Characterization of a non-human primate model of drug-induced torsades de pointes.
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Animals↗
Biomedical subjects
M J Walker
Publications and source records attributed to M J Walker.
Determination of an arylacetamide antiarrhythmic in rat blood and tissues using reversed-phase high-performance liquid chromatography.
A method was developed for quantification of (+)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzo[b-] thiophene-4-acetamide (compound I), an antiarrhythmic drug, in rat whole blood, heart, brain, liver and skeletal muscle. Blood and tissue samples were homogenized and purified by chemical extraction. Chromatographic separations were achieved using reversed-phase high-performance liquid chromatography (HPLC) coupled with UV detection (215 nm). Drug recoveries from the extraction procedure ranged from 77 to 90%. Within- and between-day reproducibility of peak area (coefficient of variation) ranged from 1.1 to 15.7%. The detection limit was 80-200 ng/ml (in a 500-microliters extracted solution) depending on the type of biological sample. This method was used in a pharmacokinetic study of compound I disposition in rats after a bolus intravenous dose of 3.1 mg/kg.
Animals↗
Transfer of a pertussis toxin expression locus to isogenic bvg-positive and bvg-negative strains of Bordetella bronchiseptica using an in vivo technique.
Bordetella pertussis is the causative agent of whooping cough, a contagious childhood respiratory disease, increasing public concern over the safety of current whole-cell vaccines has led to decreased immunization rates and a subsequent increase in the incidence of the disease. The preparation of safer vaccines is at present concentrated on the production of detoxified virulence factors such as pertussis toxin (PT) for inclusion in acellular vaccine preparations. A permanently avirulent Bordetella bronchiseptica strain was previously engineered to constitutively produce PT. An in vivo cloning technique, based on the principles of conjugal mating and chromosome transfer was employed to transfer the PT expression locus of this strain to virulent and avirulent strains of B. bronchiseptica. This transfer was confirmed by Southern hybridization. An analysis of PT secretion in isogenic virulent and avirulent strains of B. bronchiseptica revealed that the PT produced was cell-associated and not secreted to the growth medium. This evidence suggests that B. bronchiseptica does not possess functional PT secretion (ptl) genes. Therefore, to achieve a PT expression and secretion system suitable for vaccine purposes in Bordetella bronchiseptica, functional ptl genes of B. pertussis are also required.
Bordetella bronchiseptica↗
Molecular analysis of the bvg-repressed urease of Bordetella bronchiseptica.
Bordetella bronchiseptica is a ureolytic mammalian respiratory pathogen. We have investigated the regulation of urease in B. bronchiseptica and the potential role of this enzyme in eukaryotic invasion and intracellular survival. Our results indicate urease is a bordetella virulence repressed gene. Urease activity in virulent B. bronchiseptica BB7865 is up-regulated from basal levels by 5 gl1 magnesium sulphate at 37 degrees C. At 30 degrees C, urease activity remained at basal levels, even in the presence on magnesium sulphate, suggesting a second temperature dependent mechanism of urease regulation was also operating. Urease was not inducible by 10 mM urea nor up-regulated in nitrogen limiting conditions. To evaluate the role of urease in intracellular invasion and survival urease-negative mutants of B. bronchiseptica BB7865 and B. bronchiseptica BB7866 were created by transposon mutagenesis, and compared to the urease-positive parental strains in a HeLa cell invasion assay. We demonstrate that increasing the concentration of urea in the assay increased survival of the urease-positive but not urease-negative strains after 24 h, suggesting that urease does have a role in intracellular survival. Partial DNA sequence analysis of an 11.0 kb EcoRI DNA fragment encoding urease activity revealed an open reading frame containing 50%, 45%, 45%, and 41% homology to the UreA urease subunit protein of Klebsiella aerogenes, Proteus vulgaris, Helicobacter pylori and Proteus mirabilis respectively. We also show Bordetella pertussis to contain sequences homologous with a DNA probe containing the gene encoding UreA of B. bronchiseptica indicating the possible presence of cryptic urease genes in this species.
Amino Acid Sequence↗
Effects of halothane and isoflurane on rat ventricular action potentials recorded in situ.
The effects of halothane and isoflurane on ventricular intracellular action potentials recorded in situ in pentobarbital anesthetized rats were studied. Halothane (0.5, 1 and 2 vol.%) and isoflurane (0.75, 1.5 and 3 vol.%) did not have identical effects on rat epicardial action potentials recorded by floating microelectrodes. However, over the concentration range tested, both anesthetics reduced blood pressure and heart rate to a similar extent. Isoflurane did not effect the maximum rate of rise of the action potential amplitude. However, 3 vol.% isoflurane reduced the resting membrane potential from -72+/-2 to -65+/-3 mV (mean+/-SEM, p<0.05) while the highest concentration of halothane had no effect. Halothane (2 vol.%) reduced action potential amplitude from 74+/-4 to 65+/-3 mV (p<0.05) and reduced the maximum rise rate of action potential from 175+/-21 to 133+/-8 V/s (p<0.05). Both isoflurane and halothane prolonged action potential duration at 10, 25 and 50% repolarization while only halothane significantly shortened action potential duration at 75% repolarization, Thus the effects of halothane and isoflurane on ventricular transmembrane action potentials were similar, but not identical. The relevance of such observations to the antiarrhythmic actions of halothane, but not isoflurane in this species is not clear.
Action Potentials↗
Pharmacology and education in Canada: a personal perspective.
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Canada↗
A review of carcinoma of the stomach at a tertiary care referral hospital.
BACKGROUND: Carcinoma of the stomach continues to cause a significant mortality in the United States. We reviewed the characteristics, treatment modalities, and survival of a group of patients with this cancer at a tertiary care referral hospital. MATERIALS AND METHODS: A retrospective computer based review of all patients with a diagnosis of carcinoma of the stomach in the Ohio State University (OSU) tumor registry was made. One hundred ninety-two analytical cases were found and the data was entered into a computerized database and analyzed. RESULTS: The overall median survival in this series of patients is 10 months with a median survival of 16 months (n.s.) in patients who underwent curative surgery (50% of the patients). There was an increased number of cardia lesion (37%) predominately in male patients (P < 0.05). A significantly greater number of female patients presented with linitis plastica and male patients with adenocarcinoma, although there was no difference in the operability, types of operations, and survival between the genders. Patients with signet ring cell cancer were significantly younger than the other two histological types reviewed but this did not alter outcome. CONCLUSION: Carcinoma of the stomach, despite newer image modalities, continues to present at advanced stages at time of diagnosis with an overall dismal prognosis. The increased incidence of cardia lesions noted require innovative therapies if any progress is to be made.
Adenocarcinoma↗
The addition of tamoxifen to dacarbazine and cisplatin in metastatic malignant melanoma. A phase II trial of the Southwest Oncology Group, (SWOG-8921).
Based on the reports of substantial improvement in the response rate w ith the addition of tamoxifen to a multiagent chemotherapy regimen for metastatic melanoma, Southwest Oncology Group (SWOG)-8921 was initiated. A prior regimen (SWOG-8804) of dacarbazine (DTIC) 750 mg/m(2) i.v. day 1 and cisplatin 100 mg/m(2) day 1 repeated every 3 weeks produced a 13% response rate in patients with metastatic melanoma without brain metastasis. SWOG-8921 using identical chemotherapy and schedule added tamoxifen 10 mg twice daily. There were 55 eligible patients registered, median age 52, with 37 men and 18 women. Fifty (91%) patients had evidence of visceral metastasis at registration. There were 10 responders (2 complete and 8 partial responses) for an 18% response rate (95% CI, 9-31%). The response rate in women was 28% (95% CI, 10-53%; in men, 14% (95% CI, 5-29%). Tamoxifen has produced a small increase in the response rate when added to the present combination and schedule of chemotherapy. Further Phase III trials will be necessary to assess whether there is a statistical advantage to the use of tamoxifen when combined with chemotherapy and whether there are statistical differences between men and women.
Adult↗
Reduced expression of HLA-B35 in schizophrenia.
The frequencies of HLA class I (HLA-A, B, C) and class II (HLA-DR, DQ) antigens were measured in 107 unrelated schizophrenic subjects and the results compared with 264 controls from south-east Scotland and a second control group of 133 individuals from north-east England. The expression of HLA-B35 was significantly reduced in the schizophrenic population compared to both control populations and these differences remained significant after correction for multiple testing. Linkage of schizophrenia and the major histocompatibility complex region of chromosome 6p was, however, excluded in a group of 17 families multiply affected with schizophrenia. Linkage was also excluded with several red cell antigens, red cell enzymes and plasma proteins. A negative association between the frequency of an HLA antigen and schizophrenia suggests that immune mechanisms may contribute to the aetiology of the disease in some subjects.
Adolescent↗
Clusterin, a putative complement regulator, binds to the cell surface of Staphylococcus aureus clinical isolates.
The ability of Staphylococcus aureus Cowan I strain and a number of S. aureus clinical isolates to bind to the human blood glycoprotein clusterin was investigated. Binding of clusterin to these strains was tested by both enzyme-linked immunosorbent assay and flow cytometry. All of the S. aureus strains examined appeared to bind clusterin to some extent, while nonpathogenic control strains Bacillus subtilis BR151 and Escherichia coli JM109 did not. Three S. aureus isolates were selected for more detailed study; binding of labeled clusterin was saturable, inhibited in the presence of excess unlabeled clusterin, and prevented by pretreatment of bacteria with proteases. From the saturation binding studies, estimates of the affinity constants for the binding of clusterin to the bacteria ranged from 31 to 57 nM. Addition of clusterin to S. aureus cultures was also found to result in aggregation of the bacterial cells; aggregation was not detected when clusterin was added to B. subtilis BR151 or E. coli JM109 cultures. These results suggest that at least some S. aureus strains possess specific proteinaceous receptors for clusterin. Such receptors may be an important new bacterial virulence determinant for S. aureus, as clusterin has been proposed to have a role in the regulation of complement activity.
Clusterin↗
Molecular characterization of a ribonucleotide reductase (nrdF) gene fragment of Mycoplasma hyopneumoniae and assessment of the recombinant product as an experimental vaccine for enzootic pneumonia.
A Mycoplasma hyopneumoniae clone bank was screened with hyperimmune pig serum. One clone exhibited sequence homology to the prokaryotic R2 subunit of ribonucleotide reductase and was expressed as an 11-kDa protein fused to beta-galactosidase. The vaccine potential of the fusion protein was assessed in pig trials. Following experimental challenge with a virulent isolate of M. hyopneumoniae, gross lung pathology (mean Goodwin lung score) of vaccinated animals, irrespective of adjuvant treatment, was significantly reduced compared with that of control unvaccinated pigs (P < 0.05).
Amino Acid Sequence↗
Isotretinoin and recombinant interferon alfa-2a therapy of metastatic malignant melanoma.
Twenty-five patients with metastatic malignant melanoma were treated with isotretinoin (13-cis-retinoic acid) orally at 1 mg/kg daily and recombinant interferon alfa-2a (INF-alpha) subcutaneously at 3 million units daily for 16-48 weeks. Therapy was well tolerated; fatigue and hyperlipidemia were the most frequent dose-limiting toxicity and necessitated dose reductions in 14 patients. Two patients achieved a complete response, and 3 responded partially for a total response rate of 20% (95% confidence interval: 4-36%). Responses occurred primarily in patients with limited tumor burden and disease confined to the skin and lymph nodes. Significant elevations in peripheral blood 2'-5'-oligoadenylate synthetase activity and natural killer activity were observed with therapy. The magnitude of these changes, however, was not predictive of response. Biopsy specimens of two responding lesions showed extensive necrosis of tumor. One specimen showed large aggregates of melanophages in association with tumor. The combination of isotretinoin and IFN-alpha is an active, easily administered regimen with acceptable toxicity for metastatic malignant melanoma.
2',5'-Oligoadenylate Synthetase↗
The cardiac electrophysiological effects of sparteine and its analogue BRB-I-28 in the rat.
This study compares the cardiovascular and antiarrhythmic effects of sparteine and a 3,7-diheterobicyclo[3.3.1]nonane analogue of sparteine, BRB-I-28, in pentobarbitone-anaesthetized rats subjected to left-ventricle electrical stimulation and occlusion of the left anterior descending coronary artery. Sparteine and BRB-I-28 produced a dose-dependent reduction in heart rate and blood pressure over the dose range 1-64 mumol/kg/min. As well, the P-R and Q-aT intervals of the electrocardiogram (ECG) were prolonged. The thresholds for induction of premature beats and ventricular fibrillation were dose-dependently increased and both drugs increased refractoriness. While sparteine and BRB-I-28 (at 16 and 64 mumol/kg/min, respectively) did not change the incidence of premature beats or ventricular tachycardia with coronary occlusion, both drugs equally reduced the incidence of ventricular fibrillation. We characterized the actions of sparteine and BRB-I-28 on cardiac Na+, transient outward and sustained outward plateau K+ currents of rat myocytes using the whole-cell patch-clamp. Sparteine and BRB-I-28 produced a concentration-dependent reduction in Na+ current with EC50 values of 110 and 230 microM, respectively. Both drugs produced hyperpolarizing shifts of 8 and 11 mV, respectively, for Na+ channel inactivation while neither produced a change in channel activation. Both drugs produced a concentration-dependent block of the sustained plateau K+ current and increased the rate of decay of the transient outward K+ current. Thus, sparteine and BRB-I-28 possess Na+ and K+ channel blocking properties which may account for their antiarrhythmic actions against electrical and ischaemic arrhythmias.
Animals↗
Lack of selectivity for ventricular and ischaemic tissue limits the antiarrhythmic actions of lidocaine, quinidine and flecainide against ischaemia-induced arrhythmias.
The antiarrhythmic effectiveness, electrocardiographic and haemodynamic properties of three representative class I antiarrhythmics have been investigated in anaesthetized rats. Quinidine, lidocaine and flecainide were chosen as representatives of class Ia, Ib and Ic, respectively. Lidocaine showed the greatest frequency and 'ischaemia' dependency and a high dose provided complete protection against ischaemic arrhythmias induced by coronary artery occlusion. Flecainide showed the least frequency and ischaemia dependency and the least antiarrhythmic effectiveness. Quinidine was only slightly more effective than flecainide. The three drugs were approximately equi-potent in lowering blood pressure which limited the maximum dose that could be tested. The highest dose of lidocaine also caused convulsions in conscious animals. Thus, while lidocaine had selectivity for ischaemic tissue, and for high frequencies, the central nervous system and cardiovascular toxicity limited its usefulness against ischaemia-induced arrhythmias. Quinidine and flecainide's lack of selectivity for ischaemia, and/or high frequencies, probably accounted for their limited antiarrhythmic actions against ischaemia-induced arrhythmias. This study emphasizes that class I drugs can only provide useful protection against ischaemia-induced arrhythmias if they have marked cardiac selectivity as well as selectivity for ischaemic cardiac tissue.
Animals↗
Effects of anipamil, a long acting analog of verapamil, in pigs subjected to myocardial ischemia.
In this study we examined the cardiovascular and possible antiarrhythmic actions of anipamil, a long acting analog of verapamil. Initial dose-response studies for anipamil (0.25-6.0 mg/kg, i.v.) in pentobarbitone-anesthetized pigs (n = 4) were conducted to determine the effects of the drug on EKG and hemodynamic measures. In this initial study anipamil was found to produce a dose-dependent reduction in blood pressure, left-ventricular pressure and its derivative (dP/dtmax), cardiac output, and increase in heart rate. These results were used as a basis from which to choose doses for a second study to assess antiarrhythmic actions of anipamil against arrhythmias induced by regional myocardial ischemia. The antiarrhythmic effects of the two doses were compared with verapamil when the latter was given at a dose producing cardiovascular effects mid-way between those produced by the two doses of anipamil. Anesthetized pigs were randomly assigned to receive one of three drug treatments, or vehicle control, prior to occlusion of the left-anterior descending coronary artery. Antiarrhythmic effectiveness of low (1.0 mg/kg + 0.10 mg/kg/min infusion, n = 8) and high (5.0 mg/kg + 0.50 mg/kg/min infusion, n = 12) dose anipamil was compared to that of verapamil (0.5 mg/kg + 0.60 mg/kg/min infusion, n = 8) in a vehicle controlled study (n = 15). Arrhythmic events (VPB, VT and VF incidence) were monitored and grouped according to their time of occurrence after occlusion. Thus phase 1a arrhythmias occurred 0-5 min after initiation of occlusion, phase 1b, 5-30 min, and phase 2, 0.5-4 hr after occlusion. This study showed that during phase 1a there was a low incidence of arrhythmias in all groups except the one receiving 5 mg/kg anipamil where the group incidence of VT was 58% as compared to 20% in controls (n = 15). Most ventricular arrhythmias occurred in all groups during phase 1b. In this phase verapamil abolished VF and reduced VT, as compared with controls. Anipamil (high and low doses) tended to reduce VT but not VF. In the period 0.5 to 4 hours post occlusion (phase 2) all three drug treatments were associated with fewer arrhythmias but this only reached statistical significance with verapamil. Thus verapamil was more efficacious than anipamil at providing antiarrhythmic protection against both early and late onset arrhythmias. Anipamil may have been proarrhythmic in the early phase of arrhythmias and only moderately antiarrhythmic, if at all, in the later phase.(ABSTRACT TRUNCATED AT 400 WORDS)
Analysis of Variance↗
The natural history of breast cancer with more than 10 positive nodes.
BACKGROUND: Experimental protocols are being used increasingly to treat breast cancer with > 10 positive nodes. An appreciation of the natural history of this disease is crucial for choosing the optimal therapeutic approach. PATIENTS AND METHODS: We retrospectively reviewed the records of 141 patients who had breast cancer with > 10 positive nodes and received definitive therapy at our institution in the years 1969 through 1991. Because therapy evolved during this period, we compared the results from 1969 through 1981 to those from 1982 through 1991. RESULTS: Ninety-one patients (65%) were > or = 50 years of age. Fifty-four (38%) were estrogen receptor (ER) positive, the remainder were ER negative or ER status unknown. Fifty-seven (40%) had 10 to 15 positive nodes, 63 (45%) had 16 to 25, and 21 (15%) had > 25. The ratio of positive nodes to total nodes was < 50% in 22 patients, 50% to 75% in 49, and > 75% in 70. One hundred thirty-four patients (95%) underwent modified or radical mastectomy. Forty (28%) received adjuvant chemotherapy, including 16 (11%) of 58 patients treated prior to 1981. Eleven patients (8%) were treated with adjuvant radiation therapy. The median survival for all patients was 52 months, with an actuarial survival of 29% at 10 years. Patients treated after 1981 had significantly improved survival. They lived a median of 68 months postoperatively, as compared to 41 months among patients treated earlier. CONCLUSIONS: This is a high-risk group of patients, yet there is a small subset who can obtain a long survival with standard treatment modalities.
Adult↗
Assessment of dose and time responses to TRH and thyrotropin in healthy dogs.
Changes in total thyroxine (T4 [TT4]), free T4 (FT4) and total tri-iodothyronine (T3 [TT3]) in serum after the intravenous administration of different doses of thyrotropin (TSH) and thyrotropin-releasing hormone (TRH) were measured in six healthy beagles. Significant (P < 0.05) elevations in serum TT4, FT4 and TT3 were observed at each sampling time (two, four, five, six, seven, eight and 10 hours) after administration of 1, 3 or 5 iu (total dose) TSH and peak mean responses were observed six to eight hours after injection. At six hours after injection the mean TT4, FT4 and TT3 levels were approximately 2.6, 3.9, and 1.5 times basal levels, respectively, and there were no significant differences between the three doses of TSH, Significant (P < 0.05) elevations in serum TT4 and FT4 but not TT3 were observed at each sampling time (two, four, five, six, seven and eight hours) after the administration of TRH. Peak mean responses were observed at four hours after injection at which time TT4 and FT4 levels were approximately 1.7 and 1.9 times basal levels, respectively. No significant differences were observed between the four doses of TRH used (100, 200, 300, and 600 micrograms total dose). Concentrations of TT4, FT4 and TT3 were significantly (P < 0.05) higher following the administration of TSH compared with TRH, and the response to TRH showed greater individual variation.
Analysis of Variance↗
NIAID expands research on topical microbicides to prevent STDs in women. National Institute of Allergy and Infectious Diseases.
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Anti-Infective Agents↗