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Biomedical subjects

G P Rodgers

Publications and source records attributed to G P Rodgers.

At least 91 records · Page 5Linked to original sources
PubMed1990

Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea.

Because fetal hemoglobin contains gammaglobin chains instead of beta chains, it is not affected by the genetic defect that causes sickle cell disease. Increased levels of fetal hemoglobin decrease the tendency toward intracellular polymerization of sickle hemoglobin that characterizes this disease. Hydroxyurea is one of several cytostatic agents that have been shown to increase the production of fetal hemoglobin in some patients with sickle cell disease. We studied the effects of hydroxyurea administration in 10 hospitalized patients with sickle cell disease, each of whom was treated for three months. Seven patients responded with a 2- to 10-fold increase in fetal hemoglobin, from a mean (+/- SD) of 1.6 +/- 1.6 percent of total hemoglobin to 6.8 +/- 4.7 percent; three patients had fetal-hemoglobin levels of 10 to 15 percent of total hemoglobin. Three did not respond to treatment. Four of the patients who responded were retreated with hydroxyurea after one to four months without treatment and were found to have larger increases in fetal-hemoglobin levels. In most patients, levels were still rising at the end of the study, even after 90 days of therapy. Fetal-hemoglobin levels tended to peak at dosages of hydroxyurea that were myelosuppressive. In the patients who responded to treatment, there were significant increases in the percentage of reticulocytes and erythrocytes containing fetal hemoglobin and in the amount of fetal hemoglobin within these cells. The percentage of dense red cells decreased in the patients who responded to treatment. The tendency toward intracellular polymerization at physiologic oxygen saturation was reduced by about 33 percent in the cells containing fetal hemoglobin, whereas there was no change in the other cells. We conclude that hydroxyurea is effective in increasing the production of fetal hemoglobin, which in this study was found to be associated with a small decrease in hemolysis and an increase in hemoglobin levels despite myelosuppression. Controlled, prospective trials are necessary to establish whether these effects will lead to clinical benefit.

Adult↗
PubMed1990

Microcirculatory adaptations in sickle cell anemia: reactive hyperemia response.

With the technique of laser-Doppler velocimetry, cutaneous blood flows in the forearm of patients with stable sickle cell disease after graded periods of proximal ischemia were compared with normal subjects matched for age, race, and sex, and with patients with anemia caused by beta(+)-thalassemia. In the sickle cell patients the reactive hyperemia was characterized by an increased time interval between the release of the occlusion and the peak amplitude response (time-to-peak) and by a greater period of blood flow above the base-line value (payback ratio) compared with controls. In addition, prolongation of the occlusion period led to an augmentation in the magnitude of the characteristic basal flow oscillations or an induction of this phenomenon at sites not exhibiting it before ischemia. Base-line or ischemia-provoked flow oscillations of either this magnitude or frequency were only observed in normal or thalassemic controls during brief intervals in the rapidly decaying portion of the hyperemic response and in one subject with homozygous hemoglobin C disease. These results would support a model of a local integrative control of microcirculatory blood flow, which appears to become augmented, synchronized, and sustained in sickle cell subjects.

Adaptation, Physiological↗
PubMed1990

Adjuvant therapy for intracoronary stents. Investigations in atherosclerotic swine.

Early thrombosis has complicated human stent implantation in several trials. To determine the best anticoagulation/antiplatelet therapy to maintain stent patency after percutaneous transluminal coronary angioplasty, we implanted the flexible balloon-expandable coil stent into the left anterior descending coronary artery of 28 atherosclerotic 8-month-old Hanford miniature swine. Animals were randomly assigned to one of three treatment groups: group A, aspirin (1 mg/kg/day) and dipyridamole (1 mg/kg three times a day); group B, aspirin and dipyridamole (same doses) plus Coumadin (dose required to prolong prothrombin time 1.3-1.5-fold that of normal); and group C, control. Adjuvant therapy was begun 3 days before stenting. Two pigs (one from group A and one from group B) died during implantation, both without thrombosis. Twenty-six animals survived until follow-up angiography and sacrifice at 1 month. No occlusive thrombosis of the stent occurred in survivors. Reduction of the stent lumen diameter was observed in every case at follow-up. Percent lumen reduction was 19% in group A, 26% in group B, and 24% in group C. Marked smooth muscle cell hyperplasia was seen by light and transmission electron microscopy at stent struts. Scanning electron microscopy of the luminal surface showed a variable morphology consisting of normal endothelium, adherent leukocytes, stellate periluminal cells, and occasional fibrin strands and red blood cells. Luminal narrowing was not affected by anticoagulation therapy, antiplatelet drugs, cholesterol level, or stent sizing. We conclude that occlusive thrombosis does not complicate stent implantation in this model but that substantial luminal narrowing due in part to smooth muscle hyperplasia does occur. The significance of luminal narrowing at the stent site requires further study.

Angiography↗
PubMed1990

Warfarin sodium for anticoagulation of atherosclerotic miniature swine.

Warfarin sodium (Coumadin) has been used as an effective anticoagulating agent in human medicine for many years, although careful monitoring of its effects are necessary to avoid excessive anticoagulation. Previous experience with this drug for chronic anticoagulation therapy in miniature swine has been limited. The effect of warfarin sodium was studied by measuring prothrombin time in twelve 8-month-old Hanford miniature swine. The pigs had been fed a high-cholesterol diet and had undergone a prior coronary artery abrasion procedure for development of an atherosclerotic coronary disease model. Atherosclerosis was induced by feeding a high-cholesterol diet. Baseline prothrombin time ranged from 12.8 to 15.0 s (13.7 s mean). Prothrombin time was determined daily for the first 5 days of treatment and at least twice weekly thereafter until the animals were sacrificed. Animals received warfarin for 37-41 days. Prothrombin time could be increased 33-50% by once daily oral administration of warfarin 0.04-0.08 mg/kg. Oral administration of more than 0.08 mg/kg as a maintenance dose resulted in the death of two pigs. Most animals responded well to 0.08 mg/kg for the first 3 days of treatment followed by a maintenance dose of 0.06 mg/kg. Dosage was adjusted periodically when prothrombin times exceeded 50% above baseline. It is our experience that monitoring prothrombin time at least twice weekly and adjusting the maintenance dose can eliminate death losses due to warfarin intoxication.

Animals↗
PubMed1989

Intracellular polymerization. Disease severity and therapeutic predictions.

The extent of intracellular polymerization of hemoglobin S, leading to loss of erythrocyte deformability and eventual morphological sickling, is primarily determined by oxygen saturation and intracellular hemoglobin concentration and composition. Epidemiological analysis of sickle cell disease severity among the sickle syndromes and studies of the biophysics of intracellular polymerization were used to estimate the potential clinical benefit of various therapeutic strategies. These strategies include those designed to increase deoxyhemoglobin S solubility; to increase erythrocyte volume or water content, thereby reducing the intracellular hemoglobin concentration; or, most recently, to decrease the proportion of hemoglobin S by increasing the amount of non-S hemoglobin. Increasing levels of hemoglobin F is of particular interest due to its "sparing" effect in inhibiting polymerization, the well-characterized epidemiological associations of high levels of hemoglobin F with reduced disease severity, and recent studies of drug-induced increases in hemoglobin F. Our analyses of equilibrium polymer formation at physiological oxygen saturation values suggest that small decreases in polymer formation at intermediate levels of hemoglobin F may give rise to a small decrease in anemia (as associated with homozygous alpha-thalassemia coexistent with sickle cell anemia), but that greater reductions in polymer formation may be necessary to effect a significant improvement in disease severity. Current studies of hydroxyurea-induced increases of hemoglobin F give cautious optimism that therapeutically useful levels may be attainable.

Anemia, Sickle Cell↗
PubMed1989

Hemodynamic studies in sickle cell disease.

With the availability of these noninvasive imaging modalities, one can now obtain more objective information about microcirculatory pathophysiology. As a result, previously held pathophysiologic paradigms in sickle cell disease will undoubtedly require modification or abandonment. These approaches should be viewed as supplements, not substitutes, for more traditional evaluations. Nonetheless, since these techniques are amenable to sequential application, these approaches promise to define disease severity more precisely, in quantitative terms, and should provide the means to follow the results of therapy unambiguously.

Anemia, Sickle Cell↗
PubMed1988

Brain glucose metabolism in neurologically normal patients with sickle cell disease. Regional alterations.

Neurologic dysfunction is a significant source of morbidity and mortality in the sickle cell diseases, occurring with a prevalence of 6% to 34%. Because changes in brain glucose metabolism may precede gross functional or morphologic alterations, we recently applied the technique of positron emission tomography with fluorodeoxyglucose F 18 in an exploratory study to compare six patients with sickle cell disease without prior neurologic abnormalities (and with normal cranial computed tomographic scans) with six healthy age-matched controls, with respect to overall and regional cerebral metabolic rates for glucose. We found no significant difference in the global metabolic rates for the two groups. However, we observed an unusual clustering of abnormal regional cerebral metabolic rates for glucose in the frontal lobes of these subjects. These results support previous observations that frontal lobe involvement may be quite prevalent in sickle cell disease, even among individuals with normal computed tomographic scans.

Adult↗
PubMed1988

Use of selective vasodilation in treatment of sickle cell disease.

Individuals with sickle cell disease and its genetic variants demonstrate a modest to severe hemolytic anemia. They are also prone to both acute and chronic vaso-occlusive phenomena, which may lead to irreversible tissue damage, organ failure, and premature death. To better understand these vaso-occlusive phenomena, it would be useful to determine the extent to which arteriolar microvascular obstruction might contribute to the pathogenesis of sickle cell disease. We studied the hematologic and ocular effects of orally administered nifedipine in several steady-state patients and compared these with a case-control group of patients not receiving nifedipine. In the nifedipine-treated patients, a striking reversal in ischemic retinal and conjunctival changes was observed, as well as a significant improvement in color vision performance. In addition, the treated subjects showed a slight but significant decline in the levels of both indirect serum bilirubin and plasma hemoglobin, suggesting a concurrent amelioration in the rate of hemolysis. These observations are consistent with the hypothesis that inappropriate vaso-constriction, or frank vasospasm, perhaps in response to the altered rheology of red cells containing polymerized hemoglobin S, may play an important role in the pathophysiology of sickle cell disease. Furthermore, selective vasodilation may prove to be a useful adjunctive approach to the treatment of the manifestations of the sickle syndromes.

Adult↗
PubMed1988

Bretylium and diltiazem in porcine cardiac procedures.

The use of miniature swine as a model for cardiovascular diseases of humans is becoming more popular for many reasons. One of the problems involved in using swine is their propensity for fatal cardiac arrhythmias during surgical procedures requiring general anesthetics, especially cardiac procedures. In preparation for use as a model of human atherosclerotic coronary artery disease, 30 three-month-old (15 kg) Hanford miniature swine underwent left heart catheterization, coronary angiography, and abrasion of the left anterior descending coronary artery. All pigs were treated with diltiazem HCl 30-60 mg (2-4 mg/kg) three times daily and aspirin 25 mg once daily, both given orally for three days before surgery. General anesthesia was induced with a combination of ketamine HCl 25 mg/kg, atropine sulfate 0.1 mg/kg, and acepromazine 0.22 mg/kg, all given intramuscularly. Halothane 1-2% and nitrous oxide 30% were used to maintain general anesthesia after endotracheal intubation. After successful cannulation of the femoral artery, all animals were given 200 units/kg heparin and 5 mg/kg bretylium tosylate intravenously. The electrocardiogram and mean blood pressure were monitored throughout the procedure. No significant change in blood pressure was noted during the procedure. Intracoronary nitroglycerin 200 micrograms was administered prior to abrasion of the left anterior descending with a 2.0-mm angioplasty balloon. The pigs were allowed to recover after routine closure of the incision. One pig (1/30) died during the abrasion procedure as a result of ventricular fibrillation. This represents a low, acceptable mortality using the present regimen compared with other regimens.

Animals↗
PubMed1988

Is there a role for selective vasodilation in the management of sickle cell disease?

To test the hypothesis that microvascular obstruction to blood flow at the level of the arteriole may be significant in individuals with sickle cell anemia, the ophthalmologic effects of orally administered nifedipine were monitored in 11 steady-state patients. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment. Two other patients showed fading of retroequatorial red retinal lesions. Color vision performance was improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in the amount of blanching of the conjunctiva which reflects improved blood flow to this frequently involved area. Such improvements were not observable in a control group of untreated stable sickle cell subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis of the microvascular lesions of sickle cell disease and, further, that selective microvascular entrapment inhibition may offer an additional strategy to the management of this disorder. We believe a larger, placebo-controlled study with nifedipine and similar agents is warranted.

Adult↗
PubMed1987

Retroequatorial red retinal lesions in sickle cell anemia.

We report 2 patients with sickle cell anemia who showed retroequatorial localized red retinal lesions. In 1 patient these lesions were associated with closure of the retinal precapillary arteriole and capillary bed. In both patients these lesions receded during the course of therapy with a selective arteriolar vasodilator, nifedipine. These observations are discussed in relation to the possible pathogenesis of the retinopathy seen in patients with sickle cell anemia.

Adult↗
PubMed1987

The development of non-invasive methods to evaluate sickle cell patients in the steady state and in crisis.

Methodologies now exist that promise to disclose fundamental and critical information about the microvascular status of patients with sickle cell disease. Several of these modalities are in an embryonic stage of development, whereas others are close to being ready for application to clinical trials. It is important that these sophisticated diagnostic techniques not supplant our clinical approach to the patient. However, it is hoped that these strategies will allow us to understand better the extreme spectrum of disease manifestations, as well as to provide objective means of monitoring the response to therapy in patients with sickle cell disease.

Anemia, Sickle Cell↗