Biomedical subjects

B Guth

Publications and source records attributed to B Guth.

12 recordsLinked to original sources

PubMed1997

Inhibition of platelet aggregation as a surrogate marker.

Using acetylsalicylic acid-dipyridamole, a combined thromboxane receptor antagonist-thromboxane synthase inhibitor, and a fibrinogen receptor antagonist as examples, this article discusses the predictive value of several methods that may be employed in the evaluation of antiaggregatory effects and their suitability as surrogate markers for the planning of patient studies. Platelet aggregation in various ex vivo tests and the effects of drugs on these tests were investigated using platelet aggregation in platelet-rich plasma and in whole blood, and in thrombus formation on a thrombogenic surface. Drug-induced inhibition of platelet aggregation is based on the modulation of metabolic processes or interactions at the membrane-receptor level. These effects must be assessed by methods adapted specifically to each mode of action, for example, mediator synthesis inhibition (cyclooxygenase), thromboxane receptor antagonism-thromboxane synthase inhibition, or fibrinogen receptor blockade. Thus a combination of both general and specific methods adapted to the respective mode of action of the test substance can serve as surrogate markers of drug efficacy for the efficient planning of clinical trials.

Animals↗

PubMed1995

Predictive value of hCG level 14 days after embryo transfer.

OBJECTIVE: It has been reported that the quantitative serum hCG level 14 days after embryo transfer (ET) correlated with pregnancy outcome as well as a likelihood of a multiple gestation pregnancy. This prospective study was designed to assess the predictive value of a 14-day post-ET hCG level with pregnancy outcome and multiple gestation pregnancies. METHODS: Patients undergoing in vitro fertilization (IVF) and ET were monitored by serum quantitative hCG levels 14 days after ET. If positive, serial values of hCG were obtained and transvaginal ultrasound was performed 3 weeks after ET and weekly until fetal cardiac activity was seen. Ongoing pregnancies were defined as greater than 20 weeks. RESULTS: One hundred eleven patients had positive serum quantitative hCG levels 14 days post-ET; 89/111, or 80.2%, had ongoing pregnancies. The spontaneous miscarriage rate was, therefore, 19.8% (22/111). If the level was less than 300, the ongoing multiple pregnancy rate was 9% (5/57). If the level was between 300 and 600, the ongoing pregnancy rate was 40% (10/25). If the hCG level was greater than 600, the multiple pregnancy rate was 100% (7/7). CONCLUSIONS: These data support the hypothesis that hCG levels greater than 200 mIU/ml on 14 days post-ET are more likely to have ongoing pregnancies; hCG levels greater than 600 have a high likelihood of a multiple gestation pregnancy.

Chorionic Gonadotropin↗

PubMed1993

Characterization of the linker peptide of the single-chain Fv fragment of an antibody by NMR spectroscopy.

A comparison of the single-chain Fv fragment of the antibody McPC603 (scFv) with its corresponding unlinked Fv fragment has been carried out with 15N-edited NMR spectroscopy. The two Fv fragments adopt the same structure, indicating that the linker does not perturb the folding of the domains. This also directly demonstrates that folding in vivo (Fv fragment) and in vitro (scFv fragment) leads to the same structure. The main differences in the spectra of the uniformly 15N-labeled scFv and Fv fragments are due to signals of Gly and Ser from the linker peptide of the scFv fragment. The linker peptide has been mapped with NMR spectra of 15N-glycine- and 15N-glycine/15N-serine-labeled scFv fragments. The 15N T2 relaxation data indicate that the linker peptide is more flexible than the rest of the molecule.

Glycine↗

PubMed1988

Quantitative assessment of regional left ventricular function by densitometric analysis of digital-subtraction ventriculograms: correlation with myocardial systolic shortening in dogs.

Conventional wall motion analysis of contrast ventriculograms assesses only that part of the wall that is tangential to the x-ray beam. To assess regional left ventricular function in three dimensions, a new computerized method based on densitometric analysis of digital subtraction left ventriculograms was developed and validated in nine open-chest dogs instrumented with a circumflex coronary artery occluder and sonomicrometers in the anterior and posterior walls. Each dog underwent digital subtraction ventriculography at baseline and at five levels (I to V) of dysfunction of the inferior wall induced by progressive stenoses of the circumflex coronary artery. The ventriculogram was divided into six segments around the end-diastolic center of gravity. Time-volume curves were obtained by densitometry in the normal anterior and ischemic inferior segments containing the sonomicrometers. From these curves, regional ejection fraction (R-EF), regional peak ejection rate (R-PER), and regional phase (R-PH) and amplitude (R-AMP) of the first Fourier harmonic were derived. From baseline to level V of dysfunction, myocardial systolic shortening determined by sonomicrometry decreased by 124 +/- 34% of control (mean +/- SD; p less than .001) in the ischemic wall, while it increased by 12 +/- 19% (NS) in the normal wall. At the same time, R-EF, R-PER, and R-AMP decreased in the ischemic segment by 65 +/- 12%, 46 +/- 30%, and 45 +/- 15% of control, respectively (all p less than .01), while they remained unchanged or increased in the normal segment. R-PH was delayed by 14 +/- 5% (p less than .01) in the ischemic segment, but remained unchanged in the normal segment, reflecting the asynchrony of regional left ventricular contraction during ischemia. Densitometric indexes of regional function correlated well with sonomicrometric systolic shortening both in normal and ischemic segments, with r values of .84 for R-EF, .80 for R-AMP, .64 for R-PER, and .55 for R-PH (all p less than .0001). Thus, densitometric analysis of digital subtraction left ventriculograms allows three-dimensional assessment of the extent, velocity, and synchrony of regional left ventricular contraction. Densitometric indexes of regional contraction correlate well with direct measurements of myocardial systolic shortening and are useful in quantitating regional left ventricular dysfunction.

Animals↗

PubMed1986

Exercise-induced regional dysfunction with subcritical coronary stenosis.

The hypothesis was tested that regional myocardial contractile dysfunction can detect subtle regional coronary blood flow maldistribution induced by exercise. In seven dogs, left ventricular pressure (micromanometer), regional systolic wall thickening (WTh, sonomicrometry), and myocardial blood flow (MBF, microspheres) were measured when mild degrees of coronary artery stenosis were produced during treadmill exercise. During exercise without coronary stenosis, WTh increased by 21 +/- 12% (SD), and transmural MBF increased uniformly. In each dog, two levels of coronary stenosis were produced during exercise by adjusting the coronary hydraulic cuff: (1) St-Ex I, where WTh during exercise failed to increase significantly (average change 0 +/- 7%), and (2) St-Ex II, where WTh during exercise decreased moderately from the resting control value (average -20 +/- 8%). In the potentially ischemic zone coronary hyperemia occurred with each run: resting subendocardial MBF was 1.09 +/- 0.30 mg/g/min, and it was 3.04 +/- 0.83 during control exercise, 2.48 +/- 0.75 during St-Ex I, and 1.55 +/- 0.59 ml/g/min during St-Ex II (p less than .01 compared with control exercise and control area). The subendocardial-subepicardial blood flow ratio fell from 1.32 +/- 0.27 during control exercise to 1.07 +/- 0.20 (p less than .05) during St-Ex I, and to 0.64 +/- 0.15 (p less than .01) with St-Ex II. Changes in the subendocardial electrogram and reactive hyperemia occurred more consistently during St-Ex II than St-Ex I. Thus, failure of regional function to increase during exercise detected slight maldistribution of regional MBF, whereas reduction of regional function during exercise of 10% or more below the resting value was a reliable marker of a regional flow defect and was always associated with other evidence of ischemia. Therefore, regional dysfunction during exercise can detect subcritical but functionally significant coronary stenosis, which may allow regional wall motion to be used for detecting coronary artery disease at a relatively early stage.

Animals↗

PubMed1986

Regional myocardial blood flow and function in experimental myocardial ischemia.

Experiments are reviewed in conscious dogs instrumented with ultrasonic crystals for measuring systolic wall thickening and myocardial blood flow (microsphere technique), and studied under a variety of conditions during acute or chronic circumflex coronary stenosis. With acute progressive stenosis, a nearly linear relation was found between normalized subendocardial flow and function. There were no consistent ST segment changes in the body surface electrocardiogram if wall thickening was less than 25%, although changes occurred in the subendocardial electrogram. The regional flow-function relation was then examined during exercise with various degrees of coronary stenosis; the mean flow-function relation was shifted to the right of the resting relation, but when subendocardial flow was expressed per beat and function normalized as a fraction of that in normal wall the relationship was superimposable upon the resting relation, suggesting that ischemia is absolute (not relative) in the subendocardium during steady state conditions. When the normal increase of wall thickening during exercise was prevented by mild coronary stenosis ischemia could not be clearly detected, but when function during exercise averaged 20% below the resting value, subendocardial blood flow changes and other evidence of ischemia were readily apparent, indicating the sensitivity of wall motion for detecting subcritical coronary stenosis. The regional flow-function relation was also studied in chronic single vessel coronary artery stenosis (ameroid constrictor), in which function was normal at rest (collateral development) but exercise produced large decreases in both regional flow and function. At matched levels of treadmill exercise, a calcium channel blocker (diltiazem) together with beta blockade (atenolol) produced an additive effect that was greater than with either drug alone, with substantial increases in both subendocardial flow and regional function. Finally, studies showing reversible post-reperfusion dysfunction after 15 minutes or two hours of coronary occlusion are reviewed. Partial ischemia for 5-hours, followed by reperfusion also produced regional dysfunction which persisted for at least 3 days but reverted to normal by one week, with little or no histologic damage of the free wall. These studies on regional flow and function during ischemia may carry implications for a number of important clinical phenomena.

Animals↗

PubMed1985

Effects of transfusion-induced polycythemia on O2 transport during exercise in the dog.

An increased hematocrit could enhance peripheral O2 transport during exercise by improving arterial O2 content. Conversely, it could reduce maximal delivery of O2 by limiting cardiac output during exercise or by limiting the distribution of blood flow to peripheral capillaries with high O2 extractions. We studied O2 transport at rest and during graded treadmill exercise in splenectomized tracheostomized dogs at normal hematocrit (38 +/- 3%), and 48 h after transfusion of type-matched donor cells. This procedure increased hematocrit (60 +/- 3%) but also increased blood volume (P less than 0.05). Following transfusion, resting cardiac output (QT) and heart rate were not different. During exercise, QT was significantly lower at each level of O2 consumption (VO2) at high hematocrit (P less than 0.01). A reduction in QT was also seen during polycythemic exercise with hypoxemia produced by breathing 12 or 10% O2 in N2. Despite the reduction in QT, mixed venous PO2 was not lower at high hematocrit, and the increase in base deficit with VO2 was not different from control measurements. O2 delivery (QT X arterial content) was similar at each level of VO2 at both levels of hematocrit, during both normoxic and hypoxic studies. Both systemic and pulmonary arterial pressures were increased at rest after transfusion (P less than 0.05). However, pulmonary and systemic pressures were not higher than control during exercise at high hematocrit. We conclude that a hematocrit of 60% with increased blood volume is not associated with a cardiac limitation of O2 delivery, nor does it interfere with peripheral O2 extraction during exercise in the dog.

Animals↗

PubMed1985

Effect of the combination of diltiazem and atenolol on exercise-induced regional myocardial ischemia in conscious dogs.

The effect of combination therapy with diltiazem and atenolol on the regional myocardial blood flow-function relationship was studied in eight conscious dogs with chronic coronary artery stenosis. An ameroid constrictor and hydraulic occluder were placed around the left circumflex coronary artery, sonomicrometers were implanted for measuring wall thickness in control and ischemic regions, and regional myocardial blood flow was measured with the microsphere method. Eighteen days (average) after surgery, resting regional myocardial function and blood flow were normal, but treadmill exercise induced severe regional myocardial dysfunction in the posterior wall (wall thickening during systole reduced from 25.5% to 2.7%, a 90% reduction). Subendocardial blood flow decreased by 68% from the control standing value, while subepicardial flow increased. An identical exercise bout was performed 3 hr after administration of atenolol (1.0 mg/kg orally) and 15 min after administration of diltiazem (0.3 mg/kg iv). Heart rate during running was significantly lower as were left ventricular peak systolic pressure, end-diastolic pressure, and peak dP/dt. Wall thickening in the control region was not augmented during exercise after atenolol and diltiazem. There was less dysfunction in the ischemic region (35% reduction) and the improved performance was accompanied by a substantial increase in subendocardial perfusion (0.31 +/- 0.14 vs 0.61 +/- 0.30 ml/min/g, a 36% reduction from rest). Epicardial flow was unchanged, and the endocardial/epicardial ratio increased (0.27 +/- 0.13 vs 0.62 +/- 0.29). Recovery time for regional wall thickening also improved. The beneficial effects of the combination of atenolol and diltiazem in a preparation of single-vessel chronic coronary stenosis were shown to be significantly greater than those of either drug alone.

Animals↗

PubMed1985

Mechanisms of augmented segment shortening in nonischemic areas during acute ischemia of the canine left ventricle.

To examine the interaction between normal and nonischemic areas of the left ventricle during acute ischemia, we implanted midwall ultrasonic segment length gauges in the ischemic zone and in nonischemic areas of the canine left ventricle. During acute ischemia, end-diastolic pressure and segment length in the nonischemic areas increased. There was no change from control in the segment length at the time of aortic valve opening and closure. Thus, in nonischemic areas, total segment shortening, as measured by the percent change in segment length from the time of end-diastole to aortic valve closure, increased. This was due to an increase in isovolumic shortening (end-diastole to aortic valve opening) with no change in ejection shortening (aortic valve opening to closure). The progressive increase in isovolumic shortening in nonischemic areas over time was directly paralleled by the progressive development of the isovolumic lengthening or bulge in the ischemic zone. Nonischemic areas, whether adjacent, on the opposite wall, or distant to the ischemic zone, all behaved similarly. Adrenergic blockade did not qualitatively alter these findings. We conclude that acute ischemia induces a mechanical disadvantage which is greater than just the loss of contractile function by the ischemic segment. Despite the apparent hyperfunction of nonischemic areas, the increased total segment shortening is expended in stretching the ischemic zone during isovolumic systole. As a result, there is no significant "compensatory" increase in ejection shortening in nonischemic areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1984

Detection of ischemic wall dysfunction: comparison between M-mode echocardiography and sonomicrometry.

The quantification of regional ventricular function by M-mode echocardiography was compared to that by sonomicrometry in 10 closed-chest, sedated swine during temporary occlusions of the left circumflex coronary artery. Wall thickening during systole (%WT) was calculated to quantitate regional myocardial function, and percentage of fractional shortening (%FS) was calculated from both sonomicrometer tracings and M-mode echocardiograms. Ventricular dimensions at end diastole and end systole were also compared before and after 2 minutes of coronary artery occlusion. Both techniques detected significant changes in wall thickness, %WT, and %FS after occlusion. Changes in %WT during coronary artery occlusion detected by M-mode echocardiography and sonomicrometry had a significant linear relationship (p less than 0.05). Discrepancy between the two techniques in the measurement of wall thickness at end diastole was attributed to the difficulty in measuring relatively small distances with M-mode echocardiograms. However, we conclude that the clinical M-mode echocardiogram is capable of detecting acute regional wall dysfunction associated with ischemia.

Animals↗

PubMed1981

Correlation of regional myocardial blood flow and function with myocardial infarct size during acute myocardial ischemia in the conscious pig.

Regional myocardial function and blood flow were determined for 48 hours after permanent occlusion of the left circumflex coronary artery in conscious swine. Systolic wall thickening and end-diastolic wall thickness (EDWTh) were correlated with regional myocardial flow (RMBF) at 15 minutes, 24 and 48 hours after occlusion. Both regional function and blood flow were compared with the extent of myocardial necrosis (determined histologically) after 48 hours in functionally distinct zones. Group 1 (control zones) was characterized by increased systolic wall thickening, EDWTh, RMBF and had no necrosis. Group 2 (marginal zones) had depressed systolic wall thickening (35 +/- 3% [mean +/ SEM] of preocclusion level at 48 hours) and RMBF (64 +/- 6% of preocclusion values), transiently decreased EDWTh and 46 +/- 5% necrosis. In Group 3 (ischemic zones), all values were greatly reduced: systolic wall thickening was 3.6 +/- 1.2%, EDWTh 76 +/- 8% and RMBF 25 +/- 9% preocclusion values; necrosis was 90 +/- 5%. Groups 2 and 3 had increased RMBF at 24 and 48 hours from that at 15 minutes after occlusion; however, in neither case was systolic wall thickening greater than that at 15 minutes after occlusion. We conclude that there is close correlation between RMBF, systolic wall thickening and the extent of necrosis present after 48 hours of coronary artery occlusion in the conscious swine; subsequent increases in RMBF to the marginal zone after occlusion are not accompanied by improved regional function.

Animals↗

PubMedDate not supplied

Continuous assessment of multiple vital physiological functions in conscious freely moving rats using telemetry and a plethysmography system.

The general pharmacologist in the pharmaceutical industry is challenged to generate physiologically relevant data on possible safety liabilities or on secondary therapeutic uses as early as possible in drug development. This implies the need for efficient use of usually only small supplies of test article. For this reason, we have developed a new animal model combining various elements to provide a broad spectrum of data focussing on the so-called vital physiological functions: cardiovascular, respiratory, and central nervous system. This system uses rats chronically implanted with transmitters for the measurement of arterial pressure, ECG, and body temperature. Modification of the transmitters also allows for the simultaneous assessment of locomotor activity. Studies are performed with these rats in plethysmographs placed directly over the antenna units thus allowing for the additional assessment of respiratory function in the same studies. Using this system, we can generate simultaneously a wide range of relevant physiological parameters in conscious rats with a modest requirement for test article. Such an approach is highly useful for getting early safety readouts of potential drug development candidates as well as for detecting possible secondary therapeutic actions of a drug.

8-Hydroxy-2-(di-n-propylamino)tetralin↗