Journal of Veterinary Pharmacology and Therapeutics

Digoxin was administered orally and intravenously to seven healthy adult mares and geldings in two separate trials. At a dose of 44 μg digoxin/kg body weight, the oral study was characterized by an absorption phase with a mean (± 1 standard deviation) peak serum digoxin concentration of 2.21 ng/ml (± 0.45) at a mean of 2.29 h (± 1.52) after administration. A second rise in serum digoxin concentration started about 6–8 h after administration and extended to about 20 h after administration. The mean bioavailability (F) was 23.38% (± 5.96).

At a dose of 22 μg digoxin/kg body weight, the intravenous study was characterized by a two‐compartment model with the following mean pharmacokinetic measurements: distribution rate constant (α), 1.391 h^‐1 (± 0.1909); zero‐time serum digoxin concentration determined from the distribution phase (A), 21.247 ng/ml (± 5.6614); elimination rate constant (β), 0.0409 h^‐1 (± 0.0069); zero‐time serum digoxin concentration determined from the elimination phase (B), 3.82 ng/ml (± 0.433); apparent specific volume of distribution uncorrected for protein binding (V_dβ), 5.003 1/kg (± 0.5177). The mean β corresponded to a biological half‐life (t1/2 ±) of 16.9 h.

Based upon results of this study, theoretically achievable steady‐state serum digoxin concentrations were calculated for maintenance doses given by oral and intravenous routes of administration with appropriate two‐compartment, multiple‐dose formulae. Loading doses were also calculated for each route. It is the opinion of the authors that the oral route of administration of digoxin is effective in the horse and may preclude the potential risks posed by the high serum digoxin concentrations immediately following intravenous administration.

Plasma (total, systemic…) clearance is determined by all the individual metabolizing/eliminating organ clearances and involves mainly liver and kidney clearances. Plasma clearance (a volume per time, i.e. a flow) expresses the overall ability of the body to eliminate a drug by scaling the drug elimination rate (amount per time) by the corresponding plasma concentration level. The interpretation of plasma clearance and inter‐species comparisons are made easier by computing the overall body extraction ratio (from 0 to 1), which is the ratio of the body clearance divided by cardiac output. Plasma clearance is the most important pharmacokinetic parameter because it is the only one which controls the overall drug exposure (for a given bioavailability) and it is the parameter which allows computation of the dosage required to maintain an average steady‐state plasma concentration.

Sau khi tiêm tĩnh mạch (i.v.), acepromazine được phân bố rộng rãi trong ngựa (V_d= 6,6 lít/kg) và gắn chặt (>99%) vào protein huyết tương. Mức độ của thuốc trong huyết tương giảm xuống với pha α có thời gian bán thải là 4,2 phút, trong khi pha β hoặc thời gian bán thải là 184,8 phút. Ở mức liều 0,3 mg/kg, acepromazine có thể được phát hiện trong huyết tương trong 8 giờ sau khi dùng thuốc. Sự phân chia của acepromazine trong máu toàn phần là 46% trong pha huyết tương và 54% trong pha hồng cầu.

Sự tụt xuống của bộ phận sinh dục rõ ràng ở các liều từ 0,01 mg/kg đến 0,4 mg/kg i.v., và thời gian kéo dài và mức độ nhô ra phụ thuộc vào liều dùng. Mức độ hồng cầu giảm đáng kể khi sử dụng 0,002 mg/kg i.v. (khoảng 1 mg cho một con ngựa 500 kg) và tăng liều dẫn đến sự giảm hơn 20% mức độ hồng cầu so với điều kiện kiểm soát. Việc sử dụng acepromazine trước cũng làm giảm tốc độ phản ứng biến thiên (VI 60) ở tất cả các con ngựa được thử nghiệm.

Dữ liệu này cho thấy rằng sự thay đổi của hồng cầu là phản ứng dược lý nhạy cảm nhất đối với acepromazine, tiếp theo là sự thay đổi trong sự kéo dài của bộ phận sinh dục, tốc độ hô hấp, phản ứng VI và phản ứng vận động. Acepromazine khó phát hiện trong huyết tương với liều lượng lâm sàng bình thường. Tuy nhiên, do thể tích phân bố lớn của nó, việc thải ra qua nước tiểu có khả năng kéo dài, và cần thêm nghiên cứu về sự đào thải trong nước tiểu của ngựa.

Higgins, A.J. The biology, pathophysiology and control of eicosanoids in inflammation. J. vet. Pluirmacol. Therap. 8, 1–18.

The involvement in inflammatory conditions of those cyclo‐oxygenase and lipoxygenase derivatives of arachidonic acid (5, 8, 11, 14‐eicosatetraenoic acid), which are known as the eicosanoids, is reviewed iti the light of recent studies. Although it is now generally recognized that cyclo‐oxygenase products are fundamental to the inflammatory process as chemical mediators, and that inhibition of the cyclo‐oxygenase enzyme pathway explains the mode of action of most non‐steroidal anti‐inflammatory drugs (NSAIDs) commonly prescribed in veterinary practice, evidence for the involvement of lipoxygenase products of arachidonate metabolism in inflammation is increasing. The leukotrienes (LTs) are 5‐lipoxygenase‐derived eicosanoids which have been shown to be leucotactic and involved in anaphylactic and hypersensitivity reactions. Leucocytes, drawn to sites of injury by chemotaxis, themselves liberate pro‐inflammatory eicosanoids which perpetuate the response and may aggravate the clinical condition. At therapeutic dose rates, most NSAIDs have no effect on the biosynthesis of LTs, whereas corticosteroids, by inhibiting the release of arachidonic acid, may prevent the formation of both cyclo‐oxygenase and lipoxygenase products. However, because of the undesirable side‐effects of steroids, the clinical use of these agents in treating inflammatory conditions is sometimes limited. Novel non‐steroid inhibitors of cyclo‐oxygenase and lipoxygenase enzyme pathways could offer more effective and safer control of inflammation in animals.

A.J. Higgins, The Royal Veterinaiy College, North Mymms, Hatfield, Hertfordshire AL9 7TA, England.

Penethamate hydriodide was highly effective in killing Streptococcus uberis, Streptococcus dysgalactiae subsp. dysgalactiae and Staphylococcus aureus that internalized mammary epithelial cells. At higher concentrations (32 μg/mL to 32 mg/mL), killing rates ranged from 85% to 100%. At lower concentrations (0.032 μg/mL to 3.2 μg/mL), killing rates ranged from 0 to 80%. Results of this proof‐of‐concept study demonstrated that: (1) penethamate hydriodide is capable of entering mammary epithelial cells and killing intracellular mastitis pathogens without affecting mammary epithelial cell viability, (2) the in vitro model used is capable of quantifying the fate of mastitis pathogens internalized into mammary epithelial cells, and (3) this in vitro model can be used to determine the effectiveness of antibiotics at killing bacteria within the cytoplasm of mammary epithelial cells.

Terminal plasma half‐life is the time required to divide the plasma concentration by two after reaching pseudo‐equilibrium, and not the time required to eliminate half the administered dose. When the process of absorption is not a limiting factor, half‐life is a hybrid parameter controlled by plasma clearance and extent of distribution. In contrast, when the process of absorption is a limiting factor, the terminal half‐life reflects rate and extent of absorption and not the elimination process (flip‐flop pharmacokinetics). The terminal half‐life is especially relevant to multiple dosing regimens, because it controls the degree of drug accumulation, concentration fluctuations and the time taken to reach equilibrium.

Intravenous (IV) levetiracetam (LEV) is available for humans for bridge therapy when the oral route is unavailable. We investigated the safety and pharmacokinetics of LEV administered intramuscularly (IM), IV, and orally to dogs.

Six Hound dogs received 19.5–22.6 mg/kg of LEV IM, IV and orally with a wash‐out period in between. All dogs received 500 mg LEV orally and 5 mL of 100 mg/mL LEV IM. Three dogs received 500 mg of LEV IV and three dogs received 250 mg LEV IV with 250 mg given perivascularly to approximate extravasation. Safety was assessed using a pain scale at time of IM administration and histopathological examination 24 h to 5 days after injection.

Intravenous LEV half‐life was 180 ± 18 min. Bioavailability of IM LEV was 100%. Mean time to T_maxafter IM was 40 ± 16 min. The mean C_maxIM was 30.3 ± 3 μg/mL compared to the C₀of 37 ± 5 μg/mL for IV. Mean inflammation score (0–4 scale) for IM LEV was 0.28 and for saline 0.62. Extravasation did not cause tissue damage.

Parenteral LEV is well tolerated and appears safe following IM and IV injections in dogs. Parenteral LEV should be evaluated for use in dogs with epilepsy.

The purposes of the present study were to elucidate the pharmacokinetics of zonisamide, determine the presence of a drug interaction with phenobarbital, and evaluate how long any interaction lasted after discontinuation of phenobarbital in dogs. Five dogs received zonisamide (5 mg/kg, p.o. and i.v.) before and during repeated oral administration of phenobarbital (5 mg/kg, bid, for 30–35 days). Zonisamide (5 mg/kg, p.o.) was also administered 8, 10, and 12 weeks after discontinuation of phenobarbital. Blood was sampled until 24 h after each zonisamide administration and serum concentrations of zonisamide were determined. Repeated phenobarbital decreased the maximum serum concentration, area under the serum concentration vs. time curve, apparent elimination half‐life, and bioavailability of zonisamide. Total clearance increased. Time to maximum serum concentration and volume distribution were not changed. The maximum serum concentration and area under the serum concentration vs. time curve of zonisamide continued to be low until 10 weeks after the discontinuation of phenobarbital. They were restored to the same serum concentration as before phenobarbital administration 12 weeks after the discontinuation of phenobarbital. These data suggested that repeated administration of a clinical dose of phenobarbital enhanced the clearance of zonisamide and the enhanced clearance lasted at least 10 weeks after the discontinuation of phenobarbital. Caution may be necessary when zonisamide is given with phenobarbital and when antiepileptic therapy is changed from phenobarbital to zonisamide.

As part of a general study of the pharmacokinetics of drugs in the ruminant animal, the absorption and distribution kinetics of meclofenamic acid between the gastro‐intestinal tract and plasma of sheep and cattle were investigated. Meclofenamic acid is a non‐steroidal anti‐inflammatory drug which has been shown to possess anti‐anaphylactic activity in cattle (Aitken & Sanford, 1969; 1972; Wells, Eyre & Lumsden, 1973) and sheep (Alexander, Eyre, Head & Sanford, 1970) and although marketed only for the horse in the United Kingdom (Arquel, Warner‐Lambert) is known to be used in ruminant animals as an anti‐inflammatory drug, for its inhibitory effects on prostaglandin synthesis (Smith G. G. A. 1977, personal communication) and for its anti‐pyretic action (Van Miert, Van der Wal‐Komproe & Van Duin, 1977). The aims of the study were first to evaluate the contribution of reticular (oesophageal) groove closure in directing orally administered drug directly to the abomasum and to assess the rate of absorption through the ruminal epithelium. Second, since Aitken & Sanford (1975) have described the plasma levels of meclofenamate after administration of sodium meclofenamate to cattle by the oral, intravenous and intra‐ruminal routes, it was decided to complement their study and to measure the plasma levels after intra‐muscular injection of sodium meclofenamate. This route is more convenient in cattle than the oral and intravenous routes examined by them. Lastly, the biphasic pattern of plasma levels of meclofenamate observed by Aitken & Sanford (1975) following oral administration of sodium meclofenamate to cattle was further examined using weaned and unweaned calves in an attempt to confirm their view that some of the drug is delivered to the abomasum directly, by‐passing the rumen, by closure of the reticular groove.

Sodium meclofenamate is a non‐steroidal anti‐inflammatory drug with anaphylactic protective activity in cattle. The objectives of this study were to describe the pharmacokinetic behaviour of sodium meclofenamate after intravenous and oral administration to sheep and to determine the influence of closure of the reticular groove on the bioavailability of the drug. Sodium meclofenamate was administered by the intravenous (2.2 mg/kg) and oral (20 mg/kg) routes to sheep (n = 6). During the oral study the reticular groove was closed by intravenous administration of lysine vasopressin (0.3 IU/kg) or left open (saline solution). The closure of the reticular groove was assessed by determination of the blood glucose curves after oral administration of a glucose solution. After intravenous administration of meclofenamate, the distribution and elimination half‐lives of the drug were 7.2 min and 542 min respectively, V_ss was 1.68 L/kg and Cl_B was 2.47 mL/min kg. Two different patterns of the plasma concentration curves were observed after oral administration of sodium meclofenamate. When the reticular groove was closed, two peaks were observed (t_max‐2 12‐15 min, C_max‐1 3.30‐24.01 μg/mL; and t_max‐2′, 52.50‐75 min, C_max‐2′ 6.45‐11.08 μg/mL).