Fever and associated clinical haematologic and blood biochemical changes in the goat and other animal species

Summary

Acute febrile diseases are characterized by specific and non‐specific symptoms. The non‐specific responses are presented under the headings: fever, inflammation and pain, experimental models for investigating febrile reactions, haematologic changes, blood biochemical changes, cardiovascular effects, changes in gastric function, and the effects of fever upon pharmacokinetics of drugs. It was the purpose of this review to describe present concepts of thermoregulation and fever, the associated reactions produced by bacterial pyrogens and the mechanisms of these reactions. The available data illustrate, that many questions have not yet been clearly answered.

However, the entire field of research involving endogenous substances, such as interleukin‐1, is now moving ahead with great speed. Furthermore, there is some evidence which suggests that fever and the associated lower plasma zinc and iron levels act together as a co‐ordinated non‐specific host defence mechanism. Since experimental fever has a distinct effect upon the pharmacokinetics of drugs, more attention should be given to this aspect.     

Fever,anorexia and forestomach hypomotility in ruminants

Acute febrile diseases are characterized by specific and non-specific symptoms. The non-specific responses include among other signs fever, dullness, anorexia and changes in gastric function. It is the purpose of this review to describe present concepts of fever and the associated reactions produced by bacterial pyrogens and the mechanisms of those reactions. The available data indicate that interleukin-1 is a key mediator of host responses to bacterial infections. However, many questions have not yet been clearly answered. In particular, more detailed studies of the processes within the CNS responsible for anorexia are still required.     

The effect of flurbiprofen upon fever and ruminal stasis induced by Escherichia coli endotoxin, Poly I: Poly C and sodium nucleinate from yeast in conscious goats

Intravenous injection of endotoxin from Escherichia coli (0.01 μg and 0.1 μg per kg body weight), sodium nucleinate from yeast (5 mg and 10 mg per kg body weight) or Poly I: Poly C (15 μg and 30 μg per kg body weight) caused fever, changes in heart rate and stasis of the extrinsic ruminal contractions in conscious goats. It appears that ruminal stasis is associated with clinical and experimental fever. The febrile responses were abolished by the prior intravenous administration of flurbiprofen (2 mg per kg body weight), a potent non-steroidal anti-inflammatory and antipyretic agent. This agent, however, only had a partial antagonistic influence upon pyrogen-induced ruminal stasis. The secondary changes in heart rate were not prevented by the drug. It seems unlikely that the inhibition of the extrinsic ruminal contractions by exogenous pyrogens is due simply to a release of prostaglandins.     

Anorexia during febrile conditions in dwarf goats. The effect of diazepam, flurbiprofen and naloxone

The most common sign of febrile diseases is anorexia, which develops at a time when adequate caloric and micronutrient availability may be critical. In order to study the relationship of fever and anorexia, feed intake in dwarf goats was studied under conditions of fever and antipyresis. Furthermore, experiments were done to establish whether a feed intake stimulant would override the anorexia during febrile conditions. Infection with Ehrlichia phagocytophila and i.v. injection of Escherichia coli endotoxin (0(111) B4, 0.1 microgram/kg body weight) both resulted in increased rectal temperatures and significant reductions in feed intake. Administration of the antipyretic drug flurbiprofen (1 mg/kg) to febrile animals inhibited the temperature responses, but food intake was still suppressed. Diazepam (0.06 mg/kg), a feed intake stimulant, did not override the anorexia associated with fever. Blocking the febrile response of E. coli LPS-injected goats with flurbiprofen plus diazepam or with flurbiprofen plus naloxone (0.1 mg/kg) did not antagonise their reduced feed intake either. The effects of these drugs and of endotoxin on rumen motility adds an interesting aspect to their activities in the CNS, since the CNS has been shown to regulate various aspects of forestomach motility, which in turn could alter feeding behaviour. Moreover, our findings are consistent with the hypothesis that the suppression of feed intake might depend on the release of interleukin-1.     

Influence of Escherichia coli endotoxin-induced fever on pharmacokinetics of imidocarb in dogs and goats

The pharmacokinetics of imidocarb, administered as an IV bolus dose (4 mg/kg), was studied in normal and Escherichia coli endotoxin-induced febrile dogs and goats. In the febrile group, the drug was administered 1 hour after injection of the endotoxin. The plasma and urine concentrations of imidocarb were measured by spectrophotometry. The decline in plasma drug concentrations in both species was analyzed, using a 2-compartment open model. With the exception of the coefficient A and the volume of central compartment, E coli endotoxin-induced fever produced the same changes in kinetic determinants in both species. Fever significantly decreased the distribution rate constant in both dogs (P less than 0.05) and goats (P less than 0.01). The elimination rate constant and, in turn, the half-life were not altered by the endotoxin-induced fever in either species. The volume of distribution at steady-state was significantly lower (P less than 0.01) in the febrile dogs and goats. The body clearance of imidocarb was also significantly lower in the febrile dogs (P less than 0.05) and goats (P less than 0.01). The decreased apparent volume of distribution and lower body clearance of imidocarb could explain the higher plasma values of the drug in the febrile, compared with normal, animals.     

Anorexia during febrile conditions in dwarf goats. The effect of diazepam,flurbiprofen and naloxone

Summary

The most common sign of febrile diseases is anorexia, which develops at a time when adequate caloric and micronutrient availability may be critical. In order to study the relationship of fever and anorexia, feed intake in dwarf goats was studied under conditions of fever and antipyresis. Furthermore, experiments were done to establish whether a feed intake stimulant would override the anorexia during febrile conditions. Infection with Ehrlichia phagocytophila and i.v. injection of Escherichia coli endotoxin (0₁₁₁B₄, 0.1 μg/kg body weight) both resulted in increased rectal temperatures and significant reductions in feed intake. Administration of the antipyretic drug flurbiprofen (1 mg/kg) to febrile animals inhibited the temperature responses, but food intake was still suppressed. Diazepam (0.06 mg/kg), a feed intake stimulant, did not override the anorexia associated with fever. Blocking the febrile response of E. coli LPS‐injected goats with flurbiprofen plus diazepam or with flurbiprofen plus naloxone (0.1 mg/kg) did not antagonise their reduced feed intake either.

The effects of these drugs and of endotoxin on rumen motility adds an interesting aspect to their activities in the CNS, since the CNS has been shown to regulate various aspects of forestomach motility, which in turn could alter feeding behaviour. Moreover, our findings are consistent with the hypothesis that the suppression of feed intake might depend on the release of interleukin‐1.     

Modification of the Pharmacokinetics and Dosage of Cefuroxime by Endotoxin-induced Fever in Buffalo Calves

The effect of endotoxin-induced fever on the pharmacokinetics and dosage regimen of cefuroxime was investigated in buffalo calves following a single intravenous dose of 10 mg/kg body weight. The fever was induced by intravenous administration of E. coli endotoxin at a dose of 1 g/kg body weight. The distribution and elimination half-lives were 0.100 h and 1.82 h, respectively, in healthy and 0.109 h and 2.28 h, respectively, in febrile buffalo calves. About 91% of the administered dose was excreted in the urine within 24 h. There was no effect of fever on the plasma protein binding of cefuroxime. The dosage regimen for intravenous administration of cefuroxime may be reduced in febrile conditions but the probability of this was only 0.3.     

Cytochromes and cytokines: changes in drug disposition in animals during an acute phase response: a mini-review

Diseases are a major cause of variation in drug response. Although many different diseases are known that have an effect on the pharmacokinetics or sometimes the pharmacodynamics of a drug, disorders associated with a so-called acute phase response (APR) are the most important in this respect. During APR, for example caused by tissue damage or invasion of a pathogen, a group of symptoms can be observed that often include fever, lassitude, inhibition of gastric function and synthesis of acute phase proteins. All phases that together determine the pharmacokinetic profile of a drug, absorption, distribution, metabolism and excretion, can be affected during APR. From a clinical point of view however, the effects on absorption and metabolism are the most relevant. For drugs that are given orally, a slower absorption rate is often observed during APR due to a delayed gastric emptying. Even more important from a clinical point of view is the depression of biotransformation capacity in the liver during APR, especially affecting the enzymes of the cytochrome P450 (CYP450) complex. Although much has become known about the mechanism of this effect, a number of questions remain. Cytokines, nitric oxide and possibly the enzyme heme oxygenase are playing a role in a complex process that depends on a mutual interaction between Kupffer cells (macrophages) and hepatocytes in the liver. The clinician should be aware of unexpected changes in drug effects or residue levels due to cumulation of the compound during disease or after vaccination. In these situations, drugs that are excreted unchanged may be better alternatives.     

Drug therapy in cats: a therapeutic category approach

The third article of this 4-part series discusses drug therapy in cats by therapeutic category. Specifically, the use of drugs to control infections, pain, fever, inflammation, cancer, and selected parasites is described. In addition, the use of hormonally related drugs and selected miscellaneous drugs in cats is addressed. Drugs emphasized are those for which use in cats is frequently associated with adverse reactions or drugs for which use is limited to illnesses that tend to be unique in cats.     

Pharmacokinetics of sulfadimethoxine and sulfamethoxazole in combination with trimethoprim after intravenous administration to healthy and pneumonic pigs

The pharmacokinetics of two sulfonamide/trimethoprim combinations were investigated after intravenous administration to clinically healthy pigs and to the same pigs following a challenge with Actinobacillus pleuropneumoniae toxins. Endobronchial challenge with A.pleuropneumoniae toxins resulted in fever, increased white blood cell counts and decreased water and feed consumption. Healthy, as well as febrile, pigs were given sulfadimethoxine (SDM) or sulfamethoxazole (SMX) intravenously at a dose of 25 mg/kg b.w. in combination with 5 mg trimethoprim (TMP) per kg body weight. The pharmacokinetic parameters of the sulfonamides as well as their main metabolites (acetyl sulfonamides) were not significantly different in healthy and febrile pigs. In healthy and pneumonic pigs, the mean elimination half-lives of SDM were 12.9 h and 13.4 h, respectively, those of SMX 2.5 h and 2.7 h, respectively, and those of TMP 2.8 h and 2.6 h, respectively. Distribution volumes in healthy and febrile pigs of SDM and SMX varied between 0.2 and 0.4 L/kg, and those of TMP between 1.1 and 1.6 L/kg. The mean AUC of TMP was decreased and the volume of distribution and total body clearance of TMP were increased in febrile pigs. Protein binding of the drugs and metabolites studied were not significantly changed after toxin-induced fever. The extent of protein binding of SDM, SMX and TMP was in the range 94–99%, 45–56% and 40–50%, respectively. Based on knowledge of in vitro antimicrobial activity of the drug combinations against A.pleuropneumoniae it was concluded that after intravenous administration of the dose administered (30 mg/kg of the combination preparations) to healthy and pneumonic pigs, plasma concentrations of SMX and TMP were above the concentration required for growth inhibition of 50% of A., pleuropneumoniae strains for approximately 16 h, whereas bacteriostatic plasma concentrations of SDM were still present after TMP had been eliminated from plasma. Because of similar elimination half-lives of SMX and TMP in pigs this combination is preferred to the combination of SDM with TMP.     

A pharmacokinetic study of amoxycillin in febrile beagle dogs following repeated administrations of endotoxin

The pharmacokinetics of amoxycillin was studied in nine male beagle dogs under healthy and febrile conditions. In Period 1, dogs received 20 mg/kg of an oral suspension of amoxycillin. Intravenous doses of saline, 2 and 20 microg/kg of endotoxin (LPS from Escherichia coli serotype) were administered to dogs (three per group) prior to administration of 20 mg/kg of amoxycillin in Period 2. Rectal temperature and behavioral changes were recorded and blood samples were collected over 12 h for pharmacokinetic analysis. Amoxycillin was assessed in plasma using liquid chromatography coupled with mass spectrometry. Plasma concentrations were analysed using a one-compartment model with lag-time for absorption using an iterative two-stage method. As compared with control groups, amoxycillin clearance decreased significantly with preliminary treatments of 2 microg/kg endotoxin (0.209 vs. 0.140 L/h kg, P < 0.05) and 20 microg/kg endotoxin (0.214 vs. 0.075 L/h kg, P < 0.05). As a result of this, the area under curve for the 2 and 20 microg/kg endotoxin groups increased significantly 100.4 vs. 149.4 microg h/mL (P < 0.05) and 99.2 vs. 277.7 microg h/mL (P < 0.05), respectively. Other drugs currently used for the treatment of fever and septic shock should be re-evaluated using a febrile animal model to avoid improper dose administration.     

BSAVA EDUCATION COMMITTEE COMMISSIONED ARTICLE Fever of unknown origin in dogs and cats

Fever is a common, albeit, non-specific manifestation of disease. Most fevers are due to transient viral or bacterial infections which either resolve spontaneously or with appropriate therapy. Fever of unknown origin (FUO) is a syndrome characterized by prolonged, unexplained fever associated with vague, non-specific signs of illness such as lethargy, anorexia and weight loss. This paper reviews briefly the pathophysiology of fever and outlines in more detail a logical problem-orientated approach to diagnosis of FUO in the dog and cat. The major causes of FUO are discussed under four headings; (1) localized or systemic infections, (2) immune-mediated diseases, (3) neoplasia and (4) miscellaneous diseases.     

Endotoxin-induced fever and associated haematological and blood biochemical changes in the goat: the effect of repeated administration and the influence of flurbiprofen

Flurbiprofen, a potent non-steroidal anti-inflammatory and antipyretic agent, was given as an intravenous infusion (2 mg/kg) followed by a bolus injection of 1 mg/kg six hours later. After drug administration body temperature and rumen contractions were slightly depressed, whereas urea values gradually increased; serum sorbitol dehydrogenase (SDH) activity, plasma iron concentration and the number of circulating lymphocytes were significantly lower. Intravenous injection of endotoxin from Escherichia coli O111B4 (0.1 microgram/kg) caused shivering, fever, inhibition of rumen contractions, changes in heart rate, lymphopenia, neutropenia followed by neutrophylic leucocytosis, changes in urea values, hypoferraemia, hypozincaemia and a decline in serum alkaline phosphatase (ALP) activity, whereas gamma-glutamyltranspeptidase, glutamic oxalacetic transaminase, lactic dehydrogenase and SDH values were not significantly altered. Pretreatment with flurbiprofen completely abolished the febrile reactions to endotoxin. The endotoxin-induced inhibition of rumen contractions was only delayed. The drug blocked the initial tachycardia to endotoxin but did not prevent the secondary biphasic increase in heart rate. Flurbiprofen failed to modify the endotoxin-induced decrease in both plasma zinc and serum ALP activity whereas the decline in plasma iron concentration was delayed. After drug pretreatment the changes in circulating white blood cells were more pronounced. These data demonstrate that most of the haematological, blood biochemical and clinical effects of endotoxin cannot be blocked by flurbiprofen, and that these effects are not due to the increase in body temperature alone. Tolerance induced by repetitive daily intravenous administration of endotoxin resulted in an almost complete abolition of all the effects. However, the plasma iron values from tolerant goats were significantly lower than those from non-tolerant animals, which demonstrates that the development of a refractory state can result in modification of this biochemical parameter.     

Reduction of CD4+ and CD8+ T lymphocytes during febrile periods in horses experimentally infected with equine infectious anemia virus

Three horses were experimentally infected with equine infectious anemia virus (EIAV). All horses were febrile after inoculation with EIAV and then developed chronic symptoms with intermittent fever. The febrile period was characterized by a rise in body temperature with reduced PBL and erythrocyte counts. Flow cytometric analysis showed that the reduced number of lymphocytes was due to significant decreases in CD4+ and CD8+ T cells in the absence of any change in B cell number. At the end of the febrile period the body temperature began to recover and numbers of CD4+ and CD8+ T cells showed a tendency to increase. For CD8+ T cells, this increase continued for several days after the febrile period. B cell number also significantly increased after the febrile period in two out of three horses. The decrease of CD8+ T cells was greater than that of CD4+ T cells. Although the PBL numbers and the CD4/CD8 ratio returned to the level of the preinoculation period, erythrocyte numbers decreased as the body temperature normalized after each intermittent fever. These results suggest that the recurring cycle of fever accompanied with viremia is caused by a reciprocal relationship between EIAV replication and the host immune response. Furthermore, we demonstrate that the lymphocytic response mitigates fever and viremia in EIAV infection despite the absence of virus neutralizing antibody.     

Nonsteroidal antiinflammatory drugs: a review

The increasing use of nonsteroidal antiinflammatory drugs (NSAIDs) in small animals has resulted in the development of new and innovative additions to this class of drugs. Examples of NSAIDs now available for use in small animals include aspirin, etodolac, carprofen, ketoprofen, meloxicam, deracoxib, and tepoxalin. The purposes of this article are to review the pathophysiology of prostaglandin synthesis and inhibition, the mechanisms of action, pharmacokinetics, pharmacological effects, and potential adverse reactions of aspirin and the newly released NSAIDs.     

Influence of endotoxin induced fever on the pharmacokinetics of intramuscularly administered cefepime in rabbits

This study examined the effect of experimentally induced fever on the pharmacokinetics of cefepime (75 mg/kg BW) administered intramuscularly to six rabbits. The study was carried out in two consecutive phases separated by a two-week washout period. An infection was induced by an intravenous inoculation of 5 × 10⁸ colony-forming units of Escherichia coli 24 h before the pharmacokinetic investigation. A quantitative microbiological assay was employed to measure the plasma cefepime concentrations using an agar-gel diffusion method with Bacillus subtilis ATCC 6633 as the test organism. Twenty-four hour after the injection, the rectal temperature in the infected animals increased by 1–. There was a significant reduction in the elimination half-life by 21.8% in the febrile rabbits compared to healthy animals. In addition, the infection significantly increased the peak plasma concentrations by 11.9%, the mean residence time by 19.9%, the area under the plasma-concentration-time curve by 53.6% and the area under the moment curve by 62.3%. In conclusion, the endotoxin-induced febrile state produced significant changes in the plasma levels as well as some of the pharmacokinetic variables of cefepime in rabbits.     

Mixed effects modeling of the disposition of gentamicin across domestic animal species

An interspecies pharmacokinetic model for gentamicin was developed using the mixed effects modeling approach and serum disposition data obtained from the Food Animal Residue Avoidance Databank (FARAD). Data that met a priori quality criteria was obtained from the database and analysed using the traditional double logarithmic analysis and the mixed effects modeling approach. Body weight, brain weight and fever were the covariates of interest in our study. Population pharmacokinetic models across species were developed and validated with swine data. The parameter volume of distribution was modeled as a function of body weight. The total clearance was initially modeled as a function of body weight. The predictability performance of the model improved dramatically when the parameter brain weight was included in the covariate model for clearance. This was a surprising finding worthy of further study. The covariate fever seemed to influence the magnitude of the volume of distribution, although the scarcity of data pertaining to diseased animals makes this finding uncertain. We conclude that the pharmacokinetic characteristics of drugs such as gentamicin, can be predicted across species using a population pharmacokinetics modeling approach, and that clinical features that affect species in a similar manner can be also explored in this fashion.     

Influence of induced disease states on the disposition kinetics of imidocarb in goats

The influence of fever, induced by different agents, on the disposition kinetics of imidocarb was determined in goats. Escherichia coli endotoxin (0.2 microgram/kg), Trypanosoma evansi (10(7) in 1 ml sterile glucose citrate), and Infectious Bovine Rhinotracheitis virus (10(6.5)TCID50) were the agents administered to induce the febrile state. In control and febrile animals the two-compartment model was used to describe the disposition kinetics of the drug. Fever caused significant changes to occur in the apparent volume of distribution and the body (systemic) clearance of imidocarb, but the half-life remained unchanged. The statistical significance of the changes in these pharmacokinetic parameters varied with the etiology of the febrile state. E. coli endotoxin and IBR virus caused corresponding decreases in apparent volume of distribution and clearance of imidocarb, while fever induced with T. evansi caused highly significant increases in both pharmacokinetic parameters. It was concluded that the alterations in the disposition kinetics of imidocarb that occurred in the febrile goats were related not only to the febrile reaction per se but also to the pathophysiology of the disease condition.     

Ehrlichial diseases.

Equine granulocytic and monocytic ehrlichiosis caused by Ehrlichia equi and E. risticii, respectively, are seasonal diseases in horses that occur throughout the United States E. equi is transmitted by lxodes ticks and causes high fever, depression, anorexia, limb edema, petechiation, icterus, ataxia, and stiffness in gait. E. risticii, also known as the agent of Potomac horse fever, causes a febrile illness with a colitis of variable severity. Its occurrence is associated with aquatic habitats. The natural route of transmission is oral, through the ingestion of E. risticii infected trematode stages either free in water or in an intermediate host, such as aquatic animals.     

A functional model for feline P‐glycoprotein

P‐gp (ABCB1) belongs to the group of export transporters that is expressed in various species at biological barriers. Inhibition of P‐gp can lead to changes in pharmacokinetics of drugs (drug–drug interactions), which can lead to toxicity and adverse side effects. This study aimed to establish a functional assay to measure the inhibitory potential of veterinary drugs on feline P‐gp by means of fluorescence‐associated flow cytometry of feline lymphoma cells. In this model, PSC833 and ivermectin potently inhibited P‐gp function; cyclosporine and verapamil moderately inhibited P‐gp function, whereas ketoconazole, itraconazole, diazepam, and its metabolites had no effect on P‐gp function. This model can be used for testing the inhibitory potency of (new) drugs on feline P‐gp.