Effects of apomorphine on heart rate during simultaneous administration of sulpiride: a challenge of the composed concentration-effect model

Apomorphine elicits opposite concentration-dependent effects on the heart rate in rat bradycardia at low concentrations and tachycardia at higher ones. This has been modeled with a composed sigmoid Emax equation. To challenge this model, a selective antagonist, sulpiride, was administered simultaneously with apomorphine. Four short intravenous infusions of apomorphine, at different rates, were administered to rats, while a steady state concentration of sulpiride was maintained by intravenous infusion. Another group of rats was infused with apomorphine at the same rates of infusion as in the above groups, together with saline. In this latter group a biphasic concentration-response relationship was observed, while in the group receiving sulpiride and apomorphine no bradycardia was detected. A sigmoid Emax model with one term describing bradycardia and one tachycardia was used for the saline plus apomorphine data. For the sulpiride plus apomorphine data a single-term sigmoid Emax model was used. The maximal induced tachycardia was found to be the same in both groups. The tachycardia occurred at lower concentrations in the sulpiride group, probably as a result of an antagonist-induced shift of the bradycardia towards higher concentrations. The obtained results show that a composite concentration-effect curve of apomorphine has experimental validity and that it is possible to separate its pharmacodynamic characteristics on heart rate into its components, bradycardia and tachycardia, by sulpiride.     

Scanning electron microscopy of the organ of corti after intense auditory stimulation: Effects on stereocilia and cuticular surface of hair cells

Summary The organ of Corti of cats, guinea pigs and chinchillas exposed to pure tones of high intensity were first mounted on a slide in glycerol and mapped with light/phase contrast microscopy. Subsequently the same specimens were rinsed in water, freeze-dried and prepared for scanning electron microscopy. The study shows that it is well possible to use the same preparation for light microscopic and scanning electron microscopic investigations. Scanning electron microscopy permits detailed studies of the surface topography of the organ of Corti and demonstrates structural changes not visible in light/phase contrast microscopy. The changes are found on both inner and outer hair cells and include disarrangement of hairs, fusion of stereocilia and the formation of giant hairs, which exceed the normal stereocilia in length and thickness. The giant hairs are seen most frequently in cats following low frequency exposure. Moreover, the cuticular plates of the sensory cells are often extensively deformed. It is doubtful if these cells, which may look normal as studied by light/phase contrast microscopy, are still functional. In areas showing epithelial damage an increase in the number and size of the microvilli of the Deiters cells is often found.

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Zusammenfassung Häutchenpräparate des Cortischen Organs von Katzen, Meerschweinchen und Chinchillas, die reinen Tönen hoher Intensität exponiert wurden waren, wurden in Glycerol auf Objektträgern montiert and im Licht/Phasenkontrastmikroskop untersucht. Danach wurden die Präparate im Wasser gereinigt, gefrier-getrocknet und für rasterelektronenmikroskopische Studien vorbereitet. Es zeigte sich, daß es gut möglich ist, die Präparate, die zuerst im Lichtmikroskop untersucht waren, mit dem Rasterelektronenmikroskop zu studieren. Die Rasterelek-tronenmikroskopie erlaubt genaue Studien der Oberflächenstruktur des Cortischen Organs und demonstriert morphologische Veräderungen, die im Liebt/Phasenkontrastmikroskop nich zu sehen sind. Die Veränderungen sind an den inneren wie auch an den äußeren Haarzellen zu sehen und bestchen aus Disarrangement von Haaren, Fusion vieler Stereocilien und Formation von Riesenhaaren, die die normalen Stereocilien und Formation von Riesenhaaren, die die normalen Stereocilien an Länge und Dicke bei weitem übertreffen. Die Cuticularplatten der Sinneszellen sind häufig deformiert. Es ist fraglich, ob diese Sinneszellen, die im Lichtmikroskop noch normal aussehen, voll funktionstüchtig sind. In Bezirken mit epithelialen Veränderungen kann eine Erhöhung der Zahl und Größe der Mikrovilli der Deiters-Zellen gefunden werden.

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This work was supported by the National Aeronautics and Space Administration, NASA Grant: NGL 14005074 while the authors were under appointment to the Bioacoustics Research Laboratory at the University of Illinois, Urbana, Illinois, U.S.A. The authors would also like to acknowledge the cooperation of Professor B. Vincent Hall, Head of the Center for Electron Microscopy at that institution.     

A longitudinal cohort study on the prevalence of Helicobacter pylori antibodies in Swedish children and adolescents

The aim of this study was to monitor the Helicobacter pylori antibody seroprevalence of an asymptomatic cohort between the ages of 4 and 18 y. The H. pylori antibody titres in a longitudinally followed cohort of 168 native Swedish children (born between 1972 and 1974) were established at 4, 8, 12, 16, and 18 y of age. Seventeen children (10.1%) were found positive on at least one occasion when a paediatric cut-off was applied. Five children (3.0%) reached levels considered positive in adults. The seroprevalence at 4 y of age was 4.0%, at 8 y 2.5%, at 12 y 4.9%, at 16 y 5.3%, and at 18 y 6.3%. The difference in serological titres between the age groups was not significant. A change from negative to positive after the age of 4 took place in 5 of the cases. Spontaneous seroreversion appeared in 5 cases. Conclusion : Our findings showed no significant differences among the various age groups. Seventeen of the 168 children (10.1%) had been infected at some time, the prevalence ranging from 2.5% to 6.3%. Seroconversion and seroreversion occurred infrequently between the ages of 4 and 18 y.     

Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole

BACKGROUND: Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor developed as a single isomer for the treatment of acid-related diseases. AIM: To examine the pharmacokinetics and pharmacodynamics of esomeprazole. METHODS: In a crossover study, 12 healthy males received 5, 10 or 20 mg of esomeprazole, or 20 mg of omeprazole, once daily over 5 days. The pharmacokinetics and effects on pentagastrin-stimulated peak acid output of esomeprazole and omeprazole were studied on days 1 and 5. RESULTS: The area under the curve (AUC) of both esomeprazole and omeprazole increased from day 1 to day 5. The correlation between acid inhibition and AUC for esomeprazole could be well described with a sigmoid Emax model. The mean inhibition values of the pentagastrin-stimulated peak acid output on day 1 for 5, 10 and 20 mg of esomeprazole were 15%, 29% and 46%, respectively; the corresponding day 5 values were 28%, 62% and 90%. The mean inhibition values of the pentagastrin-stimulated peak acid output for omeprazole were 35% (day 1) to 79% (day 5). CONCLUSIONS: The pharmacokinetics of esomeprazole are time and dose dependent. There was a good correlation between AUC and effect for esomeprazole. These data suggest an increased acid inhibitory effect of esomeprazole compared to omeprazole.     

Bioavailability estimation by semisimultaneous drug administration: a Monte Carlo simulation study

The performance of a novel method for determination of drug absorption characteristics was evaluated by Monte Carlo simulations. In bioavailability studies with use of this method, the test and the reference doses are administered within a time interval of hours. Estimates of bioavailability are obtained by fitting an appropriate model to the concentration-time profile, which in its terminal portion is thus the summed concentration of the two doses. Drugs with different properties, mimicked by varying the kinetic rate constants (ka, lambda 1 and lambda 2), and experimental designs with different sets of conditions regarding the interval between doses, dose ratio, dose order, and duration of sampling, were simulated to determine what factors govern parameter estimation. The absorption characteristics of the simulated drugs could be adequately determined in experiments lasting for 12 hr or less, provided that a proper design was used. Fitting of a simpler or a more complex disposition model produced estimates with similar accuracy and precision to those noted with the true model. For some conditions the use of an improper absorption model resulted in slightly reduced accuracy, but as these fits were poor there was a clear need to try other models. In another set of simulations the use of the proposed method to assess the relative availability of two extravascular doses was evaluated. The relative rate and extent of absorption could be estimated with good precision for two formulations exhibiting a rapid to moderate rate of absorption.     

Postmeningitic labyrinthine ossification primarily affecting the semicircular canals

In a series of six cochlear-implant candidates, including three small children, labyrinthine ossification in various stages of development was observed at CT. In four of the candidates the ossifying process was more advanced in the semicircular canals than in the cochleae, and in two equally distributed. The ossifying process developed during a period of 4–5 months in two of the children. Asymmetry of its extension was found in four patients. The causative organisms were Hemophilus influenzae and Streptococcus pneumoniae. The radiologic assessment of cochlear-implant candidates should include the semicircular canals where the ossification may start, and herald the development of cochlear ossification. Received 9 November 1995; Revision received 17 April 1996; Accepted 25 April 1996     

Central nervous system involvement in patients with facial palsy due to borrelial infection

Patients with a peripheral facial palsy due to an underlying Ixodes-borne borreliosis often have cerebrospinal fluid findings indicating meningeal involvement. The aim of the present study was to identify signs of CNS involvement by means of brain-stem evoked response audiometry (BSER) in patients with a facial palsy due to borreliosis, as well as in patients with a facial palsy of unknown aetiology. Bell's palsy. Abnormalities in BSER were found to be significantly more common along the borrelial patients. Furthermore, a reversal of these abnormalities following treatment with benzyl-penicillin was found in the majority of patients with borreliosis. The results of the present study emphasize the importance of diagnosing and treating an underlying borreliosis in patients with a peripheral facial palsy.     

A wide spectrum of fastidious and ampicillin-susceptible bacteria dominate in animal-caused wounds

The main purpose of this study was to assess the actual occurrence of Gram-negative oxidase-positive bacteria (GNOP) in human wounds caused by animals, mostly cat and dog bites and scratches, and with signs of infection. We report a prospective series of 92 wound samples. Routine culturing was combined with a procedure optimised for fastidious GNOP. All GNOP isolates were identified by 16S rDNA sequencing to the species level. We observed a more prominent role of GNOP, including at least 30 species mostly in the families Flavobacteriaceae, Neisseriaceae and Pasteurellaceae, and less of Staphylococcus aureus and streptococci. The antibiotic susceptibility pattern was investigated, as GNOP are associated with sudden onset of serious infections, making an early decision on antibiotic treatment vital. All GNOP isolates judged to be clinically relevant displayed susceptibility to ampicillin and meropenem, but resistance to oxacillin, clindamycin and gentamicin was frequent. Our findings emphasise the need to cover GNOP as recommended in guidelines, and not only common wound pathogens, when treating an animal-caused wound.