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Biomedical subjects

T Morgan

Publications and source records attributed to T Morgan.

At least 91 records · Page 5Linked to original sources
PubMed1991

A phase I trial of alpha-interferon in combination with pentostatin in hematologic malignancies.

Pentostatin, a novel inhibitor of adenosine deaminase, has shown activity in various lymphoid malignancies of both the T and B cell lineage. This agent has unique side effects and in general myelosuppression has been mild. Interferon has both antiviral and antineoplastic properties. This agent has shown activity in hairy cell leukemia, chronic granulocytic leukemia, low grade lymphoma, and myeloma. Side effects from interferon are in general dissimilar to those that have been seen with pentostatin and in particular myelosuppression has not been a major toxicity with low doses of interferon. This current trial explored the combination of pentostatin and interferon in hematologic malignancies. Fifteen patients were enrolled in this phase I trial at a fixed dose of pentostatin of 4 mg/m2 biweekly and interferon at doses of 0.5, 1, 2, or 4 million units/m2 of interferon. At the first three dose levels of interferon nausea and vomiting were the predominant toxicity and appeared to worsen with time on study. Fatigue also was seen at the lowest level of interferon and was severe enough to cause two individuals to discontinue the study medications. At higher dose levels of interferon, myelosuppression, nausea and vomiting, and fatigue were the predominant toxicities. One patient with hairy cell leukemia had a complete response and a second patient with T cell cutaneous lymphoma had a partial response which lasted for 6 to 7 weeks. The maximum tolerated dose of interferon with pentostatin in this patient population was four million units/m2.

Adult↗
PubMed1991

The role of the macula densa in renin synthesis.

1. The role of the macula densa in renin synthesis was studied using mice with one hydronephrotic kidney. 2. Renin synthesis was assessed by measurement of renal renin, renal mRNA for renin and plasma renin. 3. Sodium depletion stimulated mRNA and renal renin to a similar extent in the hydronephrotic and contralateral kidney. 4. Enalapril stimulated mRNA concentration in both kidneys but renal renin did not rise in the hydronephrotic kidney. 5. Propranolol did not alter the response to sodium depletion in either kidney. 6. The macula densa is not crucial for the stimulation of renin synthesis following sodium depletion. However, it may regulate renin production after mRNA synthesis, possibly by controlling the conversion of prorenin to renin.

Animals↗
PubMed1991

Carotid stenosis in lacunar stroke.

The prevalence of extracranial carotid stenosis in patients with a clinical syndrome of lacunar stroke has not been extensively studied using noninvasive methods. We performed carotid duplex sonography on 168 patients referred to the neurosonology laboratory with a diagnosis of ischemic stroke. Strokes were independently classified as lacunar or nonlacunar hemispheric infarction without knowledge of the ultrasound results. We excluded patients with infarcts that were clearly vertebrobasilar, presumed to be cardioembolic, or had occurred greater than 1 year earlier, and patients for whom classification of the nature and location of the event was not possible. Fifty-five patients had lacunar and 54 had nonlacunar stroke. No differences in age, sex, distribution, or prevalence of hypertension, diabetes, prior ischemia, or Hispanic surname existed between the two groups. Tobacco use was more frequent in the nonlacunar group (p less than 0.01). The prevalence of important extracranial carotid stenosis (greater than or equal to 50% diameter reduction) in the lacunar stroke group was 13% (seven of 55) in the ipsilateral and 4% (two of 55) in the contralateral carotid artery. Of the 54 patients with nonlacunar hemispheric stroke, 41% (22) had ipsilateral (p less than 0.01) and 26% (14) had contralateral (p less than 0.01) carotid stenosis. This study suggests that important carotid stenosis is infrequent among patients presenting with a clinical syndrome of lacunar stroke. These data impact on decisions regarding cerebrovascular work-up in such patients.

Adult↗
PubMed1990

Effect of portal hypertension on in vivo bile acid-mediated small intestinal mucosal injury in the rat.

This study's purpose was to determine whether portal hypertension adversely affects small intestinal mucosal injury. Portal hypertension was produced in male Sprague-Dawley rats by two-stage ligation of the portal vein. Sham-operated rats were used as controls. Two weeks later, intestinal injury was produced by in vivo perfusion with 5 mM chenodeoxycholic acid for 30 min. Intestinal injury was assessed by quantitative morphometry and by measuring intestinal water and mannitol absorption. Portal hypertension resulted in more injury in the distal perfused intestine as manifested by increased villus tip denudation [portal hypertensive 52.5 +/- 9.6 (SEM) vs controls 28.1 +/- 5.7 microns, P = 0.05). Additionally there was a significant decrease in the unperfused duodenal villus height in portal hypertensive rats (portal hypertensive 755 +/- 22 vs controls 848 +/- 28 microns, P less than 0.02). Portal hypertension had no significant effect on the increase in mannitol absorption or water secretion caused by chenodeoxycholic acid perfusion. This study suggests that portal hypertension alters small intestinal mucosa and increases susceptibility to injury.

Absorption↗
PubMed1990

Simvastatin in the treatment of hypercholesterolaemia in patients with essential hypertension.

Mortality from coronary artery disease is a common problem in treated hypertensive patients, and these people have a high prevalence of elevated cholesterol levels. A study was undertaken to determine whether cholesterol could be lowered effectively without major side effects in patients with treated hypertension. Forty-nine patients (mean age 67.6 years) with cholesterol greater than 5.5 mmol/l were placed on a reduced-fat (less than 30% of calories from fat with a ratio of polyunsaturated to saturated fats of less than 1) diet for 3 months. If the cholesterol was between 5.5 and 7.5 mmol/l and total cholesterol divided by high-density lipoprotein cholesterol was greater than 4.5, the patients were randomly allocated either to the simvastatin (24 patients) or the placebo group (25 patients). Diet and placebo caused minor and insignificant falls in cholesterol and no change in triglycerides or lipids. Treatment with simvastatin reduced cholesterol levels from 6.85 to 4.75 mmol/l (P less than 0.001), triglycerides from 2.7 to 2.1 mmol/l (P less than 0.01), low-density lipoproteins from 4.6 to 2.6 mmol/l (P less than 0.001) and high-density lipoproteins rose from 1.09 to 1.18 mmol/l (P less than 0.01). Total cholesterol divided by high-density lipoprotein cholesterol fell from 6.3 to 4.0 (P less than 0.001). The drug was well tolerated and the side-effect profile did not differ from the placebo in clinical or biochemical events. The active drug was stopped in one patient (abdominal pain, dizziness, headache, tiredness) and in two patients taking the placebo (elevated creatine phosphokinase, cardiovascular collapse). Simvastatin effectively lowered total cholesterol and improved the lipoprotein profile. The dose required in most patients was 40 mg/day. Simvastatin may be an acceptable drug to improve the lipoprotein profile in order to determine whether this improves the prognosis in patients treated for hypertension.

Adult↗
PubMed1990

Interaction of enalapril with sodium restriction, diuretics, and slow-channel calcium-blocking drugs.

While monotherapy sometimes controls blood pressure (BP), it is often essential to add a second drug for adequate control. This study examined in a factorial fashion the interaction of enalapril with some commonly used antihypertensive therapies. There were between 10 and 16 patients in each study, and the patients had responded in part to the two drugs used. Enalapril and sodium restriction lowered BP 12 +/- 3/11 +/- 2 and 4 +/- 2/3 +/- 1 mm Hg, respectively. The effects of the two therapies were additive, and there was no interaction. Enalapril and hydrochlorothiazide lowered BP 11 +/- 3/8 +/- 3 and 8 +/- 2/6 +/- 2 mm Hg, respectively. The effect of the two drugs together indicated a positive interaction of 4 +/- 2/3 +/- 1 mm Hg (p less than 0.05). Enalapril and nifedipine both lowered BP (10 +/- 2/8 +/- 1 and 11 +/- 3/8 +/- 1 mm Hg). The two drugs combined had a strongly positive interaction of 10 +/- 3/7 +/- 2 mm Hg (p less than 0.001). Enalapril can be used with the other therapeutic methods tested. If a converting enzyme inhibitor does not reduce BP adequately, it appears appropriate to add a thiazide diuretic or a slow-channel calcium-blocking drug. The mechanism of the positive interaction with diuretics probably reflects an effect on the renin-angiotensin system, but the explanation for the synergism with slow-channel calcium-blocking drugs is unclear.

Blood Pressure↗
PubMed1990

Pharmacokinetics of carvedilol in older and younger patients.

Carvedilol, a combined beta- and alpha 1-blocking drug, was given to 8 young (age 39-47) and 21 old (age 64-79) patients with essential hypertension. Clinical and pharmacokinetic responses to 12.5, 25 and 50 mg were determined and compared. In both age groups, pharmacokinetic data were similar with all three doses of carvedilol. Peak blood levels were reached within 90 minutes and at 24 hours the trough blood level was less than 10% of the peak level. Carvedilol or its metabolite did not accumulate. Falls in systolic and diastolic BP were greater than 7 mmHg in 28 of the 29 patients. The falls in diastolic BP did not differ between groups but the older group had a greater fall in systolic BP. However, the systolic BP of the older group was higher and expressed as a percentage, the falls in BP did not differ. The time to peak fall in BP was about 4 hours and was always after the time to peak blood level. There was no correlation between blood level and BP fall. When the drug was administered 24 h after the previous dose, a further fall in BP was seen indicating a greater effect at peak drug levels. Side effects were few and, during the chronic study, there was no postural hypotension or postural hypotensive symptoms. On the study days, five patients developed postural hypotension with symptoms. These were not observed at other times and may have been due to decreased sympathetic outflow on the study days. Carvedilol lowered BP in order and younger patients. There were no significant effects of age on its pharmacokinetics. Carvedilol is an effective antihypertensive agent that can be used in people with essential hypertension in all age groups.

Adult↗
PubMed1989

Modulation of the metabolism and pharmacokinetics of 1-beta-D-arabinofuranosylcytosine by 1-beta-D-arabinofuranosyluracil in leukemic mice.

The interaction between high concentrations of 1-beta-D-arabinofuranosyluracil (HiCAU) and 1-beta-D-arabinofuranosylcytosine (ara-C) was investigated in vivo with emphasis on cell kinetics, pharmacokinetics, and drug metabolism. Mice bearing L5178Y leukemia were given a 48-h s.c. infusion of high-dose ara-U (HiDAU) to achieve a plasma level of 0.5 to 1 mM. A total dose of 7.35 g/kg/day for 2 days was nontoxic; the mean survival of control (saline treated) leukemic mice was 12.2 +/- 1.8 days and 11.7 +/- 2.0 days for the HiDAU-treated leukemic mice. Using flow cytometry, cell cycle progression of L5178Y ascites cells was monitored during HiDAU infusion. At 48 h, the proliferative index (PI) percentage of the leukemic cells is significantly different (P less than 0.001) in HiDAU-treated leukemic mice (mean = 50.8) versus control (mean = 45.6). A higher PI percentage is associated with accumulation of cells in S phase. This effect was highly variable in the ara-U-treated mice, and the ara-U "perturbed" group was defined as those mice whose cells had an increase in the PI to greater than or equal to 50%. The higher PI percentage in HiDAU-treated mice correlated with HiCAU in ascites fluid, leukemic cells, and kidney of perturbed mice. HiCAU in the "ara-U-perturbed" group altered the plasma pharmacokinetics of high-dose ara-C (HiDAC, 1 g/kg), increased the cellular metabolism of ara-C to 1-beta-D-arabinofuranosylcytidine triphosphate (ara-CTP) (3-fold), and increased ara-C-DNA synthesis (3-fold). In mice bearing the L5178Y leukemia, a 48-h infusion of ara-U followed by a 24-h s.c. infusion of 40 mg/kg resulted in a 260% increase in life span and seven 90-day survivors among 16 treated mice. In contrast, ara-U or ara-C alone had a negligible therapeutic effect. ara-U-induced alterations in the systemic pharmacokinetics of ara-C are the result of inhibition of cytidine deaminase activity by HiCAU in liver and kidneys. This results in a decrease in ara-C catabolism and prolongs the plasma half-life of ara-C. The dual alteration of the pharmacokinetics of ara-C and cytokinetics of the leukemia cells by HiCAU results in enhanced survival of leukemic mice. These results may help explain the clinical utility of HiDAC treatment programs for patients with acute leukemia.

Animals↗
PubMed1989

Effect of mineralocorticoids and salt loading on renin release, renal renin content and renal renin mRNA in mice.

1. DOCA and 9 alpha-fludrocortisone were given to mice on a high-sodium diet for periods of up to 20 weeks, resulting in decreases in plasma renin concentration, renal renin concentration and renal renin mRNA with both treatments. 2. Plasma renin concentration was suppressed prior to suppression of renin mRNA and renal renin levels, indicating that suppression of synthesis and secretion of renin occur separately. 3. The decrease in renal renin concentration that occurred with DOCA was greater and more rapid than the decrease that occurred with 9 alpha-fludrocortisone, suggesting that DOCA caused intra-renal breakdown of renin. 4. When DOCA was given to mice on a low-sodium diet, plasma renin concentration and renal renin concentration increased, indicating that the effects of DOCA on renin levels were dependent on dietary sodium. 5. Renin secretion and synthesis appeared to be controlled by different mechanisms and sodium balance has an important effect on both processes.

Animals↗
PubMed1989

Effect of calcium carbonate on blood pressure in normotensive and hypertensive people.

Forty-seven patients with mild hypertension and 48 normotensive patients entered a blinded, parallel study in which they received a placebo, 10 mmol/day calcium carbonate (CaCO3), or 20 mmol/day CaCO3. There were no significant differences in blood pressure changes among the groups. In the hypertensive group and in patients with the highest blood pressure there were individual falls in systolic pressure, particularly in the group receiving 10 mmol daily CaCO3. In the hypertensive group the changes were: with placebo, -3 +/- 2/-2 +/- 2 mm Hg; with CaCO3 (10 mmol), -7 +/- 3/-2 +/- 2 mm Hg; and with CaCO3 (20 mmol), -2 +/- 3/1 +/- 2 mm Hg. No change was significant, and no pressure changes of patients taking CaCO3 differed significantly from changes of patients taking placebo. Ten of 33 patients taking placebo, 11 of 31 taking 10 mmol/day CaCO3, and nine of 31 taking 20 mmol/day CaCO3 were classified as responders from their systolic blood pressure fall. These response rates did not differ. Eight patients had falls of systolic blood pressure greater than 15 mm Hg. Five were on 10 mmol/day CaCO3 and three on 20 mmol/day CaCO3. This response was significantly different from that with placebo. Univariate analyses failed to reveal any predictive dietary or biochemical parameter. After 3 months of not taking CaCO3, 12 patients classified as responders, including six of the eight with a fall of 15 mm Hg or more, were rerandomized to placebo or to 20 mmol/day CaCO3. In the rechallenge, responses to CaCO3 and placebo were similar, neither causing a significant pressure fall. Calcium carbonate did not reduce blood pressure. The apparent response in a few patients was not verified by rechallenge. The present study does not support calcium supplementation as a useful nonpharmacological measure for reducing elevated blood pressure.

Adult↗
PubMed1988

Enalapril & nifedipine in essential hypertension; synergism of the hypotensive effects in combination.

Twelve male hypertensive patients who had required enalapril and nifedipine to control their blood pressure were entered into a study of modified 2 x 2 factorial design (3 week study periods) to determine the effect of each drug separately and in combination. Factorial analysis indicated that enalapril alone (20 mg/d) lowered supine blood pressure by 10 +/- 2/8 +/- 1 mmHg, nifedipine alone (30 mg/d) lowered supine blood pressure by 11 +/- 2/8 +/- 1 mmHg and there was a positive interactive effect of 10 +/- 3/7 +/- 2 mmHg (P less than 0.001) such that the combination lowered supine blood pressure by 32 +/- 3/24 +/- 2 mmHg. The effects of the individual drugs were both significant (P less than 0.001) but did not differ from each other. Enalapril and nifedipine are both effective antihypertensive drugs and in some hypertensive patients their effects appear to be synergistic.

Aged↗
PubMed1988

The effect of a rechallenge with CaCO3 in patients who have been classified as responders to an initial challenge.

In a previous study 25 of 95 patients were identified as possibly having a fall in blood pressure with CaCO3 supplementation. After a 3-month period off calcium and on their usual diet, 12 of these were randomly assigned to receive placebo or CaCO3. Four crossed over to the alternate therapy after 2 months on the first agent. The change in blood pressure with placebo was 0.3 +/- 4.3/2.9 +/- 2.7 mmHg and the change in blood pressure with CaCO3 at 20 mmol/day was 1.3 +/- 4.8/-0.3 +/- 4.2 mmHg. These changes were not different from each other or from zero, and contrasted with the fall of 16.5 +/- 2.3/7.8 +/- 2.7 mmHg in the initial study. This study indicates that apparent individual falls in blood pressure with calcium supplementation need to be verified by rechallenge before such patients can be classified as responders. The absence of a predictable response, if applied to other studies, casts doubt on the conclusions made. Calcium supplementation cannot be recommended as a method of reducing blood pressure in people with mild hypertension.

Calcium Carbonate↗
PubMed1988

Interaction of slow-channel calcium blocking drugs with sodium restriction, diuretics and angiotensin converting enzyme inhibitors.

The interactions of nifedipine with sodium restriction, diuretics and enalapril were studied using a 2 x 2 factorial design. Nifedipine lowered blood pressure to a greater extent than sodium restriction or hydrochlorothiazide. With both of these therapies there was a negative interactive term, which indicated that their combination had no greater effect than the use of nifedipine alone. Enalapril and nifedipine lowered blood pressure by 10 +/- 2/8 +/- 1 and 11 +/- 3/8 +/- 1 mmHg, respectively. The combination lowered blood pressure by 32 +/- 3/24 +/- 2 mmHg. The reasons for these negative and positive interactions are not clear, but may relate to interactions that regulate the availability of calcium for initiation of contraction in smooth muscle cells of the arterioles.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Effect of atrial peptide on collecting duct function.

1. The effects of synthetic rat atrial natriuretic peptides (ANP) on diffusional 22Na+, 36Cl- and tritiated water (THO) permeability of in vitro microperfused rat papillary collecting ducts and the effect in vivo of ANP on stop-flow sodium concentrations in the terminal segment of rabbit nephrons were studied. 2. The addition of 4 x 10(-8) or 4 x 10(-7) mol/l ANP to the medium or perfusion solution did not alter diffusional 22Na+ or 36Cl- permeability of microperfused rat papillary collecting ducts. 3. The basal diffusional THO permeability of papillary collecting ducts was not altered when 4 x 10(-7) mol/l ANP was present in the medium and did not inhibit the increment in diffusional THO permeability induced by vasopressin or reduce the permeability to water in a duct previously stimulated by vasopressin. 4. The administration of ANP (2 micrograms/kg bodyweight) to rabbits in water diuresis did not alter systemic blood pressure but induced a marked natriuresis and increases in urine flow and potassium excretion. This natriuresis was not associated with alterations in stop-flow sodium reabsorptive capacity or sodium permeability of the collecting tubules and ducts. 5. Previously reported in vivo clearance data suggest that ANP causes, at least in part, a natriuresis by altering sodium transport in the medullary collecting ducts. In this study, however, a direct effect could not be demonstrated and it is possible that the medulla needs to be functioning in its normal environment for such effects to be demonstrated.

Animals↗
PubMed1988

Effect of pH on vasopressin-induced water permeability in collecting ducts of isolated rat papillae.

1. The effects of basolateral and luminal pH on diffusional water permeability of microperfused collecting ducts of isolated rat papillae were examined in the presence and absence of vasopressin at two concentrations. 2. In the absence of vasopressin, collecting duct diffusional water permeabilities did not differ when the pH of the luminal fluid was varied. Similarly, in the absence of vasopressin, collecting duct diffusional water permeabilities did not differ when the bath pH was varied. 3. In the presence of 50 microU/ml vasopressin, increases in diffusional water permeability of collecting ducts perfused with solutions at pH 5.0, 7.4 or 9.0 did not differ significantly. Similarly, increases in diffusional water permeability induced by 200 microU/ml vasopressin were not different when collecting ducts were perfused with solutions at pH 5.0, 7.4 or 9.0. 4. The presence of vasopressin (50 microU/ml) in the bathing medium at pH 6.4, 7.4 and 8.4 induced increments in diffusional water permeability of 0.40 +/- 0.21 (n = 14, P greater than 0.05), 1.56 +/- 0.27 (n = 27, P less than 0.001) and 1.67 +/- 0.24 (n = 12, P less than 0.001) microns/s, respectively. The increment in water permeability at pH 6.4 was significantly less than that at pH 7.4 (P less than 0.001). 5. The presence of vasopressin (200 microU/ml) in the bathing medium at pH 6.4, 7.4 and 8.4 induced increments in diffusional water permeability of 2.16 +/- 0.54 (n = 9, P less than 0.01), 2.55 +/- 0.51 (n = 17, P less than 0.001) and 0.98 +/- 0.34 (n = 11, P less than 0.05) microns/s respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗