Performance of the allometric power model in scaling from adult to paediatric antiretroviral dose in children at a Referral Hospital in Windhoek, Namibia

Background: World Health Organization (WHO) advocates use of weight bands in antiretroviral therapy (ART) guidelines. Allometric scaling could be a more reliable method because it uses a non-linear approach in relating dose to body weight. This study evaluates performance of the allometric ¾ power model in comparison to WHO weight band method in children receiving ART. Methods: Records of children receiving (ABC/3TC) + DTG were reviewed. Paediatric ABC/3TC dose was calculated from the adult dose using the allometric ¾ power model and compared to WHO weight band dose. Results: WHO weight band strategy grouped 50.6% of the children in the 25 kg category and therefore received the adult dose of ABC/3TC (600 mg/300 mg); only 1.1% received this dose with allometric scaling. Mean dose (3.8 tablets) for the WHO weight band dosing method was found to be significantly higher (p<0.0001) than for allometric scaling (1.5 tablets). Conclusions: WHO weight bands may result in the 25 kg weight category receiving a much higher dose leading to ADRs. Using allometric scaling, we recommend a weight band strategy that could improve paediatric ABC/3TC dosing

Contenção farmacológica do rato-do-bambu (Dactylomys dactylinus Desmarest, 1817) e relato de ocorrência da espécie na região Sul do Brasil / Chemical restraint of the Amazon Bamboo Rat (Dactylomys dactylinus Desmarest, 1817) and of the occurrence of the species in southern Brazil

Um exemplar de rato-do-bambu (Dactylomys dactylinus) subadulto saudável do sexo feminino, de vida livre, com massa corporal de 0,32 kg, recebeu por via intramuscular, em uma única injeção, doses de tiletamina, zolazepam, xilazina e atropina calculadas por meio de extrapolação alométrica interespecífica, a partir das recomendações usuais para o cão doméstico de 10,0 kg (tiletamina/zolazepam - 5,0mg/kg, xilazina - 1,0mg/kg) e atropina - 0,05mg/kg). O rato perdeu a reação postural de endireitamento em 2,3 minutos pós-injeção (MPI) e recuperou a capacidade de deambular normalmente em 135 MPI. A frequência cardíaca variou de 360 a 188 bpm (226±62), a frequência respiratória de 128 a 112mpm (120±5), e a temperatura retal de 36,2 a 33,5°C (34,4±1,0). A analgesia e o miorrelaxamento foram considerados bons para a realização de procedimentos indolores ou pouco dolorosos de curta duração, como exame físico, colheita de material biológico, biometria, exames de imagem e marcação. A associação de fármacos permitiu a manipulação segura do animal por 63 MPI. A recuperação foi considerada satisfatória, porém prolongada. Destaca-se que este é primeiro registro de ocorrência da espécie na Região Sul do Brasil, e o primeiro relato de contenção farmacológica desse roedor neotropical.(AU)

One subadult healthy free-living female Amazon Bamboo Rat (Dactylomys dactylinus), weighting 0.32 kg, received tiletamine HCl, zolazepam HCl, xilazine HCl and atropine sulfate, combined in a single intramuscular injection. All doses were calculated by interspecific allometric scaling, using as model a 10.0 kg domestic dog (tiletamine/zolazepam -5.0mg/kg), xylazine -1.0mg/kg), and atropine - 0.05mg/kg). Immobilization occurred in 2.3 minutes after injection (MAI) and returno to normal ambulation was observed in 135 MAI. Heart rate remained between 360 and 188 beats/minute (226±62), respiratory rate between 128 and 112 breaths/minute (120±5), and body temperature ranged from 36.2 to 33.5°C (34.4±1.0). Analgesia and myorelaxation were considered good for painless or mild painful fast procedures as physical examination, biological sampling, biometrics, imaging tests and tagging. The proposed anesthetic protocol was safe and effective, allowing safe manipulation of the animal during 63 MAI. The recovery was satisfactory, but prolonged. This is the first record of the species in Southern Brazil and the first report on its chemical restraint.(AU)

Calculation of a First-In-Man Dose of 7-O-Succinyl Macrolactin A Based on Allometric Scaling of Data from Mice, Rats, and Dogs

7-O-Succinyl macrolactin A (SMA) exerts several pharmacological effects including anti-bacterial, anti-inflammation, and anti-cancer activities. Recently, SMA has been extensively evaluated as an anti-cancer drug. Thus, the objectives of the present study were to characterise the pharmacokinetics of SMA via both non-compartmental and compartmental analysis in mice, rats, and dogs, and to derive an appropriate first-in-man dose based on allometric scaling of the animal data. The time courses of plasma SMA concentrations after intravenous administration to rats and dogs were analysed retrospectively, as were data collected after intraperitoneal SMA injection in mice. Pharmacokinetic parameters were estimated via both noncompartmental and compartmental analysis, and were correlated with body weight and/or the potential maximum life-span. The clearance and distribution volume of SMA in humans were predicted, and a first-in-man dose proposed. A two-compartment model best described the time courses of SMA plasma concentrations after a saturation elimination process was applied to fit the dataset obtained from rats. Incorporation of the maximum potential life-span during allometric scaling was required to improve the estimation of human clearance. The SMA clearance and the distribution volume in the steady state, in a 70-kg adult male, were estimated to be 30.6 L/h and 19.5 L, respectively. To meet the area under the curve (AUC) required for anti-tumour activity, a dose of 100 mg (∼1.5 mg/kg) was finally proposed as the first dose for a 70-kg human. Although toxicological profiles derived from non-clinical studies must be considered before any final decision is made, our work will facilitate clinical studies on SMA.

Calculation of a First-In-Man Dose of 7-O-Succinyl Macrolactin A Based on Allometric Scaling of Data from Mice, Rats, and Dogs

7-O-Succinyl macrolactin A (SMA) exerts several pharmacological effects including anti-bacterial, anti-inflammation, and anti-cancer activities. Recently, SMA has been extensively evaluated as an anti-cancer drug. Thus, the objectives of the present study were to characterise the pharmacokinetics of SMA via both non-compartmental and compartmental analysis in mice, rats, and dogs, and to derive an appropriate first-in-man dose based on allometric scaling of the animal data. The time courses of plasma SMA concentrations after intravenous administration to rats and dogs were analysed retrospectively, as were data collected after intraperitoneal SMA injection in mice. Pharmacokinetic parameters were estimated via both noncompartmental and compartmental analysis, and were correlated with body weight and/or the potential maximum life-span. The clearance and distribution volume of SMA in humans were predicted, and a first-in-man dose proposed. A two-compartment model best described the time courses of SMA plasma concentrations after a saturation elimination process was applied to fit the dataset obtained from rats. Incorporation of the maximum potential life-span during allometric scaling was required to improve the estimation of human clearance. The SMA clearance and the distribution volume in the steady state, in a 70-kg adult male, were estimated to be 30.6 L/h and 19.5 L, respectively. To meet the area under the curve (AUC) required for anti-tumour activity, a dose of 100 mg (∼1.5 mg/kg) was finally proposed as the first dose for a 70-kg human. Although toxicological profiles derived from non-clinical studies must be considered before any final decision is made, our work will facilitate clinical studies on SMA.

Influência do modelo alométrico na relação entre consumo máximo de oxigênio e desempenho de corredores fundistas / Influence of the allometric model on relationship between running economy and performance in long-distance runners / Influencia del modelo alométrico en la relación entre consumo máximo de oxígeno y rendimiento en corredores fondistas

Resumo Investigou-se o efeito do modelo alométrico na relação entre o consumo máximo de oxigênio (VO2máx) e o desempenho em corrida de longa distância. Doze corredores fundistas do sexo masculino (idade: 28,6 ± 7,4 anos; massa corporal: 67,9 ± 9,4 kg; estatura: 1,71 ± 0,7 m) foram submetidos a um teste de esforço máximo em esteira rolante para a determinação do VO2máx e a uma corrida máxima de 10.000 m. Apesar das diferenças significativas verificadas entre as formas de relativização do VO2máx (pela massa corporal total, pelo expoente alométrico amostral e pela massa corporal magra), as fortes correlações verificadas entre VO2máx e desempenho demonstram que a predição desse independe da forma de relativização da potência metabólica máxima.

Abstract The aim was investigated the effect of allometric model in relationship between maximal Oxygen uptake (VO2max ) and long-distance running performance. Twelve runners (age: 28.6 ± 7.4 years, body mass: 67.9 ± 9.4 kg, height: 1.71 ± 0.7 m) were submitted to an incremental treadmill running protocol for determination of VO 2max and participated in a trail of 10.000 m. despite the significant differences found between the forms of relativization of VO2max (by total body mass, allometric exponent for sampling and lean body mass), the strong correlations verified between VO2max and performance show that this prediction is independent of how the VO2max is relativized.

Resumen Se investigó el efecto del modelo alométrico en la relación entre el consumo máximo de oxígeno (VO2máx ) y el rendimiento en carreras de larga distancia. Doce corredores fondistas de sexo masculino (edad: 28,6 ± 7,4 años; masa corporal: 67,9 ± 9,4 kg; estatura: 1,71 ± 0,7 m) pasaron un test de esfuerzo máximo en una cinta de correr para la determinación del VO2máx y participaron en una carrera de 10.000 m. A pesar de las diferencias entre las formas de relativización del VO2máx (por la masa corporal total, por el exponente alométrico general de la muestra y por la masa corporal magra), las fuertes correlaciones encontradas entre VO2máx y rendimiento demuestran que la predicción de éste es independiente de la forma de relativización del consumo máximo de oxígeno.

Avaliação dos níveis séricos de lactato em cães submetidos a anestesia dissociativa / Evaluación de los niveles séricos de lactato en perros sometidos a anestesia dissociativa / Seric level assessment of lactate in dogs submitted to dissociative anesthesia

A mensuração da lactatemia como indicador indireto da oxigenação dos tecidos e, por conseguinte, de estresse e acidemia, tem potencial para se tornar uma ferramenta muito útil em medicina veterinária. Neste estudo, 10 cães domésticos adultos clinicamente saudáveis foram anestesiados pela associação de tiletamina, zolazepam, xilazina e atropina, em doses calculadas por meio de extrapolação alométrica intraespecífica. A lactatemia foi mensurada por meio de reação enzimática, com leitura por fotometria de reflectância, 1.140 minutos e um minuto antes da administração da associação anestésica por via intramuscular, aos 10, 20, 40, 60, 80, 180, 360, 720, 1.140, 2.880 e 14.440 minutos após a injeção. O comportamento das concentrações de lactato frente aos eventos experimentais evidenciou normalidade antes e depois da anestesia, e queda significativa durante a mesma. Concluiu-se que a anestesia dissociativa pela associação de tiletamina, zolazepam, xilazina e atropina, em doses calculadas por meio de extrapolação alométrica intraespecífica, não eleva a lactatemia. De fato, durante a anestesia ocorreu queda significativa das concentrações de lactato em relação aos níveis considerados basais.

Lactate level measuring as an indirect indicator of tissue oxygenation, and consequently stress and acidemia, isa potentially useful tool for Veterinary Medicine. In this study 10 adult healthy dogs were anesthetized with the combination of tiletamine, zolazepam, xylazine and atropine, with dosages calculated by intraespecific allometric scaling. Blood lactate was measured by enzymatic reaction with reflectancy photometry 1.140 and one minute before intramuscular administration of the anesthetic combination, and at 10, 20, 40, 60, 80, 180, 360, 720, 1,140, 2.880 and 14.440 minutes after the injection. Serum lactate concentrations were normal prior and after anesthesia, and presented significant decrease throughout it. It was concluded that the combination of tiletamina, zolazepam, xylazine and atropine in allometrically scaled dosages do not increase lactatemia. In fact, significant decrease of lactate serum concentrations in comparison with basal levels was observed during anesthesia.

La mensuración de la lactatemia como indicador indirecto de la oxigenación de los tejidos, así como de estrés y acidemia, tiene potencial para tornarse una herramienta muy útil en medicina veterinaria. En este estudio fueron anestesiados 10 perros adultos saludables con la asociación de tiletamina, zolazepam, xilacina y atropina, en dosis calculadas por medio de extrapolación alométrica intraespecífica. La lactatemia fue mensurada por medio de reacción enzimática, con evaluación porfotometría de reflectancia, 1.140 minutos y un minuto antes de la suministración de la combinación anestésica por vía intramuscular,y a los 10, 20, 40, 60, 80, 180, 360, 720, 1.140, 2.880 y 14.440 minutos después de la inyección. El comportamiento de las concentraciones de lactato delante de los eventos experimentales evidenció normalidad antes y después de la anestesia, y caída significativa durante la misma. Se concluyó que la anestesia disociativa por la combinación de tiletamina, zolazepam, xilacina y atropina, en dosis calculadas por medio de extrapolación alométrica intraespecífica, no eleva la lactatemia. De facto, durante la anestesia ocurrió caída significativa de las concentraciones de lactato en relación a los niveles considerados basales.

Contenção farmacológica do gato-do-mato-pequeno, Leopardus tigrinus, para colheita de sêmen, pela associação de tiletamina zolazepam e xilazina / Chemical restraint of tigrinas, Leopardus tigrinus, for semen collection with allometrically scaled doses of tiletamine, zolazepam, and xylazine

Foram avaliados os efeitos anestésicos da associação de cloridrato de tiletamina, cloridrato de zolazepam e cloridrato de xilazina para contenção farmacológica de gatos-do-mato-pequenos, Leopardus tigrinus Schreber, 1775 (Felidae), submetidos à colheita de sêmen por eletroejaculação. Formularam-se três diferentes protocolos, sendo as doses calculadas individualmente, por meio de extrapolação alométrica interespecífica, com base nas indicações posológicas usuais para o cão doméstico com massa de 10,0 kg. No Protocolo 1 (n=10) a base para o cálculo alométrico foi 5,0mg/kg para tiletamina + zolazepam e 0,5mg/kg para xilazina; no Protocolo 2 (n=12,) foi 5,0mg/kg para tiletamina + zolazepam e 0,75mg/kg para xilazina; e no Protocolo 3 (n=11), foi 5,0mg/ kg para tiletamina + zolazepam e 1,0mg/kg para xilazina. Os animais foram anestesiados em três ocasiões, com intervalo mínimo de 30 dias. Após a administração dos fármacos, monitorizaram-se durante 120 minutos freqüência cardíaca, freqüência respiratória, temperatura retal, miorrelaxamento e nocicepção. Também foram avaliados período de latência, período anestésico hábil e contaminação do ejaculado por urina. De um total de 32 colheitas, houve contaminação por urina em 10 colheitas (31,2 por cento) e em 18 alíquotas (0,07 por cento), as quais foram desprezadas, não inviabilizando a análise e o processamento do sêmen. Observou-se pequeno aumento da temperatura retal durante a eletroejaculação, justificado pela contração muscular, ocorrendo redução da temperatura após o procedimento. As freqüências cardíaca e respiratória oscilaram durante o experimento, porém se mantiveram dentro dos padrões fisiológicos para a espécie. Nos três protocolos analisados não houve diferença significativa de sensibilidade de membros torácicos entre momentos antes e durante a eletroejaculação (pe"0,10), caracterizando assim a eficácia dos protocolos em propiciar analgesia e anestesia durante a colheita de sêmen por tal método.

This paper reports the anesthetic effects of the combination of tiletamine HCl, zolazepam HCl, and xylazine HCl in tigrinas, Leopardus tigrinus Schreber, 1775 (Fam. Felidae), submitted to semen collection by electroejaculation. Three different protocols and the individual anesthetic doses were calculated by interspecific allometric scaling, based on the usual recommendations for a 10.0 kg domestic dog: On Protocol 1 (n=10) the basis for calculation was 5.0mg/kg for tiletamine + zolazepam and 0.5mg/kg for xylazine; on Protocol 2 (n=12) 5.0mg/kg for tiletamine + zolazepam and 0.75mg/kg for xylazine; and on Protocol 3 (n=11) 5.0mg/kg for tiletamine + zolazepam and 1.0mg/kg for xylazine. The tigrinas were anesthetized on three different occasions with a minimum interval of 30 days. During 120 minutes after the drug administration cardiac and respiratory frequencies, rectal temperature, limb myorelaxation and sensitivity to deep pain were monitored. Latency period, anesthetic period, and contamination of the semen with urine were also monitored. From a total of 32 collections, 10 samples (31.2 percent) and 18 aliquots (0.07 percent) were contaminated and rejected, but this episodes were not detrimental for semen analysis and processing. A discrete increase in rectal temperature during electroejaculation caused by muscle contraction, followed by temperature decrease, was observed. Cardiac and respiratory frequency varied during the experiment, but remained within physiological standards for the species. The three tested protocols showed to be safe and effective to produce analgesia and anesthesia in L. tigrinus during semen collection by electroejaculation.

Neurolepsia prolongada com decanoato de haloperidol no tratamento de dermatite psicogênica em um cão doméstico (Canis familiaris, 1758) / Long-term Neurolepsy with Haloperidol Decanoate in the Treatment of Psychogenic Dermatitis in a Domestic Dog (Canis Familiaris, 1758) / Neurolepsia de largo plazo con decanoato de haloperidol en el tratamiento de dermatitis psicogénica en un perro (canis familiaris 1758)

Relata-se o tratamento de um caso de dermatite psicogênica em um cão Rottweiler macho, com idade de 13 meses, pesando 42 kg. O paciente apresentava graves lesões dermatológicas devidas a auto-mutilação por lambedura, em ambas as regiões metatarsianas, e a anamnese indicava que o distúrbio psíquico tivesse origem no estresse provocado por uma mudança ambiental. Prescreveu-se tratamento com um neuroléptico de ação prolongada, o decanoato de haloperidol, com dose calculada por meio de extrapolação alométrica interespecífica, usando-se como modelo a dose total humana de 100 mg/70 kg. A dose total calculada para o cão de 42 kg foi de 70 mg, sendo administrada semanalmente, durante seis semanas. Já na segunda semana a recuperação era satisfatória, sendo que a cura completa foi obtida no 28º dia de tratamento. Mantido em observação por um período de seis meses, o paciente não apresentou quaisquer sinais de recidiva. Os resultados indicam que a droga apresenta excelentes perspectivas para o tratamento desta dermatopatia canina, e que o método de extrapolação alométrica interespecífica é plenamente eficiente no estabelecimento de protocolos posológicos individualizados.

ABSTRACT: This paper reports the results of the treatment of a 13 month-old male Rottweiler dog, weighing 42 kg, affected by psychogenic dermatitis. The patient presented serious cutaneous lesions due to self-licking, affecting both metatarsal areas. Anamnesis indicated that the psychic disturbance was caused by stress provoked by an environmental change. It was prescribed haloperidol decanoate, a long-acting neuroleptic, with dose calculated by interspecifi c allometric scaling, using as model the human total dose of 100 mg/70 kg. The total dose calculated for the 42 kg dog was 70 mg, and it was administered weekly for six weeks. Clinical recovery was already satisfactory in the second week, and complete cure was obtained in the 28th day of treatment. The patient was monitored by a six months period and did not present any relapsing signs. The results indicate that the drug presents excellent perspectives for the treatment of this canine skin disease, and that the method of interespecifi c allometric scaling is effi cient in the establishment of individualized therapeutic protocols.KEY WORDS: psychogenic dermatitis, neuroleptic, haloperidol decanoate, allometric scaling, dog

RESUMEN: Relata-se el tratamiento de un caso de dermatitis psicogénica en un perro Rottweiler macho, con edad de 13 meses y peso de 42 kg. El paciente presentaba graves lesiones dermatológicas debidas a auto-mutilación por lamedura, en ambas las regiones metatarsianas, y la anamnesia indicaba que la enfermedad tuviese origen en el estrés provocado por un cambio ambiental. Se prescribió tratamiento con un agente neuroléptico de acción prolongada, el decanoato de haloperidol, con dosis calculada por extrapolación alométrica interespecífi ca, se usando como modelo la dosis total humana de 100 mg/70 kg. La dosis total calculada para el perro de 42 kg fue de 70 mg, sendo administrada semanalmente, durante seis semanas. La recuperación clínica ya era satisfactoria en la segunda semana, y la cura completa se obtuvo en el vigésimo octavo día de tratamiento. El paciente fue supervisado por un periodo de seis meses y no presentó ninguna señal de retorno de la enfermedad. Los resultados indican que la droga presenta perspectivas excelentes para el tratamiento de esta enfermedad en perros, y que el método de extrapolación alométrica descascarar es en el establecimiento de protocolos terapéuticos individualizados.

Cross-Sectional and Longitudinal Observation of Cardiac Adaptation in Student Athletes / 体力科学

The purpose of this study was to ascertain whether exercise training cardiac adaptation exists in student rugby athletes, to define an adaptive pattern and to observe the student rugby athletics cardiac adaptive process. Subjects consisted of 42 male senior high school student rugby athletes, who participated in sports in junior high school, and a control group of sedentary students from the same senior high school who were matched for age. Student athletes were measured once a year over a three-year period. Left ventricular internal dimension at the end-diastole (LVIDd) and left ventricular posterior wall thickness at the end-diastole (PWT) were both measured by echocardiography. Because all subjects were growing adolescents, allometric scaling data (which is LVIDd/BSA<SUP>0.5</SUP> and PWT/BSA<SUP>0.5</SUP>) was used for comparison, to preclude the effect of differences in body size on LVIDd and PWT. Cross-sectional comparisons of athletic students with controls were conducted for each of the three senior high school grades, respectively. The data of student athletes during the three-year study was used for longitudinal comparisons. The results of cross-sectional comparisons showed that LVIDd/BSA<SUP>0, 5</SUP> in a student athlete group consisting of the three grades combined was greater than the corresponding control group (P<0.05, P<0.01, respectively) . PWT/BSA<SUP>0.5</SUP> in the athletic group was greater than the control group for the third grade level (P<0.05) . The results of the longitudinal comparison revealed that no significant differences were present in LVIDd/BSA<SUP>0.5</SUP> during the three-year investigation (P>0.05, respectively) . PWT/BSA<SUP>0.5</SUP> at the second and third grade level were obviously greater than at the first grade level (P<0.05, respectively) ; however, no dif. ference between the second and third grade levels existed. The results of this present study suggest that regular rugby exercise training during senior high school obviously induced left ventricular posterior wall thickening in the athletic students. An enlarged left ventricular cavity was observed at the first grade level of senior high school and did not significantly change during three years of senior high school.