Determination of grapiprant plasma and urine concentrations in horses.

OBJECTIVE: Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase (COX) in tissues and used as therapeutic agents in different species. Grapiprant, a member of the piprant class of compounds, antagonizes prostaglandin receptors. It is a highly selective EP4 prostaglandin E2 receptor inhibitor, thereby limiting the potential for adverse effects caused by wider COX inhibition. The objectives of this study were to determine if the approved canine dose would result in measurable concentrations in horses, and to validate a chromatographic method of analysis for grapiprant in urine and plasma. STUDY DESIGN: Experimental study. ANIMALS: A total of six healthy, adult mixed-breed mares weighing 502 ± 66 (397-600) kg and aged 14.8 ± 5.3 (6-21) years. METHODS: Mares were administered one dose of 2 mg kg-1 grapiprant via nasogastric tube. Blood and urine samples were collected prior to and up to 48 hours after drug administration. Drug concentrations were measured using high-performance liquid chromatography. RESULTS: Grapiprant plasma concentrations ranged from 71 to 149 ng mL-1 with the mean peak concentration (106 ng mL-1) occurring at 30 minutes. Concentrations were below the lower limit of quantification (50 ng mL-1) in four of six horses at 1 hour and in all six horses by 2 hours after drug administration. Grapiprant urine concentrations ranged from 40 to 4077 ng mL-1 and were still detectable at 48 hours after administration. CONCLUSIONS AND CLINICAL RELEVANCE: Currently, there are no published studies looking at the pharmacodynamics of grapiprant in horses. The effective concentration needed to control pain in dogs ranges 114-164 ng mL-1. Oral administration of grapiprant (2 mg kg-1) in horses did not achieve those concentrations. The dose was well tolerated; therefore, studies with larger doses could be conducted.

The influence of storage time and temperature on propofol concentrations in canine blood and plasma.

Propofol is an intravenous anesthetic commonly used due to its favorable pharmacokinetic and pharmacodynamic profile. There are discrepancies in the literature about the most appropriate sample for determining propofol concentrations. Although plasma has been used for determining propofol concentrations, whole blood has been the preferred sample. There is also a lack of consistency in the literature on the effect of storage time and temperature on propofol concentrations and this may lead to errors in the design of pharmacokinetic/pharmacodynamics studies. The purpose of this study was to determine the difference in propofol concentrations in whole blood versus plasma and to evaluate the influence of storage time (56 days) and temperature (4 °C, -20 °C, -80 °C) on the stability of propofol concentrations in blood and plasma samples. Results from the study indicate that whole blood and plasma samples containing propofol stored at -80 °C have concentrations as high as or higher than those stored at 4 °C or -20 °C for 56 days; thus, -80 °C is an appropriate temperature for propofol sample storage. Plasma propofol concentrations were consistently higher than whole blood for all three storage temperatures. Consequently, plasma is the most appropriate sample for propofol analysis due to its consistent determinations.

Hyperreactive Malarial Splenomegaly Syndrome--Can the Diagnostic Criteria Be Improved?

Hyperreactive Malarial Splenomegaly Syndrome (HMSS) was described and defined before sensitive tests for malaria were available. We present a series of seven individuals who were referred to our clinics with possible HMSS. Chronic malaria was demonstrated in those successfully treated but not in those who failed to respond to therapy. This observation suggests that the newer molecular malaria assays have a role to play in the identification of individuals who are likely to respond to treatment for HMSS in non-endemic regions.

Clinical Features of Imported Loiasis: A Case Series from the Hospital for Tropical Diseases, London.

We retrospectively analyzed the background, clinical features, and treatment response of 50 cases of imported loiasis who presented between 2000 and 2014 to the Hospital for Tropical Diseases (HTD), London, United Kingdom. Of them, 29 were migrants from, and 21 were visitors to, countries where the disease is endemic. Clinical features differed between these groups. Migrants experienced fewer Calabar swellings (odds ratio [OR] = 0.12), more eye worm (OR = 3.4), more microfilaremia (OR = 3.5), lower filarial antibody levels, and lower eosinophil counts (P < 0.05 for all tests). Among 46 patients who were started on treatment at HTD, 33 (72%) received diethylcarbamazine (DEC) monotherapy as first-line treatment, and among 26 patients who were followed up after treatment, seven (27%) needed a second course of treatment. There were 46 courses of treatment with DEC, and 20 (43%) of them had reactions. All patients with microfilaremia > 3,000 microfilariae/mL and all those with an elevated C-reactive protein (CRP) (≥ 5 mg/L) before treatment had reactions (P = 0.10 and P = 0.01, respectively). These data suggest that monotherapy with DEC may not be the optimal treatment for patients with loiasis, particularly for those with a high microfilarial load.

An unusual cause of an ankle mass.

We report the case of a patient who presented with a 7-year history of a mass over the medial aspect of his right ankle, which had been gradually increasing in size. He had given up his occupation as a bus driver due to decreased movement of his ankle. An initial diagnosis of endemic syphilis was made after treponemal antibody and treponema pallidum particle agglutination tests were positive. However, following surgical debulking, cultures grew Fusarium solani and the diagnosis was changed to eumycetoma. He received prolonged treatment with antifungal agents and at 18 months follow-up remains well.

Imported falciparum malaria among adults requiring intensive care: analysis of the literature.

BACKGROUND: Malaria is the most important imported tropical disease. Infection with Plasmodium falciparum is responsible for most of the morbidity and mortality. There are differences in both the epidemiology of imported malaria and in the facilities available to treat travellers with severe malaria between different parts of the world. There are limited data to guide clinicians caring for adults with imported malaria in an intensive care unit (ICU). Available data from the English-speaking literature concerning such patients was reviewed. METHODS: PubMed was searched for studies on adults with imported malaria treated in an ICU. Data were extracted on the epidemiology, management, rates of concomitant community-acquired bacterial infection and outcomes. RESULTS: Thirteen studies were identified, which between them included 1,001 patients over more than 40 years. Forty-one per cent were born and often still resident in an endemic country and were assumed to have at least partial immunity to the disease. Acute kidney injury (AKI) (36%), acute respiratory distress syndrome (ARDS) (31%) and impaired consciousness (25%) were common. Hyperparasitaemia (more than 2%) was seen in 57%. Thirty-four per cent required mechanical ventilation and 22% required renal replacement therapy. Community-acquired bacterial co-infection was seen in 8%; 2% had gram-negative bacteraemia at admission. Overall the case fatality rate was 9%. CONCLUSIONS: Many patients who require admission to ICU were originally from malaria-endemic countries and many did not have hyperparasitaemia. Gram-negative bacteraemia was uncommon among adults with severe malaria. The case fatality rate remains high; however, improvements in ICU care and increasing use of artemisinins may reduce this in the future.

Physiologic and antinociceptive effects following intramuscular administration of xylazine hydrochloride in combination with tiletamine-zolazepam in llamas.

OBJECTIVE: To evaluate antinociceptive and selected effects associated with IM administration of xylazine hydrochloride in combination with tiletamine-zolazepam in llamas. ANIMALS: 8 adult male llamas. Procedures-Each llama received tiletamine-zolazepam (2 mg/kg) combined with either xylazine (0.1, 0.2, or 0.4 mg/kg) or saline (0.9% NaCl) solution IM (treatments designated as TZ-Xy0.1, TZ-Xy0.2, TZ-Xy0.4, and TZ-Sal, respectively) at 1-week intervals. Selected cardiorespiratory variables were assessed during lateral recumbency and anesthesia, and recovery characteristics were recorded. Duration of antinociception was evaluated by clamping a claw every 5 minutes. RESULTS: Interval between treatment administration and lateral recumbency for TZ-Xy0.4 was shorter than that for TZ-Xy0.1 or TZ-Sal. Mean ± SEM duration of antinociception was longer for TZ-Xy0.4 (51.3 ± 7. 0 minutes), compared with findings for TZ-Xy0.2 (31.9 ± 6.0 minutes), TZ-Xy0.1 (8.1 ± 4.0 minutes), and TZ-Sal (0.6 ± 0.6 minutes). Interval between treatment administration and standing was longer for TZ-Xy0.4 (112 ± 9 minutes) than it was for TZ-Xy0.2 (77 ± 9 minutes) or TZ-Sal (68 ± 9 minutes). Mean heart and respiratory rates during the first 30 minutes for TZ-Sal exceeded values for the other treatments. Administration of TZ-Xy0.2 and TZ-Xy0.4 resulted in Pao2 < 60 mm Hg at 5 minutes after llamas attained lateral recumbency, and values differed from TZ-Sal findings at 5, 10, and 15 minutes; Paco2 was greater for TZ-Xy0.2 and TZ-Xy0.4 than for TZ-Sal at 5, 10, 15, and 20 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: Xylazine (0.2 and 0.4 mg/kg) increased the duration of antinociception in llamas anesthetized with tiletamine-zolazepam.

Acute schistosomiasis in travelers: 14 years' experience at the Hospital for Tropical Diseases, London.

We report 79 cases of acute schistosomiasis. Most of these cases were young, male travelers who acquired their infection in Lake Malawi. Twelve had a normal eosinophil count at presentation and 11 had negative serology, although two had neither eosinophilia nor positive serology when first seen. Acute schistosomiasis should be considered in any febrile traveler with a history of fresh water exposure in an endemic area once malaria has been excluded.

Gametocyte carriage in Plasmodium falciparum-infected travellers.

BACKGROUND: Gametocytes are the sexual stage of Plasmodium parasites. The determinants of gametocyte carriage have been studied extensively in endemic areas, but have rarely been explored in travellers with malaria. The incidence of gametocytaemia, and factors associated with gametocyte emergence in adult travellers with Plasmodium falciparum malaria was investigated at the Hospital for Tropical Diseases in London. METHODS: Clinical, parasitological and demographic data for all patients presenting with P. falciparum malaria between January 2001 and December 2011 were extracted from a prospective database. These data were supplemented by manual searches of laboratory records and patient case notes. RESULTS: Seven hundred and seventy three adult patients with laboratory-confirmed P. falciparum malaria were identified. Four hundred and sixty five (60%) were born in a country where malaria is endemic. Patients presented to hospital a median of four days into their illness. The median maximum parasite count was 0.4%. One hundred and ninety six patients (25%) had gametocytes; 94 (12%) on admission, and 102 (13%) developing during treatment. Gametocytaemia on admission was associated with anaemia and a lower maximum parasitaemia. Patients with gametocytes at presentation were less likely to have thrombocytopenia or severe malaria. Patients who developed gametocytes during treatment were more likely to have had parasitaemia of long duration, a high maximum parasitaemia and to have had severe malaria. There was no apparent association between the appearance of gametocytes and treatment regimen. CONCLUSIONS: The development of gametocytaemia in travellers with P. falciparum is associated with factors similar to those reported among populations in endemic areas. These data suggest that acquired immunity to malaria is not the only determinant of patterns of gametocyte carriage among patients with the disease.

ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans.

The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets.

A comparison of oxygen saturation in white-tailed deer estimated by pulse oximetry and from arterial blood gases.

Physiologic monitoring is important when chemically immobilizing wildlife. Blood oxygenation is usually monitored by pulse oximetry in the field; however, there is some question whether this technique accurately reflects oxygen saturation in wild white-tailed deer (Odocoileus virginianus). We evaluated different doses of medetomidine (125, 150, 175, or 200 µg/kg) mixed with ketamine (1.5 mg/kg), and tiletamine-zolazepam (1.0 mg/kg) in 22 female white-tailed deer at the University of Georgia Whitehall Deer Research Facility in Athens, Georgia on 14-15 and 21 May 2009. Deer were hand-injected intramuscularly while physically restrained in a squeeze chute, and then they were released into a pen for monitoring. Hemoglobin saturation estimated using pulse oximetry (SpO(2)) was compared with hemoglobin saturation value from arterial blood gases (SaO(2)) at 0, 10, and 20 min postimmobilization with deer in a sternal position. We made 56 simultaneous comparisons of oxygen saturation using SpO(2) (range, 54-95%) and SaO(2) (range, 60-95%). We used a Bland-Altman analysis for determining agreement between the two methods. Hemoglobin saturation estimated using SpO(2) was generally greater than SaO(2) when the mean of the two measurements was >80%. At mean values <80% oxygen saturation, there is not sufficient agreement between the techniques. Multiple readings over time may help recognition of outliers.

Optimal medetomidine dose when combined with ketamine and tiletamine-zolazepam to immobilize white-tailed deer.

Chemical immobilization is often needed for safe and effective capture and handling of wildlife. We evaluated medetomidine (125, 150, 175, or 200 µg/kg; for synergistic effects and relaxation) mixed with ketamine (1.5 mg/kg; for relatively shorter recovery) and tiletamine-zolazepam (1.0 mg/kg; for rapid induction) in 22 female white-tailed deer (Odocoileus virginianus) at the University of Georgia Whitehall Deer Research Facility in Athens, Georgia, USA, on 14-15 and 21 May 2009. Deer were weighed before treatment, hand-injected intramuscularly (IM) while restrained in a squeeze chute, and released into a pen for monitoring. We measured rectal temperature, respiration rate, heart rate, hemoglobin saturation (using pulse oximetry), and arterial blood gases at 0, 10, and 20 min postimmobilization. We found no differences in induction time with different doses of medetomidine. Deer became laterally recumbent for all treatments combined at a median of 4.2 (2.6-21.3) min and were approachable by a median of 4.8 (3.5-21.8) min. Twelve of the 22 deer had rectal temperatures >40 C at time 0 and were treated with a cold-water enema. Hemoglobin saturation, estimated using pulse oximetry, was 79.5, 82.0, and 82.3% at times 0, 10, and 20, respectively. We injected atipamezole (0.35 mg/kg, IM) for reversal. Recovery occurred sooner and was more consistent for 125 and 150 µg/kg medetomidine whereby deer stood with minimal sedation to moderate ataxia within 60-90 min after atipamezole administration. We recommend using 150 µg of medetomidine with ketamine (1.5 mg/kg) and tiletamine-zolazepam (1.0 mg/kg) to provide effective and safe chemical immobilization of white-tailed deer.

Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors.

BACKGROUND: Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question. METHODOLOGY: We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4(+)/CD8(+) phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro. CONCLUSIONS: ChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection. TRIAL REGISTRATION: ClinicalTrials.gov NCT01095055.

Effects of hyperbaric oxygen treatment on horses with experimentally induced endotoxemia.

OBJECTIVE: To determine the effectiveness of preinduction hyperbaric oxygen treatment (HBOT) in ameliorating signs of experimentally induced endotoxemia in horses. ANIMALS: 18 healthy adult horses. PROCEDURES: Horses were randomly assigned to 1 of 3 equal-sized treatment groups to receive normobaric ambient air and lipopolysaccharide (LPS), HBOT and LPS, or HBOT and physiologic saline (0.9% NaCl) solution. Horses were physically examined, and blood was obtained for a CBC and to determine concentration or activity of plasma tissue necrosis factor-α, blood lactate, and blood glucose before the horses were treated with HBOT and then intermittently for 6 hours after administration of LPS or physiologic saline solution. RESULTS: All LPS-treated horses developed signs and biochemical and hematologic changes consistent with endotoxemia. Treatment with HBOT significantly ameliorated the effect of LPS on clinical endotoxemia score but did not significantly improve other abnormalities associated with endotoxemia. CONCLUSIONS AND CLINICAL RELEVANCE: The protective effect of HBOT was minimal, and results did not support its use as a treatment for horses prior to development of endotoxemia.

Comparison of antibiotic regimens for treating louse-borne relapsing fever: a meta-analysis.

The optimum treatment for louse-borne relapsing fever (LBRF) has not been fully established. Eliminating spirochetes is often associated with the potentially lethal Jarisch-Herxheimer reaction (JHR). The objective of this meta-analysis was to review the evidence supporting the use of antibiotics usually employed for treating LBRF. A systematic review of the literature was performed to identify randomised controlled trials (RCT) comparing antibiotics in LBRF. The primary outcome was mortality, whilst JHR rates, relapse rates, time to fever clearance and time to spirochete disappearance were secondary outcomes. Six RCTs performed in Ethiopia were included. Trials were small and often of limited quality, using single-dose therapy with either penicillin or tetracycline. There was no significant difference between tetracycline and penicillin with regard to mortality rate. Although there was significant heterogeneity between the five trials comparing the rate of JHRs, three of them showed a significant benefit in favour of penicillin. The risk of relapse was reduced with tetracycline. Tetracycline use was associated with a lower mean fever clearance time. Tetracycline appears to be the most efficient drug but also appears to be associated with a higher rate of JHRs. Alternative regimens to treat LBRF should be investigated.

An unusual case of hypereosinophilia and abdominal pain: an outbreak of Trichostrongylus imported from New Zealand.

We report an outbreak of severe symptomatic Trichostrongylus spp. in travelers visiting a sheep farm in New Zealand. The unusual source of the outbreak was traced as the use of sheep manure as an organic fertilizer on a salad garden.