Systemic Absorption of Cyclopentolate and Adverse Events After Retinopathy of Prematurity Exams.

PURPOSE: Preterm infants undergoing Retinopathy of Prematurity Eye Exams (ROPEE) may experience adverse events, possibly from systemic absorption of cyclopentolate. The purpose of this study was to analyze the association between adverse events and drug levels found in neonates undergoing ROPEE. MATERIALS AND METHODS: 25 infants were randomized into two groups during routine ROP screening: 5 infants for blood collection before mydriatic drops and 20 for blood collection 1 h after eye drops. Blood was collected onto dried blood spot cards, extracted, and analyzed for cyclopentolate and phenylephrine using liquid chromatography and mass spectrometry. Relationships between drug levels and adverse events were assessed. RESULTS: Cyclopentolate (range 6-53 ng/ml) was observed in 15 of 18 infants, while phenylephrine was not detected. Levels of cyclopentolate were significantly higher in infants who were on oxygen (p = 0.01). There was a significant association between cyclopentolate levels and gastric residuals in tube-fed infants not receiving oxygen (p = 0.01). CONCLUSIONS: Cyclopentolate levels varied among preterm infants after ROPEE. Cyclopentolate was positively associated with increased gastric residuals. Underlying medical conditions requiring oxygen administration may affect absorption and metabolism of cyclopentolate. There is a need to predict infants at risk for high blood levels of cyclopentolate in order to prevent or treat adverse events after ROPEE.

Cuadro confusional agudo tras uso de colirio ciclopléjico en una niña de 6 años de edad / Acute confusional state following the use of cycloplegic eye drops in a 6-year-old girl

Presentamos el caso de una niña sana, de 6 años de edad, con un síndrome confusional agudo secundario a la administración tópica ocular de gotas de ciclopentolato: actitud de nerviosismo, alucinaciones y lenguaje incoherente. Esta reacción adversa fue transitoria y sin secuelas posteriores. El caso reviste interés para recordar que los agentes parasimpaticolíticos de uso tópico ocular pueden tener efectos adversos sistémicos. El personal sanitario debe conocerlos y los padres han de ser alertados sobre ellos (AU)

A case is reported of an acute confusional state due to the use of cycloplegic eye drops in a previously healthy 6-year-old girl: Nervousness, hallucinations and unintelligible language. This adverse reaction was temporary and without after effects. We think that this case is of interest because parasympatholytic agents of topic ocular use can produce systemic side effects. The public health and health care personnel should be aware of this and parents should be warned about this possibility (AU)

Systemic and ocular absorption and antagonist activity of topically applied cyclopentolate in man.

Ocular and systemic absorption and antagonist activity of topical 1% cyclopentolate were studied in 11 elderly patients undergoing extracapsular cataract extraction, and in 8 healthy female volunteers. The patients received two 35 microl drops of cyclopentolate unilaterally and the healthy volunteers one 30 microl drop bilaterally to the lower conjunctival cul-de-sac of the eye. The drug concentrations were measured with radioreceptor assay and receptor occupancies with radiooccupancy assay using isolated rat brain muscarinic cholinoceptors. In the patient group, cyclopentolate concentrations in aqueous humour were approximately 3000 times higher than those in plasma. Muscarinic cholinoceptors were occupied totally (more than 99.9%) by aqueous humour and 3-18% by plasma taken at 55-125 min. after the drug application. In healthy volunteers peak plasma concentration of cyclopentolate, 2.06+/-0.86 (mean+/-S.D.) nM, occurred at 53 min., maximum receptor occupancy being 5.9+/-2.1%. The maximum pupillary dilatation occured at 30 min. after the drug application. At the same time the near point of vision was extended to more than 50 cm in all subjects. After topical application plasma receptor occupancy was not high enough to cause any significant changes in heart rate and in PQ time. None of the subjects experienced subjectively or objectively adverse effects to be attributed to cyclopentolate.

Ocular effects and systemic absorption of cyclopentolate eyedrops after canthal and conventional application.

Ocular effects and plasma concentrations of cyclopentolate were studied in 8 volunteers after eyedrop application with two methods. While recumbent two 30 microliters drops of 1% cyclopentolate hydrochloride were instilled in randomized order either conventionally to the lower conjunctival cul-de-sac or on the inner canthus with eyes closed, followed by immediate opening of the eyes. The cycloplegic responses as well as the extent and time of maximal mydriasis did not differ significantly between the two methods. None of the parameters describing the systemic absorption of the drug differed between the treatment groups. Conventionally applied drops caused slightly longer subjective discomfort. Instilling eyedrops on the inner canthus with eyes closed is an alternative method to deliver ocular cyclopentolate with similar efficacy and safety as the conventional technique. This method could be useful especially when treating non-cooperative children.

Mucoadhesive ophthalmic vehicles: evaluation of polymeric low-viscosity formulations.

A series of polyanionic natural or semi-synthetic polymers (polygalacturonic acid, hyaluronic acid, carboxymethylamylose, carboxymethylchitin, chondroitin sulfate, heparan sulfate and mesoglycan) were evaluated as potential mucoadhesive carriers for ophthalmic drugs. Solutions containing cyclopentolate (CY) or pilocarpine (PI) as salts (or polyanionic complexes) with the acidic polymers, all showing a low viscosity, were tested for miotic (resp. mydriatic) activity in albino rabbits. In the case of some polymeric complexes, small but significant increases of the areas under the activity vs. time curves (AUC) over reference cyclopentolate hydrochloride (CYHC1) or pilocarpine nitrate (PINO3) vehicles, and significant AUC decreases after removal of precorneal mucin by treatment with N-acetylcysteine were observed. A correlation was found between these data, considered indicative of the occurrence of a mucoadhesive interaction "in vivo", and "in vitro" viscometric data expressing the polymers-mucin force of interaction. The advantages and limitations of the mucoadhesive non-viscous approach in the formulation of ophthalmic vehicles are presented and discussed.

Plasma concentrations and ocular effects of cyclopentolate after ocular application of three formulations.

1. Eight volunteers received in randomized order two 30 microliters drops of either 1% w/v cyclopentolate hydrochloride or a corresponding amount of cyclopentolate polygalacturonate in saline or in acetate buffer in one eye. Cyclopentolate concentrations in plasma were measured by a radioreceptor assay. 2. Peak plasma drug concentrations of about 3 ng ml-1 occurred within 30 min after all formulations. Occasionally, a second concentration peak in plasma, probably reflecting drug absorption from the gastrointestinal tract, was seen after 2 h. The mean elimination half-life of cyclopentolate was 111 min when all subjects and formulations were considered together. There were no statistically significant differences between the formulations with respect to the time-course of plasma drug concentration. 3. The maximal mydriatic effect was reached within about 15 min and was maintained for several hours, often being 1/3 of its peak value after 30 h. Similarly, an intense cycloplegic response was achieved within a few minutes, the peak changes in the near-point of vision being 9 to 10 dioptres. The cycloplegic response was more intense after one of the polygalacturonate complexes, especially at later time points.

Systemic absorption of ocular cyclopentolate in children.

Cyclopentolate plasma levels were quantitated and heart rate and pupil size were monitored after ocular application of the drug to juveniles. In all, 12 children were given one 35-microliters eyedrop of either 1% cyclopentolate (n = 6) or placebo (n = 6) in randomized order in the lower cul-de-sac of one eye. A sensitive radioreceptor assay was used to determine the systemic drug absorption. With the exception of one child, detectable cyclopentolate concentrations were seen in plasma at as early as 3 min after the ocular drug application. There was a marked interindividual variation in peak plasma cyclopentolate concentrations ranging from undetectably low to 5.8 ng/ml (median, 2.9 ng/ml). In some children a second drug concentration peak was detected. Cyclopentolate increased the pupillary diameter from 4.8 +/- 1 mm before drug application to 8 +/- 0.9 mm at 30 min after administration, but the children's heart rate did not alter.

The effect of some macromolecular ionic complexes on the pharmacokinetics and -dynamics of ocular cyclopentolate in rabbits.

The effect of mucoadhesive polymeric vehicles on the mydriatic efficacy, and on the systemic and ocular absorption of cyclopentolate from eyedrops was studied in albino rabbits. Combining cyclopentolate base to polygalacturonic (CY-PGA) or hyaluronic (CY-HA) acid resulted in an increased mydriatic effect when compared with cyclopentolate hydrochloride (CY-HCl). During the first half an hour, the systemic absorption of cyclopentolate was lower after CY-PGA than after CY-HCl. The ocular penetration of cyclopentolate, based on drug concentrations in aqueous humor 30 minutes after the eyedrop instillation, was increased 3 fold when the polygalacturonate complex was used. CY-PGA, as well as other polymeric salts, might offer a possibility to increase the therapeutic index of cyclopentolate.