bluuebunny/crossref_metadata_2025 huggingface dataset:
Plant programmed cell death: can't live with it; can't live without it
Authors: WILLIAMS BRETT , DICKMAN MARTY
Published: April 2008

The decision of whether a cell should live or die is fundamental for the wellbeing of all organisms. Despite intense investigation into cell growth and proliferation, only recently has the essential and equally important idea that cells control/programme their own demise for proper maintenance of cellular homeostasis gained recognition. Furthermore, even though research into programmed cell death (PCD) has been an extremely active area of research there are significant gaps in our understanding of the process in plants. In this review, we discuss PCD during plant development and pathogenesis, and compare/contrast this with mammalian apoptosis.
Expression of a bacterial flagellin gene triggers plant immune responses and confers disease resistance in transgenic rice plants
Authors: TAKAKURA YOSHIMITSU , CHE FANG‐SIK , ISHIDA YUJI , TSUTSUMI FUMIKI , KUROTANI KEN‐ICHI , USAMI SATORU , ISOGAI AKIRA , IMASEKI HIDEMASA
Published: April 2008

Flagellin is a component of bacterial flagella and acts as a proteinaceous elicitor of defence responses in organisms. Flagellin from a phytopathogenic bacterium, Acidovorax avenae strain N1141, induces immune responses in suspension‐cultured rice cells. To analyse the function of flagellin in rice, we fused the N1141 flagellin gene to the cauliflower mosaic virus 35S promoter and introduced it into rice. Many of the resulting transgenic rice plants accumulated flagellin at various levels. The transgenic rice developed pale spots in the leaves. The expression of a defence‐related gene for phenylalanine ammonia‐lyase was induced in the transgenic plants, and H2O2 production and cell death were observed in some plants with high levels of gene expression, suggesting that the flagellin triggers immune responses in the transgenic rice. Transgenic plants inoculated with Magnaporthe grisea, the causal agent of rice blast, showed enhanced resistance to blast, suggesting that the flagellin production confers disease resistance in the transgenic rice.
Cost‐utility analysis of Canadian tailored prophylaxis, primary prophylaxis and on‐demand therapy in young children with severe haemophilia A
Authors: RISEBROUGH N. , OH P. , BLANCHETTE V. , CURTIN J. , HITZLER J. , FELDMAN B. M.
Published: April 2008

Summary.  Primary prophylaxis is the emerging standard treatment for boys with severe haemophilia. Tailored (escalating‐dose) prophylaxis (EscDose), beginning at a low frequency and escalating with repeated bleeding may prevent arthropathy at a lower cost than standard prophylaxis (SP). From a societal perspective, we compared the incremental cost per joint‐haemorrhage that is avoided and quality‐adjusted‐life‐year (QALY) gained of SP and EscDose to on‐demand (Demand) therapy in severe haemophilia A boys treated to age 6 using a decision analytic model. Costs included factor VIII (FVIII), professional visits and tests, central venous placement/complications, hospitalization, home programmes and parents’ lost work‐days. Resource utilization was estimated by surveying 17 Canadian clinics. The natural history of bleeding and other probabilities were determined from a longitudinal chart review (n = 24) and published literature. EscDose costs an additional $3192 per joint‐haemorrhage that was avoided compared with Demand whereas SP costs an additional $9046 per joint‐haemorrhage that was avoided compared with EscDose. Clinic costs and lost wages were reduced by 60–80% for EscDose and SP compared with Demand. EscDose attained more QALYs than SP and Demand on account of less bleeding than Demand and lower need for ports than SP. The incremental cost per QALY for EscDose vs. Demand was $542 938. EscDose was less expensive with similar QALYs compared to SP. Sensitivity analysis was performed on all probability‐ and cost‐estimates, and showed the model was sensitive to the cost of FVIII and the SP and target joint utilities. In conclusion, prophylaxis will substantially improve clinical outcomes and quality of life compared to Demand treatment, but with substantial cost.
Single dose intravenous thioacetamide administration as a model of acute liver damage in rats
Authors: Chen Tse‐Min , Subeq Yi‐Maun , Lee Ru‐Ping , Chiou Tzyy‐Wen , Hsu Bang‐Gee
Published: April 2008

Thioacetamide (TAA) has been used extensively in the development of animal models of acute liver injury. Frequently, TAA is administered intraperitoneally to induce liver damage under anaesthesia. However, it is rarely administered by intravenous injection in conscious rats. The experiments in this study were designed to induce acute liver damage by single intravenous injection of TAA (0, 70 and 280 mg/kg) in unrestrained rats. Biochemical parameters and cytokines measured during the 60‐h period following TAA administration, included white blood cells (WBC), haemoglobulin (Hb), platelet, aspartate transferase (GOT), alanine transferase (GPT), total bilirubin (TBIL), direct bilirubin (DBI), albumin, ammonia (NH3), r‐glutamyl transpeptidase (r‐GT), tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6). Rats were sacrificed by decapitation 60 h after TAA administration and livers were removed immediately for pathology and immunohistochemical (IHC) examination. Another group of rats were sacrificed by decapitation 1, 6 and 24 h after TAA administration and livers were removed immediately for time course change of pathology and IHC examination. TAA significantly increased blood WBC, GOT, GPT, TBIL, DBIL, NH3, r‐GT, TNF‐α and IL‐6 levels but decreased the blood Hb, platelet and albumin level. The levels of histopathological damage in the liver after intravenous TAA administration were also increased with a dose‐dependent trend and more increased at 60 h after TAA administration. The levels of inducible nitric oxide synthase (iNOS) and nuclear factor‐κB (NF‐κB) detected by IHC in the liver after intravenous TAA administration were also increased with a dose‐dependent trend and more increased at 1 h after TAA administration. Single intravenous TAA administration without anaesthesia is a restorable animal model which may be used to investigate acute liver damage.
A comparison of the knowledge of, experience with and attitudes towards complementary and alternative medicine between nurses and patients in Korea
Authors: Yom Young‐Hee , Lee Kyu Eun
Published: April 2008

Aims and objectives.  To compare nurses’ and patients’ knowledge of, experience with and attitudes towards complementary and alternative medicine (CAM).

Background.  Despite increasing interest in, and use of, CAM among the public and health care providers, research on CAM‐related nursing is limited. Furthermore, the level of knowledge and attitudes towards, and use of CAM between nurses and patients have never been studied in Korea. Therefore, a comparison is called for with regard to the knowledge, experience and attitudes of patients and nurses in Korea regarding CAM.

Designs.  A cross‐sectional survey design was used.

Methods.  A convenience sample of 485 nurses and 367 patients responded to three questionnaires covering issues including their knowledge levels, attitudes towards and their use of CAM. Data were analysed using descriptive and inferential statistics.

Results.  Overall, nurses had significantly higher mean scores in their knowledge of CAM than patients. Most nurses and patients had heard about CAM, but few had sufficient knowledge to perform CAM. Nurses had more education, experience and positive attitudes regarding CAM than patients.

Conclusions.  Nurses need to be knowledgeable about CAM so that correct information and support can be provided to their patients.

Relevance to clinical practice.  Nurses need additional training or education on CAM, because they should be able to respond adequately to questions from patients. Ultimately, nurses have an important role in helping patients use CAM safely.
Cannabinoid Receptors: Where They are and What They do
Authors: Mackie K.
Published: April 2008

The endocannabinoid system consists of the endogenous cannabinoids (endocannabinoids), cannabinoid receptors and the enzymes that synthesise and degrade endocannabinoids. Many of the effects of cannabinoids and endocannabinoids are mediated by two G protein‐coupled receptors (GPCRs), CB1and CB2, although additional receptors may be involved. CB1receptors are present in very high levels in several brain regions and in lower amounts in a more widespread fashion. These receptors mediate many of the psychoactive effects of cannabinoids. CB2receptors have a more restricted distribution, being found in a number of immune cells and in a few neurones. Both CB1and CB2couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. Thus, partial agonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific cannabinoid receptor ligands.
The Role of the Endocannabinoid System in the Regulation of Hypothalamic‐Pituitary‐Adrenal Axis Activity
Authors: Cota D.
Published: April 2008

The endocannabinoid system (ECS) is a recently identified neuromodulatory system, which is involved in several physiological processes and in disease. For example, the ECS not only represents the biological substrate of marijuana’s effects, but also is known to modulate several neuroendocrine axes, including the hypothalamic‐pituitary‐adrenal (HPA) axis. Although previous pharmacological studies using plant‐derived or synthetic cannabinoids have implied a stimulating action on the HPA axis, more recent findings have led to the conclusion that an endogenous cannabinoid tone might exist, which is actually inhibiting the release of both adrenocorticotrophic hormone and glucocorticoids. Studies using mice lacking cannabinoid receptor CB1 have demonstrated that presence and activity of these receptors is essential for the regulation of HPA axis activity. Interestingly, the effects of endocannabinoids on the HPA axis are consistent with their neuromodulatory action on brain neurotransmitter systems. Endocannabinoids have been found to mediate the nongenomic glucocorticoid‐induced inhibition of the release of corticotrophin‐releasing factor within the paraventricular nucleus of the hypothalamus. Altogether, these observations suggest that alterations of the endocannabinoid tone might be associated with the development of stress‐related diseases, including anxiety, depression and obesity.
Cannabinomimetic Control of Mast Cell Mediator Release: New Perspective in Chronic Inflammation
Authors: De Filippis D. , D’Amico A. , Iuvone T.
Published: April 2008

The present review aims to elucidate the emerging role played by cannabinomimetic compounds in the control of mast cell activation. Mast cells are immune competent cells strategically localised at the sites directly interfacing with the external environment, which, in case of injury, regulate the immune response by the release of a plethora of both pre‐formed and newly‐synthesised mediators. However, although the main goal of mast cell activation is to initiate the inflammatory reaction, and thus maintain internal homeostasis, the consequences of dysregulated mast cell activation could be to chronically activate the inflammatory response as occurs in arthritis, inflammatory bowel diseases, atherosclerosis and asthma. Therefore, much effort has been made to develop compounds that act to prevent mast cell degranulation. Cannabinomimetic compounds (i.e. agents able to modulate endocannabinoid function) are considered as an emerging class of regulators of mast cell behaviour. We focus on the evidence for a cannabinomimetic control of both acute and chronic inflammatory disease, recognising a common mast cell origin for problems such as dermatitis, inflammatory gastrointestinal syndrome and granuloma formation. Special emphasis is provided for the recent promising results obtained with palmitoylethanolamide in human studies. In the light of evidence suggesting that the control of mast cell activation at an early time during an inflammatory process may account for its resolution, it is reasonable to propose that cannabinomimetic compounds, including palmitoylethanolamide and its congeners, could represent possible candidates for treating several chronic inflammatory diseases.
The Endocannabinoid System and Liver Diseases
Authors: Caraceni P. , Domenicali M. , Bernardi M.
Published: April 2008

Endogenous cannabinoids (EC) are ubiquitous lipid signalling molecules provided by a number of central and peripheral effects, which are mainly mediated by the specific cannabinoid receptors CB1 and CB2. Although the expression of these receptors is very low or even absent in the healthy liver, a considerable series of experimental studies and some clinical observations have recognised the EC system as an important player in the pathophysiology of liver diseases. The EC system is highly up‐regulated during chronic liver diseases and, to date, it has been implicated in the pathogenesis of non‐alcoholic fatty liver disease, progression of fibrosis to cirrhosis and the development of the cardiovascular abnormalities of cirrhosis, such as the hyperdynamic circulatory syndrome and cirrhotic cardiomiopathy. Furthermore, the EC system influences the mechanisms responsible for cell damage and the inflammatory response during acute liver injury, such as that resulting from ischaemia‐reperfusion. Thus, molecules targeting the CB1 and CB2 receptors may represent potential therapeutic agents for the treatment of liver diseases. At present, the CB1 antagonists represent the most attractive pharmaceutical tool to resolve fat accumulation in patients with non‐alcoholic fatty liver disease and to treat patients with cirrhosis, as they may slow the progression of fibrosis and attenuate the cardiovascular alterations associated with the advanced stage of the disease.
CB1 Receptor Blockade and its Impact on Cardiometabolic Risk Factors: Overview of the RIO Programme with Rimonabant
Authors: Scheen A. J.
Published: April 2008

Rimonabant, the first selective CB1 receptor antagonist in clinical use, has been extensively investigated in the Rimonabant in Obesity (RIO) programme, comprising four 1–2 year placebo‐controlled randomised clinical trials recruiting more than 6600 overweight/obese patients with or without co‐morbidities. Rimonabant 20 mg daily consistently reduced body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C‐reactive protein levels, and increased HDL cholesterol concentrations in both non‐diabetic and type‐2 diabetic overweight/obese patients. Adiponectin levels were increased, an effect that correlated with HDL cholesterol augmentation, while small dense LDL cholesterol levels were decreased in patients receiving rimonabant 20 mg compared with those receiving placebo in RIO Lipids. Furthermore, in RIO Diabetes, a 0.7% reduction in glycated haemoglobin (HbA1c) levels was observed in metformin‐ or sulphonylurea‐treated patients with type‐2 diabetes, an effect recently confirmed in the 6‐month SERENADE (Study Evaluating Rimonabant Efficacy in drug‐NAïve DiabEtic patients) trial in drug‐naïve diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. The positive effects observed after 1 year were maintained after 2 years. Rimonabant was generally well‐tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared with placebo. In clinical practice, rimonabant has to be prescribed to the right patient, i.e. overweight/obese subjects with cardiometabolic risk factors and with no major depressive illness and/or ongoing antidepressive treatment, in order to both maximise efficacy and minimise safety issues. New trials are supposed to confirm the potential role of rimonabant in patients with abdominal adiposity, atherogenic dyslipidaemia and/or type‐2 diabetes, i.e. at high cardiometabolic risk.
Dysregulation of the Endocannabinoid System in Obesity
Authors: Engeli S.
Published: April 2008

An activation of the endocannabinoid system (ECS) in obesity with increased concentrations of endocannabinoids in several tissues and in the circulation is described in this review. This increased availability of endocannabinoids might stimulate cannabinoid receptors in a pathophysiological manner. The successful use of the cannabinoid receptor CB1 inverse agonists rimonabant and taranabant for weight loss and the treatment of obesity‐associated metabolic disorders might well be through blocking this overstimulation of cannabinoid receptors. At present, no single mechanism has been identified that explains the increased bioavailability of endocannabinoids in obesity. Both increased synthesis and decreased degradation appear to operate in a species‐ and tissue‐dependent manner, but many pieces of the puzzle still need to be collected. For example, most data show decreased fatty acid amide hydrolase (FAAH) expression and/or activity as a result of obesity or high‐fat intake, but the endocannabinoid predominantly increased in tissues is 2‐arachidonoylglycerol (2‐AG), which is not degraded by FAAH in vivo. Furthermore, the influence of dietary fatty acids on the synthesis of endocannabinoids needs to be studied in much more detail. Although weight loss does not seem to influence activation of the endocannabinoid system (ECS) in human obesity, suggesting an underlying mechanisms independent of body weight, no such mechanism at the genetic level has yet been identified either. Thus, activation of the ECS is a hallmark of abdominal obesity, and explains the success of pharmacological CB1 blockade, but serious attempts have to be made to clarify the underlying mechanisms of this activation.
Central Versus Peripheral Antagonism of Cannabinoid CB1 Receptor in Obesity: Effects of LH‐21, a Peripherally Acting Neutral Cannabinoid Receptor Antagonist, in Zucker Rats
Authors: Pavón F. J. , Serrano A. , Pérez‐Valero V. , Jagerovic N. , Hernández‐Folgado L. , Bermúdez‐Silva F. J. , Macías M. , Goya P. , De Fonseca F. R.
Published: April 2008

The endogenous cannabinoid system plays an important modulatory role in feeding behaviour and metabolism, acting at both central and peripheral levels. Chronic administration of cannabinoid CB1 receptor antagonists has been found to be effective in experimental obesity. However, clinically available cannabinoid receptor antagonists are inverse agonists that can target CB1 receptors located in both central circuits regulating appetite and motivation and in peripheral organs regulating metabolism and energy expenditure. This profile complicates understanding of cannabinoid CB1 receptor blockade as a therapeutic strategy in obesity and metabolic disorders. This review aims to explore the relevance of both inverse agonism and peripheral cannabinoid receptor blockade on the beneficial actions of chronic cannabinoid receptor blockade, by comparing the actions of the reference antagonist/inverse agonist rimonabant and the newly designed drug LH‐21. LH‐21 is a triazol derivative and a neutral cannabinoid receptor antagonist; it has a poor penetration rate into the central nervous system. When given acutely it decreases food intake and enhances the anorectic actions of oleoylethanolamide, a feeding suppressant lipid that acts on peripheral sensory terminals in a similar way as rimonabant. Unlike rimonabant, chronic administration of LH‐21 (3 mg/kg) reduces feeding but does not improve hypertriglyceridaemia or hypercholesterolaemia; nor does it reduce liver fat deposits in Zucker rats. These results suggest that the inverse agonism and/or the antagonism of central cannabinoid CB1 receptors are necessary for the metabolic benefits of cannabinoid CB1 receptor blockade, but not for the appetite reduction.
Drug residues in food animals. I. Plasma and tissue kinetics of chloramphenicol in young cross‐bred swine
Authors: MERCER H. DWIGHT , HEATH GEORGE E. , LONG PATRICIA E. , SHOWALTER DAVID H. , POWERS THOMAS E.
Published: April 2008

Eighteen non‐fasted, 12–16 week old pigs weighing between 20 and 40 kg were dosed with chloramphenicol intravenously at a dose rate of 22 mg/kg body weight. The pharmacokinetics of chloramphenicol were determined in blood plasma and sixteen selected organs and body fluids. The elimination half‐life in plasma was estimated to be 2.66pL1.06 h and volume of distribution was 1.39pL0.32 I/kg. The body clearance of chloramphenicol was estimated to be 6.64pL1.52 ml/kg/min. The elimination half‐life in tissue was found to range from 1.25 h in kidney to 5.89 h in fat. Most major organs ranged from 2.0 to 5.0 h. Significant correlations were found to exist between plasma concentrations and most major organ concentrations. Chloramphenicol concentrations in muscle, spleen, lung, stomach content, and large intestine content were found to exist slightly beyond the time when concentrations were negative in plasma. However, urine levels exceeded tissue levels at the last slaughter interval. It appears that serum or urine would be a good body fluid for monitoring chloramphenicol residues in tissues, whereas stomach content might be used as an indicator for chloramphenicol treatment for many days after therapy with the drug.
Pre‐slaughter withdrawal times for drugs in dairy cows
Authors: NOUWS J. F. M. , ZIV G.
Published: April 2008

Using a pharmacokinetic model based on drug concentrations in tissue fluids of normal animals, calculated withdrawal times were compared with the observations made in emergency‐slaughtered diseased animals. After multiplying the calculated withdrawal times for muscle and kidney cortex tissues by a factor of 2 to 3, and 4 to 5, respectively, a good estimate was obtained for predicting drug withdrawal times for diseased animals treated with beta‐lactam antibiotics, oxytetracycline, and aminoglycoside antibiotics. Criteria for determining three different drug tolerance levels of edible tissues were presented and discussed.
Studies on the distribution and metabolism of ketamine in sheep
Authors: WATERMAN A. , LIVINGSTON A.
Published: April 2008

A comparison of the distribution and metabolism of intravenous and intra‐cerebroventricular ketamine hydrochloride in sheep showed that following intravenous administration there was a rapid biexponential decline in plasma ketamine, metabolism was rapid and both the demethylation and subsequent oxidation metabolites were detected. In the urine the second metabolite appeared to be the major one together with a third unidentified metabolite. In the CSF both ketamine and the first metabolite appeared to follow the plasma concentrations, but the entry of the second metabolite seemed to show a much slower pattern. Following injection of ketamine into the lateral cerebral ventricles the levels of ketamine in the CSF declined rapidly and the plasma concentration of ketamine showed a similar pattern to that seen following intravenous injection, indicating a rapid transfer to the blood. The levels of the metabolites found in the CSF suggest that their production does not take place in the CSF and that they penetrate back from the plasma. The findings of rapid metabolism following both routes of injection suggests that metabolism plays a major part in the termination of the effects of ketamine in the sheep, and that plasma levels of ketamine are of more importance than CSF levels in the maintenance of anaesthesia.
Rates of chlorpromazine‐induced hemolysis in seven species of animals
Authors: BIERY EDWARD A. , GIRI SHRI N. , JAIN NEMI C.
Published: April 2008

Chlorpromazine (CPZ) affects the hemolytic process in vitro. Hemolysis rates induced by CPZ at 10‐3 M concentration were measured in blood from humans, monkeys, horses, cattle, goats, rats and dogs. Hemolysis data were plotted in the form of Lineweaver‐Burke plots and the kinetics considered. The canine red cell was markedly more resistant than the other species as represented by a smaller Vmax. Basal glutathione peroxidase levels of the red cell were assayed in an attempt to correlate the enzyme activity with the haemolysis rates in the species studied. A strong correlation would have explained the dog's high resistance and would have strongly indicated lipid peroxidation as the mechanism of CPZ‐induced in vitro hemolysis. No such correlation was found.
Disposition of sulphonamides in food‐producing animals: disposition of sulphathiazole in tissues, urine, and plasma of cattle following intravenous administration
Authors: KORITZ GARY D. , BOURNE DAVID W. A. , DITTERT LEWIS W. , BEVILL RICHARD F.
Published: April 2008

Plasma, urine and tissue concentrations of sulphathiazole were determined at various times following intravenous administration to fifteen cattle. The averaged plasma and urine data were consistent with a two‐compartment pharmacokinetic model with a half‐life of elimination of 1.3 h and a total volume of distribution of 0.41 l/kg body weight. Sulphathiazole was eliminated by excretion of unchanged drug into urine (48%) and by formation of acetylated and polar metabolites. The averaged data obtained from eight selected tissue sites were consistent with the two‐compartment pharmacokinetic model presented and confirmed that residues of sulphathiazole in edible tissue can be predicted from serum and urine concentrations of the drug.
Pharmacokinetics of kanamycin in dogs
Authors: BAGGOT J. DESMOND
Published: April 2008

The pharmacokinetics of kanamycin were studied in beagle dogs. A parenteral preparation of kanamycin sulphate (5% aqueous solution), which was given at a dosage level of 10 mg/kg of body weight, was the drug product used. The disposition curve which resulted from the intravenous administration of a single bolus dose of the drug was completely described by the biexponential equation:

C
p= 50e‐0.1977t+ 36.3e‐0.0128t where Cp represents concentration of the drug in the serum at time t (in minutes) and the experimental constants are mean values. Pseudo‐distribution equilibrium was rapidly attained and the apparent volumes of the central and peripheral compartments of the two‐compartment open model were the same (ca 125 ml/kg). Body clearance (mean ± S.D., n= 6) of kanamycin was 3.21 ±0.72 ml/kg/min. The half‐life of the drug was short (58.18 ± 18.43 min) and independent of the route of parenteral (intravenous and intramuscular) administration. Absorption of kanamycin from the intramuscular site was rapid, with a half‐time of 9.08 ± 1.10 min. A systemic availability of 89.1 ± 15.8% was obtained. Based on the bioavailability and disposition kinetics a dosage regimen consisting of the intramuscular injection of the dose (10 mg/kg) at 6 h intervals is proposed. An intravenous infusion rate of 48 μg/kgymin is predicted to establish a steady state serum concentration of 15 μg/ml, which is a therapeutic level of the antibiotic for susceptible micro‐organisms.
Mode of action of common anthelmintics
Authors: REW ROBERT S.
Published: April 2008

The primary physiological mode of action of nearly all drugs used to control helminth parasites is not well understood. Examination of the general modes of action in terms of parasite requirements for survival may, however, provide guidelines to continue our present investigations and direct us for future research.

Two general areas of drug activity are (1) interference with energy‐generating metabolism, and (2) interference with proper neuromuscular coordination. Few exceptions are found to these areas because the target organisms require little else for survival.

The target of most previously effective and many presently effective anthelmintics is an adult parasite. Adult helminth parasites must maintain an advantageous feeding site and must transport and metabolize substrates (primarily glucose) to generate life‐maintaining energy. Adult worms have almost no other short‐term requirements for survival because they have little or no metabolic activity in either lipid synthesis or oxidation, nucleic acid synthesis, or protein synthesis (except egg‐laying).

Examination of specifics of energy‐generating metabolism and putative neurochemical transmitters allows us certain predictions in relating a given drug activity to an individual species. These examinations indicate that such diversity exists among helminth metabolic or nervous systems that a broad‐spectrum anthelmintic would most likely inhibit at several sensitive points.

Published information on drug action and differences in data interpretation are discussed. Two novel areas for future anthelmintic investigations may be (1) juvenile hormone or ecdysone analogs, and (2) pheromones. A combined empirical and rational approach to the development of new drugs may be the most efficient avenue of future research.
Evaluation of a new treatment for canine scabies and demodicosis
Authors: FOLZ S.D. , GENG S. , NOWAKOWSKI L.H. , CONKLIN R.D.
Published: April 2008

A total of forty‐eight dogs were utilized to titrate and evaluate the activity of a new miticide, amitraz. The treatment was applied dermally and evaluated for efficacy against experimentally induced Demodex canis and Sarcoptes scabiei infestations. Five different concentrations (2000, 1000, 500, 250, 125 p.p.m.) of the active drug, N'—(2, 4‐dimethylphenyl)N—{[(2, 4‐dimethylphenyl) imino] methyl} ‐N‐methyl‐methanimidamide, were tested. The activity of amitraz was compared to a standard treatment, placebo treatment, and no treatment.

A single dermal treatment with amitraz (all concentrations) indicated activity against both D. canis and S. scabiei. The lowest concentration of active drug (125 p.p.m.) was significantly less efficacious than the four higher concentrations (250, 500, 1000, 2000 p.p.m.). At the 250 p.p.m. (or higher) level the effectiveness of this new miticide was comparable to the standard treatment. The data indicate the 250 p.p.m. concentration is the optimal level and the recommended dilution for treatment of mange mites. Drug reactions related to amitraz were not observed.
Tissue distribution of tetraethylammonium (TEA) in dogs and goats
Authors: NEFF‐DAVIS CAROL A. , DAVIS LLOYD E. , POWERS THOMAS E.
Published: April 2008

The tissue distribution of tetraethylammonium (TEA), a highly polar drug which does not undergo biotransformation, was studied in intact and nephrectomized dogs and goats. Values for β, the overall elimination rate constant, were significantly reduced by nephrectomy but species differences were not significant. Values for apparent specific volume of distribution (V'd) were unexpectedly large and tissue to plasma ratios were 4.0 and 5.0 in the nephrectomized goat and dog, respectively. The distribution of TEA to various tissues followed closely the expected pattern of regional blood flow, although TEA attained concentrations in liver, heart, lungs and viscera in excess of the concentration in the plasma.
Pharmacokinetics of lithium in pigs
Authors: MORMEDE PIERRE , DANTZER ROBERT
Published: April 2008

Lithium was administered to young pigs in order to estimate its pharmacokinetic parameters in this species and a suitable dosage for chronic psychopharmacological experiments. Distribution time (10 h) and volume (1 l/kg), elimination half‐life (10–20 h), toxic plasma levels (about 1.4 mEq/l) are closely similar to those reported in man. A chronic oral administration of 0.5 mEq/kg twice a day provides minimal plasma levels of 0.5 to 1.0 mEq/l, without toxic side effects.
Drugs and renal function
Authors: MICHELL A.R.
Published: April 2008

This article considers the interactions between drugs and renal function, first, the adverse effects of nephrotoxic drugs and the changes in drug response associated with renal failure. It then discusses drugs intended to alter urinary sodium excretion (diuretics) and urinary pH as well as drugs which alter renal concentrating and diluting capacity. In each case emphasis is placed on the relationship between the drug effects and normal renal mechanisms. Reasons for the special vulnerability of the kidney to the toxic effects of drugs (e.g. antibiotics) are discussed and the practical problems of adjustment of drug dosage according to renal function are indicated. Finally, consideration is given to drugs, notably oral sorbents, which can partially substitute for renal function and might therefore eventually prove ideal for the management of advanced renal failure in small animals.
Bioavailability of three brands of digoxin tablets in dogs
Authors: RICK A. DE , CHAKRABARTI S. , BELPAIRE F. , BOGAERT M.
Published: April 2008

As information on the comparative bioavailability of digoxin tablets in dogs is scarce, three brands of digoxin tablets, commercially available in Belgium, were compared in 6 healthy dogs in a cross‐over randomized design. Each dog received 1 mg digoxin on four occasions (once intravenously and 3 times orally). The mean areas under the curve relative to the intravenous value were 80, 71 and 65%. For the 3 oral preparations peak plasma concentrations were reached within 1 hour after dosing and often within 30 minutes. The mean peak concentrations were 11.0, 10.0 and 8.1 ng/ml. The times for 50% dissolution were 4.5, 7.5 and 25 minutes. Although differences between brands were only significant for the dissolution rate, the same ranking order was present for all parameters. It is therefore concluded that it may be advisable not to switch a digitalized dog from one brand to another.
Pharmacokinetics of ampicillin in pigs
Authors: GALTIER P. , CHARPENTEAU J. L.
Published: April 2008

Na‐ampicillin was administered by the intravenous or intramuscular route to pigs. Blood concentrations during 4–6 h after administration and tissue distribution were measured. Pharmacokinetic parameters indicated a two‐compartment open model. The biological half‐life was found to be 60 min and four intramuscular injections per day of 10mg/kg B.W. of Na‐ampicillin were required to maintain a minimum plasma concentration of 0.4 μg/ml. Higher levels were found in both the urinary and digestive tract.
Elevation and prolongation of serum ampicillin and amoxycillin concentrations in calves by the concomitant administration of probenecid
Authors: ZIV G. , HORSEY J.
Published: April 2008

The effects of probenecid on serum ampicillin and amoxycillin concentrations were investigated in 1–5 week old calves after oral and parenteral drug administration. Ampicillin trihydrate was administered orally at 250mg/calf, after an overnight fast, alone and with 1.5g probenecid. Peak serum ampicillin concentrations were elevated from 0.60 to 1.22 μg/ml by the co‐administration of probenecid. In calves given 0.5 g amoxycillin trihydrate with the milk replacer, peak serum drug concentration increased from 1.74 to 3.16 μg/ml when 1.5 g probenecid was given too. Maximal effect of probenecid administered orally was with the 1.5 g/calf dose with considerably lesser increase in peak serum amoxycillin being observed with doses of 0.5 g, 1 g and 2 g/calf. After parenteral injection of probenecid solution at 1 g and 2 g/calf serum ampicillin concentrations peaked at more than twice the concentrations measured after equal doses of the two antibiotics were injected alone. The co‐administration of 2 g probenecid and 1 g sodium ampicillin or 0.5 g sodium amoxycillin parenterally resulted in peak antibiotic concentrations considered to be effective against some of the more resistant pathogenic Gram‐negative bacteria associated with diseases in calves and serum antibiotic concentrations 5 μg/ml were maintained during 5–6 h as opposed to 2–3 h after the antibiotics were injected alone. Oral administration of 1.5 g probenecid at three consecutive milk feeding times did not alter serum urea or serum creatinine concentrations.
Isometamidium‐dextran complex: therapeutic activity against Trypanosoma vivax infection in Zebu cattle
Authors: ALIU Y. OTARU , SANNUSI ABDULRAHIM
Published: April 2008

Isometamidium‐dextran complex was prepared by adding a 4% solution of dextran sulphate to an equal volume of a 4% solution of isometamidium chloride. The resulting 2% suspension was administered subcutaneously at 0.5, 1, and 2 mg/kg to three groups of Zebu bulls infected with Trypanosoma vivax Y58. The fourth group received isometamidium at 0.5 mg/kg intramuscularly. The parasite was cleared from all groups within 5 days, and recrudescence occurred to either preparation only at 0.5 mg/kg during the 90 day observation period. A firm movable subcutaneous nodule formed at the site of injection of the complex. The skin over the nodule appeared thickened due to oedema. Histologically, the nodule was characterized by diffuse connective tissue proliferation, with round cells and giant cell infiltration. There were focal areas of necrosis in the underlying granuloma associated with yellowish‐brown staining drug deposits at the centre. The average growth rate of the treated groups was better than the non‐treated group but inferior to the non‐infected group. It was concluded that the complex at 1 or 2 mg/kg s.c. could be expected to protect cattle against trypanosomiasis and still yield good carcass and hide grading.
Clinical pharmacology of polymyxin B, colistin and colistimethate in young dairy calves
Authors: ZIV G. , WANNER M. , NICOLET J.
Published: April 2008

The in vitro sensitivity of 592 Gram‐negative bacteria isolated from cattle against polymyxin B was determined by the agar plate dilution method. The minimal inhibitory concentration of polymyxin B for all but ten of the isolates was ≤ 2.0 μg/ml and 75% of the isolates were inhibited at 1.0 μg of polymyxin B/ml or less. Intramuscular injections of polymyxin B, colistin and colistimethate (CMS) were given to veal calves once daily for 3 days. Mean peak serum drug concentrations were observed within 0.5–1 h after treatment and were between 2.7 and 4.7 μg/ml when polymyxin B and colistin were administered at a dose rate of 2.5 mg/kg/day, and between 5.3 and 7.5 μg/ml at dose rate of 5.0 mg/kg/day. When CMS was given at 5.0 mg/kg/day mean peak drug concentration was 14.1 μg/ml. The elimination half‐life (t1/2) of polymyxin B and colistin was 4–5 h but was approximately 2 h for CMS. Kidney function tests, using the double isotope single‐injection method, were performed before and after the course of antibiotic treatment. No changes were detected in the glomerular filtration rate (GFR) or the effective renal plasma flow (ERPF) and blood urea levels were not raised following treatment. Several calves treated with the higher doses of polymyxin B and colistin exhibited transient ataxia and apathy 2–4 h after treatment but clinical signs suggesting interference with neurological function were not observed after an equivalent dose of CMS was administered.
Pharmacokinetics of clindamycin following subcutaneous administration of clindamycin phosphate in the canine
Authors: WEBER D. J. , BARBIERS A. R. , LALLINGER A. J. , NEFF A. W. , POPE D. G.
Published: April 2008

Each of two male and two female healthy, non‐fasted mongrel dogs weighing approximately 13.6 kg were given subcutaneous injections of clindamycin‐2‐phosphate sterile solution. The doses were 2.75, 5.51, 11.02 and 21.04 mg clindamycin free base as clindamycin‐2‐phosphate/kg of body weight. Serum samples were assayed for clindamycin bioactivity as a function of time and the pharmacokinetics determined. The elimination curves were biexponential with mean values for α of 0.466‐1 and 0.0498 h‐1 for β. The three lower doses demonstrated linear pharmacokinetics (constant total body clearance) while the highest dose did not. Based on the pharmacokinetics, a dosage regimen of 11.02 mg of clindamycin free base as clindamycin‐2‐phosphate/kg of body weight every 24 h is recommended.
A pharmacological study of chloramphenicol in Bubalus bubalis II*
Authors: VARMA K. J. , PAUL B. S. , GUPTA R. C.
Published: April 2008

The plasma levels of chloramphenicol were determined following i.m. administration in three groups of water buffalo (n= 4 per group). The absorption of chloramphenicol was relatively rapid since concentrations of 7.00 ± 0.62 μg/ml were detected in plasma after 1 h and peak concentrations of 9.25 ± 0.53 μg/ml were obtained 3 h following administration of 30 mg/kg. A concentration of at least 5 μg/ml was achieved at the end of 1 h and persisted up to 12 h (6.79 ± 1.19 μg/ml). With repetition of 10 and 20 mg/kg dose at 12 h, concentrations greater than 5 μg/ml persisted for an additional 8 and 12 h, respectively. The distribution studies of chloramphenicol in tissues and body fluids at 4 h post‐injection (30 mg/kg i.m., n= 4, group IV), revealed that the highest concentration was seen in bile (31.67 ± 6.21 μg/ml), followed by liver, kidney, plasma, heart, skeletal muscle and brain (4.00 ± 0.50 μg/g).
Pharmacokinetics of lithium in sheep
Authors: MORMÉDE PIERRE , LEDOUX JEAN‐MARIE
Published: April 2008

Lithium was administered to adult sheep to estimate its pharmacokinetic parameters and a suitable dosage for chronic psychopharmacological experiments. The triexponential decline of plasma lithium levels was tentatively interpreted with a three‐compartment, open‐model of distribution. Sheep differed from other species by the following features: high faecal excretion of lithium, recycling of lithium through the salivary secretion and low absorption rate of the orally‐administered drug. A chronic oral administration of 1 mmol/kg once daily provided minimal plasma levels of about 1 mmol/l, without toxic side‐effects. The results are discussed with respect to comparative pharmacokinetics of lithium and its potential use in the treatment of behavioral disorders of farm animals.
Serum digoxin concentrations in dogs before and during concomitant administration of furosemide
Authors: PEDERSOLI W. M. , NACHREINER R. F.
Published: April 2008

Healthy dogs were treated once a day for 16 days with a liquid, oral dosage form of digoxin (0.022 mg/kg). From day 9 to 16 they were also injected intramuscularly with furosemide (4.4 mg/kg). Serum digoxin was measured by a radioimmunoassay technique. Eight hours after the eighth dose of digoxin had been administered, serum digoxin concentration was in the accepted therapeutic range. After 8 days of concomitant administration of digoxin and furosemide, serum digoxin concentration was found to be in the accepted moderate‐to‐severe toxic range. Clinical signs of digitalis toxicosis were consistently observed during the combined digoxin‐plus‐furosemide treatment period. There was no significant (P>0.05) change in the serum concentrations of potassium, sodium, or in osmolality during digoxin treatment alone. Serum creatinine concentrations remained within the accepted normal range for dogs. Serum sodium concentration was significantly (P<0.05) lower during combined digoxin‐plus‐furosemide treatment when compared to digoxin treatment only.

Results indicate that an interaction between digoxin and furosemide occurred which led to significantly (P<0.05) higher concentrations of serum digoxin during combined digoxin and furosemide treatment.
Systemic availability of chloramphenicol from tablets and capsules in cats
Authors: WATSON A. D. J.
Published: April 2008

Five adult cats were given 100 mg chloramphenicol per os on five occasions: twice in tablet form, twice in capsules which also contained barium sulphate, and once in capsules without barium. Plasma samples for chloramphenicol assay were obtained on either a ‘standard’ schedule (four samples collected within 8 h of dosing with tablet, plain capsule or capsule including barium) or a ‘frequent’ schedule (nine samples collected within 8 h of dosing with tablet or capsule including barium). With frequent sampling, abdominal radiographs were taken at intervals after administration of capsules. No differences were found with the frequent schedule between tablet and capsule with regard to antibiotic concentrations at each sampling, peak concentrations, or area under the curve of plasma concentration versus time. Standard sampling gave similar drug concentrations to those obtained with frequent sampling. Delayed absorption (defined as plasma chloramphenicol concentration < 5 μg/ml for 1.5 h after dosing) occurred after six of the twenty‐five administrations: it was not related to the frequency of sample collection or the use of capsules rather than tablets, but occurred mainly in certain cats. Poor absorption was shown radiographically in one cat to be associated with delayed dispersal of capsular contents in the gut.
Relationships of Fusarium toxins to tumours and other disorders in livestock
Authors: SCHOENTAL R.
Published: April 2008

Experimental laboratory animals treated with the trichothecene T‐2 toxin, develop various acute and chronic disorders and also tumours of the digestive tract and of the brain. T‐2 toxin is teratogenic and immunosuppressive. In livestock, ingestion of fodder contaminated with T‐2 toxin and with certain other trichothecenes can cause various disorders, including a haemorrhagic syndrome, neurological and reproductive disturbances. Follow‐up studies of survivors in the flocks or herds which suffered fatalities from acute mycotoxicoses could establish whether and which chronic disorders and tumours may develop among the survivors and among their progeny, as a result of exposure to mycotoxins, which caused the acute fatalities. Outbreaks of acute mycotoxicoses are usually preceded by exceptional weather.
Autonomic responsiveness in stress‐sensitive and stress‐resistant pigs
Authors: GREGORY N. G. , LISTER D.
Published: April 2008

The responsiveness of the autonomic nervous system was studied in twenty‐six 140 day old thiopentone anaesthetized lean stress‐sensitive Pietrain (P) and fatter stress‐resistant Gloucester (G) pigs, using the Valsalva like manoeuvre (VLM), and the i.v. tyramine, noradrenaline (NA) and phenylephrine tests. The heart rate responses to the VLM and tyramine tests were greater in P. The pressor response to NA was lower in P, and the change in heart rate per unit change in blood pressure‐during phenylephrine infusion was the same in the two breeds. The sympathetic nervous system in P was, therefore, more responsive than that in G, and this was attributable to a higher pre‐adrenoreceptor responsiveness in P. The potentially greater sympathetic responsiveness in stress‐sensitive pigs could account for their greater leanness, their stress‐induced metabolic acidosis, and for their susceptibility to myocardial failure.
The pharmacokinetics of thiopentone
Authors: BRANDON ROSLYN A. , BAGGOT J. DESMOND
Published: April 2008

The pharmacokinetics of thiopentone was studied in six mongrel dogs using a high‐performance liquid chromatographic method for measurement of the drug in the plasma. An intravenous bolus dose (20 mg/kg) of 2.5% thiopentone sodium solution was injected into the cephalic vein. While the two‐ and three‐compartment models were used in the analysis of the experimental data, the disposition curve was adequately described by a biexponential equation. Plasma protein binding of thiopentone was determined in vitro using the equilibrium dialysis technique. The drug was bound to a moderately high extent (73.8 ± 4.1%). The half‐time of the initial phase, which comprises distribution/redistribution, was 14.9 ± 3.3 mins. The apparent volume of distribution was quite high for an organic acid (843 ± 194 ml/kg). This may be attributed to the high lipid solubility of the thiobarbiturate. The half‐life was 6.99 ± 2.18 h and a body clearance value of 1.51 ± 0.60 ml/kg‐min was obtained. It can be concluded from this study that the half‐time of the distribution/redistribution phase approximates the duration of anaesthetic effect. Consequently, physiological conditions and disease states which influence distribution/redistribution rather than those affecting hepatic biotransformation of the drug are likely to affect anaesthesia.