluate the absolute bioavailability (F value) of 2-chlorodeoxyadenosine (cladribine; 2-CdA) after multiple oral administrations, and the intersubject variability after oral and 2-hour intravenous (IV) administration schedules in patients with malignancy. PATIENTS AND METHODS: Patients with advanced malignancies were eligible. There were two treatment cycles; during cycle 1, patients received 2-CdA solution at 0.28 mg/kg/d orally under fasting conditions for 5 consecutive days concomitantly with omeprazole, and 4 weeks later during cycle 2 patients received 2-CdA as a 2-hour IV infusion of 0.14 mg/kg/d for 5 consecutive days. Serial blood samples for 2-CdA plasma levels were obtained after drug administrations on days 1 and 5 during each treatment cycle. RESULTS: Ten patients completed cycles 1 and 2. The F value of oral 2-CdA measured on days 1 and 5 was 37.2% and 36.7%, respectively. For both oral and IV multiple administrations, there was no significant accumulation in maximum concentration (Cmax), and the intersubject variabilities (coefficient of variation [CV], approximately 40%) in Cmax and area under the concentration-time curve from 0 to 24 hours [AUC(0-24)] values were comparable for both routes on days 1 and 5. A three-compartment open model was applied to the plasma concentration data after oral and IV administrations and resulted in good agreement between observed and simulated concentration-time profiles. Neutropenia was the principal adverse event observed when 2-CdA was administered orally and IV. CONCLUSION: The F value of 2-CdA after oral administration was approximately 37% and there were no cumulative differences in bioavailability observed on multiple dosing of the drug. The absorption and disposition characteristics of oral 2-CdA were linear and predictable with this dosing regimen.

Administration, Oral↗
PubMed1996

Therapeutic monitoring of continuous infusion etoposide in small-cell lung cancer.

PURPOSE: To investigate the feasibility of therapeutic monitoring of etoposide at different plasma concentrations of the drug, and the resulting pharmacodynamic effects of such an approach. PATIENTS AND METHODS: Forty-nine previously untreated small-cell lung cancer (SCLC) patients received single-agent etoposide every 3 weeks by continuous infusion over 5 days. Plasma etoposide concentrations were monitored 18 and 66 hours into the infusion to permit dose modification. The first cohort of 15 patients began treatment with etoposide 2 micrograms/mL, with dose escalation to 3 micrograms/mL for cycles 3 and 4 and 4 micrograms/mL for cycles 5 and 6, toxicity permitting. The second cohort of 34 patients commenced at 3 micrograms/mL, with dose escalation to 4 and 5 micrograms/mL on cycles 3 and 5, respectively. RESULTS: Mean plasma etoposide concentration during the first treatment cycle was 93.4% +/- 26.6% of the target level at 18 hours (57% of patients within +/- 20% of the target) and 98.9% +/- 14.5% of the target level at 66 hours (82% of patients within +/- 20%). Hematologic toxicity was more pronounced in those treated with 3 micrograms/mL versus 2 micrograms/mL (median nadir neutrophil count, 1.3 v 2.6 x 10(9)/L, P = .032). Tumor responses, typically documented by the third cycle, were similar in each cohort (71% in patients commenced at 2 micrograms/mL and 70% at 3 micrograms/mL). Treatment cohort was not independently predictive of survival. CONCLUSION: Therapeutic monitoring of infusional etoposide is feasible and dramatically reduces interpatient pharmacokinetic variability. Although this was a small nonrandomized trial, the observation of different hematologic toxicity at the two starting concentrations but similar antitumor activity further suggests that these effects may be associated with different plasma etoposide concentrations.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Acute psychiatric problems in an A&E Department.

A study of patients with psychiatric problems attending the Accident & Emergency Department at the Western Infirmary, Glasgow was performed over a four month period. Those requiring admission to other specialties for treatment were excluded (e.g. overdoses). Forty-seven patients presented during the study period and all were self-referred. Seventy-seven per cent had a past history of psychiatric illness. Sixty-six per cent of cases presented with self harm. Eighty-one per cent of cases presented after normal working hours. Alcohol intoxication was a contributing factor in only one quarter of patients presenting. Of all cases seen, 62% were referred to a duty psychiatrist. In this group 38% were admitted and 45% were discharged with psychiatric follow-up, three absconded and two were referred back to their general practitioners. Results indicated that the majority of patients referred to the psychiatric services from Accident & Emergency needed some form of psychiatric input. In the self harm group results showed a correlation between known risk factors for suicide and a need for admission or follow up. Due to local psychiatric referral policies, patients were referred to four different psychiatric hospitals in the area. After initial assessment by the duty psychiatrist, 52% of these patients were subsequently discharged with or without psychiatric follow up. Availability of an on site psychiatrist would alleviate many of the present delays in obtaining definitive management.

Acute Disease↗
PubMed1996

Assessment of pre-operative investigations of thyroglossal cysts.

The appropriate degree of investigation of thyroglossal cysts is uncertain. This retrospective study analyses the pre-operative investigations and correlates this with the post-operative results. The conclusion is that only radio-isotope studies are useful, but there is a limitation regarding the age of the patient and the authors only recommend this in patients over 10 years of age.

Adult↗
PubMed1995

Genomic organization of the mycobacterial sigma gene cluster.

We have previously described sigma A and sigma B and their structural genes, mysA and mysB, respectively, in Mycobacterium smegmatis. We have now sequenced the corresponding regions in the M. tuberculosis and M. leprae chromosomes, and have found the two homologous genes. The chromosomal linkage and the deduced amino acid (aa) sequences of the two genes show very high similarity in the three species of mycobacteria. We also report the finding of two other open reading frames (ORF) in these clusters. orfX, which has an unknown function, is located between mysA and mysB. The other ORF, located downstream from mysB, encodes a homolog of DtxR, the iron regulatory protein from Corynebacterium diphtheriae (Cd).

Amino Acid Sequence↗