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Biomedical subjects

P Howard

Publications and source records attributed to P Howard.

At least 91 records · Page 5Linked to original sources
PubMed1992

An analysis of the action of an analogue of almitrine bismesylate in the rat model of hypoxic lung disease.

Chronically hypoxic (CH) and normoxic control rats were used to assess the action of S9581, a water-soluble analogue of almitrine bismesylate. S9581 increased ventilation (Ve) by 34% in control and 20% in CH rats. During acute hypoxia Ve was raised and S9581 caused a further increase of 20% in both groups. Low doses of S9581 and almitrine enhanced the hypoxic ventilatory response in CH rats while high doses depressed it in both groups. Effects of S9581 on the pulmonary circulation were assessed in the isolated perfused lung of rats. As with almitrine a complex relationship of dose-dependent vasoconstriction and dilatation was revealed. In low doses, S9581 enhanced the hypoxic pulmonary vasoconstrictor response to 2% O2 whilst this was attenuated by high doses in both control and CH rats. S9581 seemed to act like almitrine bismesylate on both the ventilation (peripheral chemoreceptor) and the pulmonary circulation. For studying almitrine-like activity the water solubility of S9581 provides considerable advantages for the researcher.

Almitrine↗
PubMed1992

Comparative assessment of a new breath-actuated inhaler in patients with reversible airways obstruction.

Twenty-five patients with reversible airways obstruction inhaled salbutamol (200 micrograms) from the standard press and breathe-metered dose inhaler or a new breath-actuated metered dose inhaler (Aerolin in the Autohaler inhalation device; 3M Health Care Ltd.) in a single dose, double-blind, double-dummy, 2-period, cross-over study. Forced expiratory volume in 1 s, forced vital capacity and peak expiratory flow rate were measured in the 4-hour period after inhalation. The equivalence of the two inhaler devices was determined by analysis of the peak change and time to peak, with reference to the initial recorded baselines of the measured parameters. The efficacy of the two devices was very similar. The breath-actuated device is likely to benefit inhaler users who suffer from poor co-ordination of actuation and inhalation with a standard inhaler.

Adult↗
PubMed1992

Indications for long-term oxygen therapy.

The Medical Research Council and the Nocturnal Oxygen Therapy Trial studies clearly demonstrated that long-term oxygen therapy (LTOT) for more than 15 h/day improved mortality and morbidity in a well-defined group of patients with chronic obstructive pulmonary disease. There are no similar randomised control studies in patients with other hypoxaemic lung diseases such as pulmonary fibrosis and pneumoconiosis. The prescription of oxygen for other restrictive lung disorders is complicated by hypoventilation requiring mechanical support as well as oxygen and should be restricted to special centres. The clearest indications for LTOT are for patients with cor pulmonale, hypoxic chronic bronchitis and emphysema, and in terminally ill patients who require palliation. Before LTOT is considered, the patient must be clinically stable and on appropriate optimum therapy such as antibiotics, bronchodilators, physiotherapy and having stopped smoking tobacco. Many patients first present for LTOT with profound hypoxaemia and hypercapnia during an infective, often oedematous exacerbation of their lung disease. Assessments should occur during convalescence when the patient is clinically stable. They should be shown to have a PaO2 less than 7.3 kPa and/or a PaCO2 greater than 6 kPa on two occasions at least 3 weeks apart. FEV1 should be less than 1.5 litres, and there should be a less than 15% improvement in FEV1 after bronchodilators. All patients should be assessed by an experienced chest physician. Patients with a PaO2 between 7.3 and 8 kPa who have polycythaemia, right heart failure or pulmonary hypertension may gain benefit from LTOT but this is still to be clearly proven.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials as Topic↗
PubMed1992

The alpha- and beta-isoforms of the inhibitor protein of the 3',5'-cyclic adenosine monophosphate-dependent protein kinase: characteristics and tissue- and developmental-specific expression.

The inhibitor protein (PKI) of the cAMP-dependent protein kinase was first characterized from rabbit skeletal muscle. More recently a form of PKI was isolated and cloned from rat testis which shares relatively limited amino acid sequence with the rabbit skeletal muscle form. We have now isolated a cDNA from rat brain which encodes a protein corresponding to the rabbit skeletal muscle PKI. This establishes the presence of the "skeletal muscle" and "testis" proteins in the same species and therefore that they clearly represent distinct isoforms. We have also demonstrated that the isoform from testis, like the skeletal muscle isoform, is specific for the cAMP-dependent protein kinase and that it is able to inhibit this enzyme when expressed in cultured JEG-3 cells. Both forms contain the five specific amino acid recognition determinants which have been shown to be required for high affinity binding to the protein kinase catalytic site, although there is some noted lack of conservation of codons used for these residues. Overall, the two rat isoforms are only 41% identical at the amino acid level and 46% at the level of coding nucleotides. We propose that the rabbit skeletal muscle and rat testis forms be designated PKI alpha and PKI beta, respectively. Using Northern blot analysis, we have examined the tissue distribution of the two forms in the rat and their relative expression during development. In the adult rat, mRNA of the PKI alpha species is highest in muscle (both skeletal and cardiac) and brain (cortex and cerebellum).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Pulmonary hemodynamics and physical training in patients with chronic obstructive pulmonary disease.

The main hemodynamic abnormality in COPD is raised pulmonary vascular resistance and pulmonary hypertension. This is particularly evident when the vascular bed is stressed as in exercise; the absence of reserve collateral vessels prevents the normal reduction in pulmonary vascular resistance, and hence, pressure increases with flow. The increased afterload reduces right ventricular ejection fraction and stroke volume, but cardiac output is maintained by a relative tachycardia. Although most patients have a ventilatory limitation to exercise, in the later stages of the disease, hemodynamic factors may contribute. Studies of the effects of physical training on pulmonary hemodynamics have been few but none has shown any significant improvement. Occasionally there may be an increase in arteriovenous oxygen difference, accounting for the increase in symptom-limited oxygen consumption seen in some patients. The absence of hemodynamic effects of training may be due to insufficient training intensity. The often impressive increases in work tolerance after training may be due in part to an increase in muscular coordination and technique, as well as to metabolic training effects and psychologic factors.

Exercise↗
PubMed1992

Sequential treatment with low dose almitrine bismesylate in hypoxaemic chronic obstructive airways disease.

Daily dose schedules of 100-200 mg of almitrine bismesylate improve arterial blood gases in patients with hypoxaemic chronic obstructive airways disease (COPD) but dose related side effects are evident. In the present study, daily doses approximately half of those previously used were employed in a randomised double blind manner in 85 patients (age 35-79 years) with hypoxaemic COPD. After a one month period to check stability of arterial blood gases, patients were allocated to almitrine (A) or placebo (P) using an unequal code (60% A, 40% P). Tablets, 50-100 mg daily were stopped for one month after 3, 6 and 9 months to counteract drug accumulation. 50 patients in group A and 35 in group P were comparable on entry; mean age 65 (SD = 8) yrs., Pao2 7.8 (0.7) kPa (58.3 (5.0) mmHg), PaCO2 5.8 (0.8) kPa (43.2 (6.0) mmHg), forced expiratory volume in one second--FEV1 0.89 (0.25) l and 6 minute walking distance 296 (97) metres. The improvement in baseline PaO2 values was the same 0.8-1.3 kPa (6-9.8 mmHg) as with previous higher dose therapy. Approximately one third of patients did not respond, defined as PaO2 elevation > 0.67 kPa (5 mmHg). The sequential dosing scheme stabilised blood levels of almitrine within the therapeutic range of 280-300 ng.ml-1. After withdrawal of therapy arterial blood gases and spirometry reverted to pre-treatment levels, suggesting no permanent reversal of pathophysiology. Dose related side effects of breathlessness, indigestion and peripheral neuropathy were not observed. Nerve conduction studies revealed no difference in peripheral nerve dysfunction in hypoxaemic COPD between active and placebo therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Expression in Escherichia coli and characterization of the heat-stable inhibitor of the cAMP-dependent protein kinase.

Pure heat-stable inhibitor of the cAMP-dependent protein kinase (PKI) has been isolated in high yield by using a bacterial expression vector constructed to synthesize the complete sequence of the rabbit muscle protein kinase inhibitor, plus an amino-terminal initiator methionine and glycine. Bacterially expressed PKI has an inhibitory activity identical to that of the protein isolated from rabbit skeletal muscle and, by gel filtration and gel electrophoresis, has the same physicochemical characteristics as the native physiological form of PKI. Fourier transformed infrared spectroscopy and CD establish that PKI has unusually large amounts of random coil and turn structures, with significantly smaller amounts of alpha-helix and beta structures.

Animals↗
PubMed1991

Decreased catalytic subunit mRNA levels and altered catalytic subunit mRNA structure in a cAMP-resistant Chinese hamster ovary cell line.

The mechanisms responsible for decreased levels of cAMP-dependent protein kinase activity in a mutant Chinese hamster ovary cell line have been examined. The cAMP-resistant Chinese hamster ovary 10260 cell line was found to possess only 20% of the cAMP-dependent protein kinase activity found in wild-type cells. The presence of decreased concentrations of the catalytic subunit in these cells was confirmed through binding studies using a radiolabeled, heat-stable inhibitor of the kinase. Cloned Chinese hamster ovary catalytic subunit cDNAs were isolated, characterized, and used as hybridization probes to examine the relative concentrations of catalytic subunit mRNAs in the wild-type and 10260 cell lines. A 40-50% decrease in the concentration of the mRNA for the C alpha isozyme of the catalytic subunit was observed in 10260 cells, as compared with wild-type. This decrease in catalytic subunit mRNA concentration probably accounts for a portion of the decreased kinase activity in the mutant cells. Further analysis of C alpha mRNA by polymerase chain reaction confirmed the decreased expression of C alpha mRNA in 10260 cells and further demonstrated the presence of two different species of C alpha mRNA in the 10260 cells. One species of C alpha cDNAs was indistinguishable from the wild-type cDNA, but the other species was shorter. Nucleotide sequence analysis of the amplified cDNAs led to the identification of a 191-base pair deletion in the shorter cDNA. Gene transfer studies using wild-type and 10260 C alpha cDNAs demonstrated that the longer cDNA from the 10260 cells produced wild-type activity, but the shorter cDNA was inactive. These studies suggest that at least two alterations in gene expression are responsible for decreased cAMP-dependent protein kinase activity in the 10260 cell line. One alteration results in an approximately 2-fold decrease in the concentrations of C alpha mRNA in the cells. The other change produces two species of C alpha mRNA; one of the C alpha mRNAs does not encode an active kinase.

Amino Acid Sequence↗
PubMed1991

An unusual case using DNA polymorphisms to determine parentage of human remains.

The 2-year-old daughter of two farm laborers was reported missing while the farm owner was harvesting corn. Unidentifiable tissues and body parts were subsequently found admixed with silage. Samples of blood collected from the parents of the missing child as well as portions of the tissue recovered from the silage were subjected to analysis of DNA polymorphisms with probes usually used to identify paternity. In addition, allele-specific oligonucleotides were used to detect DNA polymorphism at the DQ alpha locus following DNA amplification using the polymerase chain reaction. In this case, the DNA results established that the tissue recovered from the silage was of human origin and confirmed the probable parentage of the two farm laborers.

Accidents↗
PubMed1991

Changes in atrial natriuretic peptide concentrations during intravenous saline infusion in hypoxic cor pulmonale.

BACKGROUND: The pathogenesis of oedema in hypoxic cor pulmonale is poorly understood. One possibility is a failure of atrial natriuretic peptide release, leading to salt and water retention. This hypothesis was tested by observing the response to an intravenous saline challenge in patients with and without cor pulmonale. METHODS: Plasma atrial natriuretic peptide concentrations were measured before and for three hours after an intravenous saline load (0.1 ml 2.7% saline/kg/min for 60 minutes) in 20 patients with chronic obstructive airways disease. Ten patients with cor pulmonale, as judged clinically by the presence of peripheral oedema with a previously documented increase in the jugular venous pressure or pleural effusions during an acute exacerbation of airway obstruction (mean (SE) age 67 (3) years, FEV1 0.73 (0.08) 1, arterial oxygen tension (PaO2) 6.4 (0.4) kPa, and arterial carbon dioxide tension (PaCO2) 6.7 (0.3) kPa), were compared with 10 patients with hypoxic chronic obstructive airways disease who had never had oedema (mean age 63 (1) years, FEV1 1.07 (0.09) 1, PaO2 8.6 (0.4) kPa, and PaCO2 5.3 (0.2) kPa). All patients were studied fasting and after diuretics had been stopped for three days. No supplemental oxygen was given. RESULTS: The mean four hourly urine sodium excretion was less in the patients who had oedema (27 (4.6) mmol, 13% of the intravenous load) than in those without oedema (82 (15.5) mmol, 43% of the load). Initial mean plasma atrial natriuretic peptide values were significantly higher in the patients with cor pulmonale (19.1 (1.6) compared with 10.2 (0.7) pmol/l) and the mean peak rise in atrial natriuretic peptide after the intravenous saline load had been given was 13 (8.0) pmol/l in the patients with cor pulmonale and 5.5 (2.3) pmol/l in the controls. There were no significant differences in plasma and urinary osmolality, blood pressure, or creatinine clearance between the groups. CONCLUSION: Patients with chronic obstructive airways disease and cor pulmonale have an impaired ability to excrete a hypertonic intravenous saline load despite a normal physiological release of plasma atrial natriuretic peptide.

Aged↗
PubMed1991

Oral almitrine in treatment of acute respiratory failure and cor pulmonale in patients with an exacerbation of chronic obstructive airways disease.

The effects of oral almitrine bismesylate, a respiratory stimulant that acts on peripheral arterial chemoreceptors, was studied in patients with chronic obstructive airways disease and hypoxaemic cor pulmonale. Twenty three patients admitted to hospital with an acute exacerbation of ventilatory failure were randomised to receive either almitrine 100 mg twice a day reducing to 50 mg twice a day over 48 hours or placebo in addition to conventional treatment. On admission the mean (SE) values for blood gas tensions were PaO2 4.8 (0.3) and PaCO2 7.7 (0.3) kPa in the 12 patients who received almitrine and PaO2 4.9 (0.1) and PaCO2 7.6 (0.3) kPa in the 11 who received placebo. After three hours of oxygen therapy at 1 1/min there was a similar rise in PaO2 in both groups, 6.4 (0.2) kPa in those receiving almitrine and 6.6 (0.4) kPa in those receiving placebo. After 24 hours of oxygen therapy values of PaO2 were again similar at 6.3 (0.8) kPa and 6.7 (2.2) kPa respectively. Arterial blood gas tensions improved during the study in those who survived but no significant differences were apparent between the two groups. There were six deaths, five in the almitrine group and one in the placebo group. There were no differences between the groups in respiratory rate, results of spirometry, oxygen requirement, or degree of dyspnoea (on visual analogue scale). The results did not show any benefit from oral almitrine in patients with acute respiratory failure secondary to chronic obstructive airways disease. Plasma almitrine concentrations, however, were often below the optimum therapeutic range, suggesting impaired drug absorption.

Administration, Oral↗
PubMed1991

An analysis of sequential physiologic changes in hypoxic cor pulmonale during long-term oxygen therapy.

Physiologic changes were studied retrospectively in 37 patients with hypoxic cor pulmonale who died during long-term oxygen therapy (LTOT). The subjects were assessed during periods of clinical stability for each year on LTOT. At the onset of treatment, their mean age (+/- SEM) was 60.0 +/- 1.3 years, and at the time of death, they were aged 65.0 +/- 1.3 years. The median duration of LTOT was five years. For each year leading up to death, mean values of FEV1, PaO2, and PaCO2 were obtained. A rate of decline of FEV1 of 73 +/- 10 ml/yr was observed, and this was accompanied by a decline in PaO2 of 0.47 +/- 0.01 kPa/yr. Patients died with a mean FEV1 of 0.55 +/- 0.04 L and a PaO2 of 5.1 +/- 0.2 kPa. A small rise in PaCO2 occurred, on average 0.25 +/- 0.09 kPa/yr, throughout the study, but accelerating in many cases during the three years before death. Hypoxic cor pulmonale appears to be associated with a rapid deterioration in airway function, a steady decline in PaO2, and a slow rise in PaCO2 during the years leading up to death. These physiologic changes measured in a stable clinical state while breathing air appear to occur in spite of LTOT. The LTOT may merely prevent death from episodes of severe hypoxemia while the pathophysiologic changes in the lung progress. Hence the benefit to be expected from LTOT is only temporary. Generally, those patients with lower levels of FEV1 will obtain diminishing clinical benefit, inversely related to the severity of airflow obstruction at the time of commencement of LTOT.

Aged↗
PubMed1991

Cardiovascular autonomic nerve function in patients with hypoxaemic chronic obstructive pulmonary disease.

Intraneural hypoxaemia is recognized as a pathogenic mechanism in diabetic neuropathy. A similar pathophysiological process may occur in chronic obstructive pulmonary disease (COPD). Autonomic neuropathy is not recognized in COPD. We compared 96 patients with hypoxaemic COPD to 22 age-matched control subjects to see whether autonomic dysfunction occurs in COPD and whether there was any correlation with the severity of hypoxaemia. The cardiovascular autonomic tests consisted of heart rate responses (mainly parasympathetic function) to a Valsalva manoeuvre, deep breathing and postural change and blood pressure responses (mainly of sympathetic origin) to postural change and sustained handgrip. Early autonomic neuropathy is defined as one abnormal test and definite autonomic neuropathy as two abnormal tests according to the normal range. These autonomic tests were reproducible in our study population. Although the symptoms and signs of autonomic neuropathy were rare, definite autonomic dysfunction was found in 35%, and early autonomic neuropathy in a further 47%, of patients whose arterial oxygen tension (PaO2) was less than 8 kPa (60 mmHg). Only 18% of the control group had evidence of an age-related early autonomic dysfunction. Parasympathetic autonomic dysfunction was significantly correlated with PaO2 whilst the sympathetic tests were relatively normal. Correction of hypoxaemia for one hour or administration of ipratropium bromide or terbutaline had no effect on autonomic function. Subclinical autonomic neuropathy is a feature of hypoxaemic COPD. Its importance in the disease process and its role in prognosis needs evaluation.

Aged↗
PubMed1991

Domiciliary oxygen--by liquid or concentrator? Working Group on Oxygen Therapy of IUATLD.

A few hypoxaemic and even less non-hypoxaemic patients with chronic obstructive pulmonary disease (COPD) benefit from portable oxygen. For these few, selected by double-blind tests against compressed air, liquid oxygen would seem more convenient and efficient. The extra cost of treating all hypoxaemic COPD patients with liquid oxygen by displacing the oxygen concentrator is not justified on the basis of current knowledge. The application of differing oxygen delivery systems to COPD patients requires more evaluation. The selection of patients for long-term oxygen therapy (LTOT) still presents major difficulties, which reflects on the numbers of patients likely to benefit from portable oxygen. No studies have yet shown the benefit of LTOT to chronic respiratory failure in other disorders such as lung fibrosis. As the pathophysiology is quite different, extension of the use of LTOT and portable oxygen to non-COPD patients must be treated with great caution.

Home Nursing↗