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S O'Reilly

Publications and source records attributed to S O'Reilly.

At least 73 records · Page 4Linked to original sources
PubMed1996

Expression of lethal mutations is suppressed in neoplastically transformed cells and after treatment of normal cells with carcinogens.

Recent evidence from our laboratory suggests that the fraction of cells with lethal mutations is lost from the population by apoptosis. The relationship of this process to genetic instability and carcinogenesis is unclear. To examine this, tumorigenic cell populations derived from spontaneously occurring, neoplastically transformed C3H 1OT1/2 foci and from radiation-induced foci were compared with wild-type C3H 10T1/2 cell populations to determine the frequency of induction of lethal mutations postirradiation. Lethal mutations did not occur in the progeny of cells from type 3 foci derived from cultures of spontaneously occurring or radiation-induced neoplastically transformed cells but were very frequent in the progeny of irradiated wild-type cells. Normal human cells (HPV-immortalized human keratinocytes and primary human normal uroepithelium) were then treated with carcinogens or transfected with the Ha-ras oncogene to see if these carcinogenic events affected the yield of lethal mutations postirradiation. In each case, cells which were exposed to a carcinogenic agent had reduced numbers of lethal mutations, elevated levels of stable p53 and Bcl-2 proteins and reduced evidence of apoptosis. It is suggested that lethal mutations may represent an active safety mechanism which may deal with radiation-induced genomic instability and which is disabled early in carcinogenesis.

Animals↗
PubMed1996

Tissue and tumor distribution of C-penclomedine in rats.

Penclomedine, a lipophilic alpha-picoline derivative, is undergoing clinical development presently because of its pronounced antitumor activity against intracerebral (i.c.) tumor xenografts. Penclomedine may be metabolized in vivo to a more potent compound. Although it may be useful in the treatment of brain tumors, the drug has caused significant neurotoxicity in early clinical trials. The possibility that antitumor activity and neurotoxicity may be mediated by different mechanisms prompted a study assessing the differential distribution of penclomedine and penclomedine metabolites to brain and i.c.-implanted tumors in rats. In the present study, quantitative autoradiographic analysis demonstrated a homogenous distribution of 14C-penclomedine in all organs within 1 h of administration. Levels of 14C-penclomedine in both i.c. and s.c. tumors were three times higher than in normal brain tissue. High-performance liquid chromatography combined with gas chromatography and mass spectrophotometry demonstrated that two metabolites, O-demethyl penclomedine and penclomic acid, were responsible for most of the plasma radioactivity. Penclomic acid was also the most common urinary metabolite of penclomedine. In liver samples, although a large number of metabolite peaks were detected, no parent compound could be identified. However, in tumors and all other tissues, penclomedine was the main compound detected. The finding of penclomedine in normal brain tissue indicates not only that this drug may be useful in tumors with normal blood-brain barrier function, but also that it may be directly neurotoxic.

Animals↗
PubMed1996

Murine and human in vivo penclomedine metabolism.

Penclomedine is a multichlorinated alpha-picoline derivative which has shown prominent activity in murine breast cancer models and is currently undergoing clinical development. Previous in vitro research has identified several penclomedine metabolites. In this study, human and murine in vivo penclomedine metabolism was examined. Upon i.v. administration to mice, no penclomedine was detectable in plasma at time points as early as 1 h postinfusion. The principle metabolite was demethyl-penclomedine [3, 5-dichloro-2-methoxy-4-hydroxy-6-(trichloromethyl)pyridine]. Both penclomedine and demethyl-penclomedine could be recovered from tissues. Greater than 60% of the penclomedine dose remaining in the body at 22 h was indelibly bound to tissue and plasma proteins. Urinary metabolites of penclomedine consisted mainly of penclomic acid and additional polar metabolites. The results obtained after p. o. administration were nearly identical to i.v. administration with respect to the extent, level, and type of metabolites found in the plasma, tissues, and urine and with respect to the extent of protein binding. In human subjects administered penclomedine daily for 5 consecutive days, demethyl-penclomedine could be detected in plasma and accumulated with successive doses of penclomedine, reaching peak plasma concentrations of up to 10 times that of penclomedine itself and plasma exposures of nearly 400 times that of the parent drug. It appears that patients eliminate penclomedine largely through metabolism and that this drug may be amenable to p.o. administration.

Animals↗
PubMed1995

Pharmacological studies of allergic cough in the guinea pig.

The pharmacological mechanisms of allergic cough in the guinea pig were studied. Actively sensitized guinea pigs were exposed to aerosols of antigen to elicit coughing. In separate experiments, naive guinea pigs were exposed to aerosols of capsaicin to elicit coughing. Both allergic and capsaicin-induced cough were inhibited by loratadine (0.3-10 mg kg-1 p.o.) and chlorpheniramine (0.1-3.0 mg kg-1 p.o.). Neither cimetidine (10 mg kg-1 s.c.), nor thioperamide (3-10 mg kg-1 s.c.), inhibited allergic or capsaicin-induced cough. Codeine (3-30 mg kg-1 p.o.), salbutamol (0.003-3.0 mg kg-1 s.c.) and ipratropium (0.03-1.0 mg kg-1 s.c.) inhibited both allergic and capsaicin-induced cough. Hexamethonium (10 and 30 mg kg-1 s.c.) inhibited allergic, but not capsaicin-induced cough. Allergic and capsaicin-induced cough were unaffected by phenidone (5.0 and 10.0 mg kg-1 s.c.). Indomethacin (5.0 and 10.0 mg kg-1 s.c.) had no effect on allergic cough but slightly inhibited capsaicin-induced cough. We conclude that allergic and capsaicin-induced cough are modulated by histamine H1 receptor and cholinergic mechanisms. Histamine H2 or histamine H3 receptor mechanisms, and lipoxygenase and cyclooxygenase products of arachidonic acid metabolism do not influence allergic and capsaicin-induced cough. Ganglionic mechanisms play a minor role in the production of allergic cough and no role in capsaicin-induced cough.

Administration, Oral↗
PubMed1995

Evan's blue dye blocks capsaicin-induced cough and bronchospasm in the guinea pig.

The influence of Evan's blue dye on capsaicin-induced bronchoconstrictor and cough responses was investigated in the guinea pig. Evan's blue (30 mg kg-1 i.v.) pretreatment shifted the bronchoconstrictor dose-response to capsaicin (0.3-100 micrograms kg-1 i.v.) to the right by 10-fold, but had no effect on the bronchospasm elicited by neurokinin A (0.3-10 micrograms kg-1 i.v.). Evan's blue (0.3-30 mg kg-1 s.c.) also inhibited capsaicin-induced cough in a dose-dependent manner. Evan's blue blocked capsaicin responses by the intravenous, subcutaneous, or inhaled routes of administration. We conclude bronchoconstrictor responses and cough in vivo.

Animals↗
PubMed1995

Vinorelbine and the topoisomerase 1 inhibitors: current and potential roles in breast cancer chemotherapy.

Vinorelbine is a semi-synthetic vinca alkaloid which was initially developed in France in the 1980's. Due to its unique structure it is considerably less neurotoxic than vincristine. Several phase II studies have shown that vinorelbine is active in metastatic breast cancer therapy with response rates of 20-30% in pretreated and 40-50% in nonpretreated patients respectively. Higher response rates have been noted when vinorelbine is used in combination regimens. The main dose-limiting toxicity seen with this agent has been neutropenia; neurotoxicity manifest as symptomatic paresthesia can be seen in 10% of treated patients. Oral and implantable forms of the drug have also been investigated. The topoisomerase 1 inhibitors topotecan and camptothecin 11 (CPT-11) have been less extensively evaluated in breast cancer therapy. Preclinical studies have indicated that both of these agents are active against breast cancer and some responses have been seen in phase 1 trials of topotecan. An 8% response rate was noted in a phase II trial of CPT-11 in patients with pretreated metastatic breast cancer. Further phase II trials are ongoing at present with both agents.

Antineoplastic Agents↗
PubMed1995

The efficacy of audiotapes in promoting psychological well-being in cancer patients: a randomised, controlled trial.

Open or uncontrolled studies have suggested that providing cancer patients with audiotapes of their clinical interviews can improve information recall and reduce psychological distress. We tested these hypotheses in a 'clinician-blind', prospective, randomised controlled trial. A total of 117 patients newly referred to a medical oncology clinic who were to be given 'bad news' had their consultations audiotaped. Blind to the clinician, patients were randomly allocated to receive a copy of the tape to play at home or not (control group). At 6 months follow-up, tape group patients reported positive attitudes to the audiotape and were shown to recall significantly more information about their illness than did controls. Overall improvement in psychological distress at 1 and 6 months follow-up, as measured with the 30-item General Health Questionnaire and the Hospital Anxiety and Depression Scale was no different in the two groups. However, a second-order interaction suggested that poor-prognosis patients were disadvantaged specifically by access to the audiotape, with less improvement in psychological distress at 6 months follow-up than non-tape controls. Patient access to audiotapes of clinical interviews promotes factual retention but does not reliably reduce psychological distress and may be actively unhelpful in some subgroups of patients.

Adult↗
PubMed1995

Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To determine whether interferon maintenance therapy improves overall survival and response duration in patients with multiple myeloma who have responded to induction therapy with melphalan and prednisone. PATIENTS AND METHODS: In a multicenter trial, patients with symptomatic clinical stage I and stage II and III multiple myeloma were registered at diagnosis and those who responded to melphalan-prednisone (MP) were randomized either to receive interferon (2 mU/m2) subcutaneously three times per week or no maintenance. MP was discontinued in both groups once a stable response plateau of the monoclonal protein was reached. Interferon was continued until relapse, and then was restarted on subsequent response to MP. Interferon toxicity was recorded using a self-report diary. Survival and response duration were calculated using life-table methods, and were adjusted in the analysis for imbalances in baseline prognostic factors. RESULTS: Four hundred two patients were registered and 176 responders were randomized (85 to interferon and 91 to control). At a median follow-up time of 43 months, the median survival duration was 43 months for interferon and 35 months for control (P = .16), but when adjusted for chance imbalances in baseline prognostic factors (mainly performance status), the median survival duration was 44 months and 33 months for interferon and control, respectively (P = .049). Progression-free survival from randomization to first relapse also favored interferon (unadjusted P < .002; adjusted P < .003). Interferon toxicity caused 58% of patients to reduce their dose, of which 84% were able to return to the initial dose; 14% had to discontinue interferon treatment. CONCLUSION: Interferon maintenance therapy improves progression-free and overall survival of patients with multiple myeloma who respond to melphalan and prednisone. Toxicity is substantial and must be weighed by patients against the potential benefits in response duration and survival.

Aged↗
PubMed1994

Detection of breast cancer micrometastases in axillary lymph nodes by using polymerase chain reaction.

Breast cancer micrometastases in axillary lymph nodes have been detected by serial sectioning and immunohistochemistry, and shown to have prognostic significance. We have used polymerase chain reaction (PCR) to see whether we could further improve the detection rate of micrometastases. Fifty-seven axillary lymph nodes from patients with breast cancer were examined histologically to assess the proportion of tumor involvement. Immunohistochemical staining with the use of an anti-keratin 19 antibody confirmed the histological findings. Reverse transcription PCR was then performed on extracted RNA by using K19 primers, and all 18 histologically involved nodes yielded the expected 460-base pair product. Of 39 histologically negative nodes, 4 (10%) gave K19 bands detectable with ethidium staining and a further 10 (28%) gave K19 bands after Southern hybridization. To further increase the detection sensitivity a two stage amplification was performed by using nested primers, and K19 product was found in lymph nodes from patients without cancer, as well as in all the nodes from cancer patients. This was shown to be genuine low level expression from endogenous mRNA template, and not derived from amplification of a K19 pseudogene. Reducing the number of PCR cycles in the two amplification steps did not allow sufficient discrimination between normal nodes and those involved nodes in which K19 expression was only detectable after Southern hybridization. The optimal "cut-off" point to distinguish involved nodes from normal nodes remained at the level of 40 cycles of PCR and Southern hybridization. PCR, using K19 as a tumor marker, has been demonstrated in this study to improve the detection of micrometastases in axillary lymph nodes in patients with breast cancer: sensitivity is limited by the specificity of the tumor marker.

Adult↗
PubMed1994

Long term acid suppressing treatment in general practice.

OBJECTIVE: To determine the current practice in selected general practices for prescribing long term (> 6 months) treatment to suppress gastric acid secretion. SETTING: Seven general practices in the Harrow area that always or usually refer to Northwick Park Hospital. SUBJECTS: 60,148 patients on lists of the general practices. DESIGN: Identification of patients receiving long term treatment through repeat prescribing data, followed by a manual and computer survey of patients' notes for indications and investigations. Patient compliance and views on treatment were sought by a postal questionnaire. MAIN OUTCOME MEASURES: Indications for treatment, treatment given, investigations undertaken before and during treatment. RESULTS: 492 patients (0.82% of the population) were taking long term acid suppressing treatment. The most common diagnosis was duodenal ulcer disease (183 (37%) of all patients); oesophageal disease (118 (24%)) was also common. 93 patients (19%) were treated for abdominal pain where no diagnosis had been reached or who had only a diagnosis of gastritis on endoscopy. Ranitidine was prescribed in 394 (80%) patients. 298 (74%) patients found treatment helpful, but 108 (27%) had a poor understanding of their diagnosis. 317 patients (78%) took their drug as prescribed. 37 patients were also taking prescribed non-steroidal anti-inflammatory drugs and an additional 43 patients took regular aspirin or ibuprofen without prescription. CONCLUSIONS: Long term acid suppressing treatment is common, and a substantial number of patients are taking these drugs long term without a diagnosis having been reached. It is hoped that protocols for investigation and treatment will improve these figures. Patients need to be better informed about their disease and the possible adverse effects of taking non-steroidal anti-inflammatory drugs in acid related upper gastrointestinal disease.

Abdominal Pain↗
PubMed1994

Intensive therapy with cyclophosphamide, carmustine, etoposide +/- cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy.

The optimal timing in which to use intensive chemotherapy and autologous bone marrow transplantation (BMT) in Hodgkin's disease (HD) is uncertain. In 1985, we initiated a program in which this modality was used as the initial salvage therapy in patients relapsing after combination chemotherapy. Fifty-eight patients with HD in first relapse after primary chemotherapy received conditioning with high-dose cyclophosphamide, carmustine, etoposide (VP16-213) +/- cisplatin (CBV +/- P) followed by autologous BMT. All but six of these patients were given a median of two cycles of conventional chemotherapy +/- involved field radiation therapy before CBV +/- P and autologous BMT. These measures were not used as a means for patients selection; all patients receiving such therapy ultimately were transplanted. The probability of nonrelapse mortality, progression of HD, and progression-free survival post-BMT were calculated, and prognostic factors for progression-free survival were evaluated using the Cox proportional hazards method. Treatment-related deaths occurred in only three patients. Thirteen patients have relapsed at a median 0.7 years (range 0.1 to 3.5) post-BMT. At a median follow-up of 2.3 years (range 0.4 to 7.2), the actuarial progression-free survival is 64% (95% confidence interval, 46% to 78%). In the statistical analysis, three similarly weighted but independent prognostic factors were identified: "B" symptoms at relapse, extranodal disease at relapse, and initial remission duration of less than 1 year. Patients with no risk factors had a 3-year progression-free survival of 100%, compared with 81% in patients with one factor, 40% in those with two factors, and 0% in patients with all three factors. CBV +/- P and autologous BMT is highly effective salvage therapy for HD patients in a first relapse, particularly in the subset of patients with less than two adverse factors. Therapy must be improved in the future for patients with > or = 2 adverse factors.

Adolescent↗
PubMed1994

Invasive pulmonary aspergillosis associated with low dose methotrexate therapy for rheumatoid arthritis: a case report of treatment with itraconazole.

Opportunistic infections complicating low dose methotrexate therapy are rare, consisting predominantly of Pneumocystis carinii pneumonia. We report a case of invasive pulmonary aspergillosis which developed in a patient being treated for seropositive rheumatoid arthritis with low dose methotrexate (5-7.5 mg weekly) for 8 years. The patient was successfully treated with itraconazole 200 mg daily for 6 months. This case adds to the growing evidence implicating low dose methotrexate with opportunistic infections and should heighten clinical awareness in patients on this treatment.

Aged↗
PubMed1994

Postirradiation expression of lethal mutations in an immortalized human keratinocyte cell line.

The quantification of the extent of delayed cell death and the rate and pattern of its occurrence in relation to the cell division cycle is important in radiotherapy and also in radiation transformation studies related to protection and dose limits. Here the numbers of lethal mutations occurring over 45 population doublings (clonal expansion to about 10(13) cells per cell originally surviving irradiation) was measured in an HPV 16 immortalized human keratinocyte cell lines used for transformation studies. The results showed that when postirradiation (dose range 1-6 Gy) growth curves were constructed, the difference in slopes could be accounted for entirely by correcting for the non-clonogenic fraction in the cell count, excluding a longer cell generation time as an explanation. When the cell loss was examined over the entire growth period of 6 weeks (about 45 doublings of the cell population), it was found to be dose dependent for the first two passages, but then to become more independent of dose. The mean loss for the population over the entire 45 cell doublings was about 15% at each cell division. There is some indication from the data that the numbers of lethal mutations actually begin to increase between passage 6 and 7 at every dose tested but this requires further investigation. The results allow a time/cell generation dependent factor to be derived for the cell line and used in survival curve equations where effects of radiation are being measured at times distant from the original exposure.

Cell Division↗
PubMed1994

Peripheral and central sites of action of GABA-B agonists to inhibit the cough reflex in the cat and guinea pig.

1. The GABA-B receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPi) have antitussive activity in the cat and guinea pig. The purpose of this study was to investigate the sites of action of these GABA-B receptor agonists to inhibit the cough reflex. 2. Single intracerebroventricular (i.c.v.) cannulas were placed in the lateral ventricles of anaesthetized guinea pigs. Approximately 1 week later, the animals were exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3. Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. Cannulas were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of baclofen, 3-APPi, the centrally active antitussive drug codeine or the peripherally active antitussive drug BW443c. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally acting drug. 4. In the guinea pig, baclofen (3 mg kg-1, s.c.) and 3-APPi (10 mg kg-1, s.c.) inhibited capsaicin-induced cough by 50% and 35% respectively. The antitussive activity of baclofen was completely blocked by i.c.v. administration of the GABA-B receptor antagonist CGP 35348 (10 micrograms). Conversely, the antitussive effect of 3-APPi was unaffected by i.c.v. CGP 35348. However, systemic administration of CGP 35348 (30 mg kg-1, s.c.) completely blocked the antitussive activity of 3-APPi (10 mg kg-1, s.c.). In separate experiments baclofen alone (1 microg, i.c.v.) inhibited capsaicin-induced cough by 78%. 3-APPi (10 and 100 microg, i.c.v.) had no effect on capsaicin-induced cough in the guinea pig.5. In the cat, potencies (ED50) of the standards and GABA-B agonists by the i.v. route were: codeine(0.34 mg kg-1), BW443C (0.17 mg kg-1), baclofen (0.63 mg kg-1) and 3-APPi (2.3 mg kg-1). Potencies of these drugs by the i.a. route were: codeine, 0.013 mg kg-1; BW443C, 0.06mg kg-1; baclofen,0.016mg kg-1; and 3-APPi, 0.87 mg kg-1. The EDRs for each drug were: codeine, 26; BW443C, 3;baclofen, 39; and 3-APPi, 3.6 We conclude that in both the cat and guinea pig baclofen inhibits cough by a central site of action,while 3-APPi inhibits cough by a peripheral site of action.

Animals↗
PubMed1994

Treatment of chronic non malignant pain in general practice.

The chronic pain patient can represent a daunting challenge to even the most experienced general practitioner. This article aims to describe the complex nature of such patients and to suggest some guidelines for their management.

Central Nervous System↗