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Sustained release ophthalmic formulations of pilocarpine.

The bioavailability of drugs from conventional ophthalmic formulations is low. To optimize the therapy, sustained release ophthalmic dosage forms are warranted. Hydrogels such as sodium-carboxymethyl cellulose, hydroxypropylmethyl cellulose, Carbopol-940, Carbopol-941 and Lutrol-FC-127 increase the duration of action of various drugs. Gels containing pilocarpine were prepared and evaluated by measuring the intensity and duration of miotic response in albino rabbits. Carbopol-940 gels, being the best of those used, were studied further for the effect of its concentration and of additives (benzalkonium chloride, phenylmercuric nitrate, chlorbutol and disodium edetate), autoclaving at 121 degrees C for 30 min and irradiation with gamma rays (2.5 Mrad), on the end product.

Animals↗

Chromosome studies in patients with defective reproductive success.

PROBLEM: The objective of this study was to evaluate the contribution of chromosomal anomalies to decreased fertility in humans. METHOD OF STUDY: In order to investigate the aetiology of infertility in our population and to assess the karyotype in a group of infertile couples and individuals with fertility problems, 782 persons (259 couples, 158 male and 106 female) with different clinical diagnoses of sterility and infertility were analysed cytogenetically. RESULTS: The overall frequency of major chromosomal aberration was 13.1% (103/783), which suggests that fertility or sterility problems in this population are due to chromosomal aberrations. Couples experiencing repeated spontaneous abortions, having malformed children or having sterility problems had chromosomal abnormalities in 18.0% (47/259 couples) of the population studied, and constituted chromosomal disorders occured in couples seeking IVF and ICSI with prevalence of 22.2% (8/38 couples), especially minor mosaicism of sex chromosomes in the female partners. The prevalence of chromosome abnormalities in infertile men was 17.7% (28/158), and in subfertile females, it was 26.4% (28/106). CONCLUSIONS: These results could indicate an increased tendency to miotic sex chromosome non-disjuction in humans.

Chromosome Aberrations↗

Timolol in operated closed-angle glaucoma.

Tonometry in 9 eyes (7 patients) provides some evidence that timolol eye drops are useful in improving control of pressure in eyes operated for closed-angle glaucoma. In cases 1 and 2 (Figs, 1 and 2) this beta 1 and 2 blocker reduced pressure consistently. Case 3 (Fig. 3) showed that timolol 0.5% twice daily was as effective as pilocarpine 2% or 4% with adrenaline 1%. The effect of timolol 0.5% in case 4 (Fig. 4) and case 6 (Fig. 6) was additive to pilocarpine and adrenaline; in case 5 (Fig. 5) it probably improved the effect of adrenaline, but in cases 4 and 5 there may have been some loss of effect with time. Case 7 (Fig. 7) showed a good effect of timolol, reversed on withdrawal, but pressure fell again in spite of continued withholding of timolol. Timolol will be especially valuable in the control of pressure if an operation involving iridectomy has not been completely successful in open-angle glaucoma or more especially in closed-angle glaucoma because it has no effect on the pupil. Miotics will tend to produce posterior pupillary synechiae because aqueous humour will go through the iridectomy, not under the edge of the pupil. The danger will be greater in eyes with closed-angle glaucoma because the pupil is closely applied to the anterior lens surface, which will also tend to produce irritative iridocyclitis.

Epinephrine↗

The Arden grating acuity: effect of age and optical factors in the normal patient, with prediction of the false negative rate in screening for glaucoma.

The Arden contrast sensitivity was investigated in normal persons, cataract eyes, and glaucoma patients with only plates 6 and 7 of the Arden grating set. The mean score of 90 normal eyes on plate 6 was 9.50 +/- 2.29 and on plate 7 it was 9.44 +/- 2.32. The mean scores of patients with early cataract were 14.51 +/- 2.99 on plate 6 and 13.74 +/- 3.26 on plate 7. Several patients with cataract missed the grating on plate 7. Mydriasis and miosis did not affect contrast sensitivity in normal eyes. Mydriasis significantly improved contrast sensitivity in patients with early cataract. In patients with glaucoma enlargement of the pupil from a miotic state to near normal size significantly improved contrast sensitivity. It is predicted that if plate 6 and 7 are used in mass screening for glaucoma in the elderly, there will be a false negative rate of 83% for plate 6 and 52% for plate 7. A false positive rate of 17% is predicted.

Adolescent↗

Effect of oxybuprocaine 0.4% in preventing surgically induced miosis.

In a group of 68 patients a double-blind study was performed to assess the effect of preoperative oxybuprocaine 0.4% (Dorsacaine, Novesin) eye drops in comparison with a placebo in preventing surgically induced miosis during extracapsular cataract extraction. One drop of oxybuprocaine 0.4% or placebo was instilled 10 and 5 minutes preoperatively. The pupil diameter was recorded at different stages of the operation. It was found that oxybuprocaine reduced the amount of pupil constriction during the operation significantly as compared with the placebo group, facilitating the removal of lens material and the implantation of an intraocular lens. The effect of oxybuprocaine is considered to be due to anaesthetic action on sensory nerves in the eye, which may inhibit the release of a miotic substance.

Adult↗

Early trabeculectomy versus conventional management in primary open angle glaucoma.

The results of a randomised, prospective, multicentre trial of the management of primary open angle glaucoma are presented at up to five years' follow up. Previously undiagnosed cases were selected with intraocular pressure of 26 mmHg or more on two occasions together with field loss characteristic of glaucoma. Analysis was performed on one eye selected at random from each of 99 patients. Conventional medical treatment followed in unsuccessful cases by trabeculectomy (group A) was compared with trabeculectomy at diagnosis followed when necessary by supplementary medical therapy (group B). The life expectancy of these glaucoma patients was found to be similar to that for the local population matched for age and sex. In group A after four years trabeculectomy had been performed in 53% of eyes because medical management had failed to control the disease. The rate of operation was lower in those patients with intraocular pressure less than 31 mmHg and mild relative field loss (17% at three years) than in those with intraocular pressure greater than 30 mmHg and dense scotomas (75% at three years). Early surgery provided much more stable control with fewer changes in treatment than in group A. The group mean intraocular pressure after trabeculectomy was 15.0 mmHg irrespective of the time of operation, and this was significantly lower than the intraocular pressure in those cases thought to be controlled on medical therapy alone at the end of the first year (20.8 mmHg). Early operation provided significantly better protection of visual field, and the extra loss of visual field with delayed operation occurred in the preoperative period. Changes in visual fields were not related to the use of miotics. There was no significant difference in the final visual acuity in the two groups, but six cases in group A lost central fixation because of progressive loss of visual field, and there were no such cases in group B. Cataract occurred in approximately 10% of cases in both groups, but in group A this happened with only half the number of operations and at a shorter postoperative follow-up than in group B. It appears that in cases of primary open angle glaucoma of this severity the risk of delaying operation are significantly greater than those of performing trabeculectomy as the primary treatment.

Aged↗

Relative bioavailability of pilocarpine from a novel ophthalmic delivery system and conventional eyedrop formulations.

Pupillary responses to pilocarpine following topical application in a novel ophthalmic delivery system (NODS) and a conventional eyedrop formulation have been compared in eight healthy subjects in a single dose crossover study. The magnitude of the miotic and light reflex responses to NODS 40, 80, and 170 micrograms and to a single 2% Minims eyedrop (delivering 518 micrograms) were recorded by infrared television pupillography over periods of 24 hours. Dosage comparisons of drug responses were obtained by interpolation and yielded the equivalence of one eyedrop to 67 +/- 11 micrograms pilocarpine from the NODS formulation. These findings indicate that in a comparison of total doses delivered pilocarpine has an approximately eight-fold greater bioavailability from NODS than from a conventional eyedrop formulation.

Adult↗

Occurrence of malignant glaucoma after laser iridotomy.

A case is described of malignant glaucoma with extreme shallowing of the anterior chamber (AC) and an abnormally high intraocular pressure (IOP) following laser iridotomy for acute angle closure glaucoma. The episode followed the use of strong miotic (pilocarpine hydrochloride 4%) and was reversed by mydriatics including phenylephrine hydrochloride. Serial estimation of anterior chamber depth is important in the management of angle closure glaucoma.

Aged↗

Convergence excess esotropia treated surgically with fadenoperation and medical rectus muscle recessions.

Convergence excess esotropia has been treated with bifocals, miotics, medial rectus recession(s), fadenoperation, or a combination of these. However, comparatively few studies on the sensory status of these patients exist. We present the sensory findings in 31 children treated surgically. Twenty-one had fadenoperations combined with bimedial rectus recessions, one had a fadenoperation alone, and nine had augmented bimedial rectus recessions. Five children (16%) achieved bifoveal fusion, 22 (71%) had varying degrees of peripheral fusion, and four (13%) had no detectable binocularity after a mean postoperative follow-up of 2.4 years.

Child↗

Laser trabeculoplasty.

Using the now well established technique ALT is a safe and effective means of lowering IOP in eyes with POAG, pigmentary glaucoma, and exfoliative glaucoma though the effect diminishes with time. Pressure reduction with ALT is seldom greater than 30% and eyes with an IOP of more than 28 mm Hg are unlikely to be controlled for any length of time without additional treatment. ALT is probably most suitable either for older patients whose glaucoma is not well controlled on medical treatment, or for patients with newly diagnosed open angle glaucoma, but without advanced field loss, as a primary treatment or in combination with a non-miotic topical medication. In many it will defer surgery, in some indefinitely.

Blindness↗

Pathology of iris in leprosy.

AIM: The histopathological features of the iris in leprosy were studied by light microscopy. METHOD: Formalin fixed and paraffin embedded iris tissue excised during cataract surgery from 20 leprosy patients were sectioned and studied with haematoxylin and eosin stain and modified Fite Faraco's stain for acid fast bacilli (AFB). RESULTS: Chronic inflammatory reactions were seen in the iris of 11 patients, seven of whom did not have any clinically demonstrable evidence of iridocyclitis. Smooth muscle disruption and destruction were seen in two specimens. AFB were found in the iris tissue of a polar lepromatous patient whose skin smears were negative for AFB and who had completed the WHO recommended antileprosy multidrug therapy (MDT). CONCLUSION: Histopathology discloses far more silent chronic iridocyclitis in leprosy patients than are diagnosed clinically. AFB can persist in the iris tissue even after completion of MDT. Smooth muscle disruption and destruction, a cause of the miotic pupil in leprosy has been conclusively demonstrated histopathologically.

Adult↗

Degree and duration of reversal by naloxone of effects of morphine in conscious subjects.

The effects of intravenous naloxone on several of the actions of intravenous morphine (mean dose 30 mg/70 kg) were studied in six volunteer subjects. Naloxone produced a well defined reversal of the respiratory depression, analgesia, and miotic and subjective effects of the morphine. The agonist action of morphine outlasted the antagonist action of a single dose of naloxone. The effect of repeated doses of naloxone was also short-lived, but continuous infusions were effective in maintaining reversal.

Arousal↗

New topical drugs for open-angle glaucoma.

When we reviewed the management of open-angle glaucoma in 1997, the topical drug treatments available included beta-blockers, a carbonic anhydrase inhibitor (dorzolamide), an alpha 2 agonist (apraclonidine), a prostaglandin analogue (latanoprost) and a variety of miotics and sympathomimetics. We concluded that a beta-blocker was the treatment of first choice. Here, we review seven new topical preparations that have been marketed, or had their licensed indications changed, since our earlier article.

Administration, Topical↗

Morphine-induced reduction of intraocular pressure and pupil diameter: role of nitric oxide.

The present study was performed to evaluate the role of nitric oxide in the intraocular pressure (IOP) lowering effect and in the miotic action of morphine. The IOP was measured in conscious, normal, dark-adapted New Zealand white rabbits using a calibrated pneumatonometer. Experiments were conducted, in which rabbits' eyes were treated with morphine topically and unilaterally, while the fellow eyes received vehicle. IOP and pupil diameter (PD) measurements were taken 0.5 and 0 h before morphine administration and 0.5, 1, 2, 3, 4, and 5 h thereafter. The effects of a nonselective opioid receptor antagonist (naloxone), a nitric oxide synthase inhibitor (Nomega-nitro-L-arginine methyl ester; L-NAME), and a sulfhydryl reagent (reduced L-glutathione; GSH) on morphine-mediated changes in IOP and PD were also determined. Morphine (10, 33, and 100 microg) produced concentration-dependent decreases in IOP and reduced PD in both treated and untreated eyes of New Zealand white rabbits. IOP-lowering effect of morphine (100 microg) and reduction in PD were both significantly inhibited by pretreatment with naloxone (100 microg), L-NAME (0.5%), or GSH (100 microg). The results from this study indicate that morphine-induced ocular hypotension and reduction in PD are opioid-receptor-mediated responses that are associated with the release of nitric oxide. Because the mu3 opioid receptor subtype has a nitric-oxide-releasing activity and is sensitive to inactivation by GSH, it is concluded that morphine-induced ocular hypotension and miosis are mediated, in part, by activation of mu3 opioid receptors.

Animals↗

Interaction between nalbuphine and alfentanil on intraocular pressure and pupil size of conscious rabbits.

The ocular hypertension caused by the mu agonist alfentanil (10 micrograms/kg, i.v.) in spontaneously breathing rabbits was reversed to ocular hypotension by pretreatment with the kappa agonist-mu antagonist, nalbuphine (0.6 mg/kg, i.v.). This is probably due to nalbuphine's mu antagonistic action which prevents the respiratory-depressant effect of alfentanil that elevates the blood pCO2 with a drop in blood pH. It is known that hypoxia and hypercarbia lead to uveal vasodilation and increase in aqueous production which cause elevation of intraocular pressure. Both alfentanil and nalbuphine have miotic effects when used individually. However, no further reduction in the pupil size was noted by their combined use. These results indicate that using nalbuphine and alfentanil together may be considered a safe combination for eye surgery because it preserves the analgesic effect of either drug while prevents the undesirable respiratory-center depression and the ocular hypertension observed with alfentanil alone.

Alfentanil↗

Characterization of the mechanism of acute ocular irritation to YAG laser capsulotomy in rabbits: effects of substance P antagonists, Met-enkephalin, tetracaine and tetrodotoxin.

This study was undertaken to characterize the mechanism of ocular irritation to YAG laser capsulotomy in rabbits. The blocking agents were administered intravitreally. (D-Arg1,D-Pro2,D-Trp7,9)-SP, a substance P antagonist, tended to reduce miosis but had no effect on intraocular pressure (IOP). It had less effect on miosis than (D-Arg1,D-Pro2,D-Trp7,9,Leu11)-SP another SP antagonist. Met-enkephalin and tetracaine had no effect on miosis or the increase in IOP after YAG laser capsulotomy, whereas tetrodotoxin reduced miosis, but had no clear-cut effect on IOP, or the increase in aqueous humor protein concentration. This indicates an involvement of sensory neurons with release of SP or a closely related peptide in the miotic component part while the increase in IOP and the barrier breakdown probably are dependent mainly on a release of prostaglandins.

Animals↗

[Experiences with transtrabecular iridectomy].

A transtrabecular iridectomy was performed in 17 eyes with narrow angle glaucoma, and in 3 eyes in which the trabecular meshwork was gonioscopically not visible. Postoperatively, the conjunctive lied directly on the sclera in 14 cases; in 6 cases a circumscribed conjunctival bleb developed in the operation field. After a follow-up of 12 or 24 months, the intraocular pressure was normalized without miotics in 15 of 17 eyes. The mechanism of transtrabecular iridectomy is discussed.

Follow-Up Studies↗

Simple glaucoma before the age of 30 years.

'Juvenile glaucoma' is a meaningless term which should not be used. Glaucoma in young subjects can be hydrophthalmus, secondary or simple glaucoma. In this paper, early simple glaucoma is described in 15 patients (8 males, 7 females) below the age of 30 years, starting in some subjects already at 8 years of age. Inheritance was dominant in 6 patients. Anticipation could be shown in 2 pedigrees through 4 and 5 generations, respectively. The course of the disease was severe in 8 patients, with intraocular pressures over 40 mm Hg and/or heavy functional loss. There were usually no subjective symptoms. The chamber angles were gonioscopically normal in all patients. Miotics were effective but did not normalize the intraocular pressure. Surgical treatment is discussed.

Adolescent↗