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Biomedical subjects

L Hendeles

Publications and source records attributed to L Hendeles.

At least 55 records · Page 3Linked to original sources
PubMed1991

Inhaled verapamil-induced bronchoconstriction in mild asthma.

Methacholine challenges were performed in ten subjects with mild asthma at 2 h before and 20 min after placebo or 5, 10, 20, 40, 80, and 160 mg of inhaled verapamil given in a single-blind randomized crossover manner on different days. While verapamil did not have a bronchodilator effect, the 10-mg dose modestly increased the concentration of methacholine required to decrease FEV1 by 20 percent (PC20). The mean (+/- SEM) increase in PC20 from baseline was 2.1 +/- 0.2 times baseline after 10 mg of verapamil, compared to 1.1 +/- 0.1 times baseline after placebo (p less than 0.001). Unexpectedly, bronchoconstriction (greater than 10 percent decrease in FEV1) associated with cough or wheezing was observed in seven of ten subjects at doses of 20 mg or more. This adverse effect was not related to the osmolarity of the nebulized solutions. Thirty minutes before a standardized exercise challenge, 13 subjects inhaled placebo, 10 mg, or the highest dose of verapamil tolerated during the methacholine study (20 to 160 mg) in a double-blind randomized crossover manner. The exercise challenge was aborted in three subjects because of bronchospasm that occurred after administration of the higher dose. The mean (+/- SEM) maximum change in FEV1 after exercise in the ten subjects completing all three regimens of treatment was -17.1 +/- 4.0 percent after placebo, -12.7 +/- 4.3 percent after 10 mg (p less than 0.05), and -6.4 +/- 3.6 percent after the highest dose (p less than 0.05). We conclude that increasing the dose of verapamil above 10 mg did not provide greater benefit but, paradoxically, induced bronchoconstriction in most of the subjects. Because of this potential bronchoconstrictor effect, high doses of oral or intravenous verapamil should be used with caution in asthmatic subjects.

Administration, Inhalation↗
PubMed1990

Treatment failure after substitution of generic pancrelipase capsules. Correlation with in vitro lipase activity.

Pancreatic enzyme products are formulated, manufactured, and sold without submitting efficacy or bioavailability data to the Food and Drug Administration because of a quirk in the law. We documented therapeutic failures in three patients with cystic fibrosis after pharmacists substituted generic pancrelipase capsules for the Pancrease brand. Gastrointestinal symptoms and fat malabsorption rapidly resolved after therapy was reinstituted with brand name products. In vitro analysis indicated that after 1 hour of exposure to simulated gastric fluid, lipase activity was less than 200 U per capsule from all three generic capsules dispensed to the patients compared with 6820 U per capsule from Pancrease. These data indicate that the enteric coating of the generic product was defective and that the substituted product was not bioequivalent to the prescribed brand. We conclude that the Food and Drug Administration should institute regulations over this group of products.

Adult↗
PubMed1989

Measurement of plasma prednisolone level to evaluate a prednisone treatment failure in an adolescent with Crohn's disease.

A 14-year-old boy experienced multiple hospitalizations because of symptoms due to Crohn's disease involving the stomach, duodenum, and ileum. He maintained that oral corticosteroids were not effective for control of his symptoms. However, i.v. corticosteroids always relieved his symptoms. To resolve the question of noncompliance versus altered corticosteroid absorption or metabolism, our patient underwent an oral prednisone absorption study. Prednisolone, the active metabolite of prednisone, was measured in his plasma using a high-pressure liquid chromatography technique. The results led to the discovery of an elaborate deception by the patient and his subsequent need for psychotherapy. This report documents the importance of measuring plasma prednisolone concentrations to diagnose noncompliance, especially in adolescents who are overly concerned about their body image.

Adolescent↗
PubMed1989

Clinical relevance of the interaction of theophylline with diltiazem or nifedipine.

The results of previously published studies indicate that calcium channel blockers are capable of competitively inhibiting cytochrome P-450 activity in hepatic microsomes, the pathway of theophylline metabolism. In addition, case reports have suggested that theophylline serum concentrations change when a calcium channel blocker has been added to or deleted from a stable theophylline regimen. To determine the clinical relevance of this potential interaction in patients with chronic asthma, we measured a peak steady-state theophylline serum concentration in 21 subjects while receiving theophylline alone (400 to 1,500 mg/day), and again, at least seven days later, after the addition of continuous therapy with maximally tolerated doses of either diltiazem (n = 18) or nifedipine (n = 16). The diltiazem dose was increased in 120 mg/day increments, as tolerated, to a maximum of 240 to 480 mg/day, while the nifedipine dose was increased in increments of 40 mg/day, to a maximum dose of 80 to 160 mg/day. The mean +/- SEM theophylline serum concentrations were 13.6 +/- 1.4 micrograms/ml before and 14.0 +/- 1.2 micrograms/ml during concurrent diltiazem therapy, and 12.6 +/- 1.0 micrograms/ml before and 12.2 +/- 1.1 micrograms/ml during nifedipine (p greater than 0.05). With this sample size there is a 5 percent chance that we missed a 20 percent change in serum concentration (type II error). Thus, maximum tolerated doses of diltiazem or nifedipine do not impair the metabolism of theophylline to a clinically relevant degree and adjustment of theophylline dosage is not required after the addition or discontinuation of diltiazem or nifedipine. In addition, these data suggest that currently available in vitro techniques for evaluating drug interactions in the hepatocyte do not predict the clinical relevance of such an interaction in patients who might require both drugs for different therapeutic indications.

Adolescent↗
PubMed1988

Duration of effect of gallopamil, a calcium channel blocker, on methacholine-induced bronchoconstriction.

We previously demonstrated a modest but significant protective effect of inhaled gallopamil (D600), the methoxy derivative of verapamil, against methacholine-induced bronchoconstriction; however, the duration of the protective effect of this and other calcium channel blockers is unknown. We therefore evaluated the duration of this protective effect in 15 asthmatic subjects in a prospective, placebo-controlled trial. Methacholine challenges (Cockcroft method) were performed 2 hours before and 30 minutes after the administration of placebo, and 1 mg and 10 mg of inhaled gallopamil. Gallopamil did not alter resting airway caliber, but significantly increased the concentration of methacholine required to decrease the FEV1 20% 30 minutes after the dose. Results with both the 10-mg and 1-mg doses were significantly different from placebo, but not from each other. The duration of this protective effect was transient in the group as a whole; the mean drug activity ratios were not significantly different with this sample 2.5 hours after the dose. Thus the short duration of effect limits the potential clinical usefulness of gallopamil in suppressing the signs and symptoms of chronic asthma.

Adolescent↗
PubMed1988

Effect of irrigation and tourniquet application on aminoglycoside antibiotic concentrations in bone.

Preoperative antibiotics are an important measure taken to prevent infection in joint replacement surgery. The local availability of these antibiotics in the operative site is absolutely necessary to ensure adequate prophylaxis against contaminant bacteria. Because pulsatile-lavage rapid-recovery systems have become a routine technique of bone preparation in joint reconstruction, we chose to study the effect of these systems on local antibiotic concentrations. We further investigated the effect of irrigation with and without use of a limb tourniquet. For our study, we obtained 23 bone specimens in 16 patients undergoing joint reconstruction (14) or amputation (2). The patients were classified into one of four groups based on whether a tourniquet was applied during the procedure and whether the bone specimens were irrigated. In addition, matched blood samples were obtained to establish that therapeutic serum levels were achieved. Nine patients contributed 13 bone specimens, which underwent vigorous irrigation in vitro. None of these specimens had detectable levels of antibiotics, regardless of whether a tourniquet was used. Seven patients yielded 10 bone specimens, which were not irrigated. Five of these seven patients had detectable levels of antibiotics. In addition, the specimens from limbs without tourniquets had levels that averaged 0.51 microgram/ml while those with tourniquets averaged below 0.2 microgram/ml. Therefore, the use of vigorous irrigation in bone preparation has a significant deleterious effect on the local presence of previously administered systemic antibiotics. This effect is compounded if the operative site is isolated from continuous blood flow by use of a tourniquet. We therefore recommend that additional measures be taken to ensure that adequate antibiotic levels are present.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Duration of protection of calcium channel blockers against exercise-induced bronchospasm: comparison of oral diltiazem and inhaled gallopamil.

The present study was conducted to determine the duration of the positive effect of oral diltiazem and inhaled gallopamil in mild asthmatic volunteers, ages 18-37 years, with a history of exercise-induced asthma and a 25-56% decrease in FEV1 after a standardized exercise challenge. Oral diltiazem 120 mg, inhaled gallopamil 10 mg, and placebo were administered in a double blind, randomized, crossover manner on different days 48 h apart. Diltiazem was administered 90 min and gallopamil 30 min before the first exercise challenge. Challenges were then repeated 3 and 6 h later. Neither diltiazem nor gallopamil significantly altered baseline FVC, FEV1, or FEF25-75. The mean maximum decrease in FEV1 after the first challenge was 16.8% after gallopamil, 25.2% after diltiazem and 30.1% after placebo. The mean post-exercise decrease in FEV1 after gallopamil was significantly smaller than after placebo. There were no significant differences in the post-exercise decreases in FEV1 between the three treatment regimens 3 and 6 h later. Thus, inhaled gallopamil provided significant protection against exercise-induced bronchospasm, but the beneficial effect was modest and short in duration.

Administration, Inhalation↗
PubMed1988

Evaluation of an office method of measuring theophylline serum concentrations.

A strip test for theophylline, with an immunoassay with a colorimetric indicator, has been developed for use in the physician's office (Seralyzer, Ames Division, Miles Laboratories, Elkhart, Ind.). Diluted serum is applied to the plastic reagent strip, which is then inserted into a reflectance photometer that quantitates the color change and displays the serum concentration in 80 seconds. To determine the reliability of this method, control sera (5.0, 10.0, 15.0, 20.0, and 25.0 micrograms/ml of theophylline) and 78 specimens, each from a different patient, were analyzed by Seralyzer and a reference method (EMIT, Syva Co., Palo Alto, Calif.). Nine replicate measurements of a 15.0 micrograms/ml control serum were performed on one day, an all five control sera were analyzed once daily for 20 days. Patient specimens were analyzed at the rate of eight per day. The coefficient of variation (mean/SD X 100) for within day precision of the 15 micrograms/ml control was 5.2% for Seralyzer and 4.1% for EMIT (p less than 0.05). Coefficients of variation for between-day precision of the Seralyzer were less than 10% at concentrations greater than 5 micrograms/ml, but were significantly greater than EMIT measurements at 5 and 10 micrograms/ml (p less than 0.05). There was a strong correlation between the two methods for the 78 patients' specimens (r2 = 0.95). The Seralyzer demonstrated a positive bias of 0.9 microgram/ml. Results analyzed by the two methods differed by greater than 25% in 10 of the 78 specimens (mean error, 3.3 micrograms/ml over the range of 2.9 to 22.2 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Asthma↗
PubMed1988

The effects of nalmefene, a potent oral opiate antagonist, on exercise-induced bronchospasm.

Endogenous opioids are released during exercise and have been demonstrated to induce mast cell degranulation when they are administered intradermally. Thus, these peptides may play a role in the pathogenesis of exercise-induced bronchospasm (EIB). However, in two previous studies, intravenous naloxone did not provide significant protection from EIB. To determine if these failures were due to inadequate dosage (pharmacokinetic failure) or lack of an inherent pharmacologic effect (pharmacodynamic failure), the present study was conducted with nalmefene (Key Pharmaceuticals, Inc., Miami, Fla.), a slowly metabolized, orally bioavailable opiate antagonist, with 30 times the potency of naloxone. Ten subjects with mild intermittent asthma and a greater than or equal to 20% decrease in FEV1 after a standardized exercise test were studied. nalmefene, 20 mg, and identically appearing placebo tablets were administered orally in a double-blind, randomized, crossover design 2 hours before bronchoprovocation. Treadmill exercise was performed for 6 minutes at a minute ventilation of 55% to 66% of the calculated maximum voluntary ventilation and not exceeding 75% to 85% maximal heart rate for age. Spirometry was performed before and 3, 5, 8, 10, and 15 minutes after exercise. The mean decrease in FEV1 after exercise was 28.6 +/- 4.5% with placebo and 30.3 +/- 4.5% with Nalmefene (p = 0.6; beta = 0.04 for a 15% difference). Thus, we conclude that narcotic antagonists do not alter airway reactivity to exercise. In addition, these data suggest that endogenous opioids probably do not play an important role in the pathogenesis of EIB.

Administration, Oral↗
PubMed1988

Dose response of inhaled gallopamil (D600), a calcium channel blocker, in attenuating airway reactivity to methacholine and exercise.

To determine if there is a dose-response relationship for calcium channel blockers in preventing experimentally induced bronchoconstriction, we evaluated the effects of inhaled gallopamil (D600), a potent methoxy derivative of verapamil, on airway reactivity to methacholine and exercise in volunteers with mild asthma. Methacholine challenges were completed by 11 subjects 2 hours before and 20 minutes after placebo, and 1, 2, 5, 10, and 20 mg of inhaled gallopamil administered in a single-blind, randomized manner on different days. Gallopamil did not significantly alter FVC, FEV1, or forced expiratory flow rate between 25% and 75% of FVC, but increased the dose of methacholine required to produce a 20% decrease in FEV1 from baseline (p less than 0.0001). The mean +/- SEM fold increase in the dose of methacholine required to produce a 20% decrease in FEV1 from baseline was 1.0 +/- 0.1 after placebo, 2.4 +/- 0.2 after 1 mg, 2.2 +/- 0.2 after 2 mg, 2.5 +/- 0.2 after 5 mg, 2.5 +/- 0.3 after 10 mg, and 2.3 +/- 0.2 after 20 mg. Thirty minutes before a standardized exercise challenge, 10 subjects inhaled 1 and 10 mg of gallopamil or placebo in a randomized, double-blind, crossover manner. The mean +/- SEM maximum decrease in FEV1 after exercise was 25.1 +/- 5% after 10 mg of gallopamil (p less than 0.01), 34.4 +/- 5% after 1 mg (p greater than 0.05), and 39.0 +/- 6% after placebo. We conclude that inhaled gallopamil only modestly alters airway reactivity to methacholine; increasing the dose greater than 1 mg did not provide greater benefit.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Relative efficacy of phenytoin and phenobarbital for the prevention of theophylline-induced seizures in mice.

We evaluated the efficacy of pretreatment with phenytoin and phenobarbital to prevent seizures in mice given convulsive doses of theophylline. The control LD50 for theophylline was determined in 48 mice by intraperitoneal injections of increasing doses without anticonvulsant treatment. Anticonvulsant effects were determined in 105 additional mice pretreated with either phenytoin 30 mg/kg (n = 35), phenobarbital 35 mg/kg (n = 30), or phenobarbital 60 mg/kg (n = 40) one hour before theophylline administration. The theophylline LD50 (95% confidence interval) was 239 mg/kg (range, 229 to 248 mg/kg) for controls, 204 mg/kg (range, 194 to 214 mg/kg) for phenytoin, 305 mg/kg (range, 288 to 323 mg/kg) for low-dose phenobarbital, and 319 mg/kg (range, 307 to 331 mg/kg) for high-dose phenobarbital. Each LD50 differed significantly from control (P less than .05). The phenobarbital groups were significantly different from phenytoin (P less than .05) but not from each other. Theophylline serum concentrations were not significantly different among groups after adjustment for different doses. The mean +/- SEM time to seizure in minutes after adjustment for theophylline dose was 23.5 +/- 4.0 minutes for controls, 5.7 +/- 7.5 minutes for phenytoin, 44.1 +/- 7.1 minutes for low-dose phenobarbital, and 63.7 +/- 6.5 minutes for high-dose phenobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Dose-response of inhaled diltiazem on airway reactivity to methacholine and exercise in subjects with mild asthma.

Methacholine challenges were performed by 10 asthmatic subjects, 2 hours before and 15 minutes after placebo (diluent alone) and 5, 10, 15, 30, and 60 mg inhaled diltiazem given in a single-blind crossover manner. There was no significant change from placebo in the dose of methacholine required to produce a 20% decrease in forced expiratory volume in the first second (FEV1) (PD20); the fold increase in PD20 from baseline was 1.1 +/- 0.1 after placebo, 1.4 +/- 0.2 after 5 mg, 1.8 +/- 0.3 after 10 mg, 1.4 +/- 0.2 after 15 mg, 1.6 +/- 0.2 after 30 mg, and 1.2 +/- 0.1 after 60 mg. There was a 1% chance that we missed a twofold difference between placebo and the 10 mg dose because of inadequate sample size. Fifteen minutes before a standardized exercise challenge, 10 subjects received placebo, 10 mg, and the highest dose tolerated during the methacholine study (20 to 45 mg) in a randomized double-blind crossover design. The mean +/- SE maximum postexercise decrease in FEV1 was 28.8% +/- 5.7% after placebo, 23.4% +/- 4.6% after 10 mg, and 20.8% +/- 3.0% after high-dose diltiazem (P greater than 0.05). There was a 12% chance that we missed a 15% difference between placebo and the high-dose regimen because of inadequate sample size. We conclude that diltiazem does not attenuate airway reactivity to methacholine or exercise even when high concentrations are delivered to the lungs.

Adult↗
PubMed1988

Clinical assessment of an enzyme immunoassay (EMIT) for measurement of serum salicylate.

Salicylic acid concentrations in serum were compared using a homogenous enzyme immunoassay (EMIT) and an automated colorimetric analysis (ACA) technique. Analysis of samples showed similar within-day and day-to-day coefficients of variation (CV): 1.3% and 4.6% by EMIT and 1.0% and 2.6% by ACA, respectively. Quantification of serum containing added salicylate and serum from patients receiving salicylate therapy showed a slight positive bias towards the ACA method over the range of 0-600 mg/l. No significant difference in reliability was found between the two methods. The EMIT assay showed no interference from other antiflammatory drugs being taken by patients who were not taking salicylates. If decisions to alter salicylate dosage are made with due regard to the drug's saturation kinetics, measurements using either EMIT or ACA should allow the clinician to titrate patients' serum concentrations accurately within the narrow therapeutic range.

Colorimetry↗
PubMed1988

Bioavailability of a slow-release theophylline capsule given twice daily to preschool children with chronic asthma: comparison with liquid theophylline.

The reliability of slow-release theophylline products in young children has been questioned. Therefore, we studied the bioavailability of a commonly prescribed slow-release theophylline formulation (Slo-Bid Gyrocaps), administered twice daily by sprinkling the beads on applesauce. Serial measurements of serum theophylline concentrations were obtained during steady state in eight children (ages 1.6 to 5 years) after receiving a reference liquid theophylline product every six hours and also while receiving the slow-release product every 12 hours. The morning dose of slow-release theophylline was given before the child had eaten, and the evening dose was given two hours after supper. The extent of absorption of the slow-release product was 98.3 +/- 20.2% (mean +/- SD) relative to the liquid reference. The serum concentration fluctuations, expressed as percentage of the measured trough, did not differ between the two products: 108 +/- 59% v 129 +/- 97% (P greater than .05) for reference and slow-release products, respectively. Three of the eight patients had unacceptably large fluctuations (greater than 100%) while receiving the slow-release regimen, and two of these three had unacceptable fluctuations while receiving the liquid reference. The rate of absorption was slower after the evening dose of slow-release product (postprandial), resulting in significantly smaller fluctuations, and lower peak concentrations. Time to peak concentration while receiving the slow-release regimen varied from two to four hours after the evening dose and from two to eight hours after the morning dose. However, the average difference between the peak concentration and the four-hour measurement after the morning dose was only 0.3 microgram/mL (range 0 to 2.6 micrograms/mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Asthma↗
PubMed1988

Death of a child associated with multiple overdoses of acetaminophen.

A case of long-term acetaminophen overdosage in a six-year-old child, which contributed to her death despite optimal medical management including oral acetylcysteine therapy, is reported. Acetaminophen 325 mg every six hours was prescribed for fever associated with measles. Believing that acetaminophen was nontoxic, the child's mother progressively increased the dose over three days, first in response to fever and subsequently for abdominal pain probably secondary to unrecognized acetaminophen toxicity. On admission to the hospital, the patient's serum acetaminophen concentration was 163 micrograms/mL (11 hours after the last dose); subsequently, the acetaminophen half-life was determined to be 15 hours. A course of oral acetylcysteine therapy (a loading dose of 140 mg/kg as the sodium salt followed by 70 mg/kg every four hours for 17 doses) was begun. Hepatic and renal failure developed within two days, followed by the onset of seizures, and brain death occurred on the 11th day. Autopsy findings consistent with acetaminophen toxicity included centrilobular hepatic and renal tubular necrosis. Aspergillis fumigatus and Cryptococcus neoformans isolates from pulmonary abscesses and bronchopulmonary lymph nodes, respectively, were an unexpected finding. However, in the absence of acetaminophen overdosage, death would have been unlikely. Cryptococcal lymphadenitis was believed to have been the initial febrile illness that was treated with supratherapeutic doses of acetaminophen. Fatalities in children from a single overdose of acetaminophen have been rare, and there is only one previous report of a fatality after long-term administration of multiple excessive doses. The lethal outcome in this case illustrates the need to educate the public on the potential toxicity of nonprescription medications.

Acetaminophen↗