Influence of Escherichia coli lipopolysaccharide-induced endotoxemia on plasma and tissue disposition of florfenicol after intramuscular administration in rabbits.

To assess the effects of the acute inflammatory response (AIR) induced by Escherichia coli lipopolysaccharide (LPS) on plasma and tissue disposition of florfenicol (FFC) and its metabolite florfenicol amine (FFC-a), after its intramuscular (IM) administration, twenty-two New Zealand rabbits were randomly distributed in two experimental groups: Group 1 (LPS) was treated with three intravenous doses of 2 µg LPS/kg bw, before an intramuscular dose of 20 mg/kg FFC twenty-four h after the first LPS or SS injection; Group 2 (Control) was treated with saline solution (SS) in equivalent volumes as LPS-treated group. Blood samples were collected before (T0) and at different times after FFC administration. Acute inflammatory response was assessed in a parallel study where significant increases in body temperature, C-reactive protein concentrations and leukopenia were observed in the group treated with LPS. In another two groups of rabbits, 4 h after FFC treatment, rabbits were euthanized and tissue samples were collected for analysis of FFC and FFC-a concentrations. Pharmacokinetic parameters of FFC that showed significantly higher values in LPS-treated rabbits compared with control rabbits were absorption half-life, area under the curve, mean residence time and clearance /F (Cl/F). Elimination half-life and mean residence time of FFC-a were significantly higher in LPS-treated rabbits, whereas the metabolite ratio of FFC-a decreased significantly. Significant differences in tissue distribution of FFC and FFC-a were observed in rabbits treated with LPS. Modifications in plasma and tissue disposition of FFC and FFC-a were attributed mainly to haemodynamic modifications induced by the AIR through LPS administration.

Modulation of the Acute Inflammatory Response Induced by the Escherichia coli Lipopolysaccharide through the Interaction of Pentoxifylline and Florfenicol in a Rabbit Model.

BACKGROUND: Experimental reports have demonstrated that florfenicol (FFC) exerts potent anti-inflammatory effects, improving survival in a murine endotoxemia model. Considering the anti-inflammatory and immunomodulatory properties of pentoxifylline (PTX) as an adjuvant to enhance the efficacy of antibiotics, the anti-inflammatory effects of the interaction FFC/PTX over the E. coli Lipopolysaccharide (LPS)-induced acute inflammatory response was evaluated in rabbits. METHODS: Twenty-five clinically healthy New Zealand rabbits (3.8 ± 0.2 kg body weight: bw), were distributed into five experimental groups. Group 1 (control): treated with 1 mL/4 kg bw of 0.9% saline solution (SS) intravenously (IV). Group 2 (LPS): treated with an IV dose of 5 µg/kg of LPS. Group 3 (pentoxifylline (PTX) + LPS): treated with an oral dose of 30 mg/kg PTX, followed by an IV dose of 5 µg/kg of LPS 45 min after PTX. Group 4 (Florfenicol (FFC) + LPS): treated with an IM dose of 20 mg/kg of FFC, followed by an IV dose of 5 µg/kg of LPS 45 min after FFC administration. Group 5 (PTX + FFC + LPS): treated with an oral dose of 30 mg/kg of PTX, followed by an IM dose of 20 mg/kg of FFC, and, 45 min after an IV dose of 5 µg/kg of LPS was administered. The anti-inflammatory response was evaluated through changes in plasma levels of interleukins (TNF-α, IL-1ß and IL-6), C-reactive protein (CRP), and body temperature. RESULTS: It has been shown that each drug produced a partial inhibition over the LPS-induced increase in TNF-α, IL-1ß, and CRP. When both drugs were co-administered, a synergistic inhibitory effect on the IL-1ß and CRP plasma concentrations was observed, associated with a synergic antipyretic effect. However, the co-administration of PTX/FFC failed to modify the LPS-induced increase in the TNF-α plasma concentrations. CONCLUSIONS: We concluded that the combination of FFC and PTX in our LPS sepsis models demonstrates immunomodulatory effects. An apparent synergistic effect was observed for the IL-1ß inhibition, which peaks at three hours and then decreases. At the same time, each drug alone was superior in reducing TNF-α levels, while the combination was inferior. However, the peak of TNF-α in this sepsis model was at 12 h. Therefore, in rabbits plasma IL-1ß and TNF-α could be regulated independently, thus, further research is needed to explore the effects of this combination over a more prolonged period.

Plasma disposition of florfenicol after intramuscular administration in rabbits pretreated with pentoxifylline.

This work aimed to assess the effects of the coadministration of pentoxifylline (PTX) on the pharmacokinetic profile of florfenicol (FFC) after intramuscular administration in rabbits. Ten New Zealand white rabbits, 1 year of age and 3.9 ± 0.1 kg body weight, were assigned according to a randomized block design to Group 1 (FFC): treated with 30 mg/kg of FFC intramuscularly, and Group 2 (PTX + FFC) treated with an oral dose of 30 mg/kg PTX 45 min before the intramuscular injection of 30 mg/kg FFC. Blood samples were collected before and at different times between 0.5 and 12.0 h after drug administration. FFC plasma concentrations were determined by high-performance liquid chromatography. Results showed that IM injection of the long-acting formulation of FFC in rabbits resulted in a slow increase in mean plasma concentrations reaching a Cmax of 3.09 ± 0.52 ug/mL at 2.8 ± 0.45 h (Tmax ) after drug administration. While coadministration of PTX and FFC decreased the time to achieve the maximal concentration by modifying the absorption of FFC without changes in the other pharmacokinetic parameters.

Magnesium Salt, a Simple Strategy to Improve Methadone Analgesia in Chronic Pain: An Isobolographic Preclinical Study in Neuropathic Mice.

Analgesic efficacy of methadone in cancer and chronic non-cancer pains is greater than that of other opioids, probably because of its unique pharmacokinetics properties and also because it targets glutamatergic receptors in addition to µ-opioid receptors. However, methadone has drawbacks which are clearly related to dosing and treatment duration. The authors hypothesized that the antinociceptive efficacy of methadone could be synergistically potentiated by magnesium and copper salts in a preclinical mouse model of chronic pain, using the intraplantar formalin test as algesimetric tool. The spared nerve injury mice model was used to generate mononeuropathy. A low dose (0.25%) formalin was injected in the neuropathic limb in order to give rise only to Phase I response, resulting from direct activation by formalin of nociceptive primary afferents. Licking/biting of the formalin-injected limb was evaluated as nociceptive behavior during a 35-min observation period. Dose-response curves for intraperitoneal magnesium sulfate (10, 30, 100, and 300 mg/kg i.p.), copper sulfate (0.1, 0.3, 1, and 3 mg/kg i.p.) and methadone (0.1, 0.3, 1, and 3 mg/kg i.p.) allowed to combine them in equieffective doses and to determine their interaction by isobolographic analysis. Magnesium sulfate, copper sulfate and methadone dose-dependently decreased the nociceptive response evoked by formalin injection, the respective ED50 being 76.38, 1.18, and 0.50 mg/kg i.p. Isobolographic analysis showed a superadditive interaction for magnesium and methadone. Indeed, despite that both ED50 are obviously equieffective, the ED50 for the MgSO4/methadone combination contained less than one third of the methadone having the ED50 for methadone alone. For the CuSO4/methadone combination, the interaction was only additive. Extrapolated to clinical settings, the results suggest that magnesium salts might be used to improve synergistically the efficacy of methadone in neuropathy, which would allow to reduce the dose of methadone and its associated side effects.

Antinociception Induced by Copper Salt Revisited: Interaction with Ketamine in Formalin-Induced Intraplantar and Orofacial Pain in Mice.

AIMS: To evaluate in mice the antinociceptive effect of copper in spinal and trigeminal nociceptive pathways by using the intraplantar and orofacial formalin tests, respectively, and to examine whether this effect may interact synergistically with ketamine-induced antinociception. METHODS: Nociceptive behaviors (licking/biting of the formalin-injected limb and rubbing/scratching of the formalin-injected orofacial area) in male mice were evaluated during a 45-minute observation period post-formalin injection. Dose-response curves for intraperitoneal (ip) copper sulfate and ketamine allowed their combination in equi-effective doses, and their interaction was determined with isobolographic analysis. The results were examined with one-way analysis of variance followed by the Bonferroni post hoc test. Significance was accepted at an alpha level of .05. RESULTS: Irrespective of the region injected with formalin (upper lip or hindlimb), copper sulfate (0.3, 1.0, and 3.0 mg/kg) and ketamine (1.0, 3.0, and 10 mg/kg) dose-dependently decreased the nociceptive behaviors evoked by formalin injection. Isobolographic analysis showed a superadditive interaction between copper and ketamine at the spinal level, but this interaction was only additive at the trigeminal level. CONCLUSION: The results suggest that copper salts could be used to synergistically improve the efficacy of some commercial centrally acting analgesic agents, such as ketamine, while reducing the possibility of side effects. However, a synergistic effect probably should not be expected if treatment is for orofacial pain.

Clinical and hematological changes in sheep induced by Escherichia coli lipopolysaccharide / alterações clínicas e hematológicas induzidas pela administração de lipopolisscarídeo de Escherichia coli em ovelhas / Alteraciones clínicas y hematológicas inducidas por la administración de lipopoliscárido de Escherichia coli en ovejas

Organic response to infection is characterized by a systemic reaction known as acute phase response (APR). In order to know the effect of the administration of Escherichia coli lipopolysaccharide (LPS) on physiological, hematological and biochemical variables, 10 sheep weighing 45 ± 5 kg were divided in two groups: Experimental group treated with 3 doses of 1 µg.kg-1 LPS and control group treated with saline solution (SS) at the same frequency as experimental group. Body temperature (BT°), heart rate (HR) and respiratory rate (RR) were monitored. Blood samples for hemogram and enzyme activity for aspartate amino transferase (AST) and gamma glutamyl transferase (GGT) were collected between 1 and 24 h post-LPS. LPS-treated sheep presented mean values of BT (41.2 ± 0.4°C), HR (132 ± 12.3 beats/min) and RR (107.2 ± 25 cycles/min) higher than those observed in control sheep (39.8 ± 0.2°C, 88.8 ± 8.7 beats/min and 53.6 ± 17.1 cycles/min respectively). Between 4 and 8 hours post-injection (hpi) of LPS the leukocyte count was associated with lymphopenia, followed by leukocytosis at 24 hours. No changes were observed in the activity of AST and GGT enzymes. The results characterize APR induced by LPS in sheep, representing a useful model to study cardiovascular, hematological and biochemical responses to infection. (AU)

A resposta orgânica à infecção é caracterizada por uma reação sistêmica conhecida como resposta de fase aguda (RFA). Para conhecer o efeito da administração de lipopolissacárideo (LPS) de Escherichia coli sobre as variáveis fisiológicas, hematológicas e bioquímicas, 10 carneiros pesando 45 ± 5 kg foram divididos em dois grupos: o grupo experimental tratado com três doses de 1 µg.kg -1 de LPS e grupo controle tratado com solução salina (SS) na mesma frequência que o grupo experimental. Temperatura corporal (T°C), frequência cardíaca (FC) e frequência respiratória (FR) foram monitoradas. As amostras de sangue foram tomadas para hemograma e atividade da enzima aspartato aminotransferase (AST) e gama- -glutamiltransferase (GGT) entre uma e 24 h pós-LPS. Ovelhas tratadas com LPS apresentaram valores médios de T°C (41,2 ± 0,4°C), FC (132 ± 12,3 batimentos/min) e FR (107,2 ± 25 ciclos/min) acima dos observados em ovelhas do tratamento controle (39,8 ± 0,2°C, 88,8 ± 8,7 batimentos/min e 53,6 ± 17,1 ciclos/min, respectivamente). Entre 4 e 8 horas após a injeção de LPS, a contagem de leucocitos foi asociado com linfopenia, seguida de leucocitose as 24 horas. Nenhuma mudança na atividade das enzimas AST e GGT foi observada. Os resultados caracterizam uma resposta de fase aguda induzida por LPS em ovelhas, o que representa um modelo útil para estudar os sistemas cardiovascular, hematológico e bioquímico em resposta à infecção.(AU)

La respuesta orgánica a la infección se caracteriza por una reacción sistémica conocida como respuesta de fase aguda (RFA). Para conocer el efecto de la administración de lipopolisacárido (LPS) de Escherichia coli sobre las variables fisiológicas, hematológicas y bioquímicas, 10 ovejas con un peso de 45 ± 5 kg se dividieron en dos grupos: grupo experimental tratado con 3 dosis de 1 µg.kg-1de LPS y grupo control tratado con solución salina (SS) en la misma frecuencia que el grupo experimental. Temperatura corporal (T°C), frecuencia cardíaca (FC) y frecuencia respiratoria (FR) fueron monitoreadas. Se tomaron muestras de sangre para hemograma y actividad enzimática para el aspartato amino transferasa (AST) y gamma glutamil transferasa (GGT) entre 1 y 24 h post-LPS. Las ovejas tratadas con LPS presentaron valores medios de T°C (41.2 ± 0.4°C), FC (132 ± 12.3 latidos / min) y FR (107.2 ± 25 ciclos/min) por encima de los observados en ovinos controles (39.8 ± 0.2°C, 88.8 ± 8.7 latidos/min y 53.6 ± 17.1 ciclos/min respectivamente). Entre las 4 y 8 horas después de la inyección de LPS, el recuento de leucocitos se asoció a linfopenia, seguida de leucocitosis a las 24 horas. No se observaron cambios en la actividad de las enzimas AST y GGT. Los resultados caracterizan una respuesta de fase aguda inducida por LPS en ovinos, representando un modelo útil para estudiar los sistemas cardiovascular, hematológico y bioquímico en respuesta a la infección.(AU)

Caracterización del uso de metadona en pacientes paliativos en el Instituto Nacional del Cáncer, Santiago de Chile / Characterization of methadone use in palliative patients at the National Cancer Institute, Santiago, Chile

OBJETIVOS: realizar un estudio de tipo descriptivo y retrospectivo para caracterizar el uso y efecto de metadona en una población de pacientes de la unidad de cuidados paliativos del Instituto Nacional del Cáncer. MATERIALES Y MÉTODOS: los datos analizados se obtuvieron desde los registros de la farmacia y las fichas clínicas de los pacientes de la unidad de cuidados paliativos del Instituto Nacional del Cáncer que estaban siendo tratados con metadona durante el mes de agosto de 2013. las variables cuantificadas fueron edad, sexo, diagnóstico oncológico, tipo de dolor, motivo de indicación de metadona, duración del tratamiento, dosis utilizadas, respuesta analgésica y uso concomitante con analgésicos no opioides. RESULTADOS: la población de pacientes bajo control mensual en la unidad de cuidados paliativos al mes de agosto fue de 445 pacientes. en el estudio se incluyeron a 31 pacientes que estaban en ese periodo tratados con metadona, lo que representa un 7% del total de pacientes. la indicación, según tipo de dolor, fue en un 80,6% por dolor de tipo neuropático o mixto. la indicación de metadona se debió, en un 68%, a una rotación de opioides y solo en un 3% fue por indicación primaria. la dosis promedio diaria fluctuó entre 16,7 mg, al inicio del tratamiento; y 26,1 mg, al momento del estudio o periodo de observación. la mediana de uso fue de 211 días. la intensidad del dolor, medida por la escala numérica verbal, fue de 8,3 ± 0,3 mg al inicio del tratamiento y 5,4 ± 0,6 mg durante el control de agosto de 2013, lo que significa una disminución promedio de 34,9%. DISCUSIÓN: el uso de metadona en la unidad de cuidados paliativos del Instituto Nacional del Cáncer está en concordancia con las propuestas internacionales, indicándose principalmente como rotación de opioides y en el tratamiento del dolor neuropático. el análisis de las fichas mostró utilización de dosis bajas de metadona (menores de 30 mg), con pequeños incrementos de dosis durante el período de tratamiento, obteniéndose como resultado una reducción significativa del dolor.

OBJETIVES: to carry out a descriptive and retrospective study to characterize the use and effect of methadone in a group of patients of the Palliative Care Unit of the National Cancer Institute. MATERIALS AND METHODS: the information was obtained from the patient pharmacy and clinical records at the palliative care unit of the National Cancer Institute who were being treated with methadone during the month of august, 2013. the variables assessed were age, sex, oncology diagnosis, type of pain, reason for methadone prescription, treatment duration, dosage, pain response and associated use of non- opioid analgesics. RESULTS: the patient group under monthly monitoring at the palliative care unit in august was made up of 445 people. the study included 31 patients who at that time were being treated with methadone, 7% of the total. the indication according to the type of pain was in an 80.6% caused by a neuropathic or mixed pain. a 68% of the methadone indication was caused by an opioid rotation and only a 3% by a primary indication. the average daily dose went from 16.7 mg at the beginning to 26.1 mg at the moment the study or observation period was carried out. the use average was of 211 days. The pain intensity, using a numeric scale, was of 8.3 ± 0.3 mg at the beginning of the treatment and a 5.4 ± 0.6 mg during the august 2013 control, which means an average decrease of 34,9 %. DISCUSSION: the use of methadone at the palliative care unit of the National Cancer Institute is in accordance with the international proposals, being indicated mostly as opioid rotation and in the neuropathic pain treatment. the record analysis showed a low dose use of methadone (lower than 30 mg), with small dose increase during the treatment period, getting a significant pain decrease as a result

Plasma and tissue disposition of florfenicol in Escherichia coli lipopolysaccharide-induced endotoxaemic sheep.

1. The purpose of this study was to understand the effects of the acute inflammatory response (AIR) induced by Escherichia coli lipopolysaccharide (LPS) on florfenicol (FFC) and FFC-amine (FFC-a) plasma and tissue concentrations. 2. Ten Suffolk Down sheep, 60.5 ± 4.7 kg, were distributed into two experimental groups: group 1 (LPS) treated with three intravenous doses of 1 µg/kg bw of LPS at 24, 16, and 0.75 h (45 min) before FFC treatment; group 2 (Control) was treated with saline solution (SS) in parallel to group 1. An IM dose of 20 mg FFC/kg was administered at 0.75 h after the last injection of LPS or SS. Blood and tissue samples were taken after FFC administration. 3. The plasma AUC0-4 h values of FFC were higher (p = 0.0313) in sheep treated with LPS (21.8 ± 2.0 µg·min/mL) compared with the control group (12.8 ± 2.3 µg·min/mL). Lipopolysaccharide injections increased FFC concentrations in kidneys, spleen, and brain. Low levels of plasma FFC-a were observed in control sheep (Cmax = 0.14 ± 0.01 µg/mL) with a metabolite ratio (MR) of 4.0 ± 0.87%. While in the LPS group, Cmax increased slightly (0.25 ± 0.01 µg/mL), and MR decreased to 2.8 ± 0.17%. 4. The changes observed in the plasma and tissue concentrations of FFC were attributed to the pathophysiological effects of LPS on renal hemodynamics that modified tissue distribution and reduced elimination of the drug.