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The mitotic and meiotic chromosomes, as well as the spermatogenesis of a male hybrid between Macaca fascicularis and M. assamensis have been studied using chromosome banding, microspreading, and tissue sectioning techniques. The band patterns of the parental chromosome complements are found highly homologous. The observation on meiosis and testis histology indicates that the hybrid should be fertile. It is suggested that the reproductive barrier between M. fascicularis and M. assamensis is not complete and may resulted from ecological isolation. The taxonomic status of M. fascicularis and M. assamensis is discussed also.
Most clinical studies demonstrate a small (0.5-1.0 mm) but significant reduction of surgical miosis by cyclooxygenase inhibitors (COIs), such as indomethacin, flurbiprofen, or suprofen. However, other studies failed to show significant inhibition by some of these agents. While this inhibition may provide a clinically useful advantage in some cases, it does not help us clarify the mediators and mechanism of the miotic response. The inhibitory effect of high doses of COIs on surgical miosis has generally been explained on the basis of inhibition of PG synthesis. However, COIs do not selectively inhibit the synthesis of PGs; they inhibit the synthesis of all cyclooxygenase products, including prostacyclin and thromboxanes. The reduction of the miotic response could also have resulted, in part, from inhibition of the lipoxygenase pathway of arachidonic acid metabolism. The effect of COIs on unrelated biochemical processes that influence the contractile responses of the iris sphincter may also have contributed to the inhibition of surgically induced miosis. In short, the mechanism by which COIs reduce miosis remains unidentified. If one assumes that PGs are the only mediators of this miosis, one must also assume that failure of COIs to block surgical miosis is due to incomplete inhibition of cyclooxygenase activity in the involved ocular tissues, even though the COIs are applied repeatedly to the eye prior to surgery. However, a more likely explanation is that other mediators are involved in the miotic response, especially since no PG has yet been shown to produce a dose-dependent miotic response leading to full sphincter contraction in any primate (see Miranda and Bito, 1989). While acetylcholine is the best-established agonist of iris sphincter contraction, surgical miosis occurs even after pretreatment with high doses of potent anti-cholinergic agents. This atropine-resistant component of the surgically induced miosis may be mediated by a number of autocoids. Several autacoids, other than PGs, have been shown to be potent miotic agents in some animals. LTC4 and LTD4, which are potent miotics in cats, have not yet been investigated for their possible role in surgical miosis in primates. Several neuropeptides are potent miotics in rabbits, although none of them has yet been found to have similar effects on human irides. Because sensory neuronal involvement in trauma-induced miosis has been demonstrated in many species, including humans (see Stjernschantz and Bito, 1989; also Unger, 1989), a search for a neuropeptide that has miotic properties in humans should continue. Much more work must be done before the mechanism of surgical miosis can be clarified.(ABSTRACT TRUNCATED AT 400 WORDS)
Cycloplegic drugs are the principal medications used in the diagnosis of accommodative esotropia. The same cycloplegics can be used as a "medical patch" in the treatment of amblyopia. Miotics may be as good as glasses in controlling accommodative esotropia but are almost never better. The response to miotics does not rule out the presence of accommodative esotropia. Miotics also may be used as a supplementary agent to glasses, bifocals, or surgery in the treatment of esotropia. The most widely used miotics today include phospholine iodide and DFP with iris cysts being the major local side effect in the eye with the use of miotics in children. Miotics and other drugs are valuable tools in the treatment of accommodative esotropia; however, the use must be correlated with other tools, including surgery, patching, glasses, and orthoptic exercises.
Effects of neurohypophyseal (NHP) and synthetic analogs on the pupil of the rabbit were explored. This was prompted by the recent emergence of synthetic analogs with selective agonist and antagonist properties. The miotic effect of the NHP was examined in an isolated iris preparation. Minimum concentrations of arginine-vasopressin (AVP) needed to cause threshold pupillary constriction were approximately 10(-10) M. The miotic potency of several NHP analogs correlated best with their pressor activity. In addition, the synthetic NHP pressor antagonist d(CH2)5 Tyr(Me)AVP specifically antagonized the miotic effect, confirming that a pressorlike receptor mediates this pharmacologic action of the NHP. We also employed the technique of in vivo intravitreal administration of pharmacologic doses of the NHP in the rabbit. Once again, potent miotic activity was demonstrated. The relative miotic potency of the NHP in vivo provided further support to the relationship between the NHP "pressor" receptor and pupillary constriction. We believe that the use of a variety of NHP natural and synthetic analogs may also prove helpful in investigating potential physiological effects of the NHP on other intraocular smooth muscle.
In the rat, the predominant pupillary effect of morphine sulfate (30 mg/kg, i.p.) is mydriasis, interrupted periodically by miotic excursions. Using infrared video pupillometry, respirometry and EEG recording, we had previously reported that miotic excursions are always correlated with the onset of EEG bursting, while mydriatic excursions are preceded by respiratory slowing and correlated with EEG burst cessation. In the current study, we found that during morphine-induced EEG bursting and related miosis, delivery of an alerting stimulus to the rat caused an immediate conversion sequence composed of respiratory slowing, burst cessation and mydriatic excursion. We also simulated morphine-induced EEG bursting through non-opioid means by delivering kindling electrical stimuli to the amygdala. When the stimulus was given during morphine-induced mydriasis, the stimulus-induced bursting resulted in a miotic excursion identical to spontaneous morphine-induced miotic excursions. These results indicate 1) that the reticular activating system is involved in morphine-induced mydriatic excursions and 2) that EEG bursting is not simply correlated with morphine-induced miotic excursions, but causes them. Collectively, these results strengthen our hypothesis that the Edinger-Westphal nucleus is not the site in which the selective, receptor-mediated pupillary effects of morphine are initiated.
Miotic-induced retinal detachment (RD) is a condition that is not recognized as such by common consent. Clinically it has been shown that all miotic agents, whether strong or weak, can precipitate an RD, if there are additional contributing factors like high myopia, peripheral lattice degeneration of the retina, pathological vitreoretinal changes and previous history of an RD in the other eye, which all increase the basic risk of RD. Pilokarpin lameller 11 mg represents a form of miotic therapy having initially only a moderate accommodative and miotic effect, which further declines to a level of steady state during the next hours. Because the time interval after which a new Pilokarpin lameller unit is required lasts up to 1 week, the total amount of accommodation and miosis is much smaller than when applying daily 2% pilocarpine drops. However, it seems important, before the start of any kind of miotic therapy, to perform a careful examination and management of virtually all detachment-prone patients. This case report deals with an RD which occurred after 2 days of treatment with Pilokarpin lameller (Ocusert) 11 mg in a myopic patient who had a juvenile type of glaucoma and previous history of an RD in the other eye.
OBJECTIVE: To investigate the prevalence of "masked" pseudoexfoliation (PEX) syndrome in eyes with circular posterior synechiae receiving antiglaucomatous therapy with miotics. DESIGN: Cross-sectional prospective study. METHODS: Twenty-eight eyes of 27 consecutive patients with circular posterior synechiae and a history of miotic drug use without previous intraocular surgery, inflammation, or trauma, and without conventional signs of PEX material in the anterior chamber were included in the study. All eyes were investigated by slitlamp biomicroscopy and gonioscopy of the anterior chamber before extracapsular cataract surgery for the presence of typical PEX-associated iris pigment epithelial changes, such as peripupillary atrophy and trabecular meshwork melanin granule deposition. The anterior chamber depth, lens thickness, and axial lengths of the eyes were measured by A-scan immersion sonography. The excised anterior lens capsules obtained during extracapsular cataract surgery were investigated for the presence of precapsular fibrillar PEX deposits by electron microscopy. MAIN OUTCOME MEASURE: The prevalence of masked PEX syndrome in eyes with circular posterior synechiae receiving antiglaucomatous therapy with miotics. RESULTS: Transmission electron microscopy of unselected nonserial sections revealed a precapsular layer consisting of typical PEX fibers or microfibrils, which indicated early stages of PEX syndrome in 18 (64%) of 28 eyes with circular posterior synechiae. Melanin granules were frequently found adhering to the fibrillar layer. Eyes with precapsular fibrillar deposits showed significantly greater trabecular meshwork pigmentation than eyes without such deposits. Differences in age, lens thickness, axial length of the eye, anterior chamber depth, and degree of peripupillary atrophy were, however, not statistically significant between the groups with and without electron microscopic evidence of PEX deposits. CONCLUSIONS: Circular posterior synechiae were more frequently associated with manifest or early stages of PEX syndrome. However, the formation of broad posterior synechiae in miosis prevented a definite clinical diagnosis based on the classic changes of the anterior lens capsule. In eyes with spontaneous or miotic-induced circular posterior synechiae without other obvious cause, the masked variant of PEX syndrome should always be considered.
Solutions of surface active triblock copolymer Pluronic F127 in the vicinity of the critical micellar concentration (cmc) were prepared with or without pilocarpine (either as the hydrochloride salt or the free base) in water and phosphate buffer. The characteristics parameters of the surface activity (cmc, Gamma and a) were determined for F127 solutions. Additionally, it was found that the pilocarpine solutions without F127 in water exhibits a certain surface activity. The solutions containing F127 (2 wt.%) well above the cmc and pilocarpine (2 wt.% for the salt, or equimolar 1.7 wt.% for the base) were further tested in vivo (miotic response) on rabbit eye. Though the entrapment efficiency of the drug in the micelles was rather low (maximal 1.9%) the pharmacokinetic parameters (duration of miotic response and the area under miotic curve) were improved when compared to the standard pilocarpine solutions. The best results were obtained for the micellar pilocarpine base solution which exhibits significant prolongation of miotic activity and an increase of AUC for 64%.
METHODS: In 146 eyes/patients who underwent Nd:YAG laser iridotomy after glaucomatous attack or after prophylactic iridotomy, we evaluated whether the frequency of posterior synechiae depends on (1) glaucomatous attack, (2) preoperative miotic therapy, (3) postoperative antiglaucomatous therapy or (4) mode of intraoperative laser therapy. Out of 616 eyes with YAG iridotomy between 1983 and 1987, 146 eyes/patients fulfilled the inclusion criteria: observation time of minimum 3 months after iridotomy, preoperative examination without signs of preexisting synechiae, postoperative examination at discharge and a later control examination in mydriasis to exclude posterior synechiae. RESULTS: Eyes with and without glaucomatous attack and eyes with an without pre-operative long-term miotic therapy showed no significant difference in frequency of posterior synechiae. Eyes with postoperative long-term therapy with miotics or beta-blockers showed posterior synechiae significantly more often than eyes without post-operative miotic or beta-blocker therapy. Eyes that received DPE in the early post-operative period developed posterior synechiae significantly less often. The number of laser pulses and the mean total energy used were significantly higher in eyes which later developed posterior synechiae. In the group of patients with glaucomatous attack women outnumbered men by four to one, but there was no significant difference in refraction between women and men. CONCLUSIONS: Patients with glaucomatous attack are not at a higher risk of developing posterior synechiae than those without glaucomatous attack. Post-operative antiglaucomatous therapy, the number of laser pulses and the total energy alter the frequency of postoperatively developed posterior synechiae.
OBJECTIVE: Our objective was to investigate whether codeine or one of its metabolites contributes substantially to central nervous effects independent from the cytochrome P450 (CYP) 2D6-mediated O-demethylation to morphine. METHODS: After oral administration of codeine, plasma concentrations of codeine and its metabolites, as well as pupil size as a measure of central nervous effects, were measured in 11 healthy volunteers representing poor, intermediate, extensive, and ultrarapid metabolizers for CYP2D6. Subsequently, the observed plasma morphine concentrations were mimicked by use of computerized morphine infusion, and the miotic effects were compared with those observed after codeine administration. The contribution of codeine, codeine-6-glucuronide, norcodeine, morphine, morphine-6-glucuronide, and normorphine to the miotic effects was analyzed by means of pharmacokinetic-pharmacodynamic modeling. RESULTS: The areas under the curve of the miotic effects after codeine were 1.7 +/- 2 times greater than after morphine (P <0.01). This contrasted to similar or even lower morphine concentrations after codeine than after morphine (area under the curve ratio, 0.5 +/- 0.4; P =.21). A pharmacokinetic-pharmacodynamic fit of the miotic effects by use of morphine as the only active moiety was most significantly (P <.0001) improved when codeine-6-glucuronide as a second active moiety was added. CONCLUSION: CYP2D6-dependent formation of morphine does not explain exclusively the central nervous effects of codeine. Codeine-6-glucuronide is the most likely additional active moiety.
For some time the medical treatment of glaucoma has consisted of topical beta-blockers, adrenergic agents, miotics and oral carbonic anhydrase inhibitors (CAIs). However, the therapeutic arsenal available for the medical treatment of glaucoma has recently extended with new classes of ocular hypotensive agents i.e. prostaglandins, local CAIs and alpha2-adrenergic agents. Beta-blockers are still the mainstay in glaucoma treatment and are first line drugs. However, even if they are applied once daily, as with timolol in gel forming solution and levobunolol, the possible cardiopulmonary adverse effects of beta-blockers remain a cause for concern. When monotherapy with beta-blockers is ineffective in reducing intraocular pressure (IOP) or is hampered by adverse effects, a change of monotherapy to prostaglandins, local CAIs, alpha2-adrenergic agonists (brimonidine) or to dipivalyl epinephrine is advised. Prostaglandins, local CAIs and alpha2-adrenergic agonists, such as brimonidine, may in time become first line drugs because they reduce IOP effectively and until now systemic adverse effects have rarely been reported with these agents. The development of a pro-drug of either a local CAI or an alpha2-adrenergic agonist with a sustained and continuous effect on IOP level, which could be applied once a day is suggested. Because of these new developments, miotics, i.e. pilocarpine and carbachol, are recommended as second or third line drugs. The cholinesterase inhibitors are considered third line drugs as better agents with fewer local and systemic adverse effects have become available. Oral CAIs may be used temporarily in patients with elevated IOPs e.g. postsurgery or post-laser, or continuously in patients with glaucoma resistant to other treatment. Combining ocular hypotensive drugs is indicated when the target pressure for an individual patient cannot be reached with monotherapy. Combination therapy of beta-blockers is additive with prostaglandins, topical CAIs and miotics. Prostaglandins such as latanoprost can be combined with beta-blockers, adrenergic agents, local CAIs and miotics. Combinations with brimonidine or local CAIs need further investigation. Treatment of glaucoma with the new ocular hypotensive agents, either in monotherapy or combination therapy, may provide lower IOPs and delay or postpone the need for surgery.
The bioavailability of seven commercially available batches of chlorpromazine hydrochloride tablets belonging to three different brands was assessed by measuring the intensity of miotic response to the tablets in six normal human subjects according to a cross-over design system. The following pharmacodynamic parameters were computed, viz., maximum miotic response intensity, tmax, half-peak time as well as the area under the percentage miotic response intensity versus time curve from time 0 to 8 h. Attempts to correlate two in vitro dissolution parameters, that is, dissolution efficiency and percentage weight of drug dissolved after 30 min to the in vivo parameter of the area under percentage miotic response intensity versus time curve revealed that the second in vitro parameter correlates better than the first one with the in vivo parameter regardless of the dissolution method. On the other hand, the two in vitro dissolution parameters obtained by the USP rotating basket method show good correlation with the in vivo parameter.
Trigeminal stimulation can induce pupillary changes. In vivo and in vitro studies have demonstrated that electrical impulses applied at the trigeminal level can provoke a miotic response, whose nature has been ascribed to the anti-dromic release of neuropeptides (substance P in particular). In order to better define the pupil response to trigeminal stimulation, we investigated the human pupil response to quantified (painless and painful) corneal stimuli by means of a combined (neurophysiological and pharmacological) technique. The response to corneal stimulation was bilateral, direct and consensual. It had a biphasic progression with an initial mydriasis (which directly correlated with the stimulus intensity), followed by a miotic phase. The mydriatic phase disappeared after thymoxamine application, while homatropine pre-treatment prevented occurrence of the miotic phase. The data obtained indicate that the pupillary response to corneal stimulation (trigemino-pupillary reflex) is a multisynaptic reflex with an afferent branch involving the trigeminal system, and an afferent branch involving both the sympathetic and the parasympathetic system. Other pathways, such as the SP-mediated release of acetylcholine, cannot be excluded. Thus the reflex appears to be a potentially useful tool for investigating pain/vegetative interactions in various clinical conditions. In turn, the description of its changes in pathologies characterized by a sympathetic/parasympathetic deficit or by a SP-ergic imbalance will allow us to better describe its inner mechanisms.
Thermoreversible gels formed in situ by aqueous solutions of an enzyme-degraded xyloglucan polysaccharide were evaluated as sustained release vehicles for the ocular delivery of pilocarpine hydrochloride. In vitro release of pilocarpine from gels formed by warming xyloglucan sols (1.0, 1.5 and 2.0% w/w) to 34 degrees C followed root-time kinetics over a period of 6 h. The miotic responses in rabbit following administration of xyloglucan sols were compared with those from in situ gelling Pluronic F127 sols and from an aqueous buffer solution containing the same drug concentration. Sustained release of pilocarpine was observed with all gels, the duration of miotic response increasing with increase of xyloglucan concentration. The degree of enhancement of miotic response following sustained release of pilocarpine from the 1.5% w/w xyloglucan gel was similar to that from a 25% w/w Pluronic F127 gel.
The effects of a novel, modified beta-cyclodextrin (SBE4-beta-CD; a variably substituted sulfobutyl ether with an average degree of substitution of four) on eye irritation and miotic response of an ophthalmically applied pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, in albino rabbits were studied. Compared to the commercial pilocarpine eyedrop solution (163 mM, equivalent to 3.4% pilocarpine), 12-24 mM pilocarpine prodrug solutions (equivalent to 0.5-1.0% pilocarpine, respectively) decreased peak miotic intensity (Imax) and increased the time to reach peak (tmax), but did not significantly affect values for the area under the miosis versus time curves (AUC), i.e. 12-24 mM pilocarpine prodrug appeared to be equivalent to 163 mM pilocarpine. Ocularly applied 12-24 mM pilocarpine prodrug solutions, however, were more irritating than a commercial pilocarpine eyedrop solution. Coadministered SBE4-beta-CD significantly decreased the eye irritation of the pilocarpine prodrug solutions. Coadministered SBE4-beta-CD did not affect the miotic response of prodrug solution when the molar ratio of SBE4-beta-CD to prodrug was low. However, increasing the molar ratio of SBE4-beta-CD to prodrug decreased the Imax and AUC values. The results show that eye irritation of the pilocarpine prodrug is prevented by levels of SBE4-beta-CD that do not affect the apparent ocular absorption of the prodrug.