Biomedical subjects

J D Swarts

Publications and source records attributed to J D Swarts.

At least 19 recordsLinked to original sources

PubMed2000

Treatment of chronic suppurative otitis media with topical tobramycin and dexamethasone.

OBJECTIVES: To investigate the safety and efficacy of a topical combination of tobramycin and dexamethasone in a primate model of chronic suppurative otitis media (CSOM) and to explore the contribution of the added topical steroid for the treatment of CSOM. DESIGN: Blinded, randomized, placebo-controlled trial. SUBJECTS: Sixty juvenile cynomolgus monkeys randomized into the following 6 treatment groups of 10 monkeys each: 0.3% tobramycin (group 1), combined 0.3% tobramycin-0.1% dexamethasone (group 2), combined 1.0% tobramycin-0.33% dexamethasone (group 3), 0.1% dexamethasone (group 4), vehicle (group 5), and phosphate-buffered saline solution (group 6). INTERVENTIONS: Chronic suppurative otitis media was established by inoculating the right ear with Pseudomonas aeruginosa. After 4 weeks of drainage, animals were treated according to the group assignment with 3 drops twice daily for 7 weeks. Hearing thresholds were monitored with repeated auditory brainstem response testing (ABR), and clinical response was monitored with repeated otoscopic examinations and cultures throughout the study. Cytocochleograms were evaluated for quantification of outer hair cell loss. RESULTS: Rapid resolution of otorrhea and eradication of P aeruginosa occurred in all groups receiving tobramycin. The inclusion of dexamethasone accelerated the resolution of otorrhea and negative yields of cultures compared with tobramycin alone. Otorrhea and positive culture findings persisted in the groups not treated with topical antibiotic. Results of ABRs at 4 and 8 weeks and cytocochleograms for outer cell hair loss were not affected by drug administration. Perilymph samples collected at the end of the study showed no detectable tobramycin. CONCLUSIONS: Combined tobramycin-dexamethasone ear drops were safe and effective in the monkey CSOM model. Dexamethasone enhanced the efficacy of tobramycin.

Administration, Topical↗

PubMed2000

Prevention of otitis media with effusion by repeated air inflation in a monkey model.

OBJECTIVES: To test the following hypotheses that (1) middle ear (ME) air inflation prevents the development of otitis media with effusion in a monkey model of functional eustachian tube obstruction, and (2) ME inflation treatment of otitis media with effusion can cause artifactual clinical improvements due to fluid displacement from the tympanum to the adjacent airspaces. DESIGN: Randomized controlled trial. SUBJECTS: Twelve cynomolgus monkeys. INTERVENTIONS: Eustachian tube dysfunction was induced by botulinum paralysis of the right tensor veli palatini muscle in all monkeys. Before and on study days 9, 15, and 21 after paralysis, the presence or absence, and distribution of ME effusion were documented using magnetic resonance imaging (MRI). Right and left ears were examined twice daily for 21 days using tympanometry, and right ME air inflation (n = 6 ears) or sham inflation (n = 6 ears) was done immediately after those examinations if the ME pressure was -100 mm H2O or less. On 10 of the scheduled MRI evaluations, the MRI was repeated immediately after an inflation to document the possible redistribution of fluid within the ME caused by the maneuver. RESULTS: Middle ear pressure remained within normal limits for the follow-up period in 11 of the 12 nonparalyzed left ears, in none of the 6 sham-inflated right ears, and in 3 of the 6 air-inflated right ears. Three air-inflated right ears developed flat tympanograms (ie, days 14 through 16). Magnetic resonance imaging documented inflammation and fluid in 1 of the 11 nonparalyzed left ears and in all sham-inflated right ears. Lesser degrees of inflammation and effusion based on MRI evaluations were noted for the 3 air-inflated right ears that retained near-ambient pressures when compared with the right 3 ears that developed a flat tympanogram. The MRI measure of effusion quantity within the tympanum was decreased acutely after inflation, but was simultaneously increased in the adjacent airspaces of the temporal bone. CONCLUSIONS: Repeated air inflation prevented the development of otitis media with effusion in 50% of the ears with functional eustachian tube obstruction. Postinflation MRI documented the displacement of fluid by inflation from the tympanum to the mastoid and petrous air cells. Using standard clinical evaluations such as tympanometry and otoscopy, this fluid redistribution can cause a false diagnosis of improvement.

Animals↗

PubMed1999

Middle ear inflation for diagnosis and treatment of otitis media with effusion.

An adult (18 years), healthy, male subject with persistent bilateral middle ear (ME) underpressure and a history of recurrent otitis media into his teen years was identified. The response of his MEs to air inflation was evaluated and showed an immediate pressure increase after a Valsalva maneuver followed by a rapid pressure drop to approach the pre-inflation levels. That response is consistent with the presence of ME effusion, which was not diagnosed by otoendoscopy or tympanometry, but was visualized bilaterally within the mastoid regions using magnetic resonance imaging (MRI). The patient was treated for 25 days with ME inflation (3/day) and then re-examined. On each treatment day, he recorded his ME pressure using tympanometry before and after one inflation maneuver. The patient's compliance with the treatment protocol was high, and successful gas transfers were documented on most days. Over the course of treatment, pre-inflation ME pressure became more normal bilaterally. When compared to the pre-treatment test, the post-treatment inflation test showed a similar rate of ME pressure decrease, but significantly higher terminal pressures. On follow-up but not during the pre-treatment period, discrete changes in ME pressure attributable to ET openings were noted during test sessions. MRI documented lesser amounts of effusion in the mastoid, but not complete disease resolution. The significance of these observations to the design of a well controlled clinical trail of ME inflation as a treatment for otitis media is discussed.

Acoustic Impedance Tests↗

PubMed1999

Effects of nasal obstruction on Eustachian tube function and middle ear pressure.

To evaluate the relationship between nasal obstruction and otitis media, 10 ferrets were studied before and after either unilateral (E = 5) or bilateral (n = 5) nasal obstruction. Observations included otomicroscopic assessments of middle ear status, tympanometric recordings of middle ear pressure and forced-response, inflation-deflation and continuous monitoring tests of Eustachian tube function. During the 6 8 week post-obstruction follow-up period no animal developed evidence of otitis media. Abnormal positive middle ear pressures lasting for the period of follow-up occurred only in the animals with bilateral nasal obstruction. Eustachian tube function test results showed these pressures to be generated during swallowing. No changes in the passive function of the tube were documented in either group, but changes in active function consistent with alterations in the pressure gradient between the middle ear and the nasopharynx were observed in both groups.

Acoustic Impedance Tests↗

PubMed1997

Effects of systemic hyperoxia on eustachian tube ventilatory function.

Middle ear negative pressure and effusions, decreased middle ear compliance, and abnormal tympanometry results have been described after diving on oxygen. Middle ear gas hyperoxia has been shown to down-regulate the eustachian tube ventilatory function (ETVF). The purpose of the present study was to investigate to what extent systemic hyperoxia in the face of air-equivalent middle ear gas composition might interfere with the ETVF. ETVF was investigated in four young adult female cynomolgus monkeys by the forced-response and inflation-deflation tests using air while the animals breathed either room air or 100% normobaric oxygen. Higher opening, closing, and steady-state pressures were observed under systemic hyperoxia. The percentage of the applied pressure equalized, and the maximal pressure change on a single swallow in the deflation test were both lower under hyperoxic conditions. The results show that systemic hyperoxia might impair ETVF. This observation adds to our understanding of the pathophysiology of middle ear dysfunction observed after diving on oxygen.

Animals↗

PubMed1997

Eicosanoid synthesis and inactivation in healthy and infected chinchilla middle ears.

Otitis media (OM) is an inflammatory reaction of the middle ear (ME) elicited by a variety of stimuli including tubal obstruction, allergy and bacterial infection. The leukotrienes and prostaglandins are among the earliest mediators produced in response to these insults. Their measured levels in human and animal models span a broad range of concentrations. However, their baseline levels and metabolic fates are unknown for the ME. Their dynamics in the ME were examined using the chinchilla animal model, tritiated eicosanoids and a lavage procedure. Prostaglandin levels in the normal ME were 10 times higher than the 34 pg/ear observed for the leukotrienes and thromboxane B2. These levels were significantly increased by the calcium ionophore A23187 and bacterial infection. Leukotrience C4 was the most and prostaglandin E2 the least persistent eicosanoid in the ME. Their residence time in the ME was increased by infection. The rank order of eicosanoid concentrations among comparable studies was surprisingly constant, with prostaglandin E2 the most abundant and the leukotrienes the least. Comparisons of eicosanoid levels from A23187 stimulation and the infectious models sampled at 3 days suggest that the higher levels observed in the infectious models may represent basal eicosanoid production for hyperplastic ME mucosa.

Animals↗

PubMed1996

Effects of middle ear oxygen and carbon dioxide tensions on eustachian tube ventilatory function.

The objective of this study was to determine the effect of middle ear (ME) gas composition on eustachian tube ventilatory function (ETVF). ETVF was evaluated by using forced-response and inflation-de-flation tests in four alert cynomolgus monkeys during test sessions with different gas compositions. The ME was flushed with one of the four gas mixtures: 1. air; 2. 12% oxygen, 88% nitrogen; 3. 100% oxygen; and 4. 5% carbon dioxide, 21% oxygen, and 74% nitrogen before and during testing. The results documented lower opening, steady-state, and closing pressures, lower passive and active resistance, and greater dilatory efficiency following ME flushes with the hypercarbic and hypoxic gas mixtures when compared to the others. Also, for applied ME overpressure, the maximum pressure change during a swallow, the average pressure drop for all swallows, and the percentage of the applied pressure equalized were greater under hypoxic and hypercarbic conditions. These results show that ME gas composition affects ETVF and support feedback modulation of ME pressure regulation.

Animals↗

PubMed1995

Effect of ibuprofen treatment during experimental acute otitis media.

In this study, the efficacy of concurrent treatment of experimental acute otitis media with ibuprofen and ampicillin was evaluated in chinchillas with respect to clearance of the effusion, presence of mucosal inflammation, and modulation of biochemical markers. Forty chinchillas were infected with non-typable Haemophilus influenzae and randomly assigned to treatment with either IM ampicillin (control) or ampicillin plus ibuprofen beginning on day 2 post inoculation. On days 5 and 10, animals from each group were killed, effusions recovered for biochemical assay, and the middle ears prepared for histological study. Differences in outcome measures favoring the control group were observed at the 5 day endpoint. However, at the 10 day endpoint, mucosal thickness was significantly less, the number of effusion free ears greater, and the concentrations of free fatty acids and thromboxane less in the animals treated with the combined therapy when compared to the control group. These results suggest that the addition of ibuprofen to ampicillin for the treatment of acute otitis media alters disease pathogenesis in this infectious model.

Acute Disease↗

PubMed1995

In vivo observation with magnetic resonance imaging of middle ear effusion in response to experimental underpressures.

In this study, magnetic resonance imaging (MRI) was used to define, in vivo, the effect of acute middle ear (ME) underpressures on vascular permeability and the development of effusion. The MEs of four cynomolgus monkeys were unilaterally inflated with oxygen and carbon dioxide on different occasions and followed for a period of approximately 4 hours by tympanometry and MRI scanning. Carbon dioxide inflations caused the rapid development of ME underpressures of less than -600 mm H2O by 10 minutes. The MRI scans showed a progressive brightening of the ME and all associated air cells, indicative of the accumulation of effusion in three of the four experiments. An MRI contrast agent was administered to the vascular compartment during the course of the experiment and was rapidly transferred to the ME space, indicating vascular permeability to the agent. The contralateral, control side did not develop significant underpressures, effusion, or increased vascular permeability. Inflation with oxygen caused lesser underpressures and no accompanying changes in the MRI scans. These data support the hydrops ex vacuo theory and confirm the usefulness of MRI for in vivo documentation of the development of ME effusions and changes in vascular permeability of the mucosa in the experimental setting.

Animals↗

PubMed1995

Otologic and systemic manifestations of experimental influenza A virus infection in the ferret.

In an effort to further validate an animal model and to better define the mechanisms relating viral upper respiratory tract infections and acute otitis media, we infected 10 ferrets intranasally with influenza A virus. Infection was monitored by cultures and antibody titers, illness was monitored by signs and temperatures, and otologic complications were monitored by otoscopy, tympanometry, and eustachian tube function testing. All animals became infected. Forced-response test results showed progressive increases in the passive function variables after inoculation. Inflation-deflation test results documented progressive impairment of active tubal function, which was accompanied by the development of middle ear underpressures. No otitis media was seen. The results suggest that influenza A virus infection results in progressive, subtotal occlusion of the eustachian tube lumen, which compromises the ventilatory function of the tube, thereby promoting the development of middle ear underpressures. These findings support the hypothesized pathophysiologic relationship between viral upper respiratory tract infections, eustachian tube dysfunction, middle ear underpressures, and acute otitis media. Given these pathophysiologic changes and previously documented physiologic similarities to the eustachian tube-middle ear system of human beings, we conclude that the ferret represents an appropriate animal model for studying the pathogenic processes related to viral upper respiratory tract infections, eustachian tube dysfunction, and otitis media and for testing of potential prophylactic and therapeutic regimens.

Animals↗

PubMed1994

An experimental study of cefixime in the treatment of Streptococcus pneumoniae otitis media.

Previous studies using the chinchilla animal model demonstrated that the third generation cephalosporin cefixime (Suprax) with split dosing was as effective as ampicillin in sterilizing the middle ear cleft when infected with S. pneumoniae. In this investigator-blinded, randomized trial, a single daily dose of cefixime (8 mg/kg per day) performed as well as split dosing of cefixime (8 mg/kg every 8 h) and ampicillin (150 mg/kg every 8 h) in the time to sterilization of the middle ear cleft. No statistically significant differences were noted between groups in otoscopy or tympanometry. All antibiotic regimens performed better than saline control (P < 0.0001) with regard to time to sterilization of the middle ear cleft. The results of this study support the daily administration of cefixime as an effective agent for the treatment of otitis media due to its extended half-life and broad antibiotic spectrum.

Acoustic Impedance Tests↗

PubMed1994

Sensorineural hearing loss from quinolinic acid: a neurotoxin in middle ear effusions.

Quinolinic acid (QUIN) is an endogenous metabolite that exerts a neurotoxic effect by binding to specific neuronal receptors. Studies involving a broad spectrum of infectious and inflammatory central nervous system diseases have suggested a role for QUIN in causing neuronal injury. Since there is evidence for presence of the QUIN receptor in mammalian cochleas, QUIN was measured in middle ear effusions (MEEs). Gas chromatography/mass spectrometry detected QUIN in each of 65 diluted human MEEs, with a mean of 482 +/- 75 (SEM) nmol/L and a range from 15 to 2667 nmol/L. QUIN was also detected in each of 197 chinchilla MEEs from five different models of otitis media, with a mean of 10.6 +/- 1.3 (SEM) mumol/L and a range from 0.23 to 146.0 mumol/L (corrected for dilution). To determine whether QUIN causes sensorineural hearing loss (SNHL), QUIN solutions were placed on round window membranes (RWM) for 20 to 240 minutes, in 20 chinchillas. SNHL was detected by electrocochleography in QUIN-exposed animals, but not in saline controls. We conclude that QUIN is present in MEEs and that QUIN in the middle ear has the potential to cross the RWM and cause sensorineural hearing loss, possibly by binding to specific neuronal receptors in mammalian cochleas.

Animals↗

PubMed1994

Middle ear mucosal inflammation: an in vivo model.

The inflammatory process underlies the pathogenesis of otitis media (OM). Although knowledge concerning this common childhood disease continues to accumulate, most of the basic science research is based on in vitro or ex vivo methodologies. Magnetic resonance imaging (MRI), although lauded for its ability to image soft tissue, is often neglected as a research tool providing real-time in vivo information. This study attempts to assess experimental middle ear (ME) inflammation using MRI. The vasoactive effects of histamine and its interaction with antihistamines and a glucocorticoid were evaluated. Histamine was chosen because it is one of the naturally occurring inflammatory mediators. The antagonists were selected on the basis of their antihistaminic and vasoactive effects, respectively. Certainly there is substantial clinical interest in these agents because their efficacy for the treatment of OM is still being debated. The chinchilla model was chosen since it is one of the best characterized species in the study of OM. The three parts of the study are as follows: the effects of histamine on chinchilla ME mucosa; histamine challenge following pretreatment using hydroxyzine hydrochloride (H1 antagonist), ranitidine chloride (H2 antagonist), and the combination; and histamine challenge following pretreatment with dexamethasone. Sequential T1-weighted spin-echo (SE) MRI was used to detect extravasation of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) into the middle ear effusion (MEE). The results indicate that the vasoactive effects of histamine are dose-related and can be assessed across a wide spectrum of histamine dosages inclusive of the human MEE levels. The H1 antagonist alone, or in combination with the H2 antagonist, was able to prevent the increased vascular permeability induced by histamine. When used alone, the H2 antagonist did not abolish the effects of histamine. The vasoactive effects of histamine were also ameliorated by pretreatment with a glucocorticoid. These findings indicate the utility of MRI for assessing mucosal inflammation in a real-time manner rather than as an accumulation of events. This study also validates the efficacy of an H1 antagonist and a glucocorticoid in counteracting the vasoactive effects of histamine. This methodology may be suited for evaluating the effects of other classes of antiinflammatory mediators.

Animals↗

PubMed1993

Otitis media in the Republic of Palau. A case-series study.

Race is a known epidemiologic determinant for the development of otitis media. This study assessed the severity of otitis media in a subpopulation (N = 73; mean age, 13.2 years) receiving care from the ear clinic in the Republic of Palau, a US Trust Territory, through a questionnaire and an otologic examination. The mean age of patients with otorrhea (2.5 years) was found to be significantly different from the mean age at which they began to swim (4 years). Otitis media-related sequelae were found to involve more than half of ears or subjects examined. No statistical difference was noted when various patient characteristics were compared with the severity of disease. Our clinical impression is that this subpopulation is severely affected by otitis media and its sequelae. Prospective studies are required to identify risk factors present in the population at large.

Adolescent↗

PubMed1993

Evaluation of mixtures of purified Haemophilus influenzae outer membrane proteins in protection against challenge with nontypeable H. influenzae in the chinchilla otitis media model.

Nontypeable Haemophilus influenzae (NTHi) is one of the leading causative agents of bacterial otitis media, and no vaccine has been shown to be effective against it. Three outer membrane lipoproteins of NTHi have been investigated extensively and are leading candidates for inclusion in a vaccine against this organism. Hi-PAL (P6), recombinant PCP (rPCP), and e (P4) proteins are antigenically conserved among NTHi strains and elicit bactericidal and protective antibodies. A genetic fusion of the rPCP and Hi-PAL proteins has also been reported. Mixtures of these proteins were used for active immunization experiments in the chinchilla model of otitis media. Chinchillas were immunized either with a mixture of all three lipoproteins or with the mixture of rPCP-PAL hybrid plus e protein. When these animals were challenged with a NTHi strain injected directly into the middle ears, no protection from infection or disease, as measured by otoscopy, was observed in either group. However, effusion and inflammation measured by tympanometry were significantly reduced in animals immunized with the three lipoproteins. Animals that had been immunized with either whole NTHi cells or total outer membranes and then challenged with the homologous strain were significantly protected from both infection and disease, as determined by tympanometry and otoscopy. Unlike other animals antisera, chinchilla antisera against the purified proteins had no bactericidal activity against NTHi but did fix complement on the cell surface. Thus, the chinchilla immune responses to mixtures of these lipoproteins differ from the immune responses observed in other animal species. Further evaluation of these proteins for their vaccine potential remains to be done.

Animals↗

PubMed1993

Efficacy of ceftibuten for acute otitis media caused by Hemophilus influenzae: an animal study.

Ceftibuten is a new oral cephalosporin with an unusual stability to beta-lactamases that can hydrolyze other extended-spectrum cephalosporins. Using the chinchilla animal model, we compared the efficacy of ceftibuten (n = 33) with that of saline (n = 34), ampicillin (n = 32), and cefixime (n = 31) for the treatment of acute otitis media caused by beta-lactamase-producing nontypeable Hemophilus influenzae. Ceftibuten was superior to ampicillin regarding the time necessary to sterilize the middle ear (p < .001) and eliminate effusion (p < .001). The mean days of therapy required for bacteriologic cure were 2.57 for ceftibuten, 2.95 for cefixime, 7.95 for ampicillin, and 8.16 for saline. At the conclusion of therapy, chinchillas treated with ceftibuten had a significantly lower prevalence of positive cultures and middle ear effusion than did animals treated with ampicillin. No significant differences were observed between ceftibuten and cefixime. The results of this randomized, investigator-blinded experiment warrant further consideration of ceftibuten as a second-line agent for acute otitis media caused by ampicillin-resistant H influenzae.

Acute Disease↗

PubMed1993

Therapeutic effects of an anticholinergic-sympathomimetic combination in induced rhinovirus colds.

This study's objective was to determine if the combination of pseudoephedrine hydrochloride and atropine sulfate attenuates the symptomatic and pathophysiologic response of individuals to experimental rhinovirus infection when given after illness begins. Forty-three susceptible adult volunteers were challenged with rhinovirus type 39 and randomly assigned to 1 of 2 treatment groups. Twenty-one subjects were treated with the active medication (0.3 mg atropine sulfate and 60 mg pseudoephedrine) and 22 subjects were treated with inert capsules identical in appearance. Treatments were administered 4 times daily beginning approximately 24 hours after rhinovirus challenge and extending for 5 days. Before challenge and on each of 5 treatment days, all volunteers were asked to rate symptom severity and were evaluated for secretion production (weighted tissues), nasal patency (active posterior rhinomanometry), nasal clearance (dyed saccharin technique), eustachian tube function (9-step test), and middle ear status (tympanometry). Twenty subjects in each group were infected with rhinovirus type 39 and were included in the efficacy analysis. Between-group comparisons showed no significant differences in total symptom scores, combined nasal symptom score, secretion production, or the frequencies of persons with eustachian tube obstruction or abnormal middle ear pressures. However, an objective measure of nasal congestion was significantly lower in the active treatment group. The nasal mucociliary clearance rate was significantly more impaired in that group. Side effects consistent with anticholinergic activity were reported more frequently in the active treatment group.

Administration, Oral↗

PubMed1993

Eustachian tube function in the ferret.

The role of viral upper respiratory tract infections (URI) in the pathogenesis of otitis media (OM) may be related to Eustachian tube (ET) dysfunction. Preliminary experimental evidence suggests that the ferret may be an appropriate animal for modeling of pathophysiologic process related to URI's and ET dysfunction. In an effort to determine the applicability of this animal model, normal ET function was evaluated in 10 ferrets using the inflation-deflation and forced-response testing protocols. The results indicate that the ET of the ferret functions as a small-scale version of its rhesus monkey and human counterparts. The ET-middle ear (ME) system could maintain applied positive and negative ME pressures in all instances. Nearly complete swallow-induced pressure equilibrations were demonstrated in all ears tested. Elevated passive function parameters suggested a small tubal lumen. The efficiency of the tubal dilatory mechanism as expressed by the normalizing calculation (R0/RA) was shown to be quite similar to that in primates and man. These findings suggest that the ferret's ET functions in a manner similar to humans and is, therefore, an appropriate animal to study the pathogenesis of otitis media in the context of ET dysfunction.

Acoustic Impedance Tests↗