A twenty-four-week, open-label study on ziprasidone's efficacy and influence on glucolipid metabolism in patients with schizophrenia and metabolic disorder.

BACKGROUND: The risks of antipsychotic drugs on metabolic syndrome (MS) present many challenges for psychiatrists. AIM: To evaluate the effectiveness and influences on glucolipid metabolism in patients with schizophrenia and metabolic disorders switched from clozapine to ziprasidone. PATIENTS AND METHODS: Schizophrenic patients with metabolic syndrome who had been treated with clozapine for ≥ 2 years were enrolled in the open-label study. All the patients were switched to ziprasidone from clozapine and followed up for 24-week. The primary endpoints included body mass index (BMI), fasting glucose (FG), triglycerides (TG), HDL cholesterol (HDL-c) and systolic pressure (SP)/diastolic pressure (DP). Secondary endpoints included scores on the Positive and Negative Syndrome Scale (PANSS) and treatment emergent symptom scale (TESS). RESULTS: A total of 213 cases satisfied the inclusion and exclusion criteria, but only 194 cases eventually completed the 24-week follow-up and were divided into ziprasidone group (n=68, complete substitution) and combined treatment group (n=126, partial substitution). In the ziprasidone group, TG at 4th and 24th week, BMI and HDL-c at 24th week were significantly improved (p < 0.05), while cognitive scores and total score of the PANSS at 4th and 24th week, negative factor, the factor of anxiety and depression at 24th week were significantly lower than those at the baseline (p < 0.05); In the combined group, cognitive factor scores (4 weekend, 24 weekends) and total score of PANSS (24 weeks) was significantly lower than baseline (p < 0.05). There was no significant difference in the TESS score (p > 0.05). CONCLUSIONS: Ziprasidone completely or partially substituting clozapine can improve both glucolipid metabolism disorders, and cognitive disorders and affective disorders of schizophrenia.

Ocular pharmacology of bicyclic hexahydroaporphines.

This paper explores the ocular hypotensive actions of bicyclic analogs of hexahydroaporphine (HHA), specifically nor-HHA, in an attempt to shed light on the mechanism(s) by which they lower intraocular pressure (IOP). Studies involving the measurement of IOP and aqueous humor production were conducted in ocular normotensive albino rabbits, while those involving smooth muscle contractility utilized isolated bovine iris. The ability of nor-HHA to produce a sustained drop in IOP is linked to both a functioning adrenergic nervous system and the availability of the products of cyclooxygenase metabolism. Although aqueous flow is not impacted by the bicyclic structures, the significant enhancement of outflow facility points to a probable mechanism of IOP-lowering action. Nor-HHA had no direct contractile or relaxant action on bovine irides, but does cause a concentration-dependent inhibition of carbachol-evoked contractions. This inhibition was reversed by inhibitors of phospholipase A(2) and cyclooxygenase, but not by inhibitors of lipoxygenase, again indicating a role for prostaglandins in the ocular pharmacological action of bicyclic HHAs. Pretreatment with a nitric oxide (NO) scavenger also reversed the ability of nor-HHA to inhibit carbachol-induced contractions, implying a role for NO in the postjunctional actions of HHAs.

Potential mechanism for the additivity of pilocarpine and latanoprost.

PURPOSE: To determine the ocular hypotensive mechanism underlying the additivity of latanoprost and pilocarpine. METHODS: This randomized, double-masked study included 30 patients with ocular hypertension on no ocular medications for at least 3 weeks. On each of six visits to the clinic, measurements were taken of aqueous flow and outflow facility by fluorophotometry, intraocular pressure by tonometry, and episcleral venous pressure by venomanometry. Uveoscleral outflow was calculated. Clinic visits were scheduled on baseline day; on day 8 of four times daily pilocarpine (2%) to one eye and vehicle to the other; on day 8 of continued pilocarpine/vehicle treatment plus latanoprost (0.005%) once daily to both eyes; after a 3-week washout period; on day 8 of once-daily latanoprost to one eye and vehicle to the other; and on day 8 of continued latanoprost/vehicle treatment plus pilocarpine four times a day to both eyes. Drug-treated eyes were compared with contralateral vehicle-treated eyes and with baseline day by paired t tests. Combined pilocarpine and latanoprost-treated eyes were compared with individual drug-treated eyes and with baseline day using the Bonferroni test. RESULTS: Compared with baseline, pilocarpine reduced intraocular pressure from 18.9 to 16.2 mm Hg (P =.001) and increased outflow facility from 0.18 to 0.23 microl per minute per mm Hg (P =.03). No other parameters were affected. Adding latanoprost further reduced intraocular pressure to 13.7 mm Hg (P <.001) and increased uveoscleral outflow from 0.82 to 1.36 microl per minute (P =.02). Latanoprost alone reduced intraocular pressure from 17.6 to 14.3 mm Hg (P <.0001) and increased uveoscleral outflow from 0.89 to 1.25 microl per minute (P =.05). Adding pilocarpine to the latanoprost treatment further reduced intraocular pressure to 12.7 mm Hg (P <.001) and increased outflow facility from 0.21 to 0.30 microl per minute per mm Hg (P =.03). CONCLUSIONS: Latanoprost and pilocarpine predominantly increase uveoscleral outflow and outflow facility, respectively, when given alone. These drugs are additive because pilocarpine does not inhibit the uveoscleral outflow increase induced by latanoprost.

Assessment of the intraocular pressure-lowering activity of bicyclic derivatives of 1-substituted benzyloctahydroisoquinoline.

In our study of IOP-lowering agents, we have synthesized several bicyclic analogs of 1-benzyloctahydroisoquinoline. The target molecules were synthesized in an eleven-step process. Structures were proved through spectrometry, elemental analysis and, in selected cases, high resolution mass spectrometry. The final products were secondary or tertiary amines containing a 1-benzyl moiety substituted at the p-position with a methoxy, methyl or chloro group. All target molecules were analyzed in 1% solution in distilled water in normotensive rabbits. After topical administration, IOP was monitored in both eyes for up to seven hours. The 1-p-methoxybenzyl molecule 2 was the most active, and caused a maximal IOP drop of 8.8 +/- 1.9 (n = 7) mm Hg in the ipsilateral eye at 4 hours post-administration, with only partial recovery at seven hours. All other compounds tested either showed very weak activity (3-6) or were inactive (1). All compounds produced a contralateral effect, and 5 induced rebound ocular hypertension. We conclude that selected tertiary bicyclic 1-p-methoxybenzyl-octahydroisoquinolines, particularly N-methylated structures, exhibit a significant IOP-lowering effect in normotensive rabbits.

Aqueous humor dynamics in monkeys with laser-induced glaucoma.

This study determines the effects of laser-induced glaucoma on aqueous humor dynamics of 18 cynomolgus monkeys. Baseline measurements of 12 monkeys included intraocular pressure (IOP) by pneumatonometry, aqueous flow by fluorophotometry and outflow facility by tonography. Beginning 4 to 14 days later, the trabecular meshwork of one eye was treated repeatedly with laser photocoagulation until elevated IOP was induced. Thirty-six to 75 days after the last laser treatment, all measurements were repeated. Between 1.7 and 11.4 years after laser treatment, the same 12 monkeys plus 6 additional monkeys underwent IOP and aqueous flow measurements. In addition, outflow facility was determined with fluorophotometry, and uveoscleral outflow was both calculated (n=18) and measured with an intracameral tracer (n=7). In glaucoma eyes compared to control eyes (n=12), IOP was increased (p<0.04) by at least 8 mmHg at Time 1 (1 to 3 months) or Time 2 (3 to 4 years) after laser treatment; aqueous flow was reduced (p=0.0007) by 46% at Time 1 but returned to baseline levels at Time 2; tonographic outflow facility was reduced (p=0.0008) by 71% at Time 1. In lasered eyes compared to control eyes, fluorophotometric outflow facility was reduced (p=0.0008; n=18) by 63%, and uveoscleral outflow was increased (p<0.05), whether calculated or measured with tracers at least 1 year after laser treatment. The increased IOP in monkeys with laser-induced glaucoma was caused by a sustained reduction in outflow facility. The uveoscleral outflow increase was not enough to prevent the rise in IOP.

Superior cervical ganglionectomy-induced lowering of intraocular pressure in rabbits: role of prostaglandins and neuropeptide Y.

At 22-24 h after unilateral ganglionectomy (SX), intraocular pressure (IOP) was significantly (p < 0.001) reduced in SX eyes compared either with the contralateral, normally innervated eyes or with baseline measurements. SX raised prostaglandin E2 (PGE2), PGF2alpha, and neuropeptide Y (NPY) concentrations in the aqueous humor but reduced these levels in the iris-ciliary body. At 22-24 h after bilateral SX, flurbiprofen (0.03%) significantly (p < 0.001) inhibited the reduction of IOP and the elevation of PGE2 and PGF2alpha levels in the aqueous humor. We conclude that PGs mediate the reduction of IOP at 22-24 h after SX.

Prostaglandin-induced iris color darkening. An experimental model.

OBJECTIVES: To determine the role of sympathetic innervation and the effect of topical prostaglandin therapy on iris color in pigmented rabbits. METHODS: Twelve Dutch-belted rabbits underwent unilateral superior cervical ganglionectomy (SCGx) at age 1 to 3 months. A second group of 11 rabbits underwent bilateral SCGx at age 1 month and were treated once or twice daily for 6 to 9 months with 1 drop (about 20 microL) of latanoprost, 0.005%, to one eye and its vehicle to the contralateral eye. Standardized color photographs of the iris of each eye were taken at 1- to 2-month intervals for 6 to 10 months and evaluated by 4 to 6 observers in a masked fashion. RESULTS: At 8 to 10 months after unilateral SCGx, 11 of 12 rabbits showed definite heterochromia, with the lighter-colored iris on the SCGx side. Of the 11 rabbits that underwent bilateral SCGx and unilateral latanoprost treatment, 9 showed heterochromia at 6 to 9 months, with the darker-colored iris on the latanoprost-treated side. CONCLUSIONS: These results demonstrate that sympathetic innervation is required for age-related, physiologic darkening of iris color in rabbits, that prostaglandins may compensate for sympathetic denervation to produce darkening in SCGx eyes, and that this model may be useful to study prostaglandin-induced iris color change.

Bunazosin reduces intraocular pressure in rabbits by increasing uveoscleral outflow.

The mechanism of the ocular hypotensive effect of bunazosin hydrochloride (an alpha1-adrenergic antagonist) and the possible intermediary role of prostaglandins were studied in New Zealand albino rabbits. Aqueous flow, outflow facility and uveoscleral outflow were determined by fluorophotometry, and intraocular pressure (IOP) was measured by pneumatonometry on the fourth day of twice daily topical treatment with 0.1% bunazosin. Uveoscleral outflow was measured with a tracer infusion technique at 1 to 2 hours after one dose of 0.1% bunazosin. Total outflow facility was measured by a two-level constant-pressure infusion method before and at one hour after one dose of 0.1% bunazosin. The effect of topically applied cyclooxygenase inhibitors, including 0.25% indomethacin and 0.03% flurbiprofen, on the IOP reduction after bunazosin was evaluated. At 3 hours after the seventh consecutive dose given twice-daily, bunazosin significantly (P<0.001) reduced IOP to 13.4+/-0.8 mm Hg (mean +/- SEM) from a baseline of 19.6+/-1.1 mm Hg. Indomethacin significantly inhibited the IOP reduction after one dose of bunazosin, whereas flurbiprofen did not (repeated measures ANOVA). Bunazosin significantly increased uveoscleral outflow (P<0.05) and total outflow facility (P<0.02), but not fluorophotometric outflow facility or aqueous flow. It is concluded that, in rabbits, 0.1% bunazosin reduces IOP predominantly by increasing uveoscleral outflow. The role of prostaglandins in this effect is equivocal.

Effect of prostaglandins on cyclic AMP production in cultured human ciliary muscle cells.

Prostaglandins (PGs) lower intraocular pressure by increasing uveoscleral outflow, presumably via a receptor-mediated mechanism coupled to a second messenger pathway in the ciliary muscle. In the present study, we examined the effect of prostanoids on cyclic AMP production in cultured human ciliary muscle cells. Cells were identified based on their expression of smooth muscle specific alpha-actin and monoclonal antibody against desmin. Cyclic AMP production in confluent cells incubated with buffer solution containing various concentrations of prostanoids was analyzed by radioimmunoassay. PGE2 caused a time-dependent increase in cyclic AMP concentrations which reached a maximum after 10 mins. With the exception of PGD2, all prostanoids produced a concentration-dependent increase in cyclic AMP levels with the following rank order of activity: PGE2 > 11-deoxy-PGE1 > 16,16-dimethyl PGE2 > sulprostone > PGF2alpha. PGE2-induced increase on cyclic AMP levels was unaffected by AH6809, an antagonist at both PGD2 (DP) and E2 (EP1) receptors. Flurbiprofen decreased basal cyclic AMP concentrations suggesting that intramurally-generated PGs stimulate the formation of the nucleotide in ciliary smooth muscle cells. PGE2-induced increases in cyclic AMP production was synergistic with those induced by the diterpene activator of adenylyl cyclase, forskolin. We conclude that prostanoids active at EP2-receptors can stimulate cyclic AMP production in cultured human ciliary muscle cells.

Steroid glaucoma: corticosteroid-induced ocular hypertension in cats.

This study was undertaken to develop a feline model of corticosteroid-induced ocular hypertension. In the first experiment, eight cats were selected whose intraocular pressure (17 +/- 0.4 mmHg) was consistently below the mean baseline intraocular pressure of our colony (24 +/- 0.5) during the preceding 2 months. Unilateral twice or thrice daily topical application of 10 microliters 1% dexamethasone sodium phosphate caused a gradual intraocular pressure increase that became significant (P less than 0.05) within 2-3 weeks. There was no significant change in body weight, but several eyes developed cataracts. Similar results were obtained with treatment of normotensive cat eyes with dexamethasone, or with 1.0% prednisolone acetate (PredForte) twice a day. Topical application of PGF2 alpha-1-isopropyl ester (0.1 or 0.25 microgram PG equivalent) to such steroid-treated eyes yielded significant intraocular pressure reduction and pupillary miosis, similar in magnitude to those exhibited by normal eyes. When dexamethasone treatment was reduced to once daily, after prolonged twice daily treatment, intraocular pressure decreased only slightly within 10 days. When dexamethasone treatment was stopped, intraocular pressure declined to normal levels within 6-7 days. These findings show that adult cat eyes develop steroid-induced ocular hypertension that is maintained and reversible. As opposed to previous findings on rabbits, steroid-induced feline ocular hypertension appears to be a good model for this clinical condition and may be suitable for the testing of potential glaucoma drugs.