Inflammatory responses to intradermal injection of platelet activating factor, histamine and prostaglandin E2 in healthy volunteers: a double blind investigation.

Sciberras, DG; Mm, Goldenberg; Bolognese, JA; James, Ian; Baber, N.

doi:10.1111/j.1365-2125.1987.tb03242.x

Cited by 31 publications

(15 citation statements)

References 15 publications

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“…In the current study, both of these irritants produced hyperalgesia (increased sensitivity to noxious temperatures) and allodynia (increased sensitivity to non-noxious temperatures). These effects of PGE 2 and capsaicin in rodents extends previous findings in rhesus monkeys (Negus et al, 1993;Brandt et al, 2001) and in humans (Sciberras et al, 1987;LaMotte et al, 1991). Given the similarities between the dose range and temperature responses in preclinical and clinical studies, these results suggest that capsaicin-and PGE 2 -induced thermal hypersensitivity could be useful surrogate endpoints when assessing novel compounds having potential clinical utility.…”

Section: Discussionsupporting

confidence: 72%

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

Brandt

Cummons²,

Potestio³

et al. 2005

J Pharmacol Exp Ther

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Effects of the N-Methyl-D-aspartate Receptor AntagonistPerzinfotel [2][3][4][5][6][7][8] ABSTRACT Perzinfotel [2][3][4][5][6][7][8].0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] is a selective, competitive Nmethyl-D-aspartate (NMDA) receptor antagonist with high affinity for the glutamate site. The current study evaluated whether perzinfotel would have antinociceptive effects or block thermal hypersensitivity associated with the administration of chemical irritants in rats. Perzinfotel lacked antinociceptive effects but dose-and time-dependently blocked prostaglandin E 2 (PGE 2 )-and capsaicin-induced thermal hypersensitivity in a warm-water tail-withdrawal assay in rats. Doses of 10 mg/kg intraperitoneal or 100 mg/kg oral blocked PGE 2 -induced hypersensitivity by 60 to 80%. The magnitude of reversal was greater than other negative modulators of the NMDA receptor studied, such as uncompetitive channel blockers (e.g., memantine, dizocilpine, and ketamine), a NR2B selective antagonist (e.g., ifenprodil), and other glutamate antagonists [e.g., selfotel, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP-39653)], up to doses that suppressed operant rates of responding. In contrast to other negative modulators of the NMDA receptor studied, which typically decreased operant rates of responding at doses that lacked antinociceptive effects, perzinfotel did not modify response rates at doses that blocked irritant-induced thermal hypersensitivity. Collectively, these studies demonstrate that perzinfotel has therapeutic ratios for effectiveness versus adverse effects superior to those seen with other competitive and uncompetitive NMDA receptor antagonists studied.Excitatory amino acids acting at NMDA receptors play a role in both acute and chronic pain. Increases in afferent input and glutamate release within the spinal cord have been observed after peripheral injection of an irritant (e.g., carrageenan) or tissue injury (Sluka and Westlund, 1993;Kawamata and Omote, 1996;Dickenson et al., 1997). Repeated stimulation of primary afferent fibers can progressively increase the magnitude and duration of action potentials in spinal cord (often termed "windup"), which can lead to central sensitization (Ma and Woolf, 1995). This neuronal hyperexcitability manifests itself in a lowered threshold to evoked activity (i.e., hyperalgesia), an expansion of receptive fields (i.e., secondary hypersensitivity), and an ability of non-noxious input to evoke neuronal activity (i.e., allodynia). In preclinical studies, NMDA receptor antagonists reverse neuronal hyperexcitability and reverse hypersensitivity in several inflammatory and neuropathic animal pain models associated with various pathophysiologic mechanisms (Mao et al., 1993;Chaplan et al., 1997;Suzuki et al., 2001). In clinical studies, NMDA receptor antagonists, such as ketamine and dextromethorphan, reduce windup pain, spontaneous pain, hyperalgesia, and allodynia in patients with postherpetic neuralgia pain, phantom ...

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Section: Discussionsupporting

confidence: 72%

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

Brandt

Cummons²,

Potestio³

et al. 2005

J Pharmacol Exp Ther

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“…Although it is not possible to be certain of the mechanism of local erythema, vancomycin degranulates Vancomycin dose (mcg/ml) human mast cells in vitro (15), suggesting that histamine is at least in part responsible. A number of other drugs demonstrate a similar dermal response following local application, including narcotics (4,6,8), neuromuscular blocking agents (9,21), and platelet-activating factor and prostaglandin E2 (27). Most of these agents have been shown to degranulate cutaneous mast cells, and the size of the weal and flare is thought to depend on the amount of histamine released and the amount of drug injected (2,4,6,8,10,14,20,21).…”

Section: Discussionmentioning

confidence: 99%

Vancomycin skin tests and prediction of "red man syndrome" in healthy volunteers

Polk

Israel

Wang

et al. 1993

Antimicrob Agents Chemother

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The purpose of the present study was to assess the cutaneous response to intradermally administered vancomycin in healthy adults and to determine whether the magnitude of the cutaneous response correlated to the severity of "red man syndrome" (RMS) following intravenous administration of vancomycin to the same subjects. Eleven healthy males were skin tested with intradermally administered histamine and saline controls and intradermally administered vancomycin at different concentrations. Vancomycin caused a dose-dependent area of flare in all subjects. The sigmoidal maximal flare model was used to fit each dose-response curve, and cutaneous responsiveness to vancomycin was quantified by various methods, including the flare area at each dose, maximum flare area (maximal flare), dose required to produce 50%o of maximum flare, dose required to produce a flare area of 400 mm2, and the slope of the dose-response curve. One week after skin testing, subjects received an infusion of vancomycin, 15 mg/kg of body weight over 60 min. For the assessment of the severity of RMS, we used previously described methods. Although all subjects experienced erythema from the intravenously administered vancomycin and 10 subjects had pruritus, there was no significant correlation between vancomycin skin test results and the severity of RMS. We conclude that vancomycin skin tests do not predict the severity of RMS. In addition, vancomycin skin tests may be of no benefit for assessing immunoglobulin E-mediated allergy to vancomycin, since all subjects had a positive reaction at concentrations of 210 Fg/ml.The most common adverse effect of vancomycin is "red man syndrome" (RMS), which is characterized by flushing and itching, especially of the upper torso (23). In severe cases, hypotension may occur. These signs and symptoms result from the nonimmunologic release of histamine, and the severity is proportional to the amount of histamine released (24). The source of histamine is believed to be primarily cutaneous mast cells, and vancomycin has been shown to result in mast cell degranulation in vitro (15). The frequency of RMS is largely determined by dose and infusion time. In healthy volunteers who receive 1 g as a 60-min infusion, the frequency is 80 to 90% (23). The frequency of RMS in infected patients who receive vancomycin (1 g over 60 min) varies from <10 to 50% in prospective studies (25,28). RMS may be prevented in most patients by a reduction in the dose or the rate of infusion or by premedication with antihistamines (23).In normal volunteers, the severity of RMS varies widely, despite administration of identical doses (24). The reason for this large difference in susceptibility to vancomycin toxicity is unknown, but it probably reflects between-subject differences in histamine release. We reasoned that if vancomycin causes a direct release of histamine by degranulation of cutaneous mast cells, then intracutaneous administration of vancomycin should produce a dose-related weal-and-flare * Corresponding author. t Present address:

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“…Given that PAF is a potent stimulator of skin inflammation (38,58,59), the next studies were designed to assess the role of the PAF system in the photosensitivity exhibited by XpaϪ/Ϫ mice. To that end, the dorsal side of ears of XpaϪ/Ϫ and wildtype SKH-1 mice were treated with UVB irradiation, and inflammation was assessed by daily measurement of ear thickness.…”

Section: Uvb Irradiation Generates Increased Paf-r Agonists In Xpaϫ/ϫmentioning

confidence: 99%

Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity

Yao

Harrison

Al-Hassani

et al. 2012

Journal of Biological Chemistry

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Background: Deficiency of the nucleotide excision repair protein xeroderma pigmentosum type A (XPA) is characterized by photosensitivity. Results: XPA-deficient cells and mice generate increased platelet-activating factor (PAF), oxidized glycerophosphocholines, and skin inflammation following ultraviolet B radiation with the skin inflammation blocked by PAF antagonists. Conclusion: PAF-R signaling mediates photosensitivity seen in XPA deficiency. Significance: These studies provide important insights into the mechanisms of photosensitivity.

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Inflammatory responses to intradermal injection of platelet activating factor, histamine and prostaglandin E2 in healthy volunteers: a double blind investigation.

Cited by 31 publications

References 15 publications

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

Vancomycin skin tests and prediction of "red man syndrome" in healthy volunteers

Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity

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