Population pharmacokinetics of rifampin in the treatment of Mycobacterium tuberculosis in Asian elephants.

The objective of this study was to develop a population pharmacokinetic model for rifampin in elephants. Rifampin concentration data from three sources were pooled to provide a total of 233 oral concentrations from 37 Asian elephants. The population pharmacokinetic models were created using Monolix (version 4.2). Simulations were conducted using ModelRisk. We examined the influence of age, food, sex, and weight as model covariates. We further optimized the dosing of rifampin based upon simulations using the population pharmacokinetic model. Rifampin pharmacokinetics were best described by a one-compartment open model including first-order absorption with a lag time and first-order elimination. Body weight was a significant covariate for volume of distribution, and food intake was a significant covariate for lag time. The median Cmax of 6.07 µg/mL was below the target range of 8-24 µg/mL. Monte Carlo simulations predicted the highest treatable MIC of 0.25 µg/mL with the current initial dosing recommendation of 10 mg/kg, based upon a previously published target AUC0-24/MIC > 271 (fAUC > 41). Simulations from the population model indicate that the current dose of 10 mg/kg may be adequate for MICs up to 0.25 µg/mL. While the targeted AUC/MIC may be adequate for most MICs, the median Cmax for all elephants is below the human and elephant targeted ranges.

The pharmacokinetics of a single oral or rectal dose of concurrently administered isoniazid, rifampin, pyrazinamide, and ethambutol in Asian elephants (Elephas maximus).

Tuberculosis, caused by Mycobacterium tuberculosis, is a disease of concern in captive Asian elephants (Elephas maximus). Treatment for tuberculosis in elephants utilizes multidrug protocols combining isoniazid, rifampin, pyrazinamide, and/or ethambutol. In this study, a single, coformulated dose of isoniazid 5 mg/kg, rifampin 10 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 30 mg/kg was administered orally to six Asian elephants, and rectally to five elephants using a cross-over design. Blood samples were collected serially over 24 h. Pyrazinamide and ethambutol concentrations were determined using validated gas chromatography assays. Isoniazid and rifampin concentrations were determined using validated high-performance liquid chromatography assays. Rectal isoniazid produced an earlier Tmax compared with oral administration. Oral isoniazid resulted in a comparatively lower Cmax , but higher AUC values compared with rectal isoniazid. Oral rifampin and oral ethambutol were well absorbed while rectal rifampin was not. Oral pyrazinamide produced comparatively higher Cmax and AUC values compared with rectal pyrazinamide. Results of this study indicate that currently recommended therapeutic monitoring sample collection times for rectal isoniazid and oral rifampin do not provide an accurate assessment of exposure for these drugs. This study demonstrates notable individual variability, indicating that dosing of these medications requires individual monitoring and provides additional information to guide the clinician when treating elephants.

Treatment of tarsal joint deformities with hinged transarticular external fixators in three young birds.

Pelvic limb deformities are common in many avian species. Three young birds, including a six-week-old Cockatoo and two three-month-old goslings, were presented with tarsal joint deformities. They were treated with an experimental prototype of a hinged linear external fixator, placed in a transarticular fashion, in order to maintain joint function during treatment. All birds had close to normal leg function at six to ten weeks postoperatively. These results suggest that the hinged external fixator may be a viable treatment option for tarsal joint deformities in young birds.

[The comorbidity of major depressive disorder, dysthymic disorder and anxiety disorders with migraine]. / Comorbilidad de trastorno depresivo mayor, trastorno distimico y trastornos de ansiedad con migrana.

INTRODUCTION: Since migraine was first reported it has been associated with psychiatric disorders. This association has clinical repercussions and common genetic, environmental and psychological predisposing factors have been suggested. AIM: To determine the prevalence of anxiety disorders, major depressive disorder and dysthymic disorder as conditions that are comorbid to migraine in patients visiting due to headaches at the Pablo Tobon Uribe Hospital (Medellin, Colombia). PATIENTS AND METHODS: We conducted a cross-sectional analytical study that evaluated all patients aged between 18 and 65 years with migraine according to the International Headache Society criteria who visited during a one-year period. Psychiatric disorders were diagnosed using the Hospital Anxiety and Depression Scale, followed by a semi-structured interview according to criteria in the Diagnostic and Statistical Manual of Mental Disorders IV, Text Revision. RESULTS: A total of 89 patients with migraine were evaluated. The frequency of migraine with aura was 35.9% and that of migraine without aura was 25.8%. The prevalence of major depressive disorder was 21.3%; that of dysthymic disorder was 4.5%; generalised anxiety disorder was 14.6%; social phobia was 6.7%; specific phobia was 5.6%; panic disorder was 5.6%; post-traumatic stress was 4.5% and obsessive-compulsive disorder was 2.2%. Seventeen people (19.1%) had two mental disorders. CONCLUSIONS: Prevalence of the mental disorders evaluated in this group of patients was found to be high. This work suggests the need to evaluate possible common risk and aetiological factors, as well as multidisciplinary treatments for these comorbid states.

Comorbilidad de trastorno depresivo mayor, trastorno distímico y trastornos de ansiedad con migraña / The comorbidity of major depressive disorder, dysthymic disorder and anxiety disorders with migraine

Desde que la migraña fue descrita, se asoció a trastornos psiquiátricos. Esta asociación tiene repercusiones clínicas y se han sugerido factores predisponentes genéticos, ambientales y psicológicos comunes. Objetivo. Determinar la prevalencia de los trastornos de ansiedad, trastorno depresivo mayor y trastorno distímico comórbidos a la migraña,en pacientes de la consulta de cefaleas del Hospital Pablo Tobón Uribe (Medellín, Colombia). Pacientes y métodos. Es un estudio analítico transversal. Se evaluó a todos los pacientes con edades entre 18 y 65 años y migraña según criterios de la Sociedad Internacional de Cefaleas que asistieron a la consulta durante el período de un año. Para el diagnóstico de los trastornospsiquiátricos se usó la escala de ansiedad y depresión hospitalaria, seguida de una entrevista semiestructurada según criterios del Manual diagnóstico y estadístico de los trastornos mentales IV, tratado revisado. Resultados. Se evaluó a 89 pacientes con migraña. La frecuencia de migraña con aura fue del 35,9%, y la de migraña sin aura, del 25,8%. El trastornodepresivo mayor tuvo una prevalencia del 21,3%; el trastorno distímico, del 4,5%; el trastorno de ansiedad generalizada, del 14,6%; la fobia social, del 6,7%; la fobia específica, del 5,6%; el trastorno de angustia, del 5,6%; el trastorno por estrés postraumático,del 4,5%; y el trastorno obsesivo-compulsivo, del 2,2%. Diecisiete personas (19,1%) tenían dos trastornos mentales.Conclusiones. Se encontró una alta prevalencia de los trastornos mentales evaluados en este grupo de pacientes. Este trabajo sugiere la necesidad de evaluar posibles factores de riesgo y etiológicos comunes, así como tratamientos multidisciplinariospara estos estados comórbidos

Since migraine was first reported it has been associated with psychiatric disorders. This associationhas clinical repercussions and common genetic, environmental and psychological predisposing factors have been suggested.Aim. To determine the prevalence of anxiety disorders, major depressive disorder and dysthymic disorder as conditions that are comorbid to migraine in patients visiting due to headaches at the Pablo Tobón Uribe Hospital (Medellín, Colombia).Patients and methods. We conducted a cross-sectional analytical study that evaluated all patients aged between 18 and 65 years with migraine according to the International Headache Society criteria who visited during a one-year period. Psychiatric disorders were diagnosed using the Hospital Anxiety and Depression Scale, followed by a semi-structuredinterview according to criteria in the Diagnostic and Statistical Manual of Mental Disorders IV, Text Revision. Results. A total of 89 patients with migraine were evaluated. The frequency of migraine with aura was 35.9% and that of migraine withoutaura was 25.8%. The prevalence of major depressive disorder was 21.3%; that of dysthymic disorder was 4.5%; generalised anxiety disorder was 14.6%; social phobia was 6.7%; specific phobia was 5.6%; panic disorder was 5.6%; post-traumatic stress was 4.5% and obsessive-compulsive disorder was 2.2%. Seventeen people (19.1%) had two mental disorders. Conclusions.Prevalence of the mental disorders evaluated in this group of patients was found to be high. This work suggests the need to evaluate possible common risk and aetiological factors, as well as multidisciplinary treatments for these comorbid states

Identification and comparison of marbofloxacin metabolites from the plasma of ball pythons (Python regius) and blue and gold macaws (Ara ararauna).

Marbofloxacin is a veterinary only, synthetic, broad spectrum fluoroquinolone antimicrobial agent. In mammals, approximately 40% of the oral dose of marbofloxacin is excreted unchanged in the urine; the remaining is excreted via the bile as unchanged drug in the feces. The Vd ranges from 1.1 (cattle) to 1.3 (dog, goat, swine) L/kg. Because of extra-label use of marbofloxacin in birds and reptiles, this study was designed to determine the profile of metabolites in plasma and compare the circulating metabolite profile between a reptile and an avian species. Six adult ball pythons (Python regius) and 10 blue and gold macaws (Ara ararauna) were used in this study. The macaws were dosed both i.v. and p.o. with a single 2.5 mg/kg administration where as the pythons received a single 10 mg/kg dose both i.v. and p.o. The metabolite profiles of marbofloxacin in the plasma of these species were determined using a high performance liquid chromatography system with a mass spectrometer for detection (LC/MS/MS). Mass spectra data generated from the snake and bird plasma samples were compared with previously reported LC/MS/MS mass spectral data. Evidence does not suggest differences due to route of administration (i.v. vs. p.o.) in either species. Four chromatographic peaks with resulting daughter spectrum were identified and represent 12 possible metabolite structures. All of the proposed metabolites, except for the N-oxide, appear to be unique to macaws. The potential metabolites identified in macaws appear to be very different than those reported for chickens.

Population pharmacokinetics of pyrazinamide in elephants.

This study was undertaken to characterize the population pharmacokinetics (PK), therapeutic dose, and preferred route of administration for pyrazinamide (PZA) in elephants. Twenty-three African (Loxodonta africana) and Asian (Elephas maximus) elephants infected with or in contact with others culture positive for Mycobacterium tuberculosis were dosed under treatment conditions. PZA was dosed daily at 20-30 mg/kg via oral (fasting or nonfasting state) or rectal (enema or suppository) administration. Blood samples were collected 0-24 h postdose. Population PK was estimated using nonlinear mixed effect modeling. Drug absorption was rapid with T(max) at or before 2 h regardless of the method of drug administration. C(max) at a mean dose of 25.6 (+/-4.6) mg/kg was 19.6 (+/-9.5 microg/mL) for PZA given orally under fasting conditions. Under nonfasting conditions at a mean dose of 26.1 +/- 4.2 mg/kg, C(max) was 25% (4.87 +/- 4.89 microg/mL) and area under concentration curve (AUC) was 30% of the values observed under fasting conditions. Mean rectal dose of 32.6 +/- 15.2 mg/kg yielded C(max) of 12.3 +/- 6.3 microg/mL, but comparable AUC to PZA administered orally while fasting. Both oral and rectal administration of PZA appeared to be acceptable and oral dosing is preferred because of the higher C(max) and lower inter-subject variability. A starting dose of 30 mg/kg is recommended with drug monitoring between 1 and 2 h postdose. Higher doses may be required if the achieved C(max) values are below the recommended 20-50 microg/mL range.

Pharmacokinetics and i.m. bioavailability of ceftiofur in Asian elephants (Elephas maximus).

Captive elephants are prone to infections of the feet, lungs, and skin. Often treatment regimens are established with no pharmacokinetic data on the agents being used for treatment in these species. A pharmacokinetic study using ceftiofur (1.1 mg/kg) was conducted in four adult female captive Asian elephants (Elephas maximus) at Busch Gardens in Tampa, Florida. Elephants were given both i.v. and i.m. administrations in a complete crossover design with a 3-week washout period between treatments. Blood samples were collected prior to drug administration and at 0.33, 0.67, 1, 1.5, 2, 4, 8, 12, 24, 48 and 72 h postadministration. Ceftiofur analysis was performed using a validated liquid chromatography/mass spectrophotometric (LC/MS) assay. Plasma concentrations for the i.m. samples were lower than expected. The mean C(max) following i.m. administration was 1.63 microg/mL with a corresponding T(max) of 0.55 h. Following i.v. administration, the median V(d(ss)) was 0.51 L/kg and a median Cl(p) of 0.069 L/kg/h. Mean i.m. bioavailability was 19%. The results indicate that ceftiofur used at 1.1 mg/kg i.m. could be useful in elephants when given two to three times a day or alternatively, 1.1 mg/kg i.v. once daily, depending upon the MIC of the pathogen.

Population pharmacokinetics of isoniazid in the treatment of Mycobacterium tuberculosis among Asian and African elephants (Elephas maximus and Loxodonta africana).

We recently described the clinical presentation and treatment of 18 elephants from six herds infected with TB. Treatment protocols and methods varied between herds to include both oral and rectal dosing using multiple drug doses and formulations. In this paper we present information regarding the pharmacokinetics (PK) of isoniazid (INH) in elephants and provide suggestions regarding initial treatment regimens. Forty-one elephants received INH daily by either oral or rectal administration with different formulations. Population PK analysis was performed using Non-linear Mixed Effect Modeling (NONMEM). Results of oral administration indicated that compared with premixed INH solution, the drug exposure was highest with a suspension prepared freshly with INH powder. When INH was concomitantly given as an admixture over food, Tmax was delayed and variability in drug absorption was significantly increased. Compared with oral administration, similar drug exposures were found when INH was dosed rectally. The data generated suggest that a starting dose of 7.5 mg/kg of INH is appropriate for initial TB treatment in elephants when premixed solution is administered directly into the oropharynx or rectal vault and 4 mg/kg are when INH is administered following immediate suspension from powdered form.

Simultaneous extraction and quantitation of fentanyl and norfentanyl from primate plasma with LC/MS detection.

The quantitation of both fentanyl and its desalkyl metabolite, norfentanyl, in plasma using LC/MS has not been previously described. The detection and quantitation of fentanyl and norfentanyl was achieved using LC/MS detection. The liquid-liquid extraction used toluene as the organic phase. Chromatography was carried out using a Zirchrom-PBD (50 mm x 2.1 mm, 3 microm) column with a mobile phase of acetonitrile-ammonium acetate (10 mM), citrate (0.1 mM, pH 4.4) (45:55, v/v) with a flow rate of 0.3 ml/min. Mass spectroscopy detection was performed using ESI in the positive mode. The LOQ for fentanyl was 25 pg/ml and norfentanyl was 50 pg/ml. For the concentrations of 75, 250, and 750 pg/ml, respectively, fentanyl had inter-day precisions of 6.6, 7.2, and 6.6% with accuracies of 4.0, 5.1, and 5.1% and intra-day precisions of 1.6, 1.9, and 1.9% with accuracies of 11.6, 9.4, and 8.4%, and norfentanyl had inter-day precisions of 7.4, 0.3, and 0.7% with accuracies of 9.1, 8.8, and 12.3% and intra-day precisions of 5.3, 1.4, and 0.1% with accuracies of 10.9, 8.9, and 12.8%. The recoveries of fentanyl were 85, 92, and 75% and of norfentanyl were 40, 49, and 46% at the 75, 250, and 750 pg/ml concentrations, respectively.

Azithromycin metabolite identification in plasma, bile, and tissues of the ball python (Python regius).

Azithromycin is the first of a class of antibiotics classified as azalides. Six ball pythons (Python regius) were given a single dose of azithromycin at 10 mg/kg p.o. and i.v. in a crossover design. Serial blood samples were collected for unchanged azithromycin and to determine, if possible, the structure and number of circulating azithromycin metabolites. After a 4-month wash-out period, the snakes were given azithromycin p.o. as a single dose of 10 mg/kg for the study of azithromycin metabolism and metabolite tissue distribution. Bile, liver, lung, kidney, and skin samples were analyzed for the metabolites identified from the first experiment. Unchanged azithromycin accounted for 80, 68, and 60% of the total material at 12, 24, and 48 h postadministration in plasma, independent of route of administration. At both 24 and 72 h postadministration, azithromycin accounted for 70% of total azithromycin- associated material in bile. In liver and kidney, unchanged azithromycin accounted for 40% of the total azithromycin-associated material; this doubled in lung and skin. Fifteen metabolites were positively or tentatively identified in plasma, bile, or tissues of all snakes. Four of these possible metabolites: 3'-desamine-3-ene-azithromycin, descladinose dehydroxy-2-ene-azithromycin, 3'-desamine-3-ene descladinose-azithromycin, and 3'-N-nitroso,9a-N-desmethyl-azithromycin are unique to this species. Descladinose-azithromycin, 3'-N-desmethyl,9a-N-desmethyl-azithromycin, and 3'-N-desmethyl, 3'-O-desmethyl-azithromycin were the only metabolites identified in skin. Kidney tissue contained a greater number of metabolites than liver tissue, with 3'-N-didesmethyl-azithromycin being identified only in the kidney. Compared with the dog and cat, a greater number of metabolites were identified in ball python plasma. The percentage of unchanged azithromycin in bile is not different between the three species.

Fatal pentastomiasis in captive African dwarf crocodile hatchlings (Osteolaemus tetraspis).

Six eggs from a captive African dwarf crocodile (Osteolaemus tetraspis) nest were artificially incubated. Two abnormal hatchlings with incomplete absorption of their yolk sacs died within 48 hr of hatching. No parasites were detected grossly or histologically in either hatchling. The remaining four apparently healthy hatchlings died without clinical signs at 3 wk of age, 1 wk after being fed live wild-caught fish and commercially raised goldfish. Necropsy revealed multiple white small wormlike organisms within the lungs, liver, and gastrointestinal tract of all four hatchlings. Histopathologic cross sections suggested that pentastomiasis was the cause of death, and whole parasites were identified as Sebekia mississippiensis. This infection was probably contracted by ingestion of live fish intermediate hosts infected with nymphal parasites. Avoiding the use of infected live fish or untreated fish products can prevent mortality of hatchling crocodilians caused by S. mississippiensis within zoological collections.

Epidemiology and diagnosis of Mycobacterium tuberculosis in captive Asian elephants (Elephas maximus).

The deaths of two Asian elephants (Elephas maximus) in August 1996 led the United States Department of Agriculture to require the testing and treatment of elephants for tuberculosis. From August 1996 to September 1999. Mycobacterium tuberculosis infection was confirmed by culture in 12 of 118 elephants in six herds. Eight diagnoses were made antemortem on the basis of isolation of M. tuberculosis by culture of trunk wash samples; the remainder (including the initial two) were diagnosed postmortem. We present the case histories, epidemiologic characteristics, diagnostic test results, and therapeutic plans from these six herds. The intradermal tuberculin test, enzyme-linked immunosorbent assay serology, the blood tuberculosis test, and nucleic acid amplification and culture are compared as methods to diagnose M. tuberculosis infection in elephants.

Persistent right aortic arch and aberrant left subclavian artery in a white Bengal tiger (Panthera tigris).

A 3-mo-old male white Bengal tiger (Panthera tigris) presented with the chief complaint of regurgitation of solid food since weaning at 2 mo of age. Compared with its littermates, the tiger was in poor body condition and weighed only 10.3 kg when its littermates were estimated at 20-25 kg. Thoracic radiographs showed a megaesophagus cranial to the heart base. A contrast esophagram more clearly outlined the megaesophagus, and fluoroscopy demonstrated normal motility of the caudal esophagus. Endoscopic examination revealed a structure coursing dorsally from right to left over the esophagus and a constrictive band on the left of the esophagus at the heart base. Nonselective angiography confirmed the presence of a persistent right aortic arch, as well as an aberrant left subclavian artery. A left fourth intercostal thoracotomy was performed, and the ligamentum arteriosum was double ligated and divided. The left subclavian artery did not cause significant compromise of the esophagus and was not manipulated at surgery. The tiger recovered well from anesthesia and surgery. Solid food was slowly introduced over a 2-mo period without any regurgitation. The cub gained weight rapidly after surgery.

Identification of monozygotic twin chimpanzees by microsatellite analysis.

Zygosity determination is important for epidemiological, biological, obstetric, and prognostic studies in both human and nonhuman primates. In this study, microsatellite loci were used to screen a pair of chimpanzee (Pan troglodytes) twins and their parents. The twins share identical alleles at all loci tested. The probability of dizygotic origin is estimated to be 2.9 x 10(-11). Even after excluding linkage of loci on the same chromosome, the probability is still low enough (3.7 x 10(-9)) to exclude dizygotic origin. MHC typing was also done on Patr-DRB and Patr-DQB loci and the twins share identical alleles at both loci, consistent with the microsatellite results. Together these results demonstrate a monozygotic origin for the chimp twins. Our results suggest that microsatellite analysis is a powerful method for zygosity determination, which can be screened reliably and efficiently.