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Biomedical subjects

P E Williams

Publications and source records attributed to P E Williams.

At least 19 recordsLinked to original sources
PubMed1992

A pharmacokinetic and tolerance study of romazarit in patients with rheumatoid arthritis.

Romazarit is a new drug for which animal pharmacology suggests a disease-modifying action in rheumatoid arthritis (RA). These animal studies predict that plasma romazarit concentrations within the range 50-100 mg l-1 may be required for efficacy in the clinic. Therefore, a pharmacokinetic study was designed to estimate the dosage required to achieve these concentrations in man. Twenty-four patients with RA entered a double-blind controlled assessment receiving either placebo, 100 mg t.i.d., 350 mg b.i.d., or 350 mg t.i.d., for 6 days. Pharmacokinetic profiles were measured after single doses and after the last of the multiple doses. Adverse events were mainly trival and were distributed almost equally between all three treatment and the placebo groups. Plasma romazarit concentrations were not dose-proportional after the single doses. Mean peak plasma drug concentrations were 11.8, 66.7, and 159 mg l-1 at steady state after 100 mg t.i.d., 350 mg b.i.d., and 350 mg t.i.d. The mean urinary recovery of drug-related material (mostly ester glucuronides) was 71 per cent of the dose during the dosage interval. The renal clearance of romazarit glucuronides correlated with creatinine clearance (p less than 0.01). Saturable tubular secretion of glucuronides coupled with reversible glucuronidation would explain these findings. It is predicted that oral doses of 450 mg romazarit given 12-hourly will result in plasma concentrations within the target range of 50-100 mg l-1.

Administration, Oral↗
PubMed1992

The effects of acute elevations in plasma cortisol levels on alanine metabolism in the conscious dog.

The present study was undertaken to determine whether an acute physiological increase in plasma cortisol level had significant effects on alanine metabolism and gluconeogenesis within 3 hours in conscious, overnight-fasted dogs. Each experiment consisted of an 80-minute tracer and dye equilibration period, a 40-minute basal period, and a 3-hour experimental period. A primed, continuous infusion of [3-3H]glucose and continuous infusions of [U-14C]alanine and indocyanine green dye were initiated at the start of the equilibration period and continued throughout the experiment. Dogs were studied with (1) a hydrocortisone infusion ([CORT] 3.0 micrograms.kg-1.min-1, n = 5), (2) hydrocortisone infused as in CORT, but with pancreatic hormones clamped using somatostatin and basal intraportal replacement of insulin and glucagon (CLAMP+CORT, n = 5), or (3) saline infusion during a pancreatic clamp (CLAMP, n = 5). Glucose production and gluconeogenesis were determined using tracer and arteriovenous difference techniques. During CLAMP, all parameters were stable except for a modest 67% +/- 6% increase in gluconeogenic conversion of alanine to glucose and a 53% +/- 26% increase in gluconeogenic efficiency. When plasma cortisol levels were increased fourfold during CLAMP+CORT, there was no change in the concentration, production, or clearance of glucose. Gluconeogenic conversion of alanine to glucose increased 10% +/- 34% and gluconeogenic efficiency increased 65% +/- 43%, while net hepatic alanine uptake (NHAU) increased 60% +/- 19% and hepatic fractional extraction of alanine increased 38% +/- 12%. Cortisol did not cause an increase in the arterial glycerol level or net hepatic glycerol uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1992

Role of hepatic nerves in response of liver to intraportal glucose delivery in dogs.

Net hepatic glucose uptake (NHGU) is much greater during oral or intraportal glucose loading than during peripheral intravenous glucose delivery even when similar glucose loads and hormone levels reaching the liver are maintained. To determine whether this difference is influenced by the hepatic nerves, nine conscious 42-h-fasted dogs in which a surgical denervation of the liver (liver norepinephrine levels postdenervation averaged 2.4% of normal) had been performed were subjected to a 40-min control period and two randomized 90-min test periods during which somatostatin (0.8 microgram.kg-1.min-1), intraportal insulin (1.2 mU.kg-1.min-1), and intraportal glucagon (0.5 ng.kg-1.min-1) were infused. The glucose load to the liver was increased twofold by infusing glucose into a peripheral vein (Pe) or the portal vein (Po). Arterial insulin and glucagon concentrations were 39 +/- 2 and 39 +/- 3 microU/ml and 55 +/- 5 and 54 +/- 7 pg/ml during Pe and Po, respectively. The hepatic glucose loads were 50.3 +/- 4.4 and 51.4 +/- 5.8 mg.kg-1.min-1 while NHGU was 2.1 +/- 0.5 and 2.2 +/- 0.7 mg.kg-1.min-1 during Pe and Po, respectively. Similar hormone levels and glucose loads reaching the liver in dogs with intact hepatic nerve supplies were previously shown to be associated with NHGU of 1.4 +/- 0.7 and 3.5 +/- 0.8 mg.kg-1.min-1 in the presence of peripheral and portal glucose delivery, respectively. In conclusion, an intact nerve supply to the liver appears to be vital for the normal response of the liver to intraportal glucose delivery.

Administration, Oral↗
PubMed1992

Metabolic regulation in peripheral tissues and transition to increased gluconeogenic mode during prolonged exercise.

To assess the means by which peripheral metabolism facilitates the transition to a gluconeogenic state, dogs were studied during 150 min of moderate treadmill exercise. Metabolism in the working hindlimb was assessed with arteriovenous difference and isotopic techniques (n = 9). In a separate group (n = 6), hepatic metabolism was assessed using arteriovenous differences. Limb glucose uptake (LGU) and oxidation (GOX) rose from 33 +/- 10 and 5 +/- 2 to 101 +/- 20 and 54 +/- 15 mumol/min at 10 min of exercise. LGU continued to rise (151 +/- 21 mumol/min at 150 min), while GOX declined. Nonoxidative glucose metabolism (GNOX) was 28 +/- 10 mumol/min at rest and 47 +/- 24 and 108 +/- 16 mumol/min at 10 and 150 min of exercise. Limb nonglycemic (predominantly glycogen) pyruvate formation rose from 52 +/- 22 to 198 +/- 54 and 242 +/- 74 mumol/min at 10 and 150 min of exercise. The gradual increase in GNOX and the high glycogenolytic rate were paralleled by accelerated lactate, pyruvate, and glutamine releases. Limb glycerol release rose promptly and remained elevated during exercise. Plasma nonesterified fatty acids (NEFAs) rose gradually and paralleled the gradual rise in GNOX (r = 0.93). The resulting rise in hepatic NEFA delivery was highly correlated to hepatic O2 uptake (r = 0.87), hepatic vein lactate-to-pyruvate ratio (r = 0.90), and intrahepatic gluconeogenic efficiency (r = 0.96). In summary, during exercise, 1) the primary fate of the added glucose consumed by the working limb is initially oxidation, but becomes GNOX as exercise duration progresses; 2) glycogenolysis rises promptly, but attains its highest rate at the end of exercise; 3) the late increases in GNOX and glycogenolysis relate to an increased gluconeogenic precursor release from the working limb; 4) although lipolysis increases promptly and is sustained, circulating NEFAs rise only gradually; and 5) the gradual rise in plasma NEFAs is highly correlated to the shift from GOX to GNOX and the adjustments in hepatic metabolism that are necessary for the full gluconeogenic response.

Amino Acids↗
PubMed1992

Importance of basal glucagon in maintaining hepatic glucose production during a prolonged fast in conscious dogs.

We undertook studies in conscious dogs to assess the role of basal glucagon in stimulating glucose production after a 7-day fast. Two protocols consisting of a 40-min basal period (-40 to 0 min), and a 180-min test period (0-180 min) were used. During the test period of the first protocol (hormone replacement; n = 4), somatostatin was infused (0.8 micrograms.kg-1.min-1) along with basal intraportal replacement amounts of insulin and glucagon, whereas in the second protocol (glucagon deficiency; n = 5), somatostatin plus insulin alone were infused. Glucose production and gluconeogenesis were measured using tracer and arteriovenous difference techniques. Plasma insulin levels were similar during the test period in both protocols (6 +/- 1 microU/ml). The plasma immunoreactive glucagon level in the control protocol averaged 50 +/- 8 pg/ml, whereas in the glucagon-deficiency protocol the level fell from 50 +/- 8 to 29 +/- 8 pg/ml (P less than 0.05). The plasma glucose level and the rate of glucose production were unchanged during bihormonal replacement. During glucagon deficiency the plasma glucose level was held constant at 100 +/- 4 mg/dl by glucose infusion. Tracer-determined endogenous glucose production fell from 1.8 +/- 0.1 to 1.0 +/- 0.1 mg.kg-1.min-1 by 30 min (P less than 0.05). After 3 h of glucagon deficiency, gluconeogenic conversion of alanine to glucagon was reduced 40% and the hepatic fractional extraction of alanine was reduced by 45%. The efficiency of the gluconeogenic process within the liver was not altered by glucagon deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1991

Use of intravenous immunoglobulin in acquired immune deficiency syndrome.

Patients infected with the human immunodeficiency virus (HIV) may have an antibody deficiency and a deficiency of cellular immunity. Intravenous immunoglobulin (IVIG) preparations may benefit HIV-infected children and adults with recurrent bacterial infections at doses of 200 to 400 mg/kg every 2 to 4 weeks. In addition, IVIG (1 to 2 g/kg) is effective at raising platelet counts to hemostatic levels in HIV-infected patients with idiopathic thrombocytopenic purpura and life-threatening bleeding. Indirect evidence also suggests that IVIG may be effective in preventing Pneumocystis carinii pneumonia. Finally, recent studies suggest that specific anti-HIV antibody preparations may have a therapeutic role, either as immunoglobulin concentrates or as immunoadhesions and immunotoxins. However, further investigations are needed to exclude antibody enhancement of HIV infection by the Fc receptor or the complement receptor.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Interaction of gut and liver in nitrogen metabolism during exercise.

The role of the gut and liver in nitrogen metabolism was studied during rest, 150 minutes of moderate-intensity treadmill exercise, and 90 minutes of recovery in 18 hour-fasted dogs (n = 6). Dogs underwent surgery 16 days before an experiment for implantation of catheters in a carotid artery and in the portal and hepatic veins, and Doppler flow cuffs on the hepatic artery and portal vein. Arterial glutamine, alanine, and alpha-amino nitrogen (AAN) levels decreased gradually with exercise (P less than .05), while arterial glutamate, NH3, and urea were unchanged. Net gut glutamine uptake was 1.3 +/- 0.5 mumol/kg.min at rest, and increased transiently to 2.5 +/- 0.3 mumol/kg.min at 60 minutes of exercise (P less than .05) as gut extraction increased. Net hepatic glutamine uptake was 0.6 +/- 0.4 mumol/kg.min at rest, and increased to 3.4 +/- 0.6 and 2.6 +/- 0.5 mumol/kg.min after 60 and 150 minutes of exercise (P less than .05) as hepatic extraction increased. Net gut glutamate and NH3 output both increased transiently with exercise (P less than .05). These increases were matched by parallel increments in the net hepatic uptakes of these compounds. Alanine output by the gut and uptake by the liver were unchanged with exercise. Net gut AAN output was -2.1 +/- 1.8 mumol/kg.min at rest (uptake occurred), and increased transiently to 11.2 +/- 3.5 mumol/kg.min after 30 minutes of exercise (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1991

Effects of small changes in glucagon on glucose production during a euglycemic, hyperinsulinemic clamp.

The aim of this study was to examine the influence of small changes in glucagon on hepatic glucose production during a euglycemic, hyperinsulinemic clamp. During 1.0 mU/kg.min insulin infusion, euglycemia was maintained by glucose infusion and glucagon was infused at various rates so as to cause plasma glucagon levels to increase, decrease, or remain unchanged. Changes in glucagon were found to be positively associated with changes in glucose production and inversely related to the degree of suppression of tracer or arteriovenous difference determined endogenous glucose production. Thus, animals in which the glucagon levels increased, appeared to have decreased hepatic insulin sensitivity, while animals in which glucagon levels decreased, appeared to have increased insulin sensitivity. In conclusion, since glucagon often declines during a euglycemic hyperinsulinemic clamp, and since small changes in glucagon can have marked effects on the suppression of hepatic glucose output even in the presence of high insulin levels, changes in glucagon should be considered when conclusions regarding hepatic insulin sensitivity are being drawn.

Animals↗
PubMed1991

The role of passive stretch and repetitive electrical stimulation in preventing skeletal muscle atrophy while reprogramming gene expression to improve fatigue resistance.

The effects of mechanical stimuli on preserving muscle mass while transforming them into slow, fatigue resistant muscles have been studied in the rabbit. When combined, stretching and electrical stimulation (10 Hz) induce rapid and marked growth of muscles. This procedure also more rapidly activates the transformation process(es) than when either stretching or electrical stimulation (10 Hz) are used alone. Stretch by itself is also anabolic causing useful lengthening of muscles and preventing collagen accumulation. In contrast, muscle inactivity leads to rapid atrophy, fiber shortening and reduced muscle compliance. We believe these findings have important implications to cardiomyoplasty.

Animals↗
PubMed1991

Dose-related effects of epinephrine on glucose production in conscious dogs.

The effects of increases in plasma epinephrine from 78 +/- 32 to 447 +/- 75, 1,812 +/- 97, or 2,495 +/- 427 pg/ml on glucose production, including gluconeogenesis, were determined in the conscious, overnight-fasted dog, using a combination of tracer [( 3-3H]glucose and [U-14C]alanine) and arteriovenous difference techniques. Insulin and glucagon were fixed at basal levels using a pancreatic clamp. Plasma glucose levels rose during the 180-min epinephrine infusion by 47 +/- 7, 42 +/- 22, and 74 +/- 25 mg/dl, respectively, in association with increases in hepatic glucose output of 1.04 +/- 0.22, 1.87 +/- 0.23, and 3.70 +/- 0.83 mg.kg-1.min-1 (at 15 min). Blood lactate levels rose by 1.52 +/- 0.24, 4.29 +/- 0.49, and 4.60 +/- 0.45 mmol/l, respectively, by 180 min, despite increases in hepatic uptake of lactate of 3.47 +/- 5.73, 12.83 +/- 3.46, and 37.00 +/- 4.20 mumol.kg-1.min-1. The intrahepatic gluconeogenic efficiency with which the liver converted the incoming alanine to glucose had risen by 84 +/- 40, 77 +/- 24, and 136 +/- 34% at 180 min, respectively. The latter effect plus the effect on net hepatic lactate uptake point to an intrahepatic action of high levels of the hormone in vivo. In conclusion, epinephrine produces dose-dependent increments in overall glucose production, which involve a progressive stimulation of both glycogenolysis (as assessed by glucose production at 15 min) and gluconeogenesis (assessed in the last 30 min of the study). The latter involves a peripheral action of the catecholamine to increase gluconeogenic substrate supply to the liver and may also involve a hepatic effect when high epinephrine levels are present.

Alanine↗
PubMed1991

Regulation of lipolysis and ketogenesis by norepinephrine in conscious dogs.

The lipolytic and ketogenic effects of norepinephrine (NE) at levels present in the circulation or the synaptic cleft during stress were examined in the overnight-fasted conscious dog. Insulin and glucagon were maintained at basal levels while NE, at a rate of either 0.04 (n = 6) or 0.32 micrograms.kg-1.min-1 (n = 5), or saline (n = 6) was infused for 3 h. NE rose from 129 +/- 17 to 442 +/- 85 pg/ml (P less than 0.05) and 100 +/- 24 to 3,244 +/- 807 pg/ml (P less than 0.05) with the low and high infusion rates, respectively (unchanged with saline infusion). There were no significant changes in lipolysis or ketogenesis with saline infusion. Both low and high NE infusion produced sustained increases in glycerol (from 72 +/- 20 to 119 +/- 24 microM and 59 +/- 19 to 248 +/- 32 microM, respectively, both P less than 0.05), while nonesterified fatty acids (NEFA) rose from 609 +/- 85 to 952 +/- 100 and 767 +/- 140 to 2,054 +/- 199 microM (both P less than 0.05). Ketone levels and net hepatic production rose significantly only with the high NE infusion (from 88 +/- 10 to 266 +/- 46 microM and 1.30 +/- 0.26 to 7.62 +/- 1.48 mumol.kg-1.min-1, respectively, both P less than 0.05). The ratio of net hepatic ketone production to NEFA uptake rose 54% with high NE infusion. In conclusion, at circulating levels seen during stress, NE stimulates lipolysis but does not directly influence ketogenesis. At circulating levels projected to exist in the synaptic cleft during stress, NE has a potent lipolytic effect and stimulates ketogenesis.

Animals↗
PubMed1991

Regulation of glucose metabolism by norepinephrine in conscious dogs.

The effects of norepinephrine (NE) at levels present in the circulation and synaptic cleft during stress on glucose metabolism were examined in overnight-fasted conscious dogs with fixed basal levels of insulin and glucagon. Plasma NE rose from 132 +/- 14 to 442 +/- 85 pg/ml and 100 +/- 20 to 3,244 +/- 807 pg/ml during 3 h of low (n = 6) and high (n = 5) NE infusion, respectively. Plasma glucose and glucose production rose only with high NE infusion (from 108 +/- 4 to 159 +/- 15 mg/dl and 2.78 +/- 0.24 to 3.41 +/- 0.38 mg.kg-1.min-1, respectively). NE infusion caused dose-dependent net hepatic lactate consumption, but net hepatic alanine uptake fell only with high NE infusion (31%). Alanine conversion to glucose rose by 67 +/- 13, 136 +/- 20, and 412 +/- 104%, and intrahepatic gluconeogenic efficiency rose by 42 +/- 27, 299 +/- 144, and 212 +/- 21% with saline and with low and high NE infusion, respectively. In conclusion, NE enhances gluconeogenesis by stimulating peripheral precursor release, by increasing substrate movement into the hepatocyte, and by increasing intrahepatic gluconeogenic efficiency. However, only the higher NE levels affected glucose metabolism profoundly enough to stimulate glucose production and to elevate the glucose level.

Alanine↗
PubMed1991

Pneumocystis carinii pneumonia in thymoma with hypogammaglobulinaemia: successful outcome of therapy including i.v. IgG replacement.

A 66-year-old patient presented with Pneumocystis carinii Pneumonia (PCP) and was found to have hypogammaglobulinaemia, associated with a thymoma that had been resected 17 months earlier. Only one previous case of PCP in association with a thymoma and hypogammaglobulinaemia has been reported, in which the patient died. We report another such patient who was successfully treated with a combination of intravenous immunoglobulin and high dose cotrimoxazole.

Agammaglobulinemia↗
PubMed1991

The amino acid-induced alteration in renal hemodynamics is glucagon independent.

The amino acid-induced alteration in renal hemodynamics is glucagon independent. An oral protein load or i.v. administration of an amino acid solution results in an increase in glomerular filtration rate and renal plasma flow in both humans and animals. The change in renal hemodynamics has been attributed to the simultaneous induced rise in glucagon. Whether glucagon is necessary for the change in renal hemodynamics after an amino acid infusion was investigated. Two groups of dogs were used, and the experimental protocol was divided into four different periods (P1 through P4). Group I animals received an amino acid solution, and group II dogs received an equiosmolar solution of mannitol. In P1, the animals in both groups were hydrated with normal saline, whereas, in P2, the pancreatic clamp technique was used to fix the plasma glucagon levels. P2 served as a basal period in which measurements of glomerular filtration rate, renal plasma flow, and plasma glucagon were obtained. IN P3, group I animals received amino acid solution, and group II received mannitol and served as controls. In this period, an increase of 32 and 27% in glomerular filtration rate and renal plasma flow, respectively, in group I dogs was observed, whereas there were no significant changes in these parameters in group II. During this period, plasma glucagon remained still at basal level in both groups. In P4, an infusion of glucagon at a rate of 5 ng/kg/min was added to both groups. This maneuver resulted in a fourfold increase in plasma glucagon levels in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1991

Effects of the inclusion of yeast culture (Saccharomyces cerevisiae plus growth medium) in the diet of dairy cows on milk yield and forage degradation and fermentation patterns in the rumen of steers.

The effects of including yeast culture (YC; Saccharomyces cerevisae plus growth medium; 5 x 10(9) organisms/g) in diets for ruminants was examined in two experiments. In Exp. 1, 32 multiparous Friesian dairy cows were fed between wk 7 to 12 of lactation one of four completely mixed diets based on either hay or straw plus rolled barley (mixed to give concentrate:forage ratios of either 50:50 or 60:40, respectively) with or without 10 g YC/d in a 2(3) factorial design. Supplementation with YC increased DM intake of the cows by a mean of 1.2 kg/d (P less than or equal to .062) and increased milk yield by 1.4 liters/d (corrected to 4% butterfat; P less than or equal to .05). There was an interaction (P less than .05) between diet composition and YC addition; effects of YC were greatest in diets containing 60:40 (concentrate:forage) ratio. In Exp. 2, three steers were fed a diet of 50% hay and 50% rolled barley (DM basis). Hay was available for the major part of the day but barley was fed in two meals/d. Addition of YC to the diet increased (P less than .05) ruminal pH for 4 h after the barley meal. This elevation in pH probably was due to a reduction (P less than or equal to .01) in the concentration of L-lactate in the ruminal liquor of steers given YC (1.43 vs 3.55 mM; P less than or equal to .01). Peak ruminal L-lactate concentration (7.75 mM) in the controls coincided with time of minimum pH values (2 h after the meal of barley); this peak was absent in steers given YC. YC had no effect on the concentration of VFA in ruminal liquor, but the ratio of acetate to propionate was reduced (P less than or equal to .01) from 3.3:1 to 2.8:1 in steers given YC. The extent of DM degradation of hay incubated in the rumen of steers fed the hay and rolled barley diet was increased (P less than .05) in the presence of YC at 12 h of incubation, but degradation was similar in all treatment groups after 24 h of incubation. Presence of yeast culture in the rumen had effects on ruminal stoichiometry. An increased rate of forage degradation may have increased forage intake and productivity of these dairy cows.

Animal Feed↗
PubMed1990

Effect of hyperglucagonemia on hepatic glycogenolysis and gluconeogenesis after a prolonged fast.

The aim of this study was to determine if glucagon can stimulate hepatic glucose production in prolonged fasted (7 days) animals. Two protocols were used; in one ("hormone replacement"; n = 4), intraportal basal replacement amounts of insulin and glucagon were given during a somatostatin infusion, whereas, in the other ("glucagon excess"; n = 5) basal insulin was given along with somatostatin and excess glucagon. Plasma insulin levels were similar and constant throughout both protocols (6 +/- 1 microU/ml). The plasma glucagon was basal in the hormone-replacement protocol (49 +/- 9 pg/ml) but rose from 46 +/- 7 to 448 +/- 35 pg/ml (P less than 0.05) in the other protocol. Plasma glucose levels and the rates of glucose production were unchanged during hormone replacement but rose from 100 +/- 5 to 199 +/- 28 mg/dl and from 1.5 +/- 0.1 to a peak of 5.6 +/- 0.2 mg.kg-1.min-1 at 15 min (P less than 0.05) and an eventual plateau of 2.7 +/- 0.2 mg.kg-1.min-1 (P less than 0.05) in response to glucagon excess. Because of the sluggish increase in gluconeogenic parameters, the early marked rise in glucose production was attributable to increased glycogenolysis. Eventually, however, the gluconeogenic rate rose, with net hepatic uptake of alanine increasing 50% and fractional alanine extraction doubling. Gluconeogenic efficiency and conversion increased in response to glucagon excess by 0.30 +/- 0.05 and 159 +/- 48%, respectively, although it should be noted that these parameters rose 0.15 +/- 0.06 and 150 +/- 49% in the hormone-replacement protocol. In conclusion, even after a prolonged fast physiological glucagon can cause hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗