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Biomedical subjects

S M Harding

Publications and source records attributed to S M Harding.

At least 37 records · Page 2Linked to original sources
PubMed1999

24-h esophageal pH testing in asthmatics: respiratory symptom correlation with esophageal acid events.

BACKGROUND: Gastroesophageal reflux (GER) may be a trigger for asthma and may be clinically silent. Twenty-four-hour esophageal pH testing accurately diagnoses GER in asthmatics. There are no reports correlating respiratory symptoms with esophageal acid events. This study examines the prevalence and severity of GER in asthmatics with and without reflux symptoms and examines respiratory symptom correlation with esophageal acid. METHODS: All esophageal manometry and 24-h esophageal pH tests performed were reviewed in asthmatics who met entrance criteria from July 1, 1989, through November 1, 1994. GER was present if esophageal pH tests were abnormal. Results of esophageal tests were compared for asthmatics with reflux symptoms and GER and asthmatics without reflux symptoms and GER. Respiratory symptoms correlated with esophageal acid events if the esophageal pH was < 4 simultaneously with the respiratory event or within 5 min before its onset. RESULTS: Of 199 asthmatics who qualified for analysis, 164 (82%) had reflux symptoms. The results of 24-h esophageal pH tests were abnormal in 118 of 164 asthmatics with reflux symptoms (72%), compared with 10 of 35 asthmatics without reflux symptoms (29%). Among asthmatics with GER, 119 of 151 respiratory symptoms (78.8%) were associated with esophageal acid. Seventy-six of 84 reported coughs (90.5%) were associated with esophageal acid. Theophylline did not alter esophageal parameters. CONCLUSIONS: There is a strong correlation between esophageal acid events and respiratory symptoms in asthmatics with GER. Respiratory symptom correlation with esophageal acid events further supports that GER may be a trigger for asthma.

Asthma↗
PubMed1999

Nocturnal asthma: role of nocturnal gastroesophageal reflux.

Gastroesophageal reflux (GER) is common in those with asthma, with 77% of asthmatics complaining of heartburn, with 41% experiencing reflux-associated respiratory symptoms. Likewise, 24% of those with asthma that is difficult to control have "clinically silent" GER. There are no studies examining nocturnal reflux symptoms in asthmatics. Esophageal dysmotility is also common, and abnormal esophageal acid contact times on 24h esophageal pH tests were found in 82% of asthmatics examined consecutively. Most asthmatics with GER also have abnormal esophageal acid contact times while in the supine position, reflecting sleep time. Endoscopic evidence of esophagitis was found in 43% of asthmatics. Two mechanisms of bronchoconstriction induced by esophageal acid have been proposed: a vagally mediated reflex, by which esophageal acid in the distal esophagus causes reflex bronchoconstriction, and microaspiration. Although there is conflicting evidence, distal esophageal acid causes a decrease in peak expiratory flow rates, an increase in respiratory resistance, and an increase in minute ventilation. If microaspiration is present, there is further augmentation of this airway response. Although only a few studies have been performed in those with nocturnal asthma with GER, one study in a pediatric population showed that esophageal acid infusions caused more airway responses at 04:00 than at 24:00. Also, asthmatic children with nocturnal asthma symptoms have a higher reflux score, with a positive correlation between reflux score and nighttime-associated wheezing. Despite these findings in children, a study performed in sleeping adults with nocturnal asthma noted no alterations in airflow resistance with esophageal acid, concluding that GER contributed little to the nocturnal worsening of asthma. There are also gastroesophageal circadian issues that may influence GER in asthmatics. Gastric acid secretion peaks at approximately 21:00, and gastric emptying is delayed when a meal is given at 20:00 versus 08:00. Esophageal acid clearance is delayed significantly during sleep, and acid clearance occurs during arousals. Upper esophageal sphincter (UES) pressure also decreases with sleep onset, which may predispose to microaspiration. Further research is needed to clarify what role nocturnal reflux has on nocturnal asthma and airway inflammation and whether circadian rhythm factors alter airway responses to esophageal acid.

Acids↗
PubMed1998

Sleep in fibromyalgia patients: subjective and objective findings.

Fibromyalgia (FM) patients report early morning awakenings, awakening feeling tired or unrefreshed, insomnia, as well as mood and cognitive disturbances; they may also experience primary sleep disorders including sleep apnea. Longitudinal studies have demonstrated the chronic nature of these disturbances in patients with FM. A distinct relationship exists between poor sleep quality and pain intensity. Polysomnographic findings during sleep in these patients include an alpha frequency rhythm, termed alpha-delta sleep anomaly, which is also seen in normal controls during stage 4 sleep deprivation; deep pain induced during sleep in normal controls also causes this anomaly. Sleep architecture is altered in FM patients showing an increase in stage 1, a reduction in delta sleep, and an increased number of arousals. Before prescribing pharmacologic compounds aimed at modifying sleep, adequate pain control and sleep habits should be achieved; tricyclic antidepressants, trazadone, zopiclone, and selective serotonin reuptake inhibitors, however, may be required. More research is needed to elucidate the cellular and molecular mechanisms involved in the sleep disturbances occurring in patients with FM.

Alpha Rhythm↗
PubMed1997

Autonomic regulation in asthmatics with gastroesophageal reflux.

STUDY OBJECTIVE: To study the role of autonomic regulation in asthmatics with gastroesophageal reflux (GER). DESIGN: Prospective study. SETTING: Autonomic function laboratory of a 908-bed university hospital. PARTICIPANTS: Fifteen nonsmoking asthmatics with GER (six men, nine women; average age, 36 years). INTERVENTIONS: Subjects were connected to an ECG monitor. BP was measured by sphygmomanometer at set intervals. After a resting period, each subject had heart rate and BP monitored during an 80 degrees passive tilt, Valsalva maneuver, quiet and deep breathing, handgrip, and an echo stress test of cortical arousal. Each autonomic function test was analyzed and defined as normal, hypervagal, hyperadrenergic, or mixed (a combination of hypervagal and hyperadrenergic responses) as compared with 23 age-matched normal control subjects from our laboratory (14 men, 9 women; average age, 35 years) and published normal control values. Each subject had an overall response score that was determined by the results of the tilt, Valsalva maneuver, and deep breathing maneuvers. RESULTS: All asthmatics with reflux had at least one autonomic function test display a hypervagal response. Overall response scores show that eight of 15 asthmatics with GER had an overall hypervagal response, and seven had a mixed response. Of the seven asthmatics with GER who had a mixed response score, two had a hypervagal predominant response. CONCLUSIONS: Asthmatics with GER have evidence of autonomic dysfunction. Heightened vagal tone may be partially responsible for the heightened airway responsiveness to esophageal acidification in asthmatics with reflux.

Adult↗
PubMed1996

Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome.

PURPOSE: To determine (1) the appropriate omeprazole (Prilosec) dose required for adequate acid suppression in asthmatics with gastroesophageal reflux, (2) whether aggressive acid suppressive therapy of gastroesophageal reflux improves asthma outcome in asthmatics with gastroesophageal reflux, (3) the time course of asthma improvement, and (4) demographic, esophageal, or pulmonary predictors of a positive asthma response to antireflux therapy. PATIENTS AND METHODS: Thirty nonsmoking adult asthmatics with gastroesophageal reflux (asthma defined by American Thoracic Society criteria and reflux defined by symptoms and abnormal 24-hour esophageal pH testing) were recruited from the outpatient clinics of a 900-bed university hospital. Patients underwent baseline studies including a demographic questionnaire, esophageal manometry, dual-probe 24-hour esophageal pH test, barium esophogram, and pulmonary spirometry. During the 4-week pretherapy phase, patients recorded reflux and asthma symptom scores and peak expiratory flow rates (PEFs) upon awakening, 1 hour after dinner, and at bedtime. Patients began 20 mg/d omeprazole, and the dose was titrated until acid suppression was documented by 24-hour pH test. Patients remained on this acid suppressive dose for 3 months. Responders were identified by a priori definitions: asthma symptom reduction by >20% and/or PEF increase by >20%. Asthma symptom scores, PEF's baseline and posttherapy pulmonary spirometry were analyzed. RESULTS: Twenty-two (73%) patients were asthma symptom and /or PEF responders: 20 (67%) were asthma symptom responders, and 6 (20%) were PEF responders. Responders reduced their asthma symptoms by 57% (P<0.001), improved their morning and night PEFs by 8% and 9% (both P <0.005), and had improvement in forced expiratory volume at 1 second (P <0.02), mean forced expiratory flow during the middle half (25% to 75%) of the forced vital capacity (P <0.04), and peak expiratory flow (P <0.01) with acid suppressive therapy. Mean acid suppressive dose of omeprazole was 27 mg/d (+/-2.2) with 27% (8) patients requiring more than 20 mg/d. The presence of regurgitation or excessive proximal esophageal reflux predicted asthma response with 100% sensitivity, 100% negative predictive value, specificity of 44% and a positive predictive value of 79%. CONCLUSIONS: Acid suppressive therapy with omeprazole improves asthma symptoms and/or PEFs by >20% and improves pulmonary function in 73% of asthmatics with gastroesophageal reflux after 3 months of acid suppressive therapy. Many asthmatics (27%) required >20 mg/d of omeprazole to suppress acid. The presence of regurgitation and/or excessive proximal esophageal reflux predicts a positive asthma outcome.

Adult↗
PubMed1995

Gastroesophageal reflux-induced bronchoconstriction. Is microaspiration a factor?

STUDY OBJECTIVE: To evaluate the role of microaspiration in gastroesophageal reflux-induced bronchoconstriction. DESIGN: Prospective study blinded to the subject. SETTING: Outpatient laboratory of a 908-bed university hospital. PARTICIPANTS: Thirty nonsmoking adults divided into two groups: asthmatics with reflux (AR), 20; and subjects with gastroesophageal reflux (R), 10. INTERVENTIONS: Dual esophageal pH probe placed. Esophageal infusions of normal saline solution, 0.1N hydrochloric acid, then normal saline solution, each lasting 18 min, were followed by two 20-min recovery periods. Subjects remained in the supine position throughout. Spirometry and specific airway resistance (SRaw) performed at baseline, after each esophageal infusion and recovery period. Proximal esophageal acid exposure, a requirement for microaspiration, was assessed by the proximal esophageal pH probe. RESULTS: Peak expiratory flow rate (PEF) decreased with esophageal acid in the AR group and did not recover immediately despite esophageal acid clearance with a significant main effect of subject groups (p < 0.021) by repeated measures analysis of covariance. This decrease in PEF was not associated with the presence of proximal esophageal acid exposure (p = 0.618). Specific airway resistance increased in the AR group with esophageal acid and worsened despite acid clearance, especially during the second recovery phase, with a significant phase (p < 0.009) and group by treatment effect (p < 0.009). The presence of proximal esophageal acid exposure was not associated with this deterioration in SRaw (p = 1.0). CONCLUSIONS: Esophageal acid infusions given in the supine position caused a decrease in PEF and an increase in SRaw in the asthma with reflux group, which did not improve despite acid clearance. These responses were not dependent on proximal esophageal acid exposure. Also, SRaw continued to worsen during the recovery phase in the AR group, which may represent a delayed bronchoconstrictor effect. These data suggest that microaspiration does not play a significant role in esophageal acid-induced bronchoconstriction.

Adult↗
PubMed1994

Gastroesophageal reflux-induced bronchoconstriction. An intraesophageal acid infusion study using state-of-the-art technology.

STUDY OBJECTIVE: To study mechanisms of gastroesophageal reflux-induced bronchoconstriction during intraesophageal infusions. DESIGN: Prospective study blinded to the subject. SETTING: Outpatient pulmonary function laboratory at a 908-bed university hospital. PARTICIPANTS: Forty-seven adult subjects divided into four groups: asthmatics with reflux, 20; asthmatics, 7; gastroesophageal refluxers, 10; and normal controls, 10. Asthmatics were defined by American Thoracic Society criteria, and refluxers were defined by symptoms and 24-hour pH monitoring. INTERVENTIONS: Dual antimony esophageal pH probe placed just below the upper esophageal sphincter and 5 cm above the lower esophageal sphincter. Intraesophageal infusions of normal saline solution followed by 0.1N hydrochloric acid then normal saline solution were given for 15 to 18 min. Spirometry and specific airway resistance (SRaw) were performed after placement of pH probes, insertion of esophageal infusion tube, and after each infusion. Bernstein tests were assessed during esophageal infusions. MEASUREMENTS AND RESULTS: Peak expiratory flow rate (PEF) decreased with intraesophageal acid in all four groups (p < 0.014). Esophageal acid clearance improved PEF in all groups except the asthmatics with reflux group that had a further decrease in PEF. These effects were not dependent on a positive Bernstein test or evidence of proximal reflux. The asthmatics with reflux group also had an increase in SRaw with intraesophageal acid, which continued to increase despite acid clearance. CONCLUSIONS: Intraesophageal acid infusions caused a decrease in PEF in all groups without evidence of microaspiration, implying a vagally mediated reflex may be involved. Esophageal mucosal inflammation, assessed by a positive Bernstein test, was not required. Asthmatics with reflux also had further decline in PEF despite acid clearance.

Adult↗
PubMed1994

Use of desmopressin acetate to reduce blood transfusion requirements during cardiac surgery in patients with acetylsalicylic-acid-induced platelet dysfunction.

OBJECTIVE: To determine whether desmopressin acetate (DDAVP) has the ability to reduce blood loss in patients with a known bleeding tendency. DESIGN: A randomized, double-blind, placebo controlled study. SETTING: A university teaching hospital. PATIENTS: Men under the age of 70 years who had taken acetylsalicylic acid within 7 days of scheduled coronary artery bypass surgery. Patients with an abnormal hematologic profile or a history of bleeding or who were receiving heparin or undergoing repeat coronary bypass surgery were excluded. Forty-four patients were randomized with restriction in blocks of 10; 20 received DDAVP and 24 received a placebo. MAIN OUTCOME MEASURES: Blood loss and blood transfusion requirements. RESULTS: Patients treated with DDAVP lost significantly (p < 0.01) less blood than those receiving a placebo (1543 mL versus 2376 mL respectively). Nineteen patients had a blood loss of more than 2000 mL; 15 of these were in the placebo group. Significantly (p < 0.02) fewer patients receiving DDAVP required blood transfusion (9 versus 18). CONCLUSIONS: DDAVP reduces blood loss during cardiac bypass surgery in patients who have taken acetylsalicylic acid within 7 days before operation.

Aspirin↗
PubMed1991

The pharmacokinetic and pharmacodynamic interaction between lacidipine and propranolol in healthy volunteers.

The pharmacokinetic and pharmacodynamic profiles of lacidipine, a 1,4-dihydropyridine calcium antagonist, and the beta-adrenoceptor blocker propranolol were determined alone and in combination in 24 healthy male volunteers. One group (I) of 12 subjects received a single oral dose of 4 mg lacidipine on two separate occasions, which was taken together with a single oral dose of either 160 mg propranolol or placebo; a second group (II) of 12 subjects received propranolol on two occasions, taken with either lacidipine or placebo. Propranolol significantly decreased the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of lacidipine (by 38% and 42%, respectively) whereas lacidipine significantly increased the Cmax and AUC of propranolol (by 35% and 26%, respectively); neither the time to maximum plasma concentration (tmax) nor the terminal half-life (t 1/2) were affected. With regard to the pharmacodynamics, in Group I, there was a greater reduction in supine systolic blood pressure (6 mm Hg) and diastolic blood pressure (4 mm Hg) compared to the reduction produced by lacidipine alone, and pulse rate was approximately 5 beats/min less. In Group II, a significantly greater reduction (6 mm Hg) in supine systolic blood pressure compared to the reduction produced by propranolol alone occurred, but there was no marked difference in supine diastolic blood pressure and pulse rate. In conclusion, a modest pharmacokinetic and pharmacodynamic interaction is evident and should be evaluated further in patients with hypertension.

Administration, Oral↗
PubMed1991

Clinical pharmacology of lacidipine.

The safety and tolerability of lacidipine was assessed in a volunteer population, and its pharmacodynamic and pharmacokinetic profiles evaluated. In normotensive subjects, single oral doses of 3-5 mg of lacidipine produced a dose-related fall in peripheral vascular resistance. This was accompanied by reflex-mediated increases in heart rate and cardiac output to maintain blood pressure. Adverse events were those typically related to the vasodilatory action of lacidipine, such as flushing and headache. A 4-mg dose of lacidipine elicited a cardiovascular response equivalent to that with 10 mg of nifedipine, given as a single oral dose. Lacidipine did not affect sinoatrial or atrioventricular conduction in the healthy subjects studied. Two specialized electrophysiologic studies in patients confirmed that lacidipine does not affect pacemaker tissue and that it exhibits relative selectivity for the vascular smooth muscle. Lacidipine is eliminated primarily by hepatic metabolism, and extensive first-pass loss occurs after oral dosing. Absolute bioavailability is less than 10%. The systemic availability of lacidipine was increased in healthy elderly subjects and in patients with impaired hepatic function, but not in patients with impaired renal function.

Adolescent↗
PubMed1990

The human pharmacology of fluticasone propionate.

Fluticasone propionate is a potent, locally active glucocorticoid which has no demonstrable systemic side-effects when given by the oral or intranasal routes. The recommended clinical dose for rhinitis is 200 micrograms once a day intranasally or twice a day if symptoms persist. Four studies are described which establish the metabolic and pharmacokinetic features of fluticasone propionate and which assess the systemic effects of oral and intranasal doses in healthy volunteers. The drug was cleared rapidly by metabolism, with a total blood clearance equivalent to hepatic blood flow. On this basis, the expected extraction ratio would approach unity and oral systemic bioavailability would approach zero. This was confirmed by the absence of unchanged drug in the plasma up to 6 h after dosing with 1 mg or 16 mg of drug. The principal metabolite found, the 17-carboxylic acid derivative, has negligible glucocorticoid activity. This rapid clearance to an inactive metabolite is the basis for the observed lack of effects on the hypothalamo-pituitary-adrenal axis after single, night-time doses of fluticasone propionate, 16 mg orally, and after fluticasone propionate, 4 mg intranasally for 1 week. The virtually zero oral bioavailability and lack of systemic effects by the oral and intranasal routes are features which are unique compared with other glucocorticoids used clinically.

Administration, Intranasal↗
PubMed1989

The clinical pharmacology of ondansetron.

Ondansetron, a 5-HT3 antagonist proposed for use in the treatment of chemotherapy-induced emesis, was first given to man in 1984 and in the 4 years subsequent to this, the drug was given to more than 220 different healthy volunteers. In pharmacodynamic studies, there was evidence to suggest that ondansetron was gastroprokinetic but reduced transit time through the small bowel. Ondansetron was of no benefit in a model of motion sickness. The pharmacokinetics of ondansetron have been defined in volunteers using intravenous and oral dosage regimens proposed for the clinic. Ondansetron had a terminal plasma half-life of 3.0-3.5 h and plasma clearance (principally metabolic) of the order of 600 ml/min, and there was no evidence of accumulation at steady state. The absolute oral bioavailability of ondansetron was 59%. Metabolic studies showed the drug to be excreted predominantly in urine and faeces, with a metabolite profile in urine similar to that seen in the animal species used for toxicological testing. Ondansetron is both safe and well tolerated at daily doses of up to 64 mg given to volunteers.

Antiemetics↗
PubMed1988

Conjunctival oxygen monitoring: relationship to ventricular arrhythmias.

The results of conjunctival oxygen monitoring in a critically ill patient whose cardiac rhythm changed from sinus tachycardia to ventricular tachycardia and ventricular fibrillation and back to sinus tachycardia are described. Monitoring revealed a significant decrease in conjunctival oxygen tension 2 minutes before ventricular tachycardia was manifested by continuous electrocardiography, and an immediate rise in conjunctival oxygen tension was seen with the resumption of sinus tachycardia. This monitoring modality may be a useful adjunct in the hemodynamic evaluation of critically ill patients.

Aged↗
PubMed1987

Aspects of the microbe: host relationship in staphylococcal hematogenous osteomyelitis.

Nasal carriage of staphylococci, and some in vitro tests of host antimicrobial defense were studied in a group of children who had recovered from staphylococcal hematogenous osteomyelitis at least one year previously. The same studies were carried out in a group of first degree relatives, and in age- and sex-matched controls. Nasal carriage was significantly more common (P = .039) in these children than in age- and sex-matched controls, and commoner (P = .19) in the first degree relatives than in controls. Total immunoglobulin G (IgG) levels were significantly lower in the children studied than in controls (P = .022), and in relatives than in controls (P = .032), but the levels remained within an accepted normal range. IgG levels were also significantly lower in carriers of Staphylococcus aureus than in non carriers (P = .033). Other immunoglobulin levels, complement levels, leukocyte phagocytic and killing power, leukocyte chemotaxis, and leukocyte migration inhibition, were indistinguishable between the children, their relatives, and controls. No statistically significant association between histocompatibility antigen profile and previous history of osteomyelitis, or nasal carriage of staphylococci, was found. More detailed studies are required to confirm and clarify the associations.

Cell Migration Inhibition↗