Potent stimuli for vasopressin release,hypertonic saline and hemorrhage,cause antipyresis in the rat

Two potent stimuli for AVP release into the blood, hemorrhage and hypertonic saline, were evaluated for their antipyretic effects in the rat. Hemorrhage of 20% of estimated blood volume reduced brain temperature of febrile but not afebrile rats confirming earlier research in the sheep. Hypertonic saline was also antipyretic in the rat. Hypertonic urea was somewhat less antipyretic whereas hypertonic glucose had no effect on febrile temperatures. AVP release into the peripheral circulation showed the relationship saline > urea > glucose and parallelled the antipyretic effectiveness of these solutes. The antipyresis caused by hypertonic saline was not significantly different in rats passively immunized intravenously with AVP antiserum than in rats which received hypertonic saline alone. These results provide indirect evidence that endogenous AVP is released in the brain following hemorrhage or hypertonic challenge and that this endogenous AVP can affect central febrile pathways.     

Management of feverish children at home.

OBJECTIVES--To compare the acceptability and effects on temperature of advice to unwrap children and give paracetamol or warm sponging treatments in the management of feverish illness at home. DESIGN--A randomised, open, parallel group study using factorial design comparison of unwrapping, warm sponging plus unwrapping, paracetamol plus unwrapping, and paracetamol and warm sponging plus unwrapping. SETTING--Homes of willing families with a feverish child recruited after consulting one of 21 participating general practitioners in Southampton. SUBJECTS--52 children aged from 3 months to 5 years with axillary temperatures before treatment of > or = 37.8 degrees C and < 40 degrees C. MAIN OUTCOME MEASURES--Response to advice assessed over four hours; temperature assessed by continuous data logging from an axillary thermistor; acceptability of treatment to child and parent scored on Likert scales immediately after treatment and on return to health. RESULTS--Response to treatment advice varied; unwrapping alone had little effect on temperature. Paracetamol increased the time below 37.2 degrees C in four hours by 109 (95% confidence interval 74 to 145) minutes compared with unwrapping; warm sponging caused the fastest reduction in temperature. Parents discriminated between treatments, preferring paracetamol. CONCLUSION--Advice to give paracetamol is more effective than sponging or unwrapping in controlling temperature in children at home and is more acceptable to parents. Warm sponging has an additive effect and reduces fever more quickly than paracetamol.     

Reliability of health information for the public on the World Wide Web: systematic survey of advice on managing fever in children at home.

OBJECTIVE: To assess the reliability of healthcare information on the world wide web and therefore how it may help lay people cope with common health problems. METHODS: Systematic search by means of two search engines, Yahoo and Excite, of parent oriented web pages relating to home management of feverish children. Reliability of information on the web sites was checked by comparison with published guidelines. MAIN OUTCOME MEASURES: Minimum temperature of child that should be considered as fever, optimal sites for measuring temperature, pharmacological and physical treatment of fever, conditions that may warrant a doctor''s visit. RESULTS: 41 web pages were retrieved and considered. 28 web pages gave a temperature above which a child is feverish; 26 pages indicated the optimal site for taking temperature, most recommending rectal measurement; 31 of the 34 pages that mentioned drug treatment recommended paracetamol as an antipyretic; 38 pages recommended non-drug measures, most commonly tepid sponging, dressing lightly, and increasing fluid intake; and 36 pages gave some indication of when a doctor should be called. Only four web pages adhered closely to the main recommendations in the guidelines. The largest deviations were in sponging procedures and how to take a child''s temperature, whereas there was a general agreement in the use of paracetamol. CONCLUSIONS: Only a few web sites provided complete and accurate information for this common and widely discussed condition. This suggests an urgent need to check public oriented healthcare information on the internet for accuracy, completeness, and consistency.     

Antipyretic effect of arginine vasotocin in toads

Arginine vasotocin (AVT) is a nonmammalian analog of the mammalian hormone arginine vasopressin (AVP). These peptides are known for their antidiuretic and pressor effects. More recently, AVP has been recognized as an important antipyretic molecule in mammals. However, no information exists about the role of AVT in febrile ectotherms. We tested the hypothesis that AVT is an antipyretic molecule in the toad Bufo paracnemis. Toads equipped with a temperature probe were placed in a thermal gradient, and preferred body temperature was recorded continuously. A behavioral fever was observed after lipopolysaccharide (LPS) was injected systemically (200 microg/kg). Systemically injected AVT (300 pmol/kg) alone caused no significant change in body temperature, but abolished LPS-induced fever. Moreover, a smaller dose of AVT (10 pmol/kg), which did not affect LPS-induced fever when injected peripherally, abolished fever when injected intracerebroventricularly. We therefore conclude that AVT plays an antipyretic role in the central nervous system, by means of behavior, in an ectotherm, a fact consistent with the notion that AVT/AVP elicits antipyresis by reducing the thermoregulatory set point.     

The Effect of Prophylactic Antipyretic Administration on Post-Vaccination Adverse Reactions and Antibody Response in Children: A Systematic Review

Background

Prophylactic antipyretic administration decreases the post-vaccination adverse reactions. Recent study finds that they may also decrease the antibody responses to several vaccine antigens. This systematic review aimed to assess the evidence for a relationship between prophylactic antipyretic administration, post-vaccination adverse events, and antibody response in children.

Methods

A systematic search of major databases including MEDLINE and EMBASE was carried out till March 2014. Randomized controlled trials (RCTs) comparing prophylactic antipyretic treatment versus placebo post-vaccination in children ≤6 years of age were included. Two reviewers independently applied eligibility criteria, assessed the studies for methodological quality, and extracted data [PROSPERO registration: CRD42014009717].

Results

Of 2579 citations retrieved, a total of 13 RCTs including 5077 children were included in the review. Prophylactic antipyretic administration significantly reduced the febrile reactions (≥38.0°C) after primary and booster vaccinations. Though there were statistically significant differences in the antibody responses between the two groups, the prophylactic PCM group had what would be considered protective levels of antibodies to all of the antigens given after the primary and booster vaccinations. No significant difference in the nasopharyngeal carriage rates (short-term and long-term) of H. influenzae or S. pneumoniae serotypes was found between the prophylactic and no prophylactic PCM group. There was a significant reduction in the local and systemic symptoms after primary, but not booster vaccinations.

Conclusions

Though prophylactic antipyretic administration leads to relief of the local and systemic symptoms after primary vaccinations, there is a reduction in antibody responses to some vaccine antigens without any effect on the nasopharyngeal carriage rates of S. pneumoniae & H. influenza serotypes. Future trials and surveillance programs should also aim at assessing the effectiveness of programs where prophylactic administration of PCM is given. The timing of administration of antipyretics should be discussed with the parents after explaining the benefits & risks.     

Antipyresis due to centrally administered vasopressin differentially alters thermoregulatory effectors depending on the ambient temperature

The intracerebroventricular (i.c.v.) administration of arginine vasopressin (AVP), in the febrile rat elicits an antipyresis at cold, warm and neutral ambient temperatures. These experiments were conducted, therefore, to elucidate the thermoregulatory effector mechanisms responsible for this antipyretic effect. At 25 degrees C, AVP-induced antipyresis was mediated by tail skin vasodilation while metabolic rate was unaffected. At 4 degrees C, the antipyresis produced by AVP was approximately double that seen at 25 degrees C. This effect appeared to be mediated exclusively by inhibition of heat production since the metabolic rate decreased markedly following AVP. This antipyresis at 4 degrees C was accompanied by cutaneous vasoconstriction. At 32 degrees C, neither vasomotor tone, metabolic rate nor evaporative heat loss could be shown to contribute to the small antipyretic effect elicited by AVP. We conclude from these data that i.c.v. AVP is producing antipyresis by affecting the febrile body temperature set-point mechanism since the thermoregulatory strategy to lose heat varies at different ambient temperatures and the decrease in body temperature cannot be shown to be due to changes in a single effector mechanism.     

Antipyretic Therapy in Critically Ill Patients with Sepsis: An Interaction with Body Temperature

Background and Objective

The effect of antipyretic therapy on mortality in patients with sepsis remains undetermined. The present study aimed to investigate the role of antipyretic therapy in ICU patients with sepsis by using a large clinical database.

Methods

The multiparameter intelligent monitoring in intensive care II (MIMIC- II) database was employed for the study. Adult patients with sepsis were included for analysis. Antipyretic therapy included antipyretic medication and external cooling. Multivariable model with interaction terms were employed to explore the association of antipyretic therapy and mortality risk.

Main Results

A total of 15,268 patients fulfilled inclusion criteria and were included in the study. In multivariable model by treating temperature as a continuous variable, there was significant interaction between antipyretic therapy and the maximum temperature (T_max). While antipyretic therapy had no significant effect on mortality in low temperature quintiles, antipyretic therapy was associated with increased risk of death in the quintile with body temperature >39°C (OR: 1.29, 95% CI: 1.04–1.61).

Conclusion

Our study shows that there is no beneficial effect on reducing mortality risk with the use of antipyretic therapy in ICU patients with sepsis. External cooling may even be harmful in patients with sepsis.     

Thermistor probe for testing an antipyretic suppository in rabbits

The thermistor probe for estimating the effects of an antipyretic suppository after its administration into the rectum of the rabbit was studied. A thermistor probe with three rubber disk stoppers was confirmed to be able to prevent the leakage of drugs from the rectum of a rabbit restrained in a neck stock. By using this newly devised thermistor probe or the usual thermistor probe without a stopper, the febrile response was determined in rabbits injected with bacterial pyrogen. There was no difference in the ability to detect rectal temperature between the two thermistor probes. From these results, it could be concluded that this newly devised thermistor prove was useful in studying the effects of antipyretic suppositories in rabbits.     

Calcium channel blockers inhibit endogenous pyrogen fever in rats and rabbits.

We have previously shown that febrile responses in both rats and rabbits are elicited by the intravenous injection of a semipurified endogenous pyrogen (EP) prepared from human monocytes. We are now presenting evidence that these febrile responses are mediated via activation of Ca2+ channels by EP. The febrile responses of male New Zealand White rabbits and Sprague-Dawley rats to a standard dose of EP were determined at their respective thermoneutral ambient temperatures. The animals were then treated with Ca2+ channel blocker verapamil (7.5 mg/kg iv) 30-60 min before the EP challenge. In every case the febrile response to EP was markedly attenuated after verapamil pretreatment, while administration of verapamil by itself had no detectable effect on body temperature. Another Ca2+ channel blocker, nifedipine (5 mg/kg iv), was shown to possess antipyretic activity in rats also. To localize where in the fever pathway these Ca2+ channel blockers were acting, we investigated the effect of verapamil at the same dose on fevers that were produced by microinjection of prostaglandin E (PGE) directly into the brain. These PGE fevers were unaffected by verapamil pretreatment, indicating that the antipyretic action of Ca2+ channel blockers occurs before the formation of PGE in response to EP stimulation. The most likely locus of action is the activation of the enzyme phospholipase A2, which regulates the production of arachidonic acid from cellular phospholipids in the prostanoid cascade.     

Intracerebroventricular and septal injections of arginine vasopressin are not antipyretic in the rabbit

Arginine vasopressin (AVP) has been reported to have an antipyretic effect in the ewe and guinea pig near term. Perfusions with AVP of sites in the septal region also reduced fever in non-pregnant sheep. In the present experiments adult rabbits with third cerebral ventricular or septal cannulas were restrained in a 23°C environment, and rectal temperature was recorded every 10 min. Fever induced by IV administration of leukocytic pyrogen was not reduced by AVP (25–100 ng) given intraventricularly 20 min later. Doses of 1–5 μg AVP injected into the septum likewise were not antipyretic but actually caused an increase in fever. This augmentation of the febrile response is consistent with results of previous studies in this laboratory in which AVP increased hyperthermia in a hot environment and enhanced hyperthermic responses to PGE₂. The data from these experiments provide no evidence that central AVP is an endogenous antipyretic in rabbits; rather, it may be that central AVP augments fever in this species.     

Central arginine vasopressin and endogenous antipyresis.

Arginine vasopressin (AVP) is a centrally synthesized nonapeptide that exerts classical endocrine effects as well as a host of centrally mediated actions. A strong case can be argued in support of a neurotransmitter-neuromodulator role for AVP. Acting within the central nervous system (CNS), AVP has been demonstrated to be involved in the modulation of febrile body temperature. Because AVP acts to reduce pyrogen-induced fevers, but not normal body temperature, its actions are deemed to be antipyretic. However, to demonstrate an endogenous antipyretic function, AVP must be shown to be active during conditions where fever is naturally suppressed. This review will focus on five such conditions where the absence of pyrogen-induced fever can be linked to the endogenous activity of AVP within the brain. In the neonatal rat pup, the use of specific antagonists to the AVP receptor has revealed a role for CNS AVP in the absence of fever following peripheral injections of bacterial endotoxin. These results may help to explain a similar lack of fever in other newborn species. In parturient animals a reduced or absent febrile response has been linked to the increased presence of AVP within the septal area of the brain. The combined use of AVP receptor antagonism as well as immunohistochemistry has shown enhanced AVP activity within the ventral septal area of the rat and guinea pig brain during tolerance to intravenous pyrogens. These results suggest that the mechanism of fever suppression following repeated systemic injections of bacterial pyrogen includes centrally acting AVP.(ABSTRACT TRUNCATED AT 250 WORDS)     

A role for natriuretic peptide in lipopolysaccharide-induced fever in Pekin ducks (Anas platyrhynchos): is natriuretic peptide an endogenous antipyretic in birds?

The febrile mechanism in all vertebrates involves endogenous molecules which mediate and attenuate the fever response. This mechanism is considered phylogenetically conserved, and the molecules are thought to be analogous in different species. The above notion is supported by evidence which show avian and mammalian fevers to have similar mediators. There is, however, a paucity of information regarding the modulators of the avian febrile response. Natriuretic peptides were shown to modulate mammalian fevers and, although natriuretic peptides are also present in birds, they have never been investigated in the context of fever. We induced fever in Pekin ducks with lipopolysaccharide and, at the same time, treated the animals with natriuretic peptide antiserum at a dose that effectively inhibited the known renal actions of endogenously secreted natriuretic peptide. We compared fever responses after ducks received either the antiserum or an appropriate control along with the lipopolysaccharide. The antiserum did not attenuate the fever responses of ducks. Our results differ from the results of a study in rats, which demonstrated natriuretic peptides to be potently antipyretic. This molecule seems to be antipyretic in mammals but not in ducks. We suggest a species variation regarding the ability of natriuretic peptides to modulate fever.     

Central vasopressin V1-blockade prevents salicylate but not acetaminophen antipyresis

Recent evidence has suggested that the endogenous antipyretic arginine vasopressin (AVP) may participate in drug-induced antipyresis. This study sought to further those investigations by comparing the effects of two other antipyretic drugs, sodium salicylate and acetaminophen, administered intraperitoneally, during AVP V1-receptor blockade within the ventral septal area (VSA) of the rat brain. During endotoxin-evoked fever, V1-receptor blockade within the VSA of the conscious unrestrained rat significantly antagonized the antipyretic effects of salicylate. The effects of the V1-antagonist on salicylate-induced antipyresis were dose related. In contrast, the antipyresis elicited by acetaminophen was unaffected by VSA V1-antagonist pretreatment. Neither saline nor the V1-antagonist microinjected into the VSA of febrile or nonfebrile rats had any significant effects on the normal progression of endotoxin fever or normal core temperature, respectively. These data suggest that the mechanism of action of salicylate-induced antipyresis includes activation of AVP V1-type receptors within the VSA, as has been shown for indomethacin. However, the lack of effect of the V1-antagonist on antipyresis induced by acetaminophen indicates that not all antipyretic drugs act through the same mechanism in the brain.     

Intravenous lysine vasopressin lowers body temperature in normal and febrile pigs.

Vasopressin has been implicated as a centrally acting endogenous antipyretic. However, in several species, including the pig, plasma vasopressin concentrations increase during the early stages of fever. This experiment investigated the effects of intravenous lysine vasopressin on core temperature in normal and febrile swine. Lysine vasopressin (20 microg/pig) stimulated cortisol release and induced a 60-min hypothermic episode in normal animals, although a 10-fold lower dose was without effect. The peptide also delayed the pyretic response to bacterial endotoxin (20 microg intravenously). It is speculated that the hypothermic action of circulating vasopressin may involve nitric oxide.     

Activation of central melanocortin-4 receptor suppresses lipopolysaccharide-induced fever in rats

Activation of central melanocortin receptors (MCR) inhibits fever, but the identity of the MCR subtype(s) mediating this antipyretic effect is unknown. To determine whether selective central melanocortin receptor-4 (MC4R) activation produces antipyretic effects, the MC4R selective agonist MRLOB-0001 (CO-His-d-Phe-Arg-Trp-Dab-NH(2)) was administered intracerebroventricularly to rats treated with Escherichia coli lipopolysaccharide (LPS, 30 microg/kg ip). Treatment with MRLOB-0001 (150 ng icv) did not lower core body temperature (T(c)) in afebrile rats but did suppress LPS-induced increases in T(c) and associated decreases in tail skin temperature (T(sk)), an indicator of vasomotor thermoeffector function. In contrast, systemic treatment with MRLOB-0001 (150 ng iv) did not produce similar antipyretic effects. Coadministration of the selective MC4R antagonist HS014 (1 microg icv) blocked the antipyretic effects of MRLOB-0001. HS014 alone (1 microg icv) had no significant effect on LPS-induced increases in T(c) or decreases in T(sk) and in afebrile rats had no significant effects on T(c) or T(sk). We conclude that pharmacological activation of central MC4R suppresses febrile increases in T(c) and that inhibition of heat conservation pathways may contribute to this effect. These findings suggest that the central MC4R may mediate the long-recognized antipyretic effects of centrally administered melanocortins.     

Is the endogenous antipyretic neuropeptide alpha-MSH responsible for reduced fever in aged rabbits?

The reduced febrile response in aged man has been noted since the beginning of clinical thermometry. Our previous research on aged rabbits and squirrel monkeys disclosed a similar reduced fever, presumably due to a decrease in central receptors for endogenous pyrogen. However, because central alpha-melanocyte stimulating hormone (MSH) appears to have a potent role in physiological control of fever, it may be that increased release of the peptide is responsible for the reduced febrile response in aged animals. To test this idea, antiserum specific to MSH was administered intracerebroventricularly to rabbits of known age. The antiserum given according to three schedules of treatment augmented fever caused by IV injections of interleukin-1 (IL-1) in young (less than 2 years) male and female rabbits. Aged female rabbits (3-5+ years) and females aged 2-3 years showed significant augmentation of fever only after pretreatment plus acute injection of antiserum. A single ICV injection of MSH (200 ng) reduced fever in all groups with the greatest antipyretic effect in the aged females. The results indicate that while aged rabbits have an increased antipyretic response to central MSH, binding of the endogenous peptide does not result in marked increases in fever in these animals. Thus, whereas a change in central MSH sensitivity may contribute to reduced fever in aged homeotherms, a reduction in central pyrogen receptors appears to be the most parsimonious explanation.     

Central and peripheral injections of ACTH (1–24) reduce fever in adrenalectomized rabbits

Central administration of ACTH (1-24) reduces fever in normal rabbits in doses that have no effect on afebrile body temperature. Previous experimental and clinical reports indicate that peripheral administration of both ACTH and corticosteroids reduces fever, and since central injection of corticosteroids can also lower fever it might be that the antipyretic effect of intracerebroventricular (ICV) ACTH (1-24) is due to adrenal stimulation. To learn whether this endogenous central peptide can produce antipyresis independently, ACTH (1-24) was injected ICV in bilaterally adrenalectomized (ADX) rabbits made febrile by IV injections of leukocytic pyrogen (LP). ACTH (250 ng) given ICV reduced fever in these animals and had a slight hypothermic effect when given to the same rabbits when they were afebrile. Doses of 25-75 ng reduced fever without influencing normal body temperature. Intravenous injections of ACTH (2.5 micrograms) also lowered fever caused by IV LP in ADX rabbits. The present findings raise the possibility that release of endogenous central ACTH, and perhaps entry into the brain of circulating ACTH, the release of which is known to increase in fever, limits the magnitude of the febrile response by influencing central temperature controls.     

ANTIPYRETIC ACTION OF DEXAMETHASONE ON EGTAZIC ACIDINDUCED FEVER IN RABBITS

本文用脑室灌注和Ｆｕｒａ２测定细胞内游离钙技术观察了地塞米松（ｄｅｘａｍｅｔｈａｓｏｎｅ,ＤＥＸ）对家兔乙二醇双（２氨基乙醚）四乙酸性发热效应和下丘脑细胞内游离钙浓度（［Ｃａ２＋］ｉ）的影响,借此深入探讨地塞米松解热作用的中枢机制。结果发现：脑室灌注乙二醇双（２氨基乙醚）四乙酸（０６ｎｍｏｌ）引起家兔结肠温度明显升高,静脉注射地塞米松（５ｍｇ／ｋｇ）显著抑制家兔乙二醇双（２氨基乙醚）四乙酸性发热,地塞米松（６０～１２０μｍｏｌ／Ｌ）并不影响下丘脑细胞内［Ｃａ２＋］ｉ,而事先脑室灌注抑制基因转录的放线菌素Ｄ（３ｎｍｏｌ）则完全取消了地塞米松对乙二醇双（２氨基乙醚）四乙酸性发热的解热作用。这些结果提示：地塞米松显著抑制家兔乙二醇双（２氨基乙醚）四乙酸性发热,其机制与地塞米松激活脑内某些基因的表达有关,而与下丘脑神经细胞跨膜钙离子流无关。     

Safety, efficacy and effectiveness of cold-adapted, live, attenuated, trivalent, intranasal influenza vaccine in adults and children.

Studies in children and adults revealed cold-adapted, live, attenuated, trivalent, intranasal influenza vaccine (CAIV-T) to be well accepted, well tolerated and highly protective against culture-confirmed influenza, and to provide significant health benefits. A 2 year, multicentre, double-blind, placebo-controlled efficacy field trial of CAIV-T in children aged 15-71 months with annual re-immunization revealed the vaccine to be highly protective against culture-confirmed influenza. Vaccine induced serum and secretory antibodies in vaccinated children. Overall, during 2 years of study, vaccine was 92% protective against culture-confirmed influenza. During the second year of study the vaccine was 86% protective against influenza A/Sydney/5/97-like virus, a significantly drifted strain not well matched to the vaccine. Antibody studies on children given CAIV-T revealed that high titres of cross-reacting antibodies to influenza A/Sydney/5/97 were induced with vaccination by live attenuated influenza A/Wuhan/359/95-like vaccine. Effectiveness measures revealed significant reductions in febrile illness (21% reduction in year 1, 19% reduction in year 2), febrile otitis media (33% reduction in year 1, 16% reduction in year 2) and associated antibiotic use among vaccinated children compared with placebo recipients. In adults, vaccination with CAIV-T resulted in protection during experimental challenge with virulent wild-type viruses. An effectiveness trial in adults demonstrated significant benefits of CAIV-T vaccine (28% reduction in days of missed work for febrile upper respiratory illness days with associated 45% reduction in days taking antibiotics). General use of CAIV-T has the potential to significantly reduce the impact of influenza in children and adults.     

Antipyretic properties of centrally administered α-MSH fragments in the rabbit

alpha-Melanocyte stimulating hormone (alpha-MSH 1-13) has marked antipyretic effects when administered centrally or peripherally in small doses. A C-terminal fragment, alpha-MSH (11-13), contains an antipyretic message sequence of alpha-MSH; however, the lesser potency of this fragment relative to that of the entire molecule suggests that other amino acids of the alpha-MSH sequence are essential for the full antipyretic effect. Graded doses of alpha-MSH (11-13) (Ac LysProVal NH2), alpha-MSH (10-13) (Ac GlyLysProVal NH2), and alpha-MSH (8-13) (Ac ArgTrpGlyLysProVal NH2), were injected into the cerebral ventricles of rabbits made febrile by IV administration of crude interleukin-1. All three fragments reduced fever in a dose-related manner. The (8-13) sequence was much more effective than the other two fragments, and the (10-13) portion was less effective than the (11-13) tripeptide. None of the fragments was as potent as alpha-MSH (1-13). The results confirm that an antipyretic message resides within alpha-MSH (11-13) and sequential addition of amino acids to alpha-MSH (11-13) can both enhance and reduce the potency of the fragment.