The Antinociceptive and Antipyretic Potentials of Cefepime

Advances in Animal and Veterinary Sciences Research Article The Antinociceptive and Antipyretic Potentials of Cefepime MOHAMED ELBADAWY1*, HUSSEIN M. EL-HUSSEINY2, MOSSAD GAMALEDDIN AHMED ELSAYED1, ASHRAF A. ELKOMY1, AMIRA ABUGOMAA3* 1 Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, 13736 Moshtohor, Toukh, Elqaliobiya, Egypt; 2Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh 13736, Elqaliobiya, Egypt; 3Faculty of Veterinary Medicine, Mansoura University, 35516 Mansoura, Dakahliya, Egypt. Abstract | The present study aimed to evaluate the analgesic and antipyretic potentials of cefepime at different therapeutic doses in vivo using hot-plate and brewer’s yeast-induced fever models in mice and rats, respectively. Twentyfive mice and/or rats were assigned into five groups, each of five animals. The first group of each was left as control and administered saline i.m. The second group was given ketoprofen (13 mg.) or metamizole sodium (150 mg) per kg BW i.m. as a standard analgesic and antipyretic, respectively. The third, fourth, and fifth groups were given cefepime at the different therapeutic doses, respectively, i.m. in saline. Cefepime induced dose-dependent and significant analgesic effect along the four h of the experiment which was indicated by the longer reaction time in treated than the control group. Cefepime at 45 mg/kg. BW had no antipyretic activity, while at 90 and 180 mg/kg BW had an antipyretic effect after 3.5 h of cefepime administration and at 180 mg/kg BW had a significant antipyretic potential 2.5 h after its injection. These findings indicate that cefepime possesses significant analgesic and antipyretic potentials that would be valuable in symptomatic relief of nociception and fever besides its well-established antibacterial effect. Keywords | Analgesic, Antinociceptive, Antipyretic, Cefepime, Cephalosporins. Received | August 29, 2021; Accepted | September 05, 2021; Published | November 01, 2021 *Correspondence | Mohamed Elbadawy, Amira Abugomaa, Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, 13736 Moshtohor, Toukh, Elqaliobiya, Egypt; Faculty of Veterinary Medicine, Mansoura University, 35516 Mansoura, Dakahliya, Egypt; Email: mohamed.elbadawy@fvtm.bu.edu. eg; s193249s@st.go.tuat.ac.jp Citation | Elbadawy M, El-Husseiny HM, Elsayed MGA, Elkomy AA, Abugomaa A (2021). The antinociceptive and antipyretic potentials of cefepime. Adv. Anim. Vet. Sci. 9(12): 2132-2138. DOI | http://dx.doi.org/10.17582/journal.aavs/2021/9.12.2132.2138 ISSN (Online) | 2307-8316; ISSN (Print) | 2309-3331 Copyright © 2021 Elbadawy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. INTRODUCTION Fever evolves in patients upon certain exogenous stimuli (mostly microbial) that stimulate bone-marrow-derived ain and fever are major symptoms of many illnesses phagocytes to discharge fever-inducing hormones (encaused by intense or damaging stimuli (Raja et al., 2020) dogenous pyrogens) as a mechanism to control infection or microbial infection (Bernheim et al., 1979). Nociception (Bernheim et al., 1979). An analgesic is a drug that relieves is the reaction of sensory nerve endings to such stimuli symptoms of pain (Tambaro et al., 2013; Tripathi, 2013). whose intensity is close to or surpassing noxious intensity Analgesic drugs act either peripherally or centrally or on (nociceptors). Damages to the peripheral nerve endings, both. Analgesics include non-steroidal anti-inflammatory spinal cord, or brain can arouse different responses result- agents (NSAIDs) such as aspirin, and opioid agents such ing in the behaviour of pain (Merskey and Bogduk, 1994). as codeine, morphine, and many others. Antipyretics are P December 2021 | Volume 9 | Issue 12 | Page 2132 NE Academic US Publishers Advances in Animal and Veterinary Sciences drugs that are administered to treat fever by triggering the hypothalamus to reverse the prostaglandin-caused rise in body temperature (BT). The selection of each depends on the severity and nature of pain, patient status, and co-administered drugs (WHO, 2006). Other than the available standard analgesics and antipyretics, many other agents may have analgesic and antipyretic potentials or other along with their basic pharmacological effect (Aboubakr et al., 2014). For example, some antibiotics, regardless its type, were demonstrated to kill pain to various levels in rats (Elbadawy, 2007; Ocana and Baeyens, 1991; Suaudeau et al., 1993). This highlights the advantage of synergism when these antibiotics are co-given with the standard analgesics and antipyretics, making sometimes, therapy more effective. Bacterial infections can change the quality or even threaten the lives of human beings and livestock or result in serious economic losses; therefore, antibacterial intervention is recommended (Elbadawy et al., 2019). Antibiotics are major drugs in many prescriptions of bacterial infection. Antibiotics have many side effects, which are sometimes harmful (Aboubakr et al., 2014; El-Safty et al., 2018; Elkomy et al., 2020; Elsayed et al., 2014) or beneficial to some patients (Aboubakr and Elbadawy, 2016; Aboubakr et al., 2014; ElMahmoudy and Gheith, 2016; Elbadawy and Aboubakr, 2017; Elbadawy et al., 2021; Elkomy et al., 2019; Elsayed et al., 2014). Cefepime, a parenteral 4th-generation cephalosporin, is a well-established, generally well-tolerated antibiotic (Okamoto et al., 1993), with broad-spectrum activity and less bacterial resistance (Yayan et al., 2016). Cefepime is active in vitro against diverse bacteria and is stable against numerous beta-lactamases (Nguyen et al., 2014). Cefepime was reported to have a low potential to produce adverse reactions at therapeutic doses (Elsayed et al., 2013; Elsayed et al., 2014). Expanded information concerning the beneficial side actions of cefepime will be of benefit to physicians and patients. Therefore, the present study aimed to assess the analgesic and antipyretic potentials of cefepime in vivo. Cefepime hydrochloride is a white to pale yellow powder with a molecular formula of C19 H25 Cl N6 O5 S2·HCl·H20 and a molecular weight of 571.5. It is highly soluble in water. Cefepime hydrochloride is supplied for i.m. or i.v. injection in a strength equivalent to 500, 1000 m, or 2000 mg of cefepime. It is produced by GSK group Co., Cairo, Egypt with the commercial name Maxipime®. Figure 1: Chemical structure of cefepime hydrochloride ANIMALS Experiments were done on mice and rats for assessing the analgesic and antipyretic potentials of cefepime. Animals were purchased from the Experimental Animal Laboratory of the Faculty of Veterinary Medicine, Benha University, Egypt. Animals were maintained in polypropylene cages with wood bedding in a controlled room with 24°C and relative humidity of 60% and a 12h light/dark cycle. Standard pellet diet and water were supplied ad libitum. Animals were kept for one week to adapt to the environment before experimentation. The experimental steps were performed following the guidelines set by the local Ethical Committee of Faculty of Veterinary Medicine, Benha University, Egypt. All efforts were followed to maintain the rest of the animals. EXPERIMENTAL DESIGN In the present investigation, mice and rats were used to assess the analgesic and antipyretic potentials of cefepime, respectively. For assessing the analgesic potential of cefepime, Numerous Swiss albino mice were tested for the ordinary response to thermal stimuli-provoked pain, and only ordiMATERIALS AND METHODS narily reacting ones were selected for the pain experiments. Twenty-five mice of both sexes and 20-25 g BW were used DRUG (CEFEPIME) and distributed into five groups, each of five mice. The cefepime is a semi-synthetic, broad-spectrum, 4th-generfirst one was left as a control and was given normal saline ation cephalosporin antibiotic formulated for injection. i.m. The second group was given ketoprofen (Orudis®) as The chemical formula is 1-[[(6R,7R)-7-[2-(2-aminoa standard analgesic at 13 mg/kg BW i.m. in saline. The 4-thiazolyl)-glyoxylamido]-2-carboxy-8-oxo-5-thiathird, fourth, and fifth groups were administered cefepime 1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methat 65, 130, and 260 mg/kg BW i.m. in saline as small, meylpyrrolidinium chloride, 72-(Z)-(O-methyloxime), dium, and large therapeutic doses, respectively. The doses monohydrochloride, monohydrate, which corresponds to were calculated following the Paget and Barnes table of structure shown at Figure 1. dose conversion from humans to mice (Paget and Barnes, December 2021 | Volume 9 | Issue 12 | Page 2133 NE Academic US Publishers Advances in Animal and Veterinary Sciences Table 1: Effects of cefepime (65, 130, and 260 mg/kg BW i.m.) and ketoprofen (13 mg/kg BW i.m.) on the reaction time (seconds) induced in the hot-plate test in mice (mean ± S.E.; n = 5). Groups Before experiment 0.5 Time post-injection (h) 1 1.5 2 2.5 3 3.5 4 Reaction time (seconds) Control group 7.18 ± 0.27 6.29 ± 0.24 Ketoprofen (13 mg/kg BW) 6.49 ± 0.17 Cefepime (65 mg/kg BW) 6.80 ± 0.22 6.72 ± 0.40 6.46 ± 0.36 5.85 ± 0.53 6.52 ± 0.41 6.58 ± 0.48 6.82 ± 0.74 17.7 ± 0.45 16.8 ± *** ΔΔΔ 0.97 *** ΔΔΔ 16.2± 0.58 *** ΔΔΔ 16.4 ± 1.03 *** ΔΔΔ 13.5 ± 13.5 ± 1.3 1.32 *** *** ΔΔΔ ΔΔΔ 13.7 ± 0.69 *** ΔΔΔ 11.8 ± 0.34 *** ΔΔΔ 6.13 ± 0.28 8.61 ± 0.58 ** ΔΔ 9.75 ± 0.39 *** ΔΔΔ 10.1 ± 0.32 *** ΔΔΔ 10.2 ± 0.15 *** ΔΔΔ 10.3 ± 0.35 *** ΔΔΔ 10.2 ± 0.50 *** ΔΔΔ 10.6 ± 0.41 ** ΔΔΔ 11.4 ± 0.30 *** ΔΔΔ Cefepime 6.44 ± 0.55 (130 mg/kg BW) 8.99 ± 0.30 *** ΔΔ 10.8 11.1 ± ±0.51 0.28 *** ΔΔΔ *** ΔΔΔ 12.1 ± 0.26 *** ΔΔΔ 13.0 ± 0.53 *** ΔΔΔ 12.8 ±1.05 *** ΔΔΔ 13.1 ± 0.59 *** ΔΔΔ 13.2 ± 1.06 ** ΔΔΔ Cefepime 6.66 ± 0.28 (260 mg/kg BW) 9.46 ± 0.30 *** ΔΔΔ 10.2 ± 0.25 *** ΔΔΔ 12.3 ± 0.18 *** ΔΔΔ 13.6 ± 0.64 *** ΔΔΔ 10.7 ± 0.35 *** ΔΔΔ 11.0 ± 12.6 ± 11.8 ± 0.25 0.44 0.52 *** ΔΔΔ *** *** ΔΔΔ ΔΔΔ * → Represents the significance with the data of the control group. Δ → Represents the significance in comparison with data of the same group before treatment. * or Δ P> 0.05 ** or ΔΔ P> 0.01 *** or ΔΔΔ P> 0.001 Table 2: Effect of cefepime (45, 90, and 180 mg/kg BW i.m.) and metamizole sodium (150 m/kg BW i.m.) on body temperature (°C) after Brewer’s yeast- induced pyrexia in rats (mean ± S.E.; n = 5). Groups Before experiment After Brewer’s yeast Time after injection (h) 0.5 1 1.5 2 2.5 3 3.5 4 37.4 ± 0.13 Rectal temperature (°C) Control group 36.7 ± 0.1 37.7 ± 0.04 37.5 ± 0.12 37.4 ± 0.12 37.5 ± 0.13 Metamizole (150 mg/kg BW) 36.4 ± 0.09 37.7 ± 0.09 37.1 ± 0.13 ΔΔ 36.7 ± 0.10 ** ΔΔΔ Cefepime (45 mg/kg BW) 36.6 ± 0.1 37.7 ± 0.1 37.6 ± 0.07 Cefepime (90 mg/kg BW) 36.4 ± 0.05 37.6 ± 0.05 Cefepime (180 mg/kg BW) 36.5 ± 0.07 37.6 ± 0.07 37.4 ± 0.13 37.6 ± 0.12 37.5 ± 0.12 37.7 ± 0.11 36.6 ± 36.5 ± 0.1 0.09 *** *** ΔΔΔ ΔΔΔ 36.4 ± 0.07 *** ΔΔΔ 36.4 ± 0.09 *** ΔΔΔ 36.4 ± 36.4 ± 0.09 0.09 *** ΔΔΔ *** ΔΔΔ 37.5 ± 0.08 37.5 ± 0.06 37.5 ± 0.06 37.4 ± 0.07 Δ 37.3 ± 0.07 Δ 37.3 ± 0.09 Δ 37.2 ± 0.09 Δ 37.5 ± 0.05 37.5 ± 0.05 37.4 ± 0.05 Δ 37.4 ± 0.05 ΔΔ 37.3 ± 0.05 ΔΔΔ 37.2 ± 0.03 ΔΔΔ 37.1 ± 0.04 * ΔΔΔ 37.0 ± 0.02 * ΔΔΔ 37.5 ± 0.04 37.4 ± 0.02 Δ 37.4 ± 0.02 ΔΔ 37.3 ± 37.1 ± 0.04 ΔΔ 0.04 * ΔΔΔ 37.0 ± 36.9 ± 0.05 0.04 ** ΔΔΔ ** ΔΔΔ 36.8 ± 0.06 ** ΔΔΔ * → Represents the significance with the data of the control group. Δ → Represents the significance in comparison with data after administration of Brewer’s yeast extract. * or Δ P> 0.05 ** or ΔΔ P> 0.01 *** or ΔΔΔ P> 0.001 1964). The hot-plate test was then performed to check the analgesic potential of cefepime. All rats were made hyperthermic by s.c. injection of 20 % suspension of Brewer’s yeast in physiological saline at 0.1 ml /100 g BW. The method described before (Alperman, For assessing the antipyretic potential of cefepime, 25 Al- 1972; Brune and Alpermann, 1983) was followed for studbino rats of both sexes weighing 150-200 g BW were used. ying the impact of cefepime on feverish BT. They were distributed into five groups, each of five rats. December 2021 | Volume 9 | Issue 12 | Page 2134 NE Academic US Publishers Advances in Animal and Veterinary Sciences activity while at 90 mg/kg BW had an antipyretic effect The analgesic potential of cefepime was assessed using the started at 3.5 h of cefepime administration. The cefepime hot-plate method as demonstrated before (Eddy et al., in a dose of 180 mg/kg BW had a significant antipyretic 1950) (Elbadawy et al., 2021). After treatment of mice as potential started at 2.5 h of injection. mentioned above, each mouse was placed singly in a 2-liter volume beaker on a hot plate (Scilogex, CT, U.S.A) kept DISCUSSION constant at 55°C for determining the analgesic potential of cefepime. The time elapsed (in seconds) until the mouse Analgesics, antipyretics, and others are generally prescribed jumps or licks its paws (as responses to the thermal stim- along with antibiotics for the remediation of systemic inulus-triggered pain sensation) was recorded at 1, 2, 3, and fections with fever and pain. However, many antibiotics 4 h post cefepime administration and considered as the including cefepime have other pharmacological actions reaction time. A “cutoff ” time of 30 seconds was followed like reducing spontaneous locomotor activity, relaxing the to prevent tissue harm to mice. skeletal muscles, stimulating intestinal movements, potentiating anesthesia in mice, inducing significant hypotherANTIPYRETIC POTENTIAL OF CEFEPIME mia and analgesia (Elsayed et al., 2013; Goto et al., 1992; Seventeen h post yeast injection, the initial BT of each rat Kadota et al., 1992). Hasegawa et al. showed that cefadroxwas recorded rectally using a medical thermometer. Nor- il inhibited gastric secretion and raised the biliary secretion mal saline was given i.m to the first group and was kept as in rats (Hasegawa et al., 1979). Takai et al. also showed that control. The second group was given metamizole sodium cefoperazone has several side actions at different doses in (Novalgin®) as a standard antipyretic drug at 150 m/kg different laboratory animals (Takai et al., 1980). CefamanBW i.m. as a standard antipyretic. The third, fourth, and dole caused very marked hypotensive effects and a decline fifth groups were administered cefepime at a dose of 45, in respiration rate in anesthetized dogs (El-Sayed et al., 90, and180 mg/kg BW i.m. in saline as small, medium, 1997). Thus investigating the other actions of drugs is imand large therapeutic doses, respectively, based on Paget portant to predict whether it has favorable or unfavorable and Barnes dose conversion from human to rats (Paget side effects. The administration of such antibiotics with and Barnes, 1964). The BT of each rat was then recorded favorable side actions may add synergism with the co-prebefore and at 30, 60, 90, 120, 150, 180, 210, 240 min after scribed drugs and fasten the cure of the patients. administrations. The difference in BT between the treated and control groups was taken as a measure of antipyretic The present investigation was performed to assess analactivity. gesic and antipyretic potentials of cefepime. Cefepime at 65, 130, and 260 mg/kg BW induced a significant analgesic effect against thermal stimuli. This was indicated by a STATISTICAL ANALYSIS Data were expressed as mean ± S.E. The obtained data were longer reaction time in the hot-plate test. The obtained reanalyzed by the Student t-test to express the differenc- sult was consistent with that reported by Goto et al. (Goto es between groups (Snedecor and Cochran, 1980). Each et al., 1992) who observed that significant analgesia was treated group was compared with the control one and itself noticed at the highest dose of cefepime in mice. Similarly, before treatment. Comparison of the mean values was car- some beta-lactams demonstrated various analgesia degrees ried out and differences were considered statistically signif- with various intensity of actions based on their administered amounts (Suaudeau et al., 1993). In animals, frequent icant when P<0.05. giving of ceftriaxone was shown to diminish visceral and neuropathic pain (Gunduz et al., 2011; Hu et al., 2010; Lin RESULTS et al., 2011; Yang et al., 2011) and lower the tolerance to ANALGESIC POTENTIAL OF CEFEPIME IN MICE the analgesic effect of nicotine (Schroeder et al., 2011) or The analgesic-like action of cefepime in mice is recorded in the Table (1). Intramuscular injection of cefepime in all morphine (Rawls et al., 2010) by upregulating glutamate tested doses caused a significant analgesic effect along the transporter-1 (GLT-1) expression. Macaluso et al. revealed four h of the experiment which was indicated by the longer that a single intraperitoneal (i.p.) giving of ceftriaxone at reaction time in treated groups compared with the control 200 mg/kg BW induced analgesia in mouse models of postsurgical or inflammatory pain, via upregulating GLTgroup and same before treatment. 1 level in the spinal cord (Macaluso et al., 2013). They also demonstarted that ceftriaxone-produced nociception ANTIPYRETIC ACTIVITY OF CEFEPIME IN RATS was additive to that induced by blocking of metabotropic Seventeen h after injection of Brewers yeast, all rats glutamate5 receptors, which are stimulated by the extrashowed hyperthermia (Table 2). The antipyretic-like action synaptic glutamate. Further, single i.v. injection of ceftriof cefepime in rats is recorded in Table 2. Intramuscular axone (2000 mg) in human patients undergoing surgery injection of cefepime at 45 mg/kg BW had no antipyretic HOT-PLATE TEST December 2021 | Volume 9 | Issue 12 | Page 2135 NE Academic US Publishers Advances in Animal and Veterinary Sciences for decompression of nerves induced analgesia revealed by a 10-fold substantial increase in the pain threshold for 4-6 h after surgery, whereas cefazoline did not (Macaluso et al., 2013). The GLT-1 regulates glutamate homeostasis which is included in the establishment and progress of pathological pain (Hu et al., 2010). The chronic constriction injury of the sciatic nerve lowered the level of GLT-1 in the dorsal horns of the spinal cord leading to significant hyperalgesia which was reversed by the i.p. injection of ceftriaxone (Hu et al., 2010). Further, they found that the intrathecal injection of ceftriaxone led to the specific GLT-1 overexpression and glutamate uptake in the spinal dorsal and similar antinociceptive effects to those of i.p. injection of ceftriaxone (Hu et al., 2010). In another study, cefepime was reported to interfere with metabotropic glutamate receptor pathways and increase glutamate leading to analgesia induction (Han et al., 2018). Therefore the analgesia induced by cefepime in the current study might be due to upregulation of spinal GLT-1 expression and its function. In the current study, cefepime at 90 and 180 mg/kg BW showed significant antipyretic potential. This was evidenced by the decline in rat’s feverish BT induced after s.c. administration of Brewer’s yeast suspension. This effect seemed to be mediated centrally through an action on the heat-regulating center in such a manner to increase heat loss by peripheral vasodilatation of skin blood vessels, as well as the direct vascular relaxant and negative inotropic effect of cefepime (Elsayed et al., 2013). This finding is consistent with that recorded by Goto et al who recorded cefepime-induced significant hypothermia in mice (Goto et al., 1992). The obtained data was inconsistent with that of Takai et al. (1982) and Honda et al. (1980). They reported that cefbuperazone and ceftizoxime, respectively, did not affect BT in rabbits and mice (Honda et al., 1980; Takai et al., 1982). Also, Takai et al. stated that cefoperazone caused pyrexia in rabbits at 1,000 mg/kg (Takai et al., 1980). Hirai et al. (1986) also confirmed that cefteram induced only a slight elevation of BT in rabbits (Hirai et al., 1986). CONCLUSION The data obtained in the current study indicates that cefepime might have the potentials of being an analgesic and antipyretic agent along with its antibacterial action. However, the detailed mechanism of action is a future perspective. Thus, the administration of cefepime may support the actions of the co-prescribed standard analgesics and antipyretics. Furthermore, the reported findings explain the eminent effectiveness of cefepime in bacterial infections which are frequently associated with pain and/or pyrexia. December 2021 | Volume 9 | Issue 12 | Page 2136 AUTHORS CONTRIBUTION Mohamed Elbadawy: designed the study, methodology, and analyzed the data. Hussein M. El-Husseiny: methodology. Mossad Gamaleddin Ahmed Elsayed: study design and supervision. Ashraf A. Elkomy: revised the manuscript. 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