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Biomedical subjects

M Green

Publications and source records attributed to M Green.

At least 19 recordsLinked to original sources
PubMed1992

Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin.

BACKGROUND: Although doxorubicin is an anticancer agent with a wide spectrum of activity, therapy with this anthracycline must often be discontinued at a time of benefit to the patient because of the drug's cumulative cardiotoxicity. ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin. PURPOSE: Our objectives in this study were to determine the maximum tolerated dose of ADR-529 (which uses a different vehicle than ICRF-187) when given with a fixed doxorubicin dose and to determine whether ADR-529 alters doxorubicin pharmacokinetics. METHODS: Twenty-five patients were treated with doxorubicin (60 mg/m2) preceded by administration of ADR-529 in escalating dosages (i.e., 60, 300, 600, 750, and 900 mg/m2) to groups of three to nine patients. ADR-529 was administered over a 15-minute period beginning 30 minutes before doxorubicin treatment; the protocol was repeated every 3 weeks. Blood was sampled frequently for drug levels, which were determined by high-pressure liquid chromatography with fluorescence (doxorubicin) and electrochemical detection (ADR-529). RESULTS: Dose-limiting neutropenia occurred in four of six previously treated patients at an ADR-529 dose of 600 mg/m2; the dose ratio of ADR-529 to doxorubicin was 10:1. For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2. Doxorubicin's estimated terminal half-life was 39.5 +/- 18.3 (mean +/- SD) hours; the area under the curve for plasma concentration of drug x time (AUC) was 1.74 +/- 0.40 (micrograms/microL) x hour. Total-body clearance was 598 +/- 142 microL/m2 per minute (N = 20), and it did not vary with ADR-529 dose. Estimated distribution and elimination phase half-lives for plasma ADR-529 were 0.46 +/- 0.30 hours and 4.16 +/- 2.94 hours, respectively. Total-body clearance was 111 +/- 87 microL/m2 per minute (N = 18); AUC was linear (r2 = .92), and the clearance rate was constant (r2 = .18) from 60 to 900 mg/m2. CONCLUSIONS: Myelotoxicity was dose limiting for ADR-529 at 600-750 mg/m2 when given with a fixed dose of doxorubicin at 60 mg/m2 (dose ratios of ADR-529 to doxorubicin ranged from 10:1 to 12.5:1). When used in combination, ADR-529 did not perturb doxorubicin's distribution, metabolism, or excretion; therefore, other mechanisms of cardioprotection must be involved. IMPLICATIONS: We recommend that an ADR-529 dose of 600 mg/m2 be given with single-agent doxorubicin at a dose of 60 mg/m2 in future studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

London after Tomlinson. Clinical research.

Sir Bernard Tomlinson's report focuses on London's health services, but his proposals have major implications for the future of clinical research--not just in London but in the United Kingdom as a whole. They must be seen in the context of a widely perceived decline in British research and development which also threatens clinical research. This article examines the implications of Tomlinson's proposals and related strategies and recommends the construction of a research market for the patient costs of clinical research to complement the NHS market for patient services introduced in 1991. These arrangements would help sustain the clinical research base and guarantee excellence.

Economic Competition↗
PubMed1992

Determination of the sequence of an expressible cDNA clone encoding ERp60/calregulin by the use of a novel nested set method.

An analysis of the N-terminal sequence of the luminal endoplasmic reticulum protein, ERp60, showed that it was identical to the well-characterized Ca2+-binding protein, calregulin. A full-length, expressible cDNA clone encoding this protein was isolated from a mouse fibroblast cDNA library. A novel nested set strategy for the production of overlapping fragments for DNA sequencing was used to determine the complete nucleotide (nt) sequence of both strands of the ERp60 clone. This method utilizes a series of nonspecific deletion primers in conjunction with a specific site primer to generate the nested set fragments. This procedure possesses several advantages over other nested set techniques, since it does not require (i) the re-cloning of the DNA insert into other vectors, (ii) any prior knowledge of the restriction sites of the nt sequence, or (iii) the transformation and analysis of bacterial subclones. ERp60 has a 17-amino acid (aa) signal sequence and the mature protein contains 399 aa with a calculated M(r) of 46,347.

Amino Acid Sequence↗
PubMed1992

HLA-DR associates with specific stress proteins and is retained in the endoplasmic reticulum in invariant chain negative cells.

The major histocompatibility complex class II molecules are composed of two polymorphic chains which, in cells normally expressing them, transiently associate with a third, nonpolymorphic molecule, the invariant chain (Ii). To determine differences in the biology of class II molecules synthesized in the presence or absence of Ii, a comparative study was performed of BALB/c 3T3 cells that had been transfected with human class II HLA-DR molecules with or without cotransfection with human Ii. It was observed that in the absence of Ii, at least three high molecular weight proteins coimmunoprecipitate with HLA-DR molecules. These proteins did not coimmunoprecipitate with HLA-DR from cells cotransfected with Ii, nor did they coimmunoprecipitate with class I molecules from any of the transfectants. NH2-terminal sequence and/or Western blot analysis revealed the identity of two of the proteins as the endoplasmic reticulum (ER) resident stress proteins GRP94 and ERp72. Neither of these proteins was found to have an increased level of synthesis in the Ii- versus the Ii+ transfectants, indicating that their synthesis was not induced over constitutive levels. Fluorescence microscopy revealed that in the Ii- transfectants, the majority of the HLA-DR molecules were present in the ER, whereas in the Ii+ transfectants, the HLA-DR molecules were found in vesicular structures. We hypothesize that in the absence of Ii, ER resident stress proteins bind to class II molecules and retain them in the ER. This process, in turn, could prevent class II molecules from exiting the ER with endogenous peptides bound in their peptide binding cleft, and therefore could minimize autoimmune responses to endogenously processed self-peptides.

3T3 Cells↗
PubMed1992

Comparison of different metronidazole therapeutic regimens for bacterial vaginosis. A meta-analysis.

OBJECTIVE: To evaluate the treatment of bacterial vaginosis with metronidazole to determine if there is a therapeutic regimen that is superior to all others with regard to cure and recurrence rates. DATA SOURCES: Computer-assisted literature search, Medical Subject Index review, and references cited in articles identified. STUDY SELECTION: Clinical trials comparing different oral metronidazole regimens in which diagnostic criteria for bacterial vaginosis and criteria to detect cure to treatment were described. DATA EXTRACTION: Articles that met inclusion criteria were critically appraised and those that passed were included in the analysis. Of 52 initial articles, 10 met criteria for inclusion and passed critical appraisal. DATA SYNTHESIS: Patients were divided in groups according to the duration of therapy received: group A (n = 413), 2-g single dose; group B (n = 193), 2-g single daily dose for 2 days; group C (n = 317), 5 days; and group D (n = 280), 7 days. Cure rates on initial evaluation for the groups were 85%, 87%, 86%, and 87%, respectively. chi 2 Contingency table analysis showed no significant difference in cure rates among the groups (P = .78). Only 465 of these patients were evaluated for recurrence of disease. There was no significant difference in cure rates after 4 weeks of therapy (P = .4). CONCLUSIONS: A 2-g single-dose metronidazole regimen is as effective as a single daily dose given for 2 days or a 5-day course or a 7-day course.

Female↗
PubMed1992

Rapid optimization of enzyme substrates using defined substrate mixtures.

A strategy is described for the rapid optimization of kcat/Km for protease substrates. Selected positions of a given peptide substrate sequence are varied through synthesis with mixtures of amino acids. Incubation of the resulting peptide mixture with the enzyme of interest and analysis by high pressure liquid chromatography provides a direct measure of analogs with enhanced kcat/Km. High performance liquid chromatography/continuous flow fast atom bombardment mass spectrometry is used to assign structure to each peak in the chromatogram. As an example of the utility and efficiency of "substrate mapping" we describe optimization of the collagenase substrate Dnp-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 (where Dnp is dinitrophenyl) at the P'1 and P'2 positions. Six different mixtures were prepared for evaluation, representing the synthesis of 128 different synthetic substrates. "Substrate mapping" has led to Dnp-Pro-Leu-Gly-Cys(Me)-His-Ala-D-Arg-NH2, a substrate that possesses a 10-fold better kcat/Km than Dnp-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2.

Amino Acid Sequence↗
PubMed1992

Ventricular performance before and after Fontan repair for univentricular atrioventricular connection: angiographic and radionuclide assessment.

OBJECTIVES: This study was designed to evaluate changes in ventricular volume, mass and cardiac function before and after creation of an atrial to pulmonary connection in patients with a univentricular atrioventricular connection. BACKGROUND: Intact systolic and diastolic performance is critical for successful establishment of an atrial dependent circulation, and few studies are available comparing cardiac performance before and after creation. METHODS: With the use of radionuclide blood pool imaging and ventricular cineangiography, 54 patients (mean age 6.4 +/- 3.4 years) were studied. Twenty-eight patients were investigated preoperatively and 36 greater than 1 year after repair and compared with a control population. RESULTS: Before operation, end-diastolic volume and wall mass were significantly increased compared with those of control subjects; however, the mass/volume ratio was normal (1.08 +/- 0.31 g/ml for the preoperative group; 0.97 +/- 0.19 for control subjects). Although end-diastolic volume returned to normal after the procedure, wall mass remained elevated and contributed to an elevated mass/volume ratio (1.20 +/- 0.38 g/ml). After the procedure, systemic vascular resistance index was significantly elevated compared with that before surgery or with that of control subjects (1,199 +/- 373, 2,120 +/- 645, 1,556 +/- 275 dynes.s.cm-5.m2: pre- and postrepair and control subjects, respectively). Radionuclide studies demonstrated that preoperative ejection fraction (52 +/- 9, 50 +/- 9, 60 +/- 8%), peak ejection (2.58 +/- 0.66, 2.95 +/- 0.81, 3.73 +/- 0.70 EDV/s) and peak filling rates (2.84 +/- 0.75, 2.75 +/- 0.79, 3.84 +/- 0.51 end-diastolic volumes [EDV/s]) were significantly reduced compared with those of control subjects and remained so after surgery. CONCLUSIONS: These data suggest that systolic and diastolic function is depressed preoperatively in these patients, remains unchanged after the creation of an atrial-dependent circulation and is associated with an increased systemic vascular resistance. Long-term issues addressing preservation of cardiac function need to be prospectively studied.

Child↗
PubMed1992

Visual search: detection, identification, and localization.

In two studies, observers searched for a single oblique target in a field of vertical distractors. In one experiment, target detection and identification (left versus right tilt) were compared. In another experiment, detection and localization were compared for the left versus the right half of the display. Performance on all three tasks was virtually identical: if a target could be detected, it could also be identified and localized. A review of previous studies generally supports the conclusion that performance on the three tasks is similar. This argues against current search theories, which rest heavily on data showing differences in identification and localization.

Attention↗
PubMed1992

The expression of murine protein disulfide isomerase in Escherichia coli.

Protein disulfide isomerase (PDI), a luminal enzyme of the endoplasmic reticulum (ER), is thought to be involved in the process that assures that the correct disulfide bonds form as a newly synthesized protein folds into its appropriate three-dimensional structure (Freeman, 1984). In recent years, the ER has been shown to have at least two additional, distinct PDI-related luminal proteins (Bennett et al., 1988; Mazzarella et al., 1990). As a potential first step toward an investigation of the structure and function of PDI and of the PDI-related proteins as well, we have developed a bacterial expression system in Escherichia coli capable of synthesizing significant levels of enzymatically active PDI under the control of the inducible tac promoter. We have observed that the use of this bacterial expression system is complicated by the fact that there is a significant amount of internal initiation of protein synthesis within the PDI coding sequence and the fact that all of the PDI-related expression products are found equally distributed between the cytoplasmic and periplasmic fractions due to a single peptide-independent mechanism. Our studies with this system have demonstrated that at least some truncated PDI molecules containing the carboxy-terminal most active site have significant PDI activity.

Amino Acid Sequence↗
PubMed1992

A phase II study of cisplatinum and continuous infusion 5-fluorouracil for metastatic melanoma.

Advanced or metastatic melanoma responds poorly to chemotherapy, which has no impact on survival. Responses have been recorded using cisplatinum as a single agent. This study tested the established combination of cisplatinum 100 mg/m2 and 5-fluorouracil 1 g/m2/day continuously intravenously for 5 days repeated every 3 weeks in patients with disseminated melanoma. Twenty-nine patients, 13 having received no prior systemic chemotherapy, received 49 cycles of therapy (median 1, range 1-4). Only one previously untreated patient achieved a partial response with a failure-free survival of 6.5 months and an overall survival of 7.7 months from the commencement of therapy. The major toxicities were nausea and vomiting, (grade 3 in eight patients), stomatitis (grade 4 in two patients, grade 3 in two patients), and myelosuppression. The study showed that cisplatin and 5-fluorouracil have a low order of activity in patients with advanced or disseminated melanoma.

Adult↗
PubMed1992

Inadequate treatment response to des-enkephalin-gamma-endorphin compared with thioridazine and placebo in schizophrenia.

The possibility of an involvement of peptidergic systems in schizophrenia has been under investigation for a number of years. Studies of the efficacy of des-tyr-gamma-endorphin were equivocal; more recent studies with des-enkephalin-gamma-endorphin have reported some activity but the peptide has only been investigated as an adjunct to neuroleptic medication, apart from one very small active reference comparator study. In the multicentre study reported here, 96 patients suffering from schizophrenia (DSM-III with a current exacerbation if chronic) were allocated randomly to double-blind treatment with either des-enkephalin-gamma-endorphin (DE-gamma-E) (Org 5878) 10 mg given as a once daily intramuscular injection for 4 weeks, thioridazine 400 mg orally in 2 divided doses or placebo using a double-dummy technique to preserve blindness. There was a significant advantage for thioridazine compared with placebo registered on all measures at weeks 3 and 4. There was no difference between DE-gamma-E and placebo. There was a significant difference between thioridazine and DE-gamma-E at weeks 3 and 4 registered on the MSS and at week 3 registered on the BPRS. The lack of efficacy of DE-gamma-E suggests that the theories that the endorphins have an important role in schizophrenia have to be revised. The need for well designed placebo controlled studies for assessing efficacy in schizophrenia is emphasized.

Adult↗
PubMed1992

Duration of rifampin chemoprophylaxis for contacts of patients infected with Haemophilus influenzae type B.

Rifampin is recommended as a prophylactic treatment for intimate contacts of young children who develop invasive infections with Haemophilus influenzae type B (Hib). A 4-day course of rifampin (20 mg/kg of body weight per day, not to exceed 600 mg as a maximum single daily dose) is 95% effective in eradicating pharyngeal colonization with Hib, thus effectively reducing the risk of both associated patients and recurrent illness in index patients less than 2 years old. This study compares rates of eradication of pharyngeal colonization with Hib for 2- and 4-day courses of rifampin therapy. One hundred sixty-three patients with Hib infection were treated at Children's Hospital of Pittsburgh between January 1986 and December 1988; prophylaxis was recommended for 128. Participating families were randomized to receive either 2- or 4-day therapy. Throat swabs were obtained from contacts prior to therapy. Repeat cultures were obtained from colonized contacts 2 days after completing rifampin and again on all contacts 7 to 10 days after completing therapy. Of 68 participating families, 34 received 2-day and 34 received 4-day therapy with rifampin. Twenty-two of 24 colonized contacts in the 2-day group and 17 of 18 in the 4-day group had negative cultures for Hib on follow-up. Two-day therapy with rifampin appears to be as effective as 4-day treatment in the eradication of Hib pharyngeal colonization.

Administration, Oral↗
PubMed1992

Human herpes virus 6 and endogenous biotin in salivary glands.

AIMS: To detect the presence of human herpes virus 6 (HHV6) and endogenous biotin in paraffin wax embedded and frozen salivary glands. METHODS: Two stage indirect and streptavidin-biotin immunoperoxidase techniques were used to visualise the antigens. RESULTS: HHV6 could not be shown in any of the tissues. However, considerable endogenous biotin antigenicity was detected in the glandular elements of the paraffin wax embedded material. CONCLUSIONS: Results obtained with avidin-biotin detection systems should be interpreted with caution, especially when glandular epithelium is being stained. This may apply to both immunoperoxidase and in situ hybridisation techniques. The use of an anti-biotin antibody as a standard control should be considered.

Biotin↗
PubMed1992

Repetitive stimulation of phrenic nerves in myasthenia gravis.

BACKGROUND: In the investigation of patients with myasthenia gravis, repetitive supramaximal stimulation of an affected peripheral nerve is commonly performed to detect abnormal transmission at the neuromuscular junction. A study was undertaken to determine whether abnormal transmission could similarly be detected during stimulation of the phrenic nerves. METHODS: The phrenic nerves were stimulated supramaximally with surface electrodes in 13 patients with myasthenia gravis and in 16 control subjects (six control patients with diaphragmatic weakness but not with myasthenia and ten normal subjects). The amplitude of diaphragm muscle action potentials was measured with surface electrodes during phrenic nerve stimulation at frequencies of 1-5 Hz for 3-4 seconds. RESULTS: In five patients with myasthenia gravis, a significant decrement (15-43% decrease) occurred in the amplitude of diaphragm muscle action potential during stimulation at 3 Hz. When stimulation frequency was reduced to 1 Hz, diaphragm muscle action potentials returned to their original amplitude within 4-5 seconds. The decrement in the amplitude of the diaphragm muscle action potential was reduced temporarily in three of four patients after the administration of intravenous edrophonium chloride (Tensilon). There was no significant change (< 10% decrease) in the amplitude of diaphragm muscle action potentials during stimulation at increased frequencies either in the 16 control subjects or in eight of the patients with myasthenia gravis. CONCLUSION: A significant reduction in the amplitude of diaphragm muscle action potential occurred in five of 13 patients with myasthenia gravis during phrenic nerve stimulation at 3 Hz but in none of the control subjects. This may be a useful and non-invasive method for identifying patients with myasthenia gravis in whom weakness of the diaphragm is suspected.

Action Potentials↗