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Biomedical subjects

W R Clarke

Publications and source records attributed to W R Clarke.

At least 37 records · Page 2Linked to original sources
PubMed1998

Developmental changes in lung cGMP phosphodiesterase-5 activity, protein, and message.

During transitional circulation, the pulmonary vascular bed undergoes a rapid and profound reduction in both tone and vascular smooth-muscle (VSM) content. 3',5'-Guanylate cyclic monophosphate (cGMP) is a crucial mediator in the regulation of pulmonary vascular resistance (PVR) and VSM proliferation. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases (PDEs). Among the cGMP-specific PDEs, PDE5 is quantitatively prevalent in lung tissue. We have investigated the levels of pulmonary PDE5 enzymatic activity, protein, and messenger RNA (mRNA) in ovine and mouse lung during perinatal development. We report that within 1 h following birth, PDE5 activity, protein, and mRNA levels decrease in both species, in a manner that correlates with known decreases in PVR in early transition. However, from 4 to 7 d following birth, a secondary increase in PDE5 activity, protein, and mRNA occurs in both ovine and mouse lung, suggesting a complex regulation of PVR and VSM proliferation in late perinatal development. Our data imply that PDE5 may be an important mediator in the regulation of PVR in normal and possibly in pathologic states, and may ultimately provide a basis for PDE5 inhibitors as a treatment for pulmonary hypertension.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1998

Effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension.

Inhaled nitric oxide (iNO) causes selective pulmonary vasodilation by increasing pulmonary vascular levels of cyclic guanosine monophosphate (cGMP). Dipyridamole, a drug with several putative vasodilator mechanisms, is an inhibitor of cGMP-specific phosphodiesterases (PDE5); it therefore has the potential to increase pulmonary vascular cGMP levels, lower pulmonary vascular resistance, augment iNO-induced pulmonary vasodilation, and attenuate excessive pulmonary vasoreactivity. To test dipyridamole in the pulmonary circulation, we studied pediatric patients undergoing cardiac catheterization who had severe resting pulmonary hypertension (Group 1; n = 11) or exaggerated acute hypoxia-induced pulmonary vasoconstriction (Group 2; n = 4). In Group 1, we compared the effects of iNO (20 ppm), dipyridamole (0.6 mg/kg), and combined treatments (iNO + dipyridamole) on pulmonary and systemic hemodynamics. In Group 2 we measured the pulmonary and systemic effects of dipyridamole while the patients were breathing room air and hypoxic gas mixtures (FIO2 = 0.16). One patient in Group 1 had a hypotensive response to dipyridamole and was exluded from study. In the remaining 12 studies done on 10 patients, iNO caused a selective decrease in mean pulmonary artery pressure (Ppa) and indexed pulmonary vascular resistance (PVRI) without affecting mean aortic pressure (Pao) or indexed systemic vascular resistance (SVRI). Dipyridamole decreased PVRI to similar values as did iNO, but this effect was primarily due to an increase in cardiac index (CI), and was not associated with any change in Ppa, and was associated with a decrease in Pao and SVRI. In comparison with individual treatments, combined therapy (iNO + dipyridamole) did not augment pulmonary vasodilation in the group as a whole; however, in 50% of patients, combined therapy decreased PVRI by 20% more than did iNO or dipyridamole alone. In Group 2, Ppa and the pulmonary-to-systemic resistance ratio (Rp/Rs) increased to suprasystemic levels during acute hypoxia. Pretreatment with dipyridamole blunted the increase in Ppa and Rp/Rs during repeat hypoxia, keeping Ppa at a subsystemic level and Rp/Rs < 1. We conclude that: (1) dipyridamole nonselectively reduces PVRI, primarily through an increase in CI; (2) in combination with iNO, dipyridamole augments the decrease in PVRI in some patients; and (3) dipyridamole blunts the severity of acute hypoxic pulmonary vasoconstriction in children with exaggerated hypoxic pressor responses.

Administration, Inhalation↗
PubMed1997

Acute right heart failure due to adenotonsillar hypertrophy.

A case is presented in which a child with underlying chronic lung disease, developed cor pulmonale and severe pulmonary hypertension as a result of adenotonsillar hypertrophy. His cardiac function acutely decompensated with an upper respiratory infection which exacerbated his obstructive sleep symptoms. Pre and postoperative documentation of cardiopulmonary function was critical in the peri-operative management of this patient. His severe pulmonary hypertension was stabilized using a nasopharyngeal airway and medications pre-operatively, in order to minimize his risk of anesthesia. He continued to require careful monitoring and manipulation of his medications after adenotonsillectomy and bronchoscopy. Serial echocardiograms documented the effects of the various interventions implemented in this patient. Severe acute right heart failure is an unusual complication of obstructive sleep apnea. However, this may become more common as more children survive prematurity and its associated chronic lung disease. These children may have subclinical lung disease and/or chronic pulmonary hypertension even after they no longer require supplemental oxygen and bronchodilators. Because these children are often tenuous, with regard to their cardiopulmonary function, they may be at increased risk to develop significant complications related to obstructive sleep apnea. It is important that a physician familiar with the management of pulmonary hypertension be involved in the care of these patients.

Adenoidectomy↗
PubMed1997

Design of the Trial of Org 10172 in Acute Stroke Treatment (TOAST).

TOAST is a multicenter, randomized, placebo-controlled clinical trial testing the usefulness of a new antithrombotic drug in improving the outcome of persons with acute ischemic stroke. Until recently, no clinical trial testing a treatment for ischemic stroke had demonstrated efficacy in outcome. Design problems of previously conducted trials with inconclusive results may partly explain their failures. During the design of TOAST, the investigators addressed several issues so the trial could test the treatment accurately. We report the strategies used in designing, implementing, and coordinating the trial.

Adult↗
PubMed1996

Silent cerebral infarction in patients enrolled in the TOAST Study.

To determine the frequency, location, size, and risk factors for silent cerebral infarctions (SCIs) on brain CT, we identified 629 patients without a history of previous stroke who were enrolled in a multicenter clinical trial of therapy for acute ischemic stroke. On the baseline CT, 143 patients (22.7%) had SCIs; 34.3% of the lesions were in the right hemisphere, 38.5% in the left hemisphere, and 27.3% were bilateral. The lesion size was < 1 cm in 65.7%, and the most common site was the basal ganglia (48.3%). Patients with SCI were compared with controls without SCI to determine the odds ratios (ORs) for each risk factor. On univariate analysis, race (black versus white) had an OR of 1.80 (95% confidence interval [CI], 1.14 to 2.85), male sex an OR of 1.68 (95% CI, 1.12 to 2.51), and congestive heart failure an OR of 1.88 (95% CI, 1.07 to 3.31). Significant risk factors on multivariate analysis include age (OR 1.03 per year, p = 0.0070), male sex (OR 1.78, p = 0.0094), and race (OR 2.43, p = 0.0004). After including interaction terms with age and hypertension and age, sex, and race, hypertension was also a significant risk factor.

Adolescent↗
PubMed1996

A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease.

A 1-year, double-blind, placebo-controlled, randomized, parallel-group study compared the efficacy and safety of acetyl-L-carnitine hydrochloride (ALCAR) with placebo in patients with probable Alzheimer's disease (AD). Subjects with mild to moderate probable AD, aged 50 or older, were treated with 3 g/day of ALCAR or placebo (1 g tid) for 12 months. Four hundred thirty-one patients entered the study, and 83% completed 1 year of treatment. The Alzheimer's Disease Assessment Scale cognitive component and the Clinical Dementia Rating Scale were the primary outcome measures. Overall, both ALCAR- and placebo-treated patients declined at the same rate on all primary and most secondary measures during the trial. In a subanalysis by age that compared early-onset patients (aged 65 years or younger at study entry) with late-onset patients (older than 66 at study entry), we found a trend for early-onset patients on ALCAR to decline more slowly than early-onset AD patients on placebo on both primary endpoints. In addition, early-onset patients tended to decline more rapidly than older patients in the placebo groups. Conversely, late-onset AD patients on ALCAR tended to progress more rapidly than similarly treated early-onset patients. The drug was very well tolerated during the trial. The study suggests that a subgroup of AD patients aged 65 or younger may benefit from treatment with ALCAR whereas older individuals might do more poorly. However, these preliminary findings are based on past hoc analyses. A prospective trial of ALCAR in younger patients is underway to test the hypothesis that young, rapidly progressing subjects will benefit from ALCAR treatment.

Acetylcarnitine↗
PubMed1995

The effect of propofol on normal and increased pulmonary vascular resistance in isolated perfused rabbit lung.

The effects of propofol and its intralipid vehicle on increased and normal pulmonary vascular resistances (PVR) were studied in an in situ perfused rabbit lung model which controlled all major determinants of PVR. Propofol at both 5 and 10 micrograms/mL significantly reduced PVR increases by the thromboxane mimetic, U46619. In contrast, similar volumes of intralipid further increased PVR. Neither propofol nor intralipid had any effect on normal PVR. We conclude that propofol at 5 and 10 micrograms/mL is able to reduce increased PVR but has no effect on normal PVR.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Group A streptococcal necrotizing fasciitis complicating primary varicella: a series of fourteen patients.

We retrospectively reviewed the clinical course of group A Streptococcus necrotizing fasciitis complicating primary varicella in children admitted to Children's Hospital and Medical Center, Seattle, WA, during a 18-month period. The potential benefit of various therapeutic interventions was examined. Fourteen children ages 6 months to 10 years were treated for group A Streptococcus necrotizing fasciitis as a complication of primary varicella. Eight patients experienced a delay in initial diagnosis as a result of nonspecific, early clinical findings of necrotizing fasciitis. Each patient underwent surgical exploration with fasciotomies and debridement. Initial antibiotic therapy was broad spectrum and included clindamycin. Hyperbaric oxygen therapy for as many as 6 treatments was used as adjunctively therapy in 12 patients, with subjective benefit in 6 patients. All 14 patients were discharged home with good function and no long term sequelae. This potentially fatal bacterial infection of the deep fascial layers requires early recognition by primary care physicians and an intensive, multidisciplinary therapeutic approach, including thorough surgical debridement and appropriate antibiotic therapy.

Anti-Bacterial Agents↗
PubMed1995

Dipyridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus.

Endogenous nitric oxide (NO) modulates fetal pulmonary vascular tone by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production in vascular smooth muscle. Because cGMP is hydrolyzed and inactivated by phosphodiesterase enzymes, we evaluated the hemodynamic effects of two cGMP-specific phosphodiesterase (PDE5) inhibitors, dipyridamole and zaprinast, in the near-term chronically prepared ovine fetus. Brief (10 min) intrapulmonary infusions of dipyridamole caused dose-dependent increases in left pulmonary artery flow and decreases in left pulmonary arterial resistance that persisted for > 40 min after termination of the infusion. Prolonged (2 h) infusions of dipyridamole caused sustained pulmonary vasodilation throughout the infusion period. To compare the hemodynamic effects of dipyridamole with the PDE5 antagonist zaprinast, we studied the responses to equimolar doses of both agents in four fetuses. Zaprinast caused dose-dependent pulmonary vasodilation that was equivalent to that noted with equimolar doses of dipyridamole. To determine whether adenosine is involved with dipyridamole-induced pulmonary vasodilation, we compared the hemodynamic response to dipyridamole before and after administration of the potent adenosine receptor (P1) antagonist 8-phenyltheophylline (8-PT). Pretreatment with 8-PT markedly attenuated adenosine-induced pulmonary vasodilation but had no effect on the hemodynamic response to dipyridamole. We conclude that cGMP-specific phosphodiesterase activity is important in regulating fetal pulmonary vascular tone. In addition, dipyridamole administration causes dose-dependent pulmonary vasodilation that is equivalent to zaprinast and not primarily due to its effects on adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1995

Accuracy of initial stroke subtype diagnosis in the TOAST study. Trial of ORG 10172 in Acute Stroke Treatment.

Rapid identification of stroke subtype is valuable for both practicing clinicians and the optimal design of clinical stroke trials. Mechanisms of ischemic injury might differ among different stroke subtypes. Certain subtypes might be clinically identified as suboptimal for future therapeutic or prophylactic stroke trials. Some subtypes might be so clinically distinct that extensive laboratory investigation is unwarranted. Investigators in the ongoing Trial of ORG 10172 in Acute Stroke Treatment are using criteria to categorize stroke etiology among enrolled patients into one of five subtypes: large-artery atherothromboembolic, cardioembolic, small-vessel thrombotic, other etiology, or undetermined etiology. As part of the study, physicians initially predict the most likely subtype of stroke based on clinical features and baseline CT. Three months after stroke, investigators use the criteria, which also incorporate results of diagnostic testing, to reclassify stroke subtype. Initial clinical impression of subtype agreed with final determination in 62% of patients, and the rate was similar for all stroke subtypes. No stroke subtype was more accurately diagnosed than others by initial assessment. No subtype was more commonly identified by diagnostic studies. Fifteen percent of patients remained without a clear etiologic subtype diagnosis at 3 months. We conclude that clinical trials in stroke should not attempt to restrict entry into trials based on presumed stroke subtype. A careful evaluation for etiology is justified in all patients presenting with stroke, regardless of presumed subtype.

Cerebrovascular Disorders↗
PubMed1994

The type III phosphodiesterase inhibitor milrinone and type V PDE inhibitor dipyridamole individually and synergistically reduce elevated pulmonary vascular resistance.

The effects of the phosphodiesterase (PDE) inhibitors milrinone and dipyridamole were studied in an in situ perfused rabbit lung model in which the pulmonary vascular resistance (PVR) was elevated by infusion of the thromboxane-A2 mimetic U46619. Dose-response curves for reduction of elevated PVR were generated for each of these drugs. The EC50 for milrinone was approximately 2 microM. The EC50 for dipyridamole was approximately 0.2 microM. In separate experiments, 0.1 microM milrinone was found to reduce elevated PVR by 4.6 +/- 2.4%, 0.06 microM dipyridamole reduced elevated PVR by 8.2 +/- 2.8%, whereas the combination of 0.1 microM milrinone and 0.06 microM dipyridamole reduced elevated PVR by 41.9 +/- 7.3%. In more limited experiments, it was determined that the PDE type V inhibitor zaprinast also caused a synergistic reduction of PVR when used with milrinone. We concluded that both the type III PDE inhibitor milrinone and the type V PDE inhibitors dipyridamole or zaprinast are effectively able to reduce elevated PVR and that the combination of PDE type III and type V inhibitors is synergistic in the ability to reduce elevated PVR. We speculate that type V PDE may play a more important role than type III PDE in the regulation of pulmonary vascular tone. It is proposed that the combination of milrinone and dipyridamole has the potential to be useful in the clinical treatment of elevated PVR.

Animals↗
PubMed1994

The dose-response relationship for hypoxic pulmonary vasoconstriction.

In 12 pentobarbital anesthetized dogs the lungs were independently ventilated with a double piston ventilator. The right lung was ventilated throughout with 100% oxygen. Blood was drawn from the right atrium and pumped through a bubble oxygenator to a cannula in the ligated left main pulmonary artery. The pressures in the left main pulmonary artery and the left atrium were recorded during constant flow while the oxygen tension in the left lung alveolar gas and the perfusate were varied either to match each other (Protocol 1) or differ (Protocol 2) over the range from "zero" to "100%" oxygen. From the combined data a three dimensional response surface for hypoxic pulmonary vasoconstriction was derived. The maximum increase of pulmonary vascular resistance (r%PVRmax) was defined at a stimulus oxygen tension (PSO2) of 10 mmHg amounting to a 3.15 +/- (0.18)-fold increase of the vascular resistance on "100%" oxygen. The stimulus oxygen tension was shown to be PSO2 = PVO2(0.41) x PAO2(0.59) and the dose-response sigmoid for hypoxic pulmonary vasoconstriction in canine lungs was derived as r%PVRmax = 100 (PSO2(-2.616))/(6.683 x 10(-5) + PSO2(-2.616)) These results appear to reconcile observations from a number of laboratories and to be of quite general application.

Animals↗
PubMed1994

Ensuring reliability of outcome measures in multicenter clinical trials of treatments for acute ischemic stroke. The program developed for the Trial of Org 10172 in Acute Stroke Treatment (TOAST).

BACKGROUND AND PURPOSE: Ensuring the reliability and validity of outcome measures used in clinical trials is essential to the success of the trial. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) is a multicenter clinical trial that is recruiting patients with acute ischemic stroke seen at medical centers across the United States. METHODS: This paper describes an approach to train physicians to use three clinical measures: the National Institutes of Health (NIH) Stroke Scale, a supplemental motor examination, and the Glasgow Outcome Scale. The program included education, certification, remediation when needed, monitoring, and reliability assessment. The goal was to ensure that interrater assessments were as equivalent to one another as possible. RESULTS: Of the first 95 clinicians who began the certification process, 75 passed during the first evaluation. Eighteen of the other physicians were able to complete the process after remediation. The intraclass correlations of both the NIH Stroke Scale and supplemental motor examination exceeded 0.95. The kappa values for the Glasgow Outcome Scale were 0.61 and 0.62 for the first and second ratings of the videotape, respectively. CONCLUSIONS: Our experience suggests that a program that includes educational and certification processes can be performed as part of the design of a multicenter clinical trial. The method of providing educational and testing videotapes to each site so that physicians can be trained and certified is an effective, inexpensive, and practical approach for enhancing and certifying the expertise of the large number of physicians involved in a multicenter study.

Brain Ischemia↗
PubMed1993

Effect of amrinone during group B Streptococcus-induced pulmonary hypertension in piglets.

Intravenous infusion of group B Streptococcus (GBS) into neonatal animals produces pulmonary hypertension, ventilation/perfusion (VA/Q) mismatch, and an increase in serum levels of thromboxane B2 (TxB2) and tumor necrosis factor (TNF) alpha. The vasodilator amrinone (amr) is a cGMP-inhibited phosphodiesterase inhibitor and is reported to inhibit thromboxane A2 and TNF production. We hypothesized that infusion of amr would cause pulmonary vasodilation and reduce serum TxB2 and TNF levels in piglets with late phase GBS-induced pulmonary hypertension. The effect of amr on gas exchange was also determined. A continuous infusion of GBS was administered for 5 hr to 4 groups of anesthetized, mechanically ventilated neonatal piglets. An amr bolus of 8 mg/kg was given at 4 hr followed by a 1 hr continuous infusion of either 10 or 20 micrograms/kg/min of amr (amr 10 and amr 20, respectively). Control piglets received a bolus and 1 hr infusion of amr carrier. The infusion of amr, but not of carrier reversed late phase GBS-induced pulmonary hypertension. Piglets infused with amr 20 showed transient selective pulmonary vasodilation, based on a reduced ratio of pulmonary to systemic vascular resistance (PVR/SVR ratio) value at 30 min but not at 1 hr, compared to pre-amr treatment values. The PVR/SVR ratio values for amr 10 and control group did not change after treatment with either amr or carrier. Treatment with amr 10 or 20 did not decrease serum TxB2 or TNF levels or increase VA/Q mismatch.(ABSTRACT TRUNCATED AT 250 WORDS)

Amrinone↗
PubMed1993

The HPV response is different with constant pressure vs constant flow perfusion.

Hypoxic pulmonary vasoconstriction (HPV) may be manifest in one of two ways: either an increase in the pulmonary artery pressure, or flow diversion away from the portion of the pulmonary bed with reduced conductance. We tested the hypothesis that the magnitude of the HPV response differs under conditions of constant flow perfusion, where pulmonary artery pressure (Ppa) rises during hypoxia, vs conditions of constant pressure perfusion, where Ppa remains constant and flow (Q) is diverted away from the lungs during hypoxia. In isolated, perfused rabbit lungs, the HPV response to four levels of hypoxia (12, 6, 3 and 0% oxygen) was of greater magnitude and more sustained under conditions of constant pressure perfusion as compared to constant flow perfusion. The possible significance of these findings as they relate to interpretation of studies in both the perinatal and mature pulmonary circulation is discussed.

Animals↗
PubMed1993

Childhood predictors for high adult blood pressure. The Muscatine Study.

In adult populations, elevated blood pressure is related to the development of stroke, renal disease, and occlusive atherosclerosis. The significance of blood pressure levels in childhood, unless extremely elevated, has not been related to disease outcomes. In a study carried out in Muscatine, Iowa, the risk of high blood pressure in young adult life was evaluated based on the observations of blood pressure and other factors made during the school-aged years. Subjects, 2445 in number, were first observed at ages 7 through 18 years and again between 20 and 30 years. During childhood, measurements of blood pressure, height, and weight were made on alternate years. At adult ages, the same measurements were again made and a health questionnaire was administered. Adult blood pressure was correlated with childhood blood pressure, body size, and change in ponderosity from childhood to adult life. Adult ponderosity was related to childhood ponderosity, and those who were most obese as adults showed the greatest increase in weight from their childhood years. These observations suggest that strategies to prevent the acquisition of excess ponderosity during childhood may be useful in preventing adult hypertension.

Adolescent↗
PubMed1993

Does childhood obesity track into adulthood?

Between 1971 and 1981 the Muscatine Coronary Risk Factor Project measured, in six biennial school surveys, 2631 schoolchildren 9 to 18 years of age. Beginning in 1981, these individuals were measured near their 23rd, 28th, and 33rd birthday. This article examines the tracking from childhood into young adult years of the heights, weights, body mass indices (BMI), and triceps skinfold thicknesses (TSF) of these individuals. Depending on age and gender, tracking correlations for height ranged from 0.41 to 0.97; for weight they ranged from 0.51 to 0.88; for BMI they ranged from 0.58 to 0.91; and for TSF they ranged from 0.26 to 0.58. From 49 to 70% of children in the upper quintile of weight were found in the upper quintile of weight as adults, from 48 to 75% of children in the upper quintile of BMI were again in the upper quintile as adults, and from 25 to 56% of children in the upper quintile of TSF were again in the upper quintile as adults. These measures track from childhood into young adult life, and the majority of obese children become obese adults. However, about 31% of children from the upper quintile of BMI became adults with substantially lower levels, while a similar number of lean children become obese adults. Why some obese children become obese adults and others do not remains an unanswered question. The data presented herein indicate that obesity is often acquired during childhood and adolescence when preventive measures could be applied.

Adolescent↗