Disposition kinetics and distribution of demeclocycline in various biological fluids in female goats

A pharmacokinetic study of demeclocycline was carried out following intravenous administration at 5 mg/kg body weight in lactating goats. Demeclocycline appeared within 5 min in plasma, interstitial fluid (isf) and urine, while it appeared at 1 h in milk. Peak concentrations of 21.70±4.06, 2.67±0.23, 5.65±0.45 and 82.23±10.06 g/ml were attained at 5 min and at 6, 8 and 8 h in plasma, isf, milk and urine respectively. A potentially therapeutic concentration of 0.5 g/ml was maintained from 5 min–36 h, 30 min–30 h, 1–36 h and 5 min–48 h in plasma, isf, milk and urine respectively. The drug was detectable in all the above biological fluids for at least 48 h. A low distribution half life (t_1/2) of 0.44±0.04 h and a high elimination half life (t_1/2) of 19.24±1.22 h denote rapid distribution but very slow elimination of the drug in goats. A high tissue plasma concentration ratio [K₁₂:(K_2I–)] of 5.12±0.97 during the elimination phase and a Vd_area of 1.59±0.18 L/kg indicate uniform distribution of demeclocycline in the tissues and body fluids of goats. The dosage regimen for maintaining minimum plasma concentration (C min = MIC) of 0.5, 1.0 and 1.5 g/ml at selected dosage intervals of 12 and 24 h was also calculated.     

Pharmacokinetic profile of cefotaxime in goats

Cefotaxime was administered to goats intravenously, intramuscularly and subcutaneously to determine blood and urine concentration, kinetic behaviour and bioavailability. Following a single intravenous injection, the blood concentration-time curve indicated a two compartment open model, with an elimination half-life value (t1/2 beta) of 22.38 +/- 0.41 minutes. Both intramuscular and subcutaneous routes showed slower values, that is, 38.64 and 69.58 minutes. The apparent volume of distribution of cefotaxime in goats was less than 1 litre kg-1 and suggested a lower distribution in tissues than in blood. After intramuscular and subcutaneous injections peak plasma cefotaxime concentrations were 77.8 +/- 1.7 and 44.0 +/- 0.8 micrograms ml-1 at 29.6 and 40.4 minutes, respectively. The average bioavailability of cefotaxime given by intramuscular and subcutaneous injection was 1.08 and 1.25 times the intravenous availability, respectively. The cefotaxime concentration remained in urine 24 hours longer after subcutaneous injection than after intramuscular administration.     

Pharmacokinetic profile of cefotaxime in goats

Cefotaxime was once administered in goats via intravenous, intramuscular and subcutaneous routes for determination of blood and urine concentration, kinetic behaviour and bioavailability. Following a single intravenous injection, the blood concentration-time curve indicated two compartments open model, with an elimination half-life value (t1/2 beta) of 22.38 +/- 0.41 minutes. Both intramuscular and subcutaneous routes showed lower values i.e. 38.64 and 69.58 minutes. The lower apparent volume of distribution of cefotaxime in goats than one liter/kg elucidated lower distribution in tissues than in blood. After intramuscular and subcutaneous injections peak plasma cefotaxime concentrations were 77.8 +/- 1.7 and 44.0 +/- 0.8 micrograms/ml at 29.6 and 40.4 minutes, respectively. The average bioavailability of cefotaxime given by intramuscular and subcutaneous injection was 1.08 and 1.25, respectively. The cefotaxime concentration remained in urine 24 hours longer after subcutaneous injection than after intramuscular administration.     

Pharmacokinetic properties of florfenicol in Egyptian goats

The single-dose disposition kinetics of florfenicol was determined in healthy, non-lactating Egyptian goats, after its intravenous (i.v.) and intramuscular (i.m.) administration at 20 mg kg-1 b.wt. Drug concentrations in serum and urine were determined using microbiological assay method and data was subjected to a kinetic analysis. Florfenicol concentrations in serum decreased in a bi-exponential manner after intravenous administration with distribution (t1/2 alpha) and elimination (t1/2 beta) half-lives of 10.256 +/- 0.938 and 56.237 +/- 3.102 minute, respectively. The steady-state volume of distribution (Vdss) and total body clearance (Cltot) were 3.413 +/- 0.304 l kg-1 and 3.306 +/- 0.333 l kg h-1. After intramuscular administration, the peak serum concentration (Cmax) was 0.859 +/- 0.025 micrograms ml-1, achieved at (Tmax) 1.220 + 0.045 h. Florfenicol was detected in urine up to 24 and 96 hour after i.v. and i.m. administration, respectively. The extent of the protein binding and systemic bioavailability of florfenicol were 22.45 +/- 1.727% and 65.718 +/- 3.372%, respectively.     

“一针肥”注射液中硒元素在山羊体内的药代动力学研究

为研究＂一针肥＂注射液中硒元素在山羊体内的血硒水平及药动学变化规律,采用单剂量肌肉注射＂一针肥＂注射液0.2mL/kg（相当于硒用量6μg/kg）,用原子荧光法测定血硒浓度,通过3p97药物动力学程序软件分析药时数据。结果显示,肌注＂一针肥＂注射液后,血硒的药时数据符合二室开放模型,主要的药代动力学参数分别为：t1/2Ka（0.148 4±0.051 0）h,t1/2α（6.832 4±0.397 7）h,t1/2β（362.324 3±17.789 5）h,Kel（0.004 3±0.000 3）h,AUC（22 414.233 5±2 512.959 8）（μg/L）.h。结果表明,肌注＂一针肥＂注射液后硒在山羊体内吸收迅速,消除缓慢。     

Pharmacokinetic profiles of metamizole (dipyrone) active metabolites in goats and its residues in milk

Metamizole (dipyrone, MET) is a nonopioid analgesic drug commonly used in human and veterinary medicine. The aim of this study was to assess two major active metabolites of MET, 4‐methylaminoantipyrin (MAA) and 4‐aminoantipyrin (AA), in goat plasma after intravenous (IV) and intramuscular (IM) administration. In addition, metabolite concentration in milk was monitored after IM injection. Six healthy female goats received MET at a dose of 25 mg/kg by IV and IM routes in a crossover design study. The blood and milk samples were analyzed using HPLC coupled with ultraviolet detector and the plasma vs concentration curves analyzed by a noncompartmental model. In the goat, the MET rapidly converted into MAA and the mean maximum concentration was 183.97 μg/ml (at 0.08 hr) and 51.94 μg/ml (at 0.70 hr) after IV and IM administration, respectively. The area under the curve and mean residual time values were higher in the IM than the IV administered goats. The average concentration of AA was lower than MAA in both groups. Over 1 μg/ml of MAA was found in the milk (at 48 hr) after MET IM administration. In conclusion, IM is considered to be a better administration route in terms of its complete absorption with long persistence in the plasma. However, this therapeutic option should be considered in light of the likelihood of there being milk residue.     

Pharmacokinetic and pharmacodynamic interactions of tolfenamic acid and marbofloxacin in goats

Pharmacokinetic and pharmacodynamic properties in goats of the non-steroidal anti-inflammatory drug tolfenamic acid (TA), administered both alone and in combination with the fluoroquinolone marbofloxacin (MB), were established in a tissue cage model of acute inflammation. Both drugs were injected intramuscularly at a dose rate of 2 mg kg⁻¹. After administration of TA alone and TA + MB pharmacokinetic parameters of TA (mean values) were C_max = 1.635 and 1.125 μg ml⁻¹, AUC = 6.451 and 3.967 μg h ml⁻¹, t_1/2K₁₀ = 2.618 and 2.291 h, Vdarea/F = 1.390 and 1.725 L kg⁻¹, and ClB/F = 0.386 and 0.552 L kg⁻¹ h⁻¹, respectively. These differences were not statistically significant. Tolfenamic acid inhibited prostaglandin (PG)E₂ synthesis in vivo in inflammatory exudate by 53-86% for up to 48 h after both TA treatments. Inhibition of synthesis of serum thromboxane (Tx)B₂ ex vivo ranged from 16% to 66% up to 12 h after both TA and TA + MB, with no significant differences between the two treatments.From the pharmacokinetic and eicosanoid inhibition data for TA, pharmacodynamic parameters after dosing with TA alone for serum TxB₂ and exudate PGE₂ expressing efficacy (E_max = 69.4 and 89.7%), potency (IC₅₀ = 0.717 and 0.073 μg ml⁻¹), sensitivity (N = 3.413 and 1.180) and equilibration time (t_1/2K_e0 = 0.702 and 16.52 h), respectively, were determined by PK-PD modeling using an effect compartment model. In this model TA was a preferential inhibitor of COX-2 (COX-1:COX-2 IC₅₀ ratio = 12:1). Tolfenamic acid, both alone and co-administered with MB, did not affect leucocyte numbers in exudate, transudate or blood. Compared to placebo significant attenuation of skin temperature rise over inflamed tissue cages was obtained after administration of TA and TA + MB with no significant differences between the two treatments. Marbofloxacin alone did not significantly affect serum TxB₂ and exudate PGE₂ concentrations or rise in skin temperature over exudate tissue cages. These data provide a basis for the rational use of TA in combination with MB in goat medicine.     

Metronidazole: a method for its determination in biological fluids and its disposition kinetics in the dog

A method for the analytical determination of metronidazole concentrations in biological tissues was developed using high performance liquid chromatography. The procedure was employed to investigate the pharmacokinetics of metronidazole in dogs following intravenous and oral administration (44 mg/kg). The overall elimination rate constant β was 0.0027 ± 0.0005 min^-1, the apparent specific volume of distribution (V'_d) was 0.948 ± 0.096 L/kg overall clearance (Cl_B) was 2.49 ± 0.54 ml/kg/min and the rate constant for absorption K_ab was 0.0456 ± 0.0353 min^-1. Oral bioavailability was high but variable (59%–100%). Implications of these data for chemotherapy of infections caused by anaerobic bacteria, trichomonads, and Giardia and for the sensitization of hypoxic neoplastic cells to radiotherapy are discussed.     

Pharmacokinetic comparison of six anthelmintics in sheep,goats, and cattle

This study was initiated to determine whether a comparative pharmacokinetic (PK) approach could be used to expand the pool of approved anthelmintics for minor ruminant species. Accordingly, the PK profiles of six anthelmintics (levamisole, albendazole, fenbendazole, moxidectin, doramectin, and ivermectin) in sheep, goats, and cattle were determined. The PK values determined for each anthelmintic included T_max, T_last, C_max, AUC, AUC/dose, and C_max/dose. The results of this study demonstrate that a comparative PK approach does not show commonality in the way these six anthelmintics are individually processed by these three ruminants. While some drugs demonstrated identical PK profiles between sheep and goats, none of these drugs demonstrated PK profiles in sheep and goats comparable to the PK profiles found in cattle. The results from this study suggest drug approval across these three ruminants is not a viable concept. However, the resulting PK profiles for each combination of drug and ruminant species represents a new dataset that can be used to support the US FDA Center for Veterinary Medicine's Minor Use/Minor Species indexing process for drug approvals in minor species such as sheep and goats.     

磷在崂山奶山羊体内消化、分配和利用的研究

选用9只装有永久性瘤胃瘘管的崂山奶山羊,采用单因子随机分组试验设计,试验分为3组,即低磷日粮组（LPD,P0.29%）、中磷日粮组（MPD,P0.41%）和高磷日粮组（HPD,P0.59%）,每组3只羊,采用全收粪尿法进行消化代谢试验。结果表明,LPD和MPD组的进食磷、粪磷和排出磷显著低于HPD组,LPD组的可消化磷显著低于HPD组,LPD组干物质采食量（DMI）显著高于MPD组,LPD和HPD组乳磷显著高于MPD组;LPD和MPD组的进食钙、粪钙和排出钙显著低于HPD组,LPD和HPD组乳钙显著高于MPD组,MPD组可消化钙显著低于HPD组;其他指标各组间差异不显著。在采食后不同时间点HPD组瘤胃液钙含量均值显著低于MPD组,3组间试验羊瘤胃液磷含量和pH差异不显著。分析表明,日粮磷水平在0.29%～0.41%可满足崂山奶山羊对磷的需要量,不影响瘤胃微生态正常的消化代谢。在满足崂山奶山羊磷需要量的条件下,随着磷摄入量的增加,磷总排出量增加,磷表观消化率降低,这与奶牛对磷的利用规律相一致。     

Evaluation of neutrophil function in female goats

Polymorphonuclear neutrophils (PMN) were isolated from the blood of healthy adult female goats on each of 3 consecutive days. The PMN isolated were evaluated, using random migration, chemotaxis, Staphylococcus aureus ingestion, cytochrome C reduction, iodination, and antibody-dependent cell-mediated cytotoxicity assays. Over the 3 days, mean values for each of the assays ranged as follows: area of random migration, 11.3 to 19.9 mm2; chemotactic index, 6.4 to 11; chemotactic difference, 2.8 to 4.2 mm; S aureus ingestion, 18.3% to 26.1% ingested; cytochrome C reduction, 2.7 to 3.2 nmoles of O2- produced/well; iodination, 19.4 to 25.1 nmoles of NaI/10(7) PMN/h; and antibody-dependent cell-mediated cytotoxicity 59% to 90% 51Cr released. Significant (P less than 0.05) day-to-day variations were found for all assays. Parallel increases and decreases for all test results on a per day basis indicated a common denominator influencing cell functional status rather than variability inherent in the assays themselves. Alterations induced in the cells during the cell isolation procedure were considered a probable cause.     

Pharmacokinetic study of an injectable long-acting parenteral formulation of doxycycline hyclate in calves

Doxycycline hyclate (DOX-h) can be regarded as a time-dependant antibacterial. Hence, a parenteral long-acting formulation may be regarded as more pharmacologically sound. A poloxamer-based matrix was used to produce a long-acting injectable preparation (DOX-h-LA) and its serum concentrations vs. time profile investigated after its s.c. injection to calves. Serum concentrations profiles for such a prepartion were compared to the corresponding profiles obtained with an aqueous formulation of DOX-h injected either i.m. or i.v. in 10 calves in a crossover study at dose of 10mg/kg, with washout periods. DOX-h-LA showed the greatest values for bioavailability (602%); maximum serum concentration (C(max)) value was 1.99microg/mL with a time to reach C(max) (T(max)) of 25h and an elimination half-life of 40.81h. Considering minimum effective serum concentration of 0.5microg/mL a dose-interval of 80h can be achieved for DOX-h-LA, and only 9.7h and 17h after the i.v. or i.m. administration of DOX-h, respectively.     

Pharmacokinetic behavior of marbofloxacin after intravenous and intramuscular administrations in adult goats

The pharmacokinetic behavior of marbofloxacin was studied in goats after single-dose intravenous (i.v.) and intramuscular (i.m.) administrations of 2 mg/kg bodyweight. Drug concentration in plasma was determined by high performance liquid chromatography (HPLC) and the data collected were subjected to compartmental and noncompartmental kinetic analysis. This compound presented a relatively high volume of distribution (Vss=1.31 L/kg), which suggests good tissue penetration, and a total body clearance (Cl) of 0.23 L/kg small middle doth, which is related to a long elimination half-life (t1/2beta=7.18 h and 6.70 h i.v. and i.m., respectively). Pharmacokinetic parameters were not significantly different between both routes of administration. Marbofloxacin was rapidly absorbed after i.m. administration (Tmax=0.9 h) and had high bioavailability (F=100.74%).     

Pharmacokinetics of oral doxycycline and concentrations in body fluids and bronchoalveolar cells of foals

The objective of this study was to determine the disposition of orally administered doxycycline in foals. Six healthy 4- to 8-week-old foals were used. Doxycycline was administered to each foal via the intragastric (IG) route at dosages of 10 and 20 mg/kg, in a cross-over design. After the first 10 mg/kg dose, five additional doses were administered at 12-h intervals. A microbiological assay was used to measure doxycycline activity in serum, urine, peritoneal fluid, synovial fluid, cerebrospinal (CSF), pulmonary epithelial lining fluid (PELF), and bronchoalveolar (BAL) cells. Following administration at 10 mg/kg, mean+/-SD time to peak serum doxycycline activity (tmax) was 3.0+/-1.2 h, maximum serum activity (Cmax) was 2.54+/-0.27 microg/mL, and terminal half-life (t1/2) was 8.5+/-2.8 h. Administration at a dose of 20 mg/kg resulted in a significantly longer tmax (5.5+/-1.8 h) as well as a tendency toward higher Cmax (2.89+/-0.33 microg/mL) and longer t1/2 (11.9+/-2.6 h). After multiple IG doses, doxycycline activity in CSF was significantly lower than concurrent serum activity, whereas peritoneal fluid, synovial fluid, and BAL cell doxycycline activity was similar to concurrent serum activity. Doxycycline activity in urine and PELF was significantly higher than that found at other sites. Oral administration at a dosage of 10 mg/kg every 12 h would maintain serum, PELF, and BAL cell activity above the minimum inhibitory concentrations of Rhodococcus equi, beta-hemolytic streptococci, and other susceptible bacterial pathogens for the entire dosing interval.     

催产素受体在雌性山羊颈胸神经节的分布

为探讨催产素(OT)是否可以影响雌性山羊颈胸神经节的活动.采用免疫组化SP法观察催产素受体在雌性山 羊颈胸神经节的分布特点.催产素受体在颈胸神经节分布广泛,节内的神经细胞、卫星细胞和过路纤维均有OTR 免疫阳性产物分布;OTR主要在神经细胞中表达,相对表达量与其他非神经结构相比差异性显著(P＜0.05);在神经 细胞中,OTR免疫阳性产物主要存在于胞膜、胞质、核仁,核膜不着色.雌性山羊颈胸神经节神经元对OT具有反应 性,提示OT可能通过影响颈胸神经节神经元的活动,从而经其发出的交感节后神经这一途径调节其所支配的靶器 官如心血管、汗腺、呼吸等的生理活动.     

Ventricular septal defects in three familially-related female Saanen goats

SUMMARY Ventricular septal defects were diagnosed in 3 familially-related Saanen goats, a 4-year-old doe and 2 female kids aged 18 weeks, by clinical examination, electrocardiography, phonocardiography and thoracic radiography. Findings were contrasted with those from 3 clinically normal goats. Cardiac catheterisation was attempted on the 2 affected kids before euthanasia. Blood pressure tracings and selective contrast cardioangiography successfully demonstrated the defect in one case, but the other died shortly after anaesthetic induction. The adult goat, suspected paternal grand-dam of the affected twins, died without premonitory signs at 4.5 years of age. Necropsy confirmed the diagnosis in all 3 cases.     

Pharmacokinetic behavior and pharmacokinetic/pharmacodynamic integration of marbofloxacin after subcutaneous administration in goats

The pharmacokinetic behavior of marbofloxacin was studied in goats after single-dose subcutaneous (SC) administration of 2mg/kg bodyweight. Drug concentration in plasma was determined by high performance liquid chromatography and the data obtained were subjected to non-compartmental kinetic analysis. Marbofloxacin peak plasma concentration (C(max)=1.77+/-0.24microg/mL) was reached 1.25+/-0.50h (T(max)) after SC administration. The elimination half-life (t(1/2beta)) and area under curve (AUC) were 5.74+/-1.21h and 8.15 vs 2.33microg h/mL, respectively. Taking into account the values obtained for the efficacy indices, it was concluded that a SC dose of 2mg/kg/24h of marbofloxacin could be adequate to treat infections caused by high susceptible bacteria like Escherichia coli or Salmonella spp.     

Pharmacokinetics after administration of an injectable experimental long-acting parenteral formulation of doxycycline hyclate in goats

OBJECTIVE: To determine the pharmacokinetics after SC administration of an experimental, long-acting parenteral formulation of doxycycline hyclate in a poloxamer-based matrix and after IV and IM administration of an aqueous formulation of doxycycline hyclate in goats. ANIMALS: 30 clinically normal adult goats. PROCEDURES: Goats were allocated to 3 groups (10 goats/group). One group of goats received doxycycline hyclate (10 mg/kg) IM, a second group received the same dosage of doxycycline hyclate IV, and the third group received the long-acting parenteral formulation of doxycycline hyclate SC. Serum concentrations of doxycycline were determined before and at various intervals after administration. RESULTS: The long-acting parenteral formulation of doxycycline hyclate had the greatest bioavailability (545%); mean +/- SD maximum serum concentration was 2.4 +/- 0.95 microg/mL, peak time to maximum concentration was 19.23 +/- 2.03 hours, and elimination half-life was 40.92 +/- 4.25 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the long-acting parenteral formulation of doxycycline hyclate distributed quickly and widely throughout the body after a single dose administered SC, and there was a prolonged half-life. Bioavailability of the longacting parenteral formulation of doxycycline hyclate after SC administration was excellent, compared with bioavailability after IV and IM administration of an aqueous formulation of doxycycline hyclate. Although no local tissue irritation and adverse effects were detected, clinical assessment of drug-residues and toxicologic evaluations are warranted before this long-acting parenteral formulation of doxycycline hyclate can be considered for use in goats with bacterial infections.