Search PubMed⌕ Search

Biomedical subjects

J G Smith

Publications and source records attributed to J G Smith.

At least 73 records · Page 4Linked to original sources
PubMed1997

Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis.

The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.

Administration, Oral↗
PubMed1997

Evaluation of experimental therapeutics in a new mouse model of Helicobacter felis utilizing 16S rRNA polymerase chain reaction for detection.

BACKGROUND: A new mouse model of Helicobacter felis infection, which mimics the human infection observed with H. pylori, has recently been developed utilizing polymerase chain reaction (PCR) based on the 16S rRNA gene sequence for detection of infection. METHODS: We tested several therapeutic regimens in this model, including some currently utilized in the clinic and some shown ineffective in the clinic. RESULTS: The therapeutic results obtained by PCR with this model are consistent with results observed in the published human H. pylori clinical trials and also with results obtained in another H. felis mouse model utilizing culture and histology. CONCLUSIONS: These results support further use of this new model in screening for new therapeutic regimens for the management of Helicobacter disease.

Animals↗
PubMed1996

Concurrent radiotherapy and continuous ambulatory infusion 5-fluorouracil in advanced head and neck cancer.

Patients with locally advanced stage 3 or 4 recurrent squamous cell carcinoma of the head and neck received 5-fluorouracil (5-FU) 200 or 300 mg/m2/day by prolonged ambulatory infusion concomitantly with radiotherapy (60-66 Gy) to the primary site and neck nodes in 30-33 fractions at five fractions per week, boosting to smaller volumes after 60 Gy. Of 39 patients, the complete response rate was 82% (95% CI: 67-93%). The estimated percentage without failure at 2 years was 59% (S.E. 8%) and at 4 years was 50% (S.E. 8%). Estimated head and neck cancer specific survival was 64% (S.E. 8%) at 2 years and 52% (S.E. 8%) at 4 years. Acute toxicities included moist desquamation in 49% and dry desquamation in 28%, confluent mucositis in 56% and patchy mucositis in 44%. Late effects, more than 6 months after completing treatment, assessed in 35 patients, included severe salivary dysfunction in 3 patients and moderate in 21, severe osteonecrosis in 4 patients and moderate toxicity in subcutaneous tissues in 13, skin in 3 and mucosa in 2 patients. It is feasible to give continuous 5-FU concurrently with radiotherapy in locally advanced or recurrent head and neck cancer, albeit with increased toxicity. The response rate and survival obtained in this trial justify further investigation of the combined treatment in a randomised trial.

Adult↗
PubMed1996

Postoperative radiotherapy for Dukes' B and C rectal cancer: Peter MacCallum Cancer Institute experience.

This retrospective study reviews the outcome of patients with Dukes' B and C rectal cancer treated with adjuvant post-operative pelvic radiotherapy at the Peter MacCallum Cancer Institute from 1981 to 1990. Sixty-one patients (22 Dukes' B, 36 Dukes' C and 3 unknown stage) received a median dose of 50 Gy of pelvic irradiation. Locoregional relapse occurred in 33% of patients. Estimated median progression-free survival was 1.7 years with 46% surviving without progression at 2 years and 30% at 5 years. There was no difference according to Dukes' stage. The estimated median survival was 2.6 years, with no difference according to disease stage. These results with postoperative radiotherapy alone are inferior to results achievable by combination chemotherapy and radiotherapy as adjuvant therapy which should now be considered standard therapy following surgical resection for Dukes' B and C rectal cancer.

Adenocarcinoma↗
PubMed1996

New model of oropharyngeal and gastrointestinal colonization by Candida albicans in CD4+ T-cell-deficient mice for evaluation of antifungal agents.

A new model for the evaluation of antifungal compounds against oropharyngeal and gastrointestinal mucosal colonization by Candida albicans was developed. To simulate the immune deficiency observed in AIDS patients, mice were depleted of CD4+ T lymphocytes by the injection of either GK1.5 hybridoma cells or purified anti-CD4+ T lymphocytes by the injection of either GK1.5 hybridoma cells or purified anti-CD4+ monoclonal antibody derived from GK1.5 hybridoma cells in tissue culture. Fluorescence-activated cell sorter analysis of splenic lymphocytes confirmed the elimination of the CD4+ T-cell population. Gentamicin, a broad-spectrum, nonabsorbable aminoglycoside antibiotic, was given via the drinking water to reduce the normal gastrointestinal microflora, allowing less competition for colonization of the gastrointestinal tract by the C. albicans isolates. Mice were challenged by gavage and swabbing their oral mucosae with a pure culture of C. albicans. Gentamicin was withdrawn 3 days postchallenge, and antifungal compounds were administered via the drinking water ad libitum at concentrations ranging from 25 to 400 micrograms/ml. L-693989, a water-soluble phosphorylated cyclic lipopeptide prodrug of pneumocandin Bo, and L-733560, a semisynthetic derivative of pneumocandin Bo, are inhibitors of 1,3-beta-D-glucan synthesis that exhibit potent in vivo anti-Candida spp. and anti-Pneumocystis carinii activities. The efficacies of L-693989, L-733560, fluconazole, ketoconazole, and nystatin were evaluated in this new oropharyngeal and gastrointestinal model of mucosal colonization. L-693989, L-733560, fluconazole, and ketoconazole showed superior efficacies in reducing the numbers of C. albicans CFU per gram of feces and the numbers of oral CFU relative to those in sham-treated controls in this model, while nystatin was moderately effective in reducing oral and fecal colonization by C. albicans in this model.

Animals↗
PubMed1996

PCR detection of colonization by Helicobacter pylori in conventional, euthymic mice based on the 16S ribosomal gene sequence.

Many animal models of Helicobacter infection have been described, including infection in rhesus monkeys, ferrets, gnotobiotic piglets, and mice. These animal models utilize a combination of detection methods, including culture, urease testing, and histopathology, all of which may be unreliable, insensitive, or labor-intensive. Development of new animal models of Helicobacter pylori requires new methods of detection with increased sensitivity and specificity. We have developed sensitive and specific PCR primers based on the 16S ribosomal gene sequence of H. pylori. The primers detected single-copy 16S DNA representing 0.2 cell of pure H. pylori (2 cells in the presence of mouse stomach mucosal DNA) and did not cross-react with closely related bacteria. We were able to detect colonization by H. pylori in conventional, euthymic, outbred mice up to 4 weeks postinoculation with a high percentage of isolates tested. One isolate of H. pylori was detected by PCR in 100% of the mice at 6 months and 60% of the mice 1 year after inoculation. Approximately 10(3) to 10(4) H. pylori cells per stomach were detected by utilizing this PCR methodology semiquantitatively. These primers and PCR methodology have facilitated detection of H. pylori colonization in conventional, euthymic mice, colonization which may not have been detectable by other methods.

Animals↗
PubMed1996

A sensitive and specific PCR method to detect Helicobacter felis in a conventional mouse model.

Although many detection methods have been used to determine Helicobacter colonization in small animal models, the sensitivity and specificity of these detection methods are limited. To improve the Helicobacter felis conventional mouse model for accurate evaluation of therapeutic regimens, we developed a PCR for detection of, and a competitive PCR for quantitation of, H. felis in viral antibody-free (VAF) mice. The PCR was based on the H. felis 16S rRNA gene. An internal control DNA was used for competitive quantitation of the PCR. VAF conventional Swiss-Webster mice were infected with an H. felis culture by oral gavage. At various times after H. felis challenge and therapy, stomach mucosa was collected and evaluated by PCR. PCR detected approximately 50 to 100 H. felis cells per mouse stomach and showed no cross-reaction with other bacteria commonly found in mouse stomachs. Colonization of H. felis in the mouse stomach was confirmed by culture isolation from germfree mice and histological examination of VAF mice. Response to therapy in this H. felis model correlated well with results seen in human clinical trials with H. pylori. A model utilizing PCR detection which may be useful for discovering new antibiotics and/or vaccines against Helicobacter ulcer disease has been developed.

Animals↗
PubMed1996

Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-one patients with advanced measurable or assessable NSCLC and performance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mg/m2 over 3 hours with premedication. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57%), extrathoracic metastatic disease (65%), and measurable disease (75%). Twenty-two percent had previously untreated stage III disease. RESULTS: The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organization (WHO) grade IV neutropenia in only 16% of patients. Grade III/IV myalgia/athralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred. CONCLUSION: The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase II trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.

Adult↗
PubMed1996

Haemopoietic growth factors, the cell cycle of acute myeloblastic leukaemia progenitors and sensitivity to cytosine arabinoside.

We describe an 'in vitro' model which permits assessment of acute myeloblastic leukaemia (AML) progenitor cells' response to Ara-C alone and in conjunction with recombinant human (rh) cytokines by evaluating cell cycle characteristics of purified AML blast progenitors and their chemosensitivity in clonogenic culture before and after cytokine priming. Parallel investigation of Ara-C/cytokine treatment on normal CFU-GM progenitors was included as these cells are important for post-therapeutic reconstitution of haemopoiesis. Kinetic and clonogenic findings for AML marrows were extremely variable with G+GM-CSF or IL-3 priming. However, inclusion of rhSCF and resultant synergism with the other cytokines, introduced a pronounced element of consistency in AML results. Normal CFU-GM responded to rhG+GM-CSF or IL-3 with increased kinetic activity and sensitivity to Ara-C. rhSCF synergised strongly with the other factors, causing increased cell cycling and attainment of maximal chemosensitivity 'in vitro'. No correlation was evident between 'in vitro' findings for AML samples, patient FAB types or clinical outcome. This study highlights the fact that both normal and AML cells can be targeted by rh cytokines, particularly when rhSCF is included in priming cocktails.

Antimetabolites, Antineoplastic↗
PubMed1996

Fatal autoimmune pancytopenia following bone marrow transplantation for aplastic anaemia.

We report a case of autoimmune pancytopenia 10 months after allogeneic bone marrow transplantation (BMT) for severe aplastic anaemia (SAA). The autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenic purpura (ITP) were refractory to conventional immunosuppressive therapy which included steroids, azathioprine, vincristine and intravenous immunoglobulin. Splenectomy led to a recovery of the thrombocytopenia but the haemolysis continued despite further immunosuppressive therapy. Four months after the onset of haemolysis granulocyte-specific antibodies were detected. The patient subsequently received total lymph node irradiation (TLI) with a peripheral blood stem cell transplant (PBSCT) from his original donor, but died 9 days later from cerebral aspergillosis. The severe nature of autoimmune cytopenias and their lack of response to conventional treatment following allogeneic BMT is discussed further.

Adult↗
PubMed1996

The role of midazolam-induced sedation in bone marrow aspiration/trephine biopsies.

This study was undertaken in 102 adult patients to evaluate the safety and efficacy of intravenous (i.v.) midazolam in the setting of bone marrow aspiration and trephine biopsy (BMAT). Combined local anaesthetic (LA) and sedation was used in 87% of patients and 13% received LA alone. Amnesia occurred in all sedated patients with only 9% experiencing a mild degree of post-procedure pain. This contrasted sharply with the non-sedated group, in whom 85% had intense pain during the biopsy followed by protracted local discomfort in approximately 54%. Drowsiness and some psychomotor impairment were the only notable sedation-related side-effects in approximately 20%. None required assisted ventilation. There was a resounding patient preference for BMAT with sedation. Considering the ease of use, safety and efficacy of i.v. midazolam, the availability of flumazenil as a reversal agent and the undoubted positive effects on quality of life, we would advocate using it in BMAT provided that there were no contraindications.

Adolescent↗
PubMed1995

Treatment of brain metastases from primary lung cancer.

PURPOSE: A retrospective study of patients treated at the Peter MacCallum Cancer Institute for brain metastases from primary carcinoma of the lung is presented. METHODS AND MATERIALS: The medical records of 416 patients with the diagnosis of primary carcinoma of the lung who presented with, or subsequently developed, brain metastases during the period January 1984 to December 1987 were reviewed. Information on a number of factors of potential prognostic significance (sex, age, histology, performance status and interval between diagnosis of the primary and brain metastases) was collected. Details of surgery, radiation and steroid usage were recorded, and any steroid side effects documented. Survival was calculated from the date of diagnosis of brain metastases. Stepwise regression based on Cox's proportional hazards model was used to determine significant prognostic factors affecting survival. Patients with and without steroid side effects were compared using Yates's corrected chi-square test. RESULTS: The overall estimated median survival was only 3.3 months (95% confidence interval 2.9-3.7 months). Only two factors were found to be associated with a significantly improved survival--surgical intervention and good performance status. After taking these two factors into account, the dose of radiation used (< 30 Gy or > or = 30 Gy) did not influence survival. There was a 3% incidence of gastric bleeding or perforation in patients taking steroids, with a 40% fatality rate. Predisposing factors to gastric side effects were a prior history of peptic ulcer and/or aspirin or nonsteroidal anti-inflammatory drug consumption. CONCLUSION: Radiation of brain metastases from primary lung cancer results in modest survival benefit. Radiation dose (< 30 Gy or > or = 30 Gy) is not a significant determinant of survival. Other treatment modifications, such as concurrent radiation and chemotherapy, should be explored. Steroids should be used with caution as fatal side effects can occur.

Adult↗
PubMed1995

Autonomous replication in Drosophila melanogaster tissue culture cells.

This study addresses the ability of DNA fragments from various sources to mediate autonomous DNA replication in cultured Drosophila melanogaster cells. We created a series of plasmids containing genomic DNA fragments from the Ultrabithorax gene of Drosophila and test ed them for autonomous replication after transfection into Schneider line 2 cells. We found that all plasmids containing Drosophila DNA were able to replicate autonomously, as were random human and Escherichia coli genomic DNA fragments. Most of the plasmids were detectable 18 days after transfection in the absence of selection, suggesting that transfected DNA is maintained in Drosophila cells without rapid loss or degradation. The finding that all plasmids containing Drosophila, human or bacterial DNA replicate autonomously in Drosophila cells suggests that the signals that direct autonomous replication in Drosophila contain a low degree of sequence specificity. A two-dimensional gel analysis of initiation on one of the plasmids was consistent with many dispersed initiation sites. Low sequence specificity and dispersed initiation sites also characterize autonomous replication in human cells and Xenopus eggs and may be general properties of autonomous replication in animal cells.

Animals↗
PubMed1995

Netherton's syndrome: a syndrome of elevated IgE and characteristic skin and hair findings.

Netherton's syndrome is a rare symptom complex characterized by greatly elevated IgE levels with atopic manifestations, an ichthyotic skin disorder (ichthyosis linearis circumflexa and/or congenital lamellar ichthyosis), and the characteristic hair abnormality trichorrhexis invaginata. It may be confused with atopic dermatitis but does not respond to topical corticosteroid treatment. Netherton's syndrome is therefore of considerable importance to allergists. In this article we report the results of the clinical and immunologic evaluation of a previously unreported patient who responded to treatment with 12% ammonium lactate lotion and management of his allergic disease. Furthermore, we have reviewed the English literature and compared the findings in our patient with those of 43 other reported patients. Our patient shared the features of other previously reported patients with this disorder. We conclude that this disease should be included among the other disorders with elevated IgE. Patients may benefit from evaluation and treatment of their allergic symptoms and topical skin treatment with ammonium lactate.

Biopsy, Needle↗