The inhibitory and anticancer properties of Annona squamosa L. seed extracts / Propriedades inibitórias e anticancerígenas de extratos de sementes de Annona squamosa L

Although Annona squamosa Linn. (Annonaceae) has been used in traditional medicine and is known to have several pharmacological properties, its impact on EGFR kinase has not been fully investigated. An assay (biochemical) was used to govern the potential of different A. squamosa seed extracts to scavenge free radicals in petroleum ether, acetone, ethanol, and methanol. We also tested A. squamosa leaf extracts for their ability to inhibit the growth of HEK 293, MCF7, and HepG2 cell lines. The PSE, ASE, ESE, and MSE all contained anti-cancer substances like anethole, cyclopentane, 1,1,3-trimethyl, and phosphonate oxide tributyl, according to phytochemical analysis. ESE extracts from A. squamosa seeds have been selected based on free radical generation probabilities, cytotoxicity studies, and phytochemical analysis. Subsequent insilico studies have been conducted, and the results have shown that interactions between compounds present in ESE extracts and the EGFR kinase are what give these compounds their inhibitory effects. Preliminary phytochemical and pharmacological activities were studied and reported. A. squamosa ESE extracts inhibited the growth of MCF7 cells, and a pharmacokinetic study showed that the compounds anethole, cyclopentane, 1,1,3-trimethyl, and phosphonium oxide tributyl had few undesirable side effects. These substances can be used to both prevent and treat cancer diseases.

Embora a Annona squamosa Linn. (Annonaceae) tenha sido utilizada na medicina tradicional e seja conhecida por diversas propriedades farmacológicas, seu impacto na EGFR quinase ainda não foi totalmente investigado. Um ensaio bioquímico foi utilizado para controlar o potencial de diferentes extratos de sementes de A. squamosa para eliminar radicais livres em éter de petróleo, acetona, etanol e metanol. Extratos de folhas de A. squamosa também foram analisados em relação à sua capacidade de inibir o crescimento de linhagens celulares HEK 293, MCF7 e HepG2. O PSE, ASE, ESE e MSE continham substâncias anticancerígenas como anetol, ciclopentano, 1,1,3-trimetil e óxido de fosfonato tributil, de acordo com a análise fitoquímica. Extratos de ESE de sementes de A. squamosa foram selecionados com base em probabilidades de geração de radicais livres, estudos de citotoxicidade e análise fitoquímica. Estudos in silico subsequentes foram realizados e os resultados mostraram que as interações entre os compostos presentes nos extratos de ESE e a EGFR quinase são o que confere a esses compostos seus efeitos inibitórios. As atividades fitoquímicas e farmacológicas preliminares foram estudadas e relatadas. Os extratos de ESSE de A. squamosa inibiram o crescimento de células MCF7, e um estudo farmacocinético mostrou que os compostos anetol, ciclopentano, 1,1,3-trimetil e óxido de fosfônio tributil tiveram poucos efeitos colaterais indesejáveis. Essas substâncias podem ser usadas para prevenir e tratar doenças cancerígenas.

The investigation of the pharmacokinetics of two enrofloxacin preparations following parenteral administration in calves

Background: Enrofloxacin is a bactericidal antimicrobial drug in the fluoroquinolone group, developed for use only in the veterinary field. It is effective against gram negative and gram positive bacteria, Mikoplazma, Rickettsia, Ehrlichia ve Chlamydia. Enrofloxacin is converted to several effective and ineffective metabolites including ciprofloxacin. Ten to fifty percent of the drug is eliminated via urine and bile in unmetabolized form. Enrofloxacin is used in all domestic animal including ruminant and winged animals. In calves, enrofloxacin finds utilization in the respiratory system infections, septicemia caused by colibacillosis and in cases of intestinal inflammation by oral and parenteral ways. There are around 1920 enrofloxacin preparations with different formulations in Turkey. Eight hundred fifty-five of these preparations are in the form of parenteral solutions that are ready for use. In this study, the pharmacokinetics of two enrofloxacin preparations that are used in calves were investigated.Materials, Methods & Results: Ten female calves (Jersey strain, 46-50 day-old) were included. The animals were taken to a separate environment 15 days in advance, and medication administration was restrained. Throughout the trial, the animals were fed with unmedicated feed. Calf growing feed, water, and hay were given freely as feed. They continued to be fed by 3 liters of milk twice a day. The study was reviewed by Ankara University Animal Trials Local Ethics Committee and approved with decision number 2007-7-17 and file number 2007-56. The calves were divided into two groups including five calves each. Reference drug and test drug were administered intramuscularly at a dose of 2.5 mg per kg to group 1 and group 2, respectively. Blood samples were taken before (0.0 min) and after the drug administration at 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24 and 36th h. The method used by Anadon et al. was used for plasma enrofloxacin extraction and concentration.[...]

The investigation of the pharmacokinetics of two enrofloxacin preparations following parenteral administration in calves

Background: Enrofloxacin is a bactericidal antimicrobial drug in the fluoroquinolone group, developed for use only in the veterinary field. It is effective against gram negative and gram positive bacteria, Mikoplazma, Rickettsia, Ehrlichia ve Chlamydia. Enrofloxacin is converted to several effective and ineffective metabolites including ciprofloxacin. Ten to fifty percent of the drug is eliminated via urine and bile in unmetabolized form. Enrofloxacin is used in all domestic animal including ruminant and winged animals. In calves, enrofloxacin finds utilization in the respiratory system infections, septicemia caused by colibacillosis and in cases of intestinal inflammation by oral and parenteral ways. There are around 1920 enrofloxacin preparations with different formulations in Turkey. Eight hundred fifty-five of these preparations are in the form of parenteral solutions that are ready for use. In this study, the pharmacokinetics of two enrofloxacin preparations that are used in calves were investigated.Materials, Methods & Results: Ten female calves (Jersey strain, 46-50 day-old) were included. The animals were taken to a separate environment 15 days in advance, and medication administration was restrained. Throughout the trial, the animals were fed with unmedicated feed. Calf growing feed, water, and hay were given freely as feed. They continued to be fed by 3 liters of milk twice a day. The study was reviewed by Ankara University Animal Trials Local Ethics Committee and approved with decision number 2007-7-17 and file number 2007-56. The calves were divided into two groups including five calves each. Reference drug and test drug were administered intramuscularly at a dose of 2.5 mg per kg to group 1 and group 2, respectively. Blood samples were taken before (0.0 min) and after the drug administration at 0.25, 0.5, 1, 2, 4, 8, 12, 18, 24 and 36th h. The method used by Anadon et al. was used for plasma enrofloxacin extraction and concentration.[...](AU)

Pharmacokinetic of florfenicol in pulmonary epithelial lining fluid of swine and effects of anesthetic agent on drug plasma disposition kinetics / Farmacoqu'imica de florfenicol em fluido de epitélio pulmonar de suínos e efeitos de agente anestésico em cinética de droga em plasma

The primary objective of the current study was to compare the pharmacokinetic (PK) of florfenicol (FFL) in pulmonary epithelial lining fluid and the plasma in swine. The second objectives were to evaluate the effect of anesthesia with ketamine and propofol on the PK of FFL in plasma. Bronchoaveolar lavage was utilized for quantification of PELF volume and the urea dilution method was used to determine the concentration of FFL in PELF. FFL was administered intramuscularly (IM) to swine in a single dose of 20mg/kg body weight. The main PK parameters of FFL in plasma and PELF were as follows: the area under the concentration-time curve, maximal drug concentration, elimination half-life and mean residence time were 69.45±4.36 vs 85.03±9.26μg·hr/ml, 4.65±0.34 vs 5.94±0.86μg/ml, 9.87±1.70 vs 10.69±1.60hr and 12.75±0.35 vs 14.46±1.26hr, respectively. There was no statistically significant difference between the PK profiles of FFL for the anesthetized and unanesthetized pigs. This study suggest that (i) FFL penetrated rapidly into the pulmonary and the drug concentration decay faster in plasma than in the pulmonary, (ii) the PK profile of FFL in swine was not interfered after administration of anesthetic agent.(AU)

O objetivo primário desse estudo foi comparar a farmacocinética de florfenicol (FFL) em fluido epitelial pulmonar à farmacocinética (PK) de FFL em plasma suíno. O segundo objetivo foi avaliar o efeito de anestesia com ketamina e propofol no PK de FFL em plasma. Lavagem broncoalveolar foi utilizada para quantificar volume de fluido epitelial pulmonar (PELF) e método de diluição de uréia para determinar FFL em PELF. Injeção de FFL foi administrada intramuscular a suínos em dose única de 20mg/kg de peso corporal. Os principais parâmetros de PK em FFL em plasma e PELF foram os seguintes: a área sob a curva de concentração-tempo, concentração máxima da droga, eliminação de meia-vida e média de tempo de permanência foram 69,45±4,36 vs 85,03±9,26μg·hr/ml, 4,65±0,34 vs 5,94±0,86μg/ml, 9,87±1,70 vs 10,69±1,60hr e 12,75±0,35 vs 14,46±1,26hr, respectivamente. Não houve diferença estatisticamente significante entre os perfis de PK de FFL para os porcos anestesiados e não anestesiados. Esse estudo sugere que (i) FFL penetrou rapidamente no pulmão e concentração da droga sofre queda mais veloz em plasma que líquido pulmonar, (ii) o perfil de PK de FFL em suínos não modificou após administração de agente anestésico.(AU)

Pharmacokinetic of florfenicol in pulmonary epithelial lining fluid of swine and effects of anesthetic agent on drug plasma disposition kinetics / Farmacoqu'imica de florfenicol em fluido de epitélio pulmonar de suínos e efeitos de agente anestésico em cinética de droga em plasma

The primary objective of the current study was to compare the pharmacokinetic (PK) of florfenicol (FFL) in pulmonary epithelial lining fluid and the plasma in swine. The second objectives were to evaluate the effect of anesthesia with ketamine and propofol on the PK of FFL in plasma. Bronchoaveolar lavage was utilized for quantification of PELF volume and the urea dilution method was used to determine the concentration of FFL in PELF. FFL was administered intramuscularly (IM) to swine in a single dose of 20mg/kg body weight. The main PK parameters of FFL in plasma and PELF were as follows: the area under the concentration-time curve, maximal drug concentration, elimination half-life and mean residence time were 69.45±4.36 vs 85.03±9.26µg·hr/ml, 4.65±0.34 vs 5.94±0.86µg/ml, 9.87±1.70 vs 10.69±1.60hr and 12.75±0.35 vs 14.46±1.26hr, respectively. There was no statistically significant difference between the PK profiles of FFL for the anesthetized and unanesthetized pigs. This study suggest that (i) FFL penetrated rapidly into the pulmonary and the drug concentration decay faster in plasma than in the pulmonary, (ii) the PK profile of FFL in swine was not interfered after administration of anesthetic agent.(AU)

O objetivo primário desse estudo foi comparar a farmacocinética de florfenicol (FFL) em fluido epitelial pulmonar à farmacocinética (PK) de FFL em plasma suíno. O segundo objetivo foi avaliar o efeito de anestesia com ketamina e propofol no PK de FFL em plasma. Lavagem broncoalveolar foi utilizada para quantificar volume de fluido epitelial pulmonar (PELF) e método de diluição de uréia para determinar FFL em PELF. Injeção de FFL foi administrada intramuscular a suínos em dose única de 20mg/kg de peso corporal. Os principais parâmetros de PK em FFL em plasma e PELF foram os seguintes: a área sob a curva de concentração-tempo, concentração máxima da droga, eliminação de meia-vida e média de tempo de permanência foram 69,45±4,36 vs 85,03±9,26µg·hr/ml, 4,65±0,34 vs 5,94±0,86µg/ml, 9,87±1,70 vs 10,69±1,60hr e 12,75±0,35 vs 14,46±1,26hr, respectivamente. Não houve diferença estatisticamente significante entre os perfis de PK de FFL para os porcos anestesiados e não anestesiados. Esse estudo sugere que (i) FFL penetrou rapidamente no pulmão e concentração da droga sofre queda mais veloz em plasma que líquido pulmonar, (ii) o perfil de PK de FFL em suínos não modificou após administração de agente anestésico.(AU)

Pharmacokinetic of florfenicol in pulmonary epithelial lining fluid of swine and effects of anesthetic agent on drug plasma disposition kinetics / Farmacoqu'imica de florfenicol em fluido de epitélio pulmonar de suínos e efeitos de agente anestésico em cinética de droga em plasma

The primary objective of the current study was to compare the pharmacokinetic (PK) of florfenicol (FFL) in pulmonary epithelial lining fluid and the plasma in swine. The second objectives were to evaluate the effect of anesthesia with ketamine and propofol on the PK of FFL in plasma. Bronchoaveolar lavage was utilized for quantification of PELF volume and the urea dilution method was used to determine the concentration of FFL in PELF. FFL was administered intramuscularly (IM) to swine in a single dose of 20mg/kg body weight. The main PK parameters of FFL in plasma and PELF were as follows: the area under the concentration-time curve, maximal drug concentration, elimination half-life and mean residence time were 69.45±4.36 vs 85.03±9.26µg·hr/ml, 4.65±0.34 vs 5.94±0.86µg/ml, 9.87±1.70 vs 10.69±1.60hr and 12.75±0.35 vs 14.46±1.26hr, respectively. There was no statistically significant difference between the PK profiles of FFL for the anesthetized and unanesthetized pigs. This study suggest that (i) FFL penetrated rapidly into the pulmonary and the drug concentration decay faster in plasma than in the pulmonary, (ii) the PK profile of FFL in swine was not interfered after administration of anesthetic agent.(AU)

O objetivo primário desse estudo foi comparar a farmacocinética de florfenicol (FFL) em fluido epitelial pulmonar à farmacocinética (PK) de FFL em plasma suíno. O segundo objetivo foi avaliar o efeito de anestesia com ketamina e propofol no PK de FFL em plasma. Lavagem broncoalveolar foi utilizada para quantificar volume de fluido epitelial pulmonar (PELF) e método de diluição de uréia para determinar FFL em PELF. Injeção de FFL foi administrada intramuscular a suínos em dose única de 20mg/kg de peso corporal. Os principais parâmetros de PK em FFL em plasma e PELF foram os seguintes: a área sob a curva de concentração-tempo, concentração máxima da droga, eliminação de meia-vida e média de tempo de permanência foram 69,45±4,36 vs 85,03±9,26µg·hr/ml, 4,65±0,34 vs 5,94±0,86µg/ml, 9,87±1,70 vs 10,69±1,60hr e 12,75±0,35 vs 14,46±1,26hr, respectivamente. Não houve diferença estatisticamente significante entre os perfis de PK de FFL para os porcos anestesiados e não anestesiados. Esse estudo sugere que (i) FFL penetrou rapidamente no pulmão e concentração da droga sofre queda mais veloz em plasma que líquido pulmonar, (ii) o perfil de PK de FFL em suínos não modificou após administração de agente anestésico.(AU)

A biodistribution study of Hemiscorpius lepturus scorpion venom and available polyclonal antivenom in rats

The purpose of the present study was to investigate the biodistribution profile of the venom of Hemiscorpius lepturus, the most dangerous scorpion in Iran. Blood and tissue samples were taken at various predetermined intervals during a 400-minute period for the venom and a 360-minute period for the antivenom in rats. The radio-iodination was carried out using the chloramine-T method. The results showed that the descending order of venom uptake was skin, kidneys and intestine, respectively. The descending order of polyclonal antivenom uptake was kidneys, intestine, heart and lungs. The calculated pharmacokinetic parameters of the venom were Telimination half-life = 521.5 ± 12.6 minutes; Vd/F (apparent volume of distribution) = 14.9 ± 3.3 mL; clearance (CL/F, apparent total clearance of the drug from plasma) 0.02 ± 0.005 mL/minute and for the antivenom Telimination half-life = 113.7 ± 7.4 minutes; Vd/F = 13 ± 1.2 mL and CL/F 0.08 ± 0.01 mL/minute. The pharmacokinetics profile comparison of the venom with that of the antivenom shows that serotherapy may be more effective if administered within 2-4 hours following envenomation by H. lepturus.(AU)

A biodistribution study of Hemiscorpius lepturus scorpion venom and available polyclonal antivenom in rats

The purpose of the present study was to investigate the biodistribution profile of the venom of Hemiscorpius lepturus, the most dangerous scorpion in Iran. Blood and tissue samples were taken at various predetermined intervals during a 400-minute period for the venom and a 360-minute period for the antivenom in rats. The radio-iodination was carried out using the chloramine-T method. The results showed that the descending order of venom uptake was skin, kidneys and intestine, respectively. The descending order of polyclonal antivenom uptake was kidneys, intestine, heart and lungs. The calculated pharmacokinetic parameters of the venom were Telimination half-life = 521.5 ± 12.6 minutes; Vd/F (apparent volume of distribution) = 14.9 ± 3.3 mL; clearance (CL/F, apparent total clearance of the drug from plasma) 0.02 ± 0.005 mL/minute and for the antivenom Telimination half-life = 113.7 ± 7.4 minutes; Vd/F = 13 ± 1.2 mL and CL/F 0.08 ± 0.01 mL/minute. The pharmacokinetics profile comparison of the venom with that of the antivenom shows that serotherapy may be more effective if administered within 2-4 hours following envenomation by H. lepturus.(AU)

Bioequivalence studies: relevance for veterinary medicine / Estudos de bioequivalência: importância para Medicina Veterinária

Bioequivalence (BE) studies are scientific methods that allow comparison of different medicinal products containing the same active substance, or different batches of the same medicinal products or, ina broad sense, different routes of administration of the same product. Actually, legislation on generic drugs and bioequivalence only exist in Brazil for drugs intended for human purposes. In the field of Veterinary Medicine, BE is being used in many countries as part of the necessary requirements for registration of animal health products,i.e., to provide efficacy and safety animal data and to allow consumers safety; indeed, they also assure the quality of the food derived from treated animals. The present manuscript was designed to review and discuss BE; for that, it was divided into three major parts: 1-understanding bioequivalence: importance of BE studies for animal and human health; 2- type of BE studies included; 3- general consideration on experimental design involved o BE studies.(AU)

Os estudos de Bioequivalência (BE) são utilizados para a comparação de diferentes produtos farmacêuticos que contêm o mesmo princípio ativo, de diferentes lotes de um mesmo produto ou, ainda e de uma maneira ampla, de diferentes vias deadministração de um mesmo medicamento. No Brasil dos dias de hoje, encontramos legislações sobre medicamentos genéricos e bioequivalência apenas na área de Medicina Humana. No campo da Medicina Veterinária, os testes de BE têm sido considerados,em muitos países, como requerimentos necessários para o registro de produtos destinados aos animais visto que eles asseguram, ao mesmo tempo, a eficácia do produto, a saúde dos animais tratados e a qualidade dos alimentos provenientes desses animais. O presente trabalho faz uma revisão crítica sobre BE. Para tanto, o assunto foi dividido em três grandes partes: 1- Entendendo a bioequivalência: importância de estudos de BE para a saúde animal e humana; 2- tipos de estudos de BE; 3- considerações gerais sobre delineamentos experimentais que envolvam estudos de bioequivalência.(AU)

Pharmacokinetics of sodium meclofenamate in pre-ruminant cattle / Farmacocinética do meclofenamato sódico em bezerros pré-ruminantes

The pharmacokinetic profile of sodium meclofenamate, a non-steroidal antiinflammatory drug, was determined in six pre-ruminant calves after intravenous and intramuscular administration at a dose of 2.2mg/kg of body weight. Meclofenamate concentrations were measured using a high performance liquid chromatography assay. The pharmacokinetics of sodium meclofenamate after intravenous and intramuscular administration to calves were characterised by a rapid distribution phase (t½a ), 15.45± 4.85min and 23.14± 7.24min for the intravenous and intramuscular administration, respectively, followed by a longer elimination phase (t½b ) after intramuscular treatment (17.55± 6.52h.). The apparent volume of distribution (Vd) of the drug after intravenous administration was moderate (0.72± 0.12l/kg), and high (3.51± 1.05l/kg) after intramuscular administration. This can be explained by the flip-flop effect or by enterohepatic shunting. The bioavailability achieved after intramuscular administration was 61%.(AU)

O perfil do meclofenamato sódico, uma droga antiinflamatória não-esteroidal, foi determinado em seis bezerros pré-ruminantes após administração intravenosa e intramuscular na dose de 2,2mg/kg de peso vivo. As concentrações de meclofenamato foram medidas empregando-se cromatografía líquida de alta performance. A farmacocinética do meclofenamato sódico, após as administrações intravenosa e intramuscular, caracterizou-se por rápida fase de distribuição (t½a ), 15,45±4,85min e 23,14± 7,24min para a administração intravenosa e intramuscular, respectivamente, seguida por longa fase de eliminação (t½b ), após a aplicação intramuscular (17,55±6,52h.). O volume aparente de distribuição (Vd) da administração intravenosa da droga foi moderado (0,72±0,12l/kg), e após um lapso da aplicação intramuscular, foi alta (3,51±1,05l/kg). Isso pode ser explicado pelo efeito flip-flop ou por evitar a via enteroépatica. A biodisponibilidade obtida após administração intramuscular foi de 61%.(AU)