Análisis de las prescripciones nuevas al alta de un Servicio de Urgencias Hospitalario. Impacto en la seguridad y eficiencia / Analysis of new prescriptions at discharge in an Emergency Deparment. Impact on drug safety and efficiency

Objetivo: Analizar las prescripciones nuevas al alta del Servicio de Urgencias Hospitalario: perfil de utilización, grado de adecuación a la Guía Farmacoterapéutica del hospital (GFT), calidad de la prescripción y estimación de costes.Método: Estudio descriptivo transversal. Las variables incluyeron número de medicamentos prescritos, si se hizo según Denominación Oficial Española, financiación por el Sistema Nacional de Salud, adecuación a la GFT y existencia de alternativa más económica. También se comprobó la cumplimentación de datos básicos y coste de las prescripciones.Resultados: En un total de 1.252 episodios hubo 2.152 prescripciones nuevas al alta. Del total de prescripciones, se adecuaron a la Guía Farmacoterapéutica del hospital el 78,0% y estaban financiadas el 88,9%. Los fármacos más comunes fueron: paracetamol metamizol, ibuprofeno, dexketoprofeno y omeprazol. La cumplimentación deficitaria de la prescripción comprometió la dispensación en 231 prescripciones (10,7%). En 20 presentaciones se concentra el 57,5% del gasto y el 73% del ahorro. Extrapolando los resultados a las prescripciones de un año se obtiene que el gasto farmacéutico sería de 1.161.608,8€, esperándose una reducción en 370.846,2€ tras la adecuación a la guía o de 571.323,3€ añadiendo la entrega de medicación. Conclusiones: Las prescripciones nuevas al alta se concentran en un número bajo de medicamentos. Actuar sobre los mismos permite un amplio margen de mejora económico y aumenta la seguridad. Evitar la prescripción de medicamentos no financiados y garantizar la entrega de la medicación al alta en el Servicio de Urgencias, son otro de las puntos de mejora identificados. (AU)

Objective: To analyze the new prescriptions at discharge from the Emergency Department: utilization profile, degree of adaptation to the Pharmacotherapeutic Guide, quality of the prescription and cost estimation.Method: Cross-sectional descriptive study. The variables included the number of prescribed medications, if it was done according to the Spanish Official Denomination, financing by the National Health System, adaptation to the Pharmacotherapeutic Guide and the existence of a cheaper alternative. The completion of basic data and cost of prescriptions was also checked.Results: A total of 1,252 episodes received 2,152 prescriptions with a mean of 2.1 per episode. Out of them 78% were adapted to the hospital pharmacotherapeutic guide and 88.9% financed drugs. Most common drugs were: acetaminophen, metamizole, ibuprofen, desketoprofen and omeprazole. The deficit filling of the prescription compromised the dispensation in 231 prescriptions (10.7%). In 20 drugs, 57.5% of spending and 73.0% of saving were concentrated. Extrapolating the results to the prescriptions of one year, it is obtained that the expense would be €1,161,008.8, expecting for a reduction in €370,846.2 after adaptation to the guide or € 571,323.3 by adding the medication delivery strategy.Conclusions: New prescriptions at discharge are concentrated in a low number of medications. Acting on them allows a wide margin of economic improvement and increases security. Avoiding the prescription of non-financed medicines and guaranteeing the delivery of the medication upon discharge from the Emergency Department are another of the points of improvement identified. (AU)

Actualización en neurobiología de la sensibilidad corneal: una necesidad / Actualization on the neurobiology of the corneal sensitivity: a need

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Three-dimensional reconstruction of scleral cold thermoreceptors of the cat eye.

Sensory endings that respond to local cooling were identified electrophysiologically in the cat's sclera. Functionally identified scleral thermal fibers were then used to analyze the structural characteristics of cold receptor endings. Four Adelta units sensitive to controlled cooling of their scleral receptive fields were recorded. The receptive areas were mapped, demarcated with pins and examined electron microscopically using extensive three-dimensional reconstructions. The supporting tissue within the receptive areas of cold units consisted of dense collageneous tissue with a small number of blood vessels that were either veins or capillaries. Adelta nerve fibers were found within these tissue blocks presumably corresponding with cold sensitive fibers. Small nerves and single nerve fibers devoid of a perineurium were found in all parts of the tissue, only occasionally passing a blood vessel. The terminal portions showed axonal swellings all along the unmyelinated segment filled with mitochondria, glycogen particles, and some vesicles. About 30% of the terminal axonal membrane is not covered by Schwann cells. In the unmyelinated distal portion, the mitochondrial content ranged from 0.012 to 0.038 microm(3) mitochondrial volume per microm(2) nerve fiber membrane. In comparison with sensory endings in the cat's knee joint, cold receptors in the cat sclera showed many similarities in their three-dimensional structure with polymodal nociceptor endings of the knee joint but contain less mitochondria. This suggests that cold sensory endings do not require specialized cellular processes for the transduction of cold stimuli, as is the case for multimodal transduction and sensitization in the terminal portion of polymodal nociceptors.

Sensations evoked by selective mechanical, chemical, and thermal stimulation of the conjunctiva and cornea.

PURPOSE: To study the sensations evoked by selective mechanical, chemical, and thermal stimulation of the conjunctiva and compare them with those elicited by similar stimulation of the cornea. METHODS: Six young subjects participated in the study. Using a gas esthesiometer, selective mechanical (air puffs at flows from 0 to 264 ml/min), chemical (0--80% CO(2) in air), and thermal (air at temperatures from -10 degrees C to +80 degrees C) stimulation was performed on the center of the cornea and on the temporal conjunctiva. The intensity, degree of irritation, stinging and burning pain components, and thermal characteristics of the evoked sensation were evaluated after each stimulus in separate, 10-cm continuous visual analogue scales (VASs). The ability of the subjects to identify the quality of the stimulus applied to the cornea and the conjunctiva was also studied. RESULTS: The subjective intensity and thermal components (cooling or warming) of the sensation reported after mechanical, chemical, and heat stimulation were similar in the conjunctiva and cornea, although lower VAS scores were always reported in the conjunctiva for the irritation and the stinging and burning pain components. In the cornea, stimulation with low temperatures was perceived as a cooling sensation with an irritative component. In the conjunctiva, cooling was perceived as a purely cold sensation. Subjects showed similar discrimination capability in the cornea and the conjunctiva for the various types of stimuli. CONCLUSIONS: Sensations evoked in the cornea by selective mechanical, chemical, and heat and cold stimulation always presented an irritation component. In the conjunctiva, stimuli of the same intensity are always perceived as less irritating than in the cornea. Cold and other non-noxious subqualities of sensation can be evoked in the conjunctiva.

Sensory experiences in humans and single-unit activity in cats evoked by polymodal stimulation of the cornea.

1. The cornea of human subjects and of anaesthetised cats was stimulated with a jet of air of controlled flow, temperature and CO(2) concentration delivered by a gas aesthesiometer. 2. In humans, the intensity and magnitude of various components of the sensory experience (intensity of the sensation, degree of irritation, magnitude of burning and stinging pain, magnitude of the cold and warm components of the sensation) were measured using separate visual analog scales. In anaesthetised cats, the impulse response to the same stimuli was recorded from single mechanosensory, polymodal and cold-sensitive corneal fibres in the ciliary nerves. 3. Intensity-response curves for mechanical stimulation showed that all parameters of the sensation experienced by humans increased with the intensity of the stimulus. Mechanical stimuli recruited mainly phasic mechanosensory and polymodal afferents in the cat. 4. Acidic stimulation with gas mixtures of increasing CO(2) concentration evoked irritation, burning and to a lesser extent stinging pain of a magnitude roughly proportional to the intensity of the stimulus in humans. CO(2) primarily recruited polymodal afferents and weakly excited cold-sensitive fibres in the cat's cornea. 5. Heat stimuli evoked in humans a sensation profile similar to CO(2) but accompanied by a warmth component. In the cat's cornea, heat excited only polymodal fibres and silenced cold-sensitive corneal units. 6. Cold stimuli applied to the human cornea elicited a sensation of cooling that became irritant at the lowest temperatures. Corneal cold-sensitive fibres of the cat were activated in a manner proportional to the temperature drop, while polymodal nociceptor fibres were recruited only by the lowest temperatures. Topical menthol (0.2 mM) applied to humans evoked and later eliminated cold sensations produced by cold stimuli while the irritation sensation caused by low temperature stimuli still persisted. 7. Human subjects were able to identify masked mechanical, thermal and chemical stimuli applied to the cornea. 8. Irritation and cold sensations can therefore be evoked separately from the cornea by selective activation of mechanosensory, polymodal and cold corneal sensory afferents. Stimulation with different forms of energy usually leads to combined activation and/or inhibition of the different populations of sensory afferent fibres, evoking blended sensations that include irritation and thermal components in a variable degree.

Corneal morphology and sensitivity in lattice dystrophy type II (familial amyloidosis, Finnish type).

PURPOSE: To describe the corneal abnormalities and to measure different modalities of corneal sensitivity in corneal lattice dystrophy type II (familial amyloidosis, Finnish type, also known as gelsolin-related amyloidosis and originally as Meretoja syndrome). METHODS: Twenty eyes of 20 patients were examined by in vivo confocal microscopy and noncontact gas esthesiometry. RESULTS: Pleomorphism of, and dense deposits between or posterior to, the basal epithelial cells were frequently observed, as well as a reduction of long nerve fiber bundles in the subbasal nerve plexus. The anterior stroma was altered in most cases, with fibrosis and abnormal extracellular matrix. In 15 corneas, thick anterior and midstromal filaments, corresponding to lattice lines, and in 11 corneas, thin undulated structures were observed. The average mechanical sensitivity threshold of 12 subjects was increased, and in the remaining 8 subjects there was no response, even to the highest intensity of stimuli used. Three patients did not respond to CO(2), 11 to heat, and 2 to cold, but those patients who responded had normal thresholds. Patients with more long nerve fiber bundles per confocal microscopic image had better mechanical and cold sensitivity than patients with fewer nerve fiber bundles. CONCLUSIONS: Lattice lines seem to be related to amyloid material and not to corneal nerves. However, the subbasal nerve density appears reduced, which results mainly in a decrease in mechanical and, to a lesser extent, thermal sensitivity. The location of stromal filaments and undulated structures changes with increasing age.

Arginine-rich peptides are blockers of VR-1 channels with analgesic activity.

Vanilloid receptors (VRs) play a fundamental role in the transduction of peripheral tissue injury and/or inflammation responses. Molecules that antagonize VR channel activity may act as selective and potent analgesics. We report that synthetic arginine-rich hexapeptides block heterologously expressed VR-1 channels with submicromolar efficacy in a weak voltage-dependent manner, consistent with a binding site located near/at the entryway of the aqueous pore. Dynorphins, natural arginine-rich peptides, also blocked VR-1 activity with micromolar affinity. Notably, synthetic and natural arginine-rich peptides attenuated the ocular irritation produced by topical capsaicin application onto the eyes of experimental animals. Taken together, our results imply that arginine-rich peptides are VR-1 channel blockers with analgesic activity. These findings may expand the development of novel analgesics by targeting receptor sites distinct from the capsaicin binding site.

Responses of nerve fibres of the rat saphenous nerve neuroma to mechanical and chemical stimulation: an in vitro study.

The response of neuroma nerve endings to different stimuli was studied in a saphenous nerve neuroma preparation in vitro. Electrical activity was recorded from 141 single fibres dissected of saphenous nerve. One-third (27 %) displayed spontaneous activity. Based on their response to mechanical and chemical stimuli, neuroma nerve fibres were classified as mechanosensory fibres (47.5 %), mechanically insensitive chemosensory fibres (17.0 %), polymodal nociceptor fibres (28.4 %) and unresponsive fibres (7.1 %). Mechanosensory and polymodal neuroma endings responded to von Frey hair stimulation either with a few impulses (phasic units) or a sustained discharge (tonic units). Polymodal units were additionally activated by at least one of the following stimuli: acidic solutions; a combination of bradykinin, prostaglandin E2, serotonin, substance P and histamine (all at 1 microM) plus 7 mM KCl (inflammatory soup); 600 mM NaCl and capsaicin. Low pH solutions increased the firing discharge of polymodal endings proportionally to the proton concentration. The 'inflammatory soup' evoked a firing response characterized by the absence of tachyphylaxis, which appeared when its components were applied separately. Both stimuli sensitized polymodal fibres to mechanical stimulation. Hypertonic NaCl (600 mM) and capsaicin (3.3 mM) induced a prolonged discharge that outlasted the stimulus duration. Mechanically insensitive chemosensory neuroma fibres exhibited responses to chemical stimuli analogous to polymodal fibres. They became mechanically sensitive after chemical stimulation. These findings show that neuroma nerve endings in the rat saphenous nerve neuroma in vitro are functionally heterogeneous and exhibit properties reminiscent of those in intact mechanosensory, polymodal and 'silent' nociceptor sensory afferents, including their sensitization by algesic chemicals.

Variaciones en el trofismo y la sensibilidad corneal tras la queratoplastia penetrante / Corneal trophism and sensitivity after penetrating keratoplasty

Objetivo: Valorar la correlación entre las variaciones en la sensibilidad de contacto y la función trófica del epitelio corneal del ojo de conejo, tras la denervación periférica que originan heridas circulares (trepanaciones) en la córnea, similares a las realizadas durante las queratoplastias penetrantes en humanos. Métodos: El estudio incluyó 40 ojos de conejo, de los que en 12 fueron practicadas trepanaciones completas con rotación del botón corneal (TCR) y en otros 12, trepanaciones parciales que afectaron al menos dos terceras partes del espesor total de la córnea (TSR). Los 16 ojos restantes no fueron intervenidos y sirvieron como controles. La sensibilidad y trofismo epiteliales fueron evaluados tres meses después de las queratoplastias experimentales. La sensibilidad mecánica fue explorada con el estesiómetro de Cochet y Bonnet (filamento de nylon n.º 12). La función trófica se valoró calculando la velocidad de reepitelización de desepitelizaciones producidas en la superficie de la córnea mediante la aplicación de un papel impregnado en n-heptanol. Resultados: A los tres meses de la intervención, la sensibilidad de contacto en el centro de las córneas intervenidas registraba variaciones muy importantes (umbrales mecánicos: 240ñ0 mg/S en las TCR y 179ñ20 mg/S en las TSR, vs 88ñ10 mg/S en los ojos control, p<0,001 en ambos casos). En cambio, la capacidad de las córneas trepanadas para regenerar las lesiones practicadas en su epitelio fue similar a la de los ojos controles, no intervenidos. Tampoco se encontraron diferencias en la función reepitelizadora al comparar las córneas con trepanaciones completas con las de trepanación de espesor parcial. Conclusiones: Los resultados obtenidos sugieren que el epitelio de las córneas trasplantadas no debe presentar problemas en su mantenimiento trófico, a pesar de la profunda hipoestesia que habitualmente se registra en su superficie. La trascendencia clínica de este hallazgo nos obliga a profundizar en las bases anatómicas, fisiológicas y bioquímicas de esta interacción entre neuronas y epitelio corneal (AU)

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Autosomal recessive cornea plana: in vivo corneal morphology and corneal sensitivity.

PURPOSE: Autosomal recessive corneal plana (RCP) is a rare corneal anomaly with unknown pathogenesis and a high incidence in Finland. The aim was to examine corneal sensitivity and the morphology of different corneal layers and subbasal nerves in RCP patients. METHODS: Three patients with a diagnosed autosomal recessive cornea plana were examined. Corneal sensitivity to different modalities of stimulation was tested in four corneas using noncontact esthesiometry. Tissue morphology of three corneas was evaluated, and in two corneas thickness of corneal layers was measured using in vivo confocal microscopy. RESULTS: Corneas of RCP patients appear to have mechanosensory, polymodal, and cold-sensitive nerve terminals. RCP patients had normal sensation thresholds for chemical, heat, and cold stimulation but a high threshold for mechanical stimulation. Their capacity to discriminate increasing intensities of stimulus was reduced, except for cold stimuli. Thickness of the epithelial layer was reduced, whereas total corneal and stromal thicknesses were slightly reduced or close to normal values. In all cases Bowman's layer was absent. Subbasal nerves had abnormal branching patterns. The arrangement of anterior keratocytes was altered, showing clustered and irregularly shaped nuclei. Increased backscattering of light in confocal microscopy through focusing (CMTF) profiles was observed throughout the stroma. Epithelial and endothelial cells appeared to be regular in shape. CONCLUSIONS: The present study revealed qualitative and quantitative alterations in corneal sensitivity, cellular morphology, and the thickness of corneal layers in RCP patients.

Effects of oleoresin capsicum pepper spray on human corneal morphology and sensitivity.

PURPOSE: To examine the potential harmful effects on corneal structure, innervation, and sensitivity of a spray containing the neurotoxin capsaicin (oleoresin capsicum, OC). METHODS: Ten police officers who volunteered for the study were exposed to OC. Clinical signs were assessed. Corneal sensitivity was measured using a Cochet-Bonnet or a noncontact esthesiometer that provides separate measurements of mechanical, chemical, and thermal sensitivity. Tear fluid nerve growth factor (NGF) was measured. Corneal cell layers and subbasal nerves were examined by in vivo confocal microscopy. The subjects were examined before application and 30 minutes, 1 day, 1 week, and 1 month after OC exposure. RESULTS: OC spray produced occasional areas of focal epithelial cell damage that healed within 1 day. Each eye showed conjunctival hyperemia and in two subjects, mild chemosis. All except one eye had unchanged best corrected visual acuity (BCVA). A transient decrease (day 1) of mechanical sensitivity was observed with the Cochet-Bonnet esthesiometer. With the gas esthesiometer, mechanical sensitivity remained below normal values for 7 days. Chemical sensitivity to CO2 was high for as much as 1 day and decreased below normal 1 week later, whereas sensitivity to cold was unaffected. Two subjects had measurable tear NGF that increased after exposure. Basal epithelial cell morphology suggested temporary corneal epithelial swelling, whereas keratocytes, endothelial cells, and subbasal nerves remained unchanged. CONCLUSIONS: Although OC causes immediate changes in mechanical and chemical sensitivity that may persist for a week, a single exposure to OC appears harmless to corneal tissues. The changes are possibly associated with damage of corneal nerve terminals of mainly unmyelinated polymodal nociceptor fibers.

[Corneal trophism and sensitivity changes after penetrating keratoplasty]. / Variaciones en el trofismo y la sensibilidad corneal tras la queratoplastia penetrante.

PURPOSE: To evaluate in the rabbit eye the changes in mechanical sensitivity and trophic function of the corneal epithelium after the denervation consecutive to circular trephinations of the peripheral cornea, similar to those produced by penetrating keratoplasty. METHODS: Complete trephination (8 mm diameter) with rotation of corneal button (PK) was performed in 12 eyes. Non-penetrating trephination, affecting 2/3 of the corneal depth, was made in a group of 12 eyes (NPK). A separate group of 16 nonoperated eyes served as control. Mechanical corneal sensitivity was measured with the Cochet-Bonnet esthesiometer (No. 12 filament). Trophic function of the corneal epithelium was assessed by determining the healing rate of epithelial wounds performed with n-heptanol. RESULTS: Three months after surgery, sensitivity in the center of the cornea was significantly reduced in both PK and NPK eyes (240+/-0 mg/S and 179+/-20 mg/S, respectively) when compared with control (88+/-10 mg/S, p<0.001). The ability of denervated corneas to regenerate corneal epithelial defects was similar in both, operated and non-operated eyes. Also, no differences were found between PK and NPK eyes. CONCLUSIONS: Results suggest that three months after corneal graft, throphic maintenance of the epithelium remains unaffected in spite of the significant hypoesthesia recorded at this time. Further experiments are needed to analyze the interaction between corneal epithelial cells and the trigeminal neurons innervating the cornea

The influence of eye solutions on blinking and ocular comfort at rest and during work at video display terminals.

The aim of this work was to study blink frequency changes and levels of ocular discomfort during work at a video display terminal, and the effects on these parameters of augmented or reduced humidification of the ocular surface. Blink rate was measured from recordings of the electrical signal evoked by the contraction of the orbicularis oculi muscle. Blink rate and interblink intervals were analyzed at rest and during performance of a task with a computer (playing a card game) for 10 or 30 min in steady environmental conditions and during application of a continuous stream of air to the face. In two separate sessions, the effect of pretreatment with humidifying ocular solutions of different elastoviscosity (balanced salt solution or elastoviscous 0.1% Hylan A solution) was assayed. At the end of each experimental period, the subjects marked the level of ocular discomfort experienced on a 0-10 cm visual analogue scale. The blink frequency at rest (12.4+/-1.2 blinks min-1) was reduced significantly (to 10.3+/-1.1 blinks min-1) by pretreatment with elastoviscous eyedrops both with and without air applied to the face. This effect was not obtained with balanced salt solution. During performance of the visual task for 10 or 30 min, basal blink rate decreased significantly, to about 40% of the control value. Neither application of an air jet on the face nor application of eye solutions of different viscosity modified this reduced blink rate.A low degree of ocular discomfort developed after performance of the visual task that was enhanced by air application to the face. This discomfort was reduced by pretreatment with ocular solutions, the elastoviscous eye solution being more efficient than the balanced salt solution. Interblink interval duration was also more regular after treatment with the elastoviscous solution. These data suggest that blink rate at rest is maintained in part by activation of sensory receptors of the cornea and conjunctiva, which are stimulated by desiccation of the ocular surface. Reduction of eye blink frequency elicited by the performance of a visual task with a computer appears to depend on central neural mechanisms that are quite independent of peripheral sensory inputs. The reduction of blink frequency consecutive to computer use was associated with a sensation of discomfort that was attenuated more effectively by elastoviscous eyedrops than by regular balanced salt solution.

Measurement of corneal sensitivity to mechanical and chemical stimulation with a CO2 esthesiometer.

PURPOSE: To develop an instrument to measure corneal sensitivity. Mechanical stimulation was performed with increasing air flow. Chemical stimulation consisted of local pH decreases induced by a mixture of air and CO2 at different concentrations. METHODS: Air and 98.5% CO2 were mixed with an electronic, proportional-direction control valve to obtain gas mixtures from 0% to 80% CO2. The regulated outflow of gas was carried to a probe mounted on a slit lamp holder, where it was warmed and its CO2 concentration monitored. An electronic valve directed gas pulses of controlled duration to the cornea. Corneal stimulation was performed in 17 young human subjects. The intensity of the experienced sensation was recorded in a continuous visual analog scale (VAS). To obtain threshold values and intensity-response curves, 3-second pulses were applied. For mechanical stimulation, air pulses of increasing flow were used. For chemical stimulation, gas mixtures of increasing CO2 concentration at subthreshold flow and CO2 in stepped increases of 5% was applied. RESULTS: Mechanical and chemical stimulation of the cornea evoked a brief sensation of irritation. Mechanical threshold (flow values) varied among subjects but were reproducible within each subject and were higher with warmed air. The magnitude of the sensation increased proportionally to the flow of air. The mean chemical stimulation threshold (CO2 concentration) was 25% +/- 3%. Increases in CO2 concentration from 10% to 80% augmented proportionally the intensity of the evoked sensation. CONCLUSIONS: The gas esthesiometer, which combines variable air flow and CO2 concentrations, permits application to the cornea of mechanical stimuli of controlled force and pH reductions of increasing magnitude. This instrument may be useful in a separate exploration of mechanical and chemical sensitivity of the cornea in human subjects.

Quantification and immunocytochemical characteristics of trigeminal ganglion neurons projecting to the cornea: effect of corneal wounding.

The number and immunocytochemical characteristics of trigeminal ganglion neurons providing sensory innervation to the cornea were studied in the mouse. Corneal neurons were retrogradely labelled with fluorogold placed on the cornea after removal of the epithelium with n-heptanol. Corneal neurons were counted, sized and characterized immunocytochemically with antisera against substance P (SP), calcitonin gene-related peptide (CGRP), calbindin, calretinin, and with a monoclonal antibody (RT97) against neurofilament proteins. A total of 258 corneal neurons were counted, most of them located in the ophthalmic division of the trigeminal ganglion. They represent only a small fraction (1.3%) of the population of trigeminal ganglion neurons. More than 70% of corneal neurons were classified as 'small dark' according to their cell body area and the absence of immunoreactivity to RT97. A low percentage of corneal neurons, usually large in size, contained calcium binding proteins. Fifty-eight percent of the corneal neurons were immunoreactive to CGRP, and 20% to SP. Corneal wounding with NaOH, which affects stromal nerve trunk, did not modify the total number of corneal neurons or their neuropeptide content. However, this increased the total number of calbindin-positive and decreased the RT97-positive neurons. Thus, unlike in other nociceptive neurons, peripheral axotomy did not modify the SP/CGRP content of corneal neurons.Trigeminal ganglion neurons projecting to the cornea are similar in size and neuropeptide content to nociceptive neurons of other territories. Their number is high in relation to the corneal surface, thus confirming that the cornea has a large nociceptive representation in the trigeminal ganglion. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

Reduction by antiinflammatory drugs of the response of corneal sensory nerve fibers to chemical irritation.

PURPOSE: Nonsteroidal antiinflammatory drugs (NSAIDs) have been applied topically to reduce ocular pain caused by corneal injury or anterior segment surgery. The authors investigated whether the analgesic effects of the NSAIDs diclofenac, indomethacin, and flurbiprofen and of the calcium channel antagonist diltiazem on corneal pain are mediated by a reduction of nerve activity in corneal polymodal nociceptive fibers. METHODS: Impulse activity of single A-delta and C corneal nerve fibers was recorded from the ciliary nerves of anesthetized cats. Polymodal units were identified by their response to both touching with the Cochet-Bonnet esthesiometer and to acidic stimulation with 30-second pulses of 80% or 98.5% CO2 or 60 microl of 10 mM acetic acid, applied to the corneal receptive area. Ongoing impulse activity, firing responses to CO2 or acetic acid, and mechanical threshold of single fibers were recorded before and at various times (5 to 90 minutes) after topical application of 0.1% sodium diclofenac, 0.03% sodium flurbiprofen, 0.1% indomethacin, and 0.045% diltiazem hydrochloride or of their vehicles. RESULTS: Indomethacin, diclofenac, and flurbiprofen, in decreasing order of potency, gradually reduced the mean frequency of the impulse response of corneal polymodal nerve fibers evoked by CO2 stimuli. The progressive increase of ongoing activity, observed in vehicle-treated eyes after repeated CO2 stimulation was also prevented by NSAIDs. Diltiazem also attenuated the response to CO2 for a shorter period of time and with a faster time course. The mechanical threshold of corneal polymodal fibers was not affected by treatment with any of these drugs. CONCLUSIONS: Indomethacin, diclofenac, and flurbiprofen, as well as the calcium antagonist diltiazem, diminish the responsiveness of corneal polymodal nociceptors to chemical stimuli. This appears to be caused, in part, by a direct effect of these drugs on the excitability of polymodal nerve endings, but also by an inhibition by NSAIDs of the formation of cyclooxygenase products such as prostaglandins, thus reducing the enhanced responsiveness of nociceptors caused by local release of arachidonic acid metabolites from injured cells.

Endogenous circadian rhythm of basal pupil size in rabbits.

PURPOSE: The authors examined the circadian change of basal pupil size in light-dark entrained normal rabbits and in entrained rabbits with unilaterally decentralized ocular sympathetic nerves. The pattern of the circadian pupillary rhythm was compared with the circadian patterns of intraocular pressure (IOP) and body temperature in the same rabbits. METHODS: Adult male New Zealand albino rabbits were entrained to a daily 12-hour light-12-hour dark cycle. Using an infrared camera recording system, basal pupil sizes in seven entrained rabbits were videotaped under a constant dark environment at 1-hour intervals for 24 hours. Hourly IOP and rectal temperature in the same rabbits were measured separately under both the regular light-dark cycle and constant dark. In 10 entrained rabbits that underwent unilateral transection of the cervical sympathetic trunk, measurements of pupil size and IOP in constant dark were performed. RESULTS: In normal rabbits, a smaller basal pupil size in the subjective light phase and a consistently larger pupil size in the subjective dark phase were observed. Notably, pupil size increased sharply at the beginning of the subjective dark phase and peaked shortly. Circadian rhythms of IOP and body temperature were present under the regular light-dark cycle and in constant dark. As did pupillary enlargement, IOP rose sharply at the beginning of the subjective dark phase and peaked shortly thereafter. Body temperature, however, increased gradually and peaked in the late subjective dark phase. In rabbits with unilaterally decentralized ocular sympathetic nerves, the circadian rhythm of pupil size was present only in the intact eye. In addition, the circadian IOP elevation in the decentralized eye was reduced significantly. CONCLUSIONS: In light-dark entrained rabbits, basal pupil size changes in a circadian pattern and peaks at the beginning of the dark phase. The circadian pupillary rhythm disappears after ocular sympathetic decentralization. There are similar characteristics in the circadian rhythm of IOP. The increase of basal pupil size in the early dark phase is not related to the nocturnal increase of body temperature.

In vivo cAMP level in rabbit iris-ciliary body after topical epinephrine treatment.

PURPOSE: The present study estimates the in vivo cyclic AMP (cAMP) level in the rabbit iris-ciliary body after topical treatment with epinephrine. METHODS: Epinephrine 1% was applied unilaterally to pigmented rabbits. At selected time points between 10 min and 6 hr, a 2.5-mm diameter iris-ciliary body, in the treated eye, was irradiated with 2 J diode laser (2 W for 1 sec). Instant heat generated by the irradiation deactivated the cellular enzymes used in the synthesis and degradation of cAMP. Rabbits were sacrificed immediately, and samples of the iris-ciliary body were isolated from the irradiated area, the non-irradiated area, and from the contralateral, untreated eye. Levels of cAMP in these samples and in the aqueous humor were determined by radioimmunoassay. Further experiments were performed in rabbits pretreated with an alpha 2-adrenergic antagonist, yohimbine, and a beta-adrenergic antagonist, timolol, 30 min before the epinephrine treatment. Unilateral laser photocoagulation of the iris-ciliary body was performed at 10 min and 1 hr after the epinephrine treatment. RESULTS: The cAMP level in the photocoagulated iris-ciliary body did not change in parallel to the change in the aqueous humor. An increase of aqueous humor cAMP was observed for 6 hr. However, a reduction of cAMP level in the photocoagulated iris-ciliary body was observed at 1 hr after the epinephrine treatment. In yohimbine-pretreated rabbits, the reduction of cAMP level in the photocoagulated iris-ciliary body was absent. Pretreatment with timolol had no effect. CONCLUSIONS: These observations suggest that, at 1 hr after the epinephrine treatment, the cellular signal via the alpha 2-adrenergic receptors in the iris-ciliary body, which reduces the intracellular cAMP level, is stronger than that via the beta-adrenergic receptors.