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Influence of apraclonidine and pilocarpine alone and in combination on post laser trabeculoplasty pressure rise.

Apraclonidine and pilocarpine have been shown to be effective in reducing the incidence of intraocular pressure (IOP) spikes following argon laser trabeculoplasty. An additional reduction in the incidence of acute pressure rise might theoretically be expected by combining these two effective agents. In a prospective randomised study we compared the ability of apraclonidine and pilocarpine alone and in combination to prevent post laser pressure spikes. Patients receiving regular pilocarpine to either eye were excluded. Seventy five eyes received either apraclonidine (26 eyes), pilocarpine (23 eyes), or both drugs (26 eyes). Apraclonidine 1% was instilled 1 hour before and immediately after, and pilocarpine 4% immediately after trabeculoplasty. IOP was measured before and at 1, 2, and 3 hours following trabeculoplasty. In only two (8%) eyes receiving combined treatment was a pressure rise observed. This frequency was significantly lower than that seen in eyes treated with apraclonidine alone (38%), or pilocarpine alone (39%). The mean fall in IOP at 1, 2, and 3 hours was significantly greater in those eyes receiving combined treatment than in the other two groups.

Adrenergic beta-Agonists↗

Pilocarpine induces an increase in the anterior chamber angular width in eyes with narrow angles.

AIM: To determine the mechanical effects of pilocarpine on the trabecular-iris angle opening in eyes with narrow angles, compared with its effects on healthy control subjects with wide angles. METHODS: A narrow angle was defined as 25 degrees or less of trabecular-iris angle on ultrasound biomicroscopic examination. The change in anterior chamber depth (ACD), trabecular-iris angle (TIA), angle opening distance (AOD, distance between trabecular meshwork and iris) measured at 250 microm and 500 microm from the scleral spur (AOD250 and AOD500), and iris thickness was determined in 30 eyes of 30 patients (13 men and 17 women, between 63 and 82 years (mean 70.4 years)) with narrow angles and in 30 sex and age matched control subjects with wide angles before and 1 hour after the instillation of 2% pilocarpine hydrochloride by ultrasound biomicroscopy. RESULTS: In all eyes with narrow angles, pilocarpine increased the TIA, AOD250, and AOD500; these changes increased significantly and linearly as the corresponding pretreatment values decreased (r = 0.807, p = 0.0001; r = 0.787, p = 0.0001; r = 0.852, p = 0.0001). Of 30 eyes with wide angles, 23 eyes whose ACD was 2670 microm and more showed a decrease in the TIA, AOD250, and AOD500; the changes in TIA, AOD250, and AOD500 also significantly correlated with the corresponding pretreatment values (r = 0.913, p = 0.0001; r = 0.882, p = 0.0001; r = 0.895, p = 0.0001). Pilocarpine induced a smaller decrease in ACD in eyes with narrow angles than in those with wide angles (p = 0.0001). There was a linear correlation between the increase in ACD change and the decrease in pretreatment ACD in eyes with narrow angles and those with wide angles (r = 0.781, p = 0.0003; r = 0.798, p = 0.0001). CONCLUSIONS: The finding that pilocarpine increases angular width in patients with narrow angles indicates that this agent is useful for treating patients with narrow angles and angle closure glaucoma. The prediction of the pilocarpine induced change in the angle may assist ophthalmologists in treating such patients.

Aged↗

Comparison of the intraocular pressure lowering effect of latanoprost and a fixed combination of timolol-pilocarpine eye drops in patients insufficiently controlled with beta adrenergic antagonists. French Latanoprost Study Group, and the Swedish Latanoprost Study Group.

AIMS: To compare the effect on intraocular pressure (IOP) of latanoprost monotherapy and timolol-pilocarpine in patients with glaucoma or ocular hypertension with inadequately controlled IOP on topical beta adrenergic antagonists. METHODS: This was a multicentre, randomised, observer masked, 6 week study performed in France and Sweden. 23 centres enrolled 237 patients with glaucoma or ocular hypertension and an IOP of at least 22 mm Hg on treatment with topical beta adrenergic antagonists, alone or in combination. After a 21 day run in period on timolol 0.5% twice daily, patients were randomised either to latanoprost 0.005% once daily or to a fixed combination of timolol-pilocarpine twice daily. Changes in mean diurnal IOP from the baseline to the 6 week visit were determined with an analysis of covariance. RESULTS: Mean diurnal IOP was statistically significantly decreased from baseline in both groups (p<0.001). Switching to latanoprost treatment reduced mean diurnal IOP by 5.4 (SEM 0.3) mm Hg (ANCOVA -22%) and switching to timolol-pilocarpine treatment reduced mean diurnal IOP by 4.9 (0.4) mm Hg (-20%). Blurred vision, decreased visual acuity, decreased twilight vision, and headache were statistically significantly more frequent in the timolol-pilocarpine group. CONCLUSIONS: Latanoprost monotherapy was at least as effective as fixed combination timolol-pilocarpine twice daily treatment in reducing mean diurnal IOP in patients not adequately controlled on topical beta adrenergic antagonists. Latanoprost was better tolerated than timolol-pilocarpine regarding side effects. These results indicate that a switch to latanoprost monotherapy can be attempted before combination therapy is initiated.

Adult↗

Ultrasound biomicroscopic analysis of the human ciliary body after 1 and 2% pilocarpine instillation.

We examined ciliary body thickness (CBT) of 11 human eyes after 1% followed by 2% pilocarpine instillation using ultrasound biomicroscopy. The examination revealed that CBT decreased in 2 eyes after 1% pilocarpine treatment but increased after 2% pilocarpine. In the eyes with decreased CBT by 1% pilocarpine, the pretreatment ciliary bodies were thicker and the changing rate of CBT induced by 2% pilocarpine, although not decreased, was also smaller than that in CBT-increased eyes. These findings showed that the ciliary body was under relatively strong stimulus of endogenous acetylcholine and has subsensitivity to both 1 and 2% pilocarpine in CBT-decreased eyes. Configurative changes in CBT-decreased eyes may be explained by the localization of different muscarinic receptor subtypes in different portions of the ciliary muscle.

Adult↗

Involvement of the central nervous system in the salivary secretion induced by pilocarpine in rats.

The effect of rats of an anteroventral third ventricle (AV3V) electrolytic lesion on salivary secretion induced by intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection of a cholinergic agonist (pilocarpine) was investigated. Sham- or AV3V-lesioned rats anesthetized with urethane and with a stainless steel cannula implanted into the lateral ventricle (LV) were used. The amount of salivary secretion was studied over a seven-minute period after i.c.v. or i.p. injection of pilocarpine. In sham-operated rats, i.p. injection of pilocarpine (1 mg/kg b.w.) (after 6 h, 2, 7, and 15 days) produced salivary secretion (486 +/- 21, 778 +/- 85, 630 +/- 50, and 560 +/- 55 mg/7 min, respectively). This effect was reduced 6 h, 2, and 7 days after an AV3V lesion (142 +/- 22, 113 +/- 32, and 290 +/- 62 mg/7 min, respectively), but not 15 days after an AV3V lesion (516 +/- 19 mg/7 min). I.c.v. injection of pilocarpine (120 micrograms in 1 microL), in sham-operated rats after 6 h, 2, 7, and 15 days also produced salivary secretion (443 +/- 20, 417 +/- 81, 496 +/- 14, and 427 +/- 47 mg/7 min, respectively). The effects of i.c.v. pilocarpine were also reduced 6 h, 2, and 7 days after an AV3V lesion (143 +/- 19, 273 +/- 14, and 322 +/- 17 mg/7 min, respectively), but not after 15 days (450 +/- 28 mg/7 min). The results demonstrate that the central nervous system, and particularly the AV3V region, is important for the effect of pilocarpine on salivary secretion in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Pilocarpine alters caries development in partially-desalivated rats.

This study examined the effect of pilocarpine on caries and saliva composition in rats with compromised salivary gland function. Eight litters of specific-pathogen-free female Sprague-Dawley rats were divided into five groups for surgery. Partial desalivation was performed in either of three ways: (1) Both parotid ducts were ligated; (2) both submandibular/sublingual (SM/SL) glands were excised, or (3) one parotid duct was ligated, and submandibular/sublingual glands were removed unilaterally. Completely desalivated animals and unoperated animals served as positive and negative controls, respectively. One week following surgery, groups were subdivided so that half of each group had osmotic pumps implanted which delivered pilocarpine HCl (24 mg/kg/day). All animals were infected with Streptococcus sobrinus 6715 and fed cariogenic diet ad libitum for 28 days. Caries scores, microbiological data, and saliva flow rate and composition were determined for all animals. Animals which had both SM/SL glands removed and received pilocarpine developed significantly lower sulcal caries (p < or = 0.05) compared with the animals that had both SM/SL removed but did not receive pilocarpine. The concentration of protein in parotid saliva in these pilocarpine-treated animals was unaffected, and no differences were observed in the electrophoretic profiles on SDS-PAGE. Pilocarpine appears to exert its greatest caries-protective effect when the parotid glands remain intact.

Analysis of Variance↗

Pilocarpine-induced salivation and thirst in conscious rats.

The muscarinic receptor agonist pilocarpine is widely used as a sialogogue. It has been well-established that it also induces water intake in animals. However, the mechanisms underlying the relationships between these events are unknown. To address this problem, we examined water intake and parotid salivary secretion in conscious rats. Intraperitoneally injected pilocarpine increased both water intake and salivary secretion. Intracerebroventricularly injected pilocarpine also induced water intake, but not salivary secretion. Intracerebroventricularly applied atropine, a muscarinic receptor antagonist, suppressed the water intake produced by pilocarpine applied intraperitoneally and intracerebroventricularly. However, it did not affect the salivary secretion induced by pilocarpine applied peripherally. We conclude that peripherally applied pilocarpine affects the parotid glands and the thirst center in the central nervous system, while it may induce salivary secretion mainly via peripheral responses, but water intake mainly via the central nervous system.

Animals↗

Effect of pilocarpine on striatal acetylcholine release in dopamine-depleted rats.

We have previously demonstrated that the systemic administration of pilocarpine stimulates striatal acetylcholine (ACh) release in rats using a brain microdialysis technique. In the present study, we investigated whether a nigro-striatal dopaminergic system is involved in the pilocarpine-induced increase in striatal ACh release using dopamine-depleted rats under urethane anesthesia. The application of pilocarpine (0.1-10 mM) via the microdialysis tube increased striatal ACh release in normal rats in a concentration-dependent manner, but it had no effect on the release of glutamate or gamma-aminobutyric acid (GABA) from the striatum. The increase in striatal ACh release caused by pilocarpine (1 mM) was enhanced by reserpine and alpha-methyl-p-tyrosine treatment, which completely depleted dopamine in the striatum. These results suggest that pilocarpine selectively increases striatal ACh release by acting at the striatum, and that the nigro-striatal dopaminergic neurons play an inhibitory role in the pilocarpine-induced ACh release.

Acetylcholine↗

Salivary gland-sparing prophylactic pilocarpine treatment has no effect on tumor regrowth after irradiation.

Radiotherapy of head and neck cancer frequently damages the salivary glands. Prophylactic administration of the muscarinic receptor agonist pilocarpine reduces subsequent radiation damage to the salivary glands in rats, but its effects on tumor cell radiosensitivity and tumor regrowth after irradiation had not been assessed. In the current study, we first tested the effect of pilocarpine on clonogenic cell survival in vitro. No effect of pilocarpine on radiosensitivity was observed in a panel of cell lines either with or without expression of muscarinic receptors. Second, a single dose of pilocarpine known to protect salivary gland tissue from radiation damage was given to rats transplanted with subcutaneously growing rhabdomyosarcomas 1 h prior to irradiation with a single dose of 35 Gy. No alterations in growth delay were detected (26 +/- 2 days for controls compared to 26 +/- 2 days for pilocarpine treatment). Our data indicate that pilocarpine pretreatment, which has been shown previously to protect salivary glands from radiation, does not protect tumor cells or tumors. Use of this drug therefore may lead to therapeutic gain in the treatment of head and neck cancer.

Animals↗

[Preparation and testing of buffered eye drops containing pilocarpine chloride with timolol maleate].

BACKGROUND/AIM: In glaucoma therapy beta-blocator, timolol-maleate, is the first-line medicine of selection, whereas a miotic, pilocarpine chloride, is one of the oldest medicines used for the treatment of this illness. They are applied as eye drops. In order to achieve a better therapeutic effect and improve life quality of the ill, we produced and tested eye drops formulations based on combining pilocarpinechloride and timolol maleate in buffers of diferent pH values. METHODS: Following the general pharmacopoeial eye drops preparation regulation, we prepared formulations, of solution type, of pilocarpine chloride and timolol maleate combination, of pilocarpine choloride alone and of timolol maleate alone. A modified phosphate buffer according to Sorensen at 7.4, 7.7 and 8.0 pH values was used as a solvent. The quality of the produced formulations was examined using physical and physico-chemical methods and biological tests. Following pharmacopoeial regulations, we examined clarity, pH value and sterilty. Pilocarpine chloride level was determined by means of ion-par (High Performance Liguid Chromatography) RP-HPLC method, whereas UV/VIS absorption spectrophotometry was used for determining the level of both timolol maleate, and timolol. RESULTS: Results showed that monocomponent and combined preparations complied with the regulation demands. With the increase in the pH value of the solution pilocarpine chloride level decreased in relation to its initial content, whereas timolol level showed a tendency of moderate increase. CONCLUSION: Magistrally prepared pilocarpine chloride eye drops with timolol maleate have satisfied all the required conditions for an ophtalmological preparation. A modified phosphate buffer according to Sorensen at 7.4 pH value proved to be the most optimal solvent.

Adrenergic beta-Antagonists↗

Pilocarpine hydrochloride for symptomatic relief of xerostomia due to chronic graft-versus-host disease or total-body irradiation after bone-marrow transplantation for hematologic malignancies.

Xerostomia due to chronic graft-versus-host disease (GVHD) or total-body irradiation (TBI) is an important cause of morbidity after BMT. The ophthalmic or oral form of pilocarpine, a parasympathomimetic agent with predominantly muscarinic activity, was given orally to 13 patients with moderate (n = 6) or severe (n = 7) xerostomia due to chronic GVHD (n = 7) or TBI (n = 6). The duration of 19 courses of therapy was 7-245 days (median 73). Ten patients (77%) noticed significant improvement in salivation and relief of symptoms which reached its maximum after 7-186 days (median 46). Difficulty in eating and speaking reduced, and there was a beneficial effect on the oral mucosa and teeth. Xerophthalmia improved in one of six patients. Five patients had adverse reactions: wheezing (n = 1), and increased sweating without (n = 3) or with (n = 1) abdominal cramps (n = 1): leading to discontinuation of pilocarpine in one. Three patients stopped pilocarpine, became symptomatic again, but the benefits were reproducible on restarting pilocarpine. The ophthalmic preparation was as effective as the oral, and was one-tenth the cost of the oral. We conclude that oral pilocarpine is effective in relieving xerostomia associated with chronic GVHD and TBI. The time taken for a response to be seen is variable, and unless significant adverse effects are encountered, pilocarpine should be continued for 6-8 weeks before it is considered to have failed.

Bone Marrow Transplantation↗

Pilocarpine in the management of overcorrection after radial keratotomy.

BACKGROUND: Induced hyperopia is a potential complication of radial keratotomy with few effective treatments. We report the results of a retrospective study to evaluate the effectiveness of pilocarpine in the treatment of eyes overcorrected by radial keratotomy. METHODS: Sixteen eyes of 14 patients, from a consecutive pool of 200 eyes who underwent radial keratotomy, had hyperopia. The patients were subsequently treated with topical pilocarpine. The patients were treated from 3 to 14 weeks (mean, 8.2 weeks). RESULTS: The mean time of diagnosis of hyperopia was 3 weeks after the surgery (range, 1 to 12 weeks). The mean spherical equivalent of the manifest (fogging) refraction was +1.92 diopters (D) (range, +0.75 D to +5.00 D) and the keratometric power ranged from 31.25 D to 41.00 D (mean, 36.05 D). Mean uncorrected visual acuity before the treatment with pilocarpine was 20/50. After the treatment with pilocarpine, the mean spherical equivalent refraction was -0.31 D (range, -1.75 D to +0.50 D). The mean keratometric power was 38.32 D (range, 34.87 D to 43.12 D), with a mean uncorrected visual acuity at 20/25. The patients were followed for 8 to 49 weeks after treatment without pilocarpine (mean, 21 weeks). The mean spherical equivalent refraction and keratometric readings after that period were -0.71 D (range, -2.25 D to +0.25 D) and 38.33 D (range, 36.12 D to 43.12 D), respectively. All eyes in this study had more than 1.00 D of reduction of hyperopia at the conclusion of the study. CONCLUSION: Pilocarpine effectively reduced overcorrections after radial keratotomy. After termination of treatment, the steepening of corneal curvature was maintained.

Adult↗

Candida albicans levels in patients with Sjögren's syndrome before and after long-term use of pilocarpine hydrochloride: a pilot study.

OBJECTIVE: The purpose of this study was to compare the quantities of oral Candida albicans in patients with primary and secondary Sjögren's syndrome before and after the use of orally administered pilocarpine hydrochloride for 1 year. METHOD AND MATERIALS: Twelve female subjects with primary (n = 4) and secondary (n = 8) Sjögren's syndrome (mean age +/- SEM = 56.7 +/- 5.7 years) were enrolled in the study, after meeting rigid enrollment criteria. Oropharyngeal collection of samples and culturing was performed on each subject. Cultures specific for Candida albicans were plated into a culture media tube using the Oricult kit and also by serial dilutions and plating by a streptomycin-vancomycin technique. Cultures were incubated for 48 hours at 37 degrees C. The subjects used 5 mg of pilocarpine hydrochloride, administered orally three times daily, for 1 year, after which both of the Candida cultures were repeated. None of the subjects used antifungal medications, none smoked, and all were dentate. RESULTS: There was a significant difference in the prevalence of Candida after the use of pilocarpine hydrochloride for both groups. At the start of the study, 75% of all subjects were positive for Candida. Following the use of pilocarpine, 25% had positive cultures. There was also a decrease in the prevalence of clinical manifestations of infection from 75% of subjects to 25%. There was a significant decrease in the numbers of Candida cultured following the use of pilocarpine. CONCLUSION: Long-term administration of pilocarpine hydrochloride resulted in a significant reduction in Candida albicans colonization in patients with primary or secondary Sjögren's syndrome.

Adult↗

Pharmacokinetics of pilocarpine in subjects with varying degrees of renal function.

Data from three separate single-center studies were combined to assess the pharmacokinetics of orally administered pilocarpine. Pilocarpine concentration-time data were used to generate a data set including 42 subjects (34 males, 8 females) with varying degrees of renal function (average of two estimated creatinine clearance rates of 10 to 112 mL/min). Age ranged from 19 to 88 years. Subjects received single oral doses (range: 2.5-20 mg) of pilocarpine. Plasma samples were collected at time 0; at 20 and 40 minutes; and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours following dose administration. Cmax and AUC were normalized to a 5 mg exposure in those subjects who received doses other than 5 mg. Plasma pilocarpine concentrations were determined by gas chromatography/mass spectrometry. The pharmacokinetic parameters (elimination rate constant, Cmax, tmax, AUC, Vd/F, and Cl/F) in subjects with impaired renal function were similar to results found in other pharmacokinetic studies involving normal healthy volunteers with only Cmax being significantly higher (p < 0.05). No significant regression relationships were noted between creatinine clearance and pilocarpine elimination rate constant, tmax, Vd/F, Cl/F, or AUC. Pilocarpine clearance does not appear to be impaired in patients with varying degrees of renal insufficiency.

Adolescent↗

[Acetylcholine of bovine iris and cholinergic effects of pilocarpine].

The authors extracted acetylcholine (ACh) from bovine iris and carried out biological assay on guinea pig ileum. One of the pairs of irides were subjected in vivo for an hour to an aqueous solution of pilocarpine HCl 3 per cent, with the loading dose instilled in the conjunctival sac at the rate of ten times three drops in intervals of three minutes. The bio-assays of tissue extracts of pilocarpinised iris after one hour's action and the control studies present the following values: the amount of ACh in the pilocarpinised irides was 0,70 mug and in the controls it was 0,58 mug of ACh/150 mg of tissue. The remaining proportion of the elevated dose of pilocarpine applied to the iris tissue, one hour after the in vivo action, was comparable only to 1,5 mug of free pilocarpine or to a fifth of the ACh in the iris (0,12 mug). The results of these experiments demonstrate a complete decomposition of the pilocarpine as well as the existence of a certain limitation of elevation of the cholinergic tone in the iris tissues. The authors support data in the literature which indicates that pilocarpine raises the ACh levels. They do not attribute a fundamental importance to the raised loading dose of pilocarpine concerning the desired effect of a maximal elevation of cholinergic tone in order to achieve a favourable clinical effect in glaucoma.

Acetylcholine↗

A study of replacement of timolol-pilocarpine with latanoprost in pseudoexfoliation glaucoma.

The aim of the study was to evaluate the efficacy of replacing current dual local therapy (timolol and pilocarpine) with latanoprost 0.005% in 71 pseudoexfoliation glaucoma patients with controlled intraocular pressure (IOP). 39 patients switched to latanoprost 0.005%) and 32 patients continued timolol-pilocarpine therapy. Mean diurnal (IOP) was measured at baseline, after 0.5, 1, 3 and 6 months of treatment. After 6 months 38 patients with latanoprost and 30 patients with timolol-pilocarpine had completed the study. At baseline the mean diurnal IOP was 20.4 +/- 2.0 mmHg for patients in latanoprost treatment group and 21.4 +/- 2.1 mmHg for patients in timolol-pilocarpine group. At the end of the study, after 6 months of treatment, the mean diurnal IOP values were 16.6 +/- 2.4 and 17.9 +/- 2.0 mmHg respectively. IOP was statistically significantly reduced from baseline (p < 0.001). The mean diurnal IOP change from baseline was -3.3 +/- 0.5 mmHg (mean +/- SEM, ANCOVA) for the patients treated with latanoprost and -3.2 +/- 0.4 mmHg for the patients treated with timolol + pilocarpine. This difference in IOP reduction between groups was not statistically significant (z = 0.69; p = 0.49). This study showed that combination therapy (timolol plus pilocarpine) in pseudoexfoliation glaucoma can effectively be replaced by latanoprost monotherapy.

Aged↗

Possible mechanisms of sustained tremor induction by nicotine in pilocarpine treated animals.

Alterations of steady state and metabolism of putative neurotransmitters were studied in the brain of rats with a sustained tremor evoked by nicotine and pilocarpine. The norepinephrine content in several brain regions was decreased whereas striatal dopamine was unchanged. Homovanillic acid concentrations were slightly increased, while 5-hydroxyindoleacetic acid concentrations were markedly increased. Pilocarpine alone increased the 5-hydroxytryptamine (5-HT) turnover rate at high ambient temperature (30-32 degrees C), but not at normal ambient temperature (22 +/- 2 degrees C), atropine partially blocked the increase of 5-HT turnover rate by pilocarpine. Pretreatment with p-chlorophenylalanine and hemicholinium-3 decreased the tremor intensity elicited by nicotine and pilocarpine . It is proposed that the increase of cholinergic function caused by nicotine and the activation of muscarinic receptors and the increase in 5-HT function caused by pilocarpine might be involved in the mechanisms of tremor induction by nicotine and pilocarpine.

Animals↗

[Analysis of the effectiveness of pilocarpine in the management of xerostomia].

The authors have studied the "sympathetic like" side effect of pilocarpine after single injection (1 mg/100 g b.w., i.p.) of the drug. They developed a system for the continuous automatic recording the amylase activity of the saliva secreted by the parotid glands of rats, "in situ". Pilocarpine stimulus was characterized by a peak in amylase activity--regularly observed in the first 40-60 min--which was additive to the cholinergic amylase secretory response. After this the amylase secretion was continued with lower activity. The role of a beta-adrenergic component in the pilocarpine stimulus appears to be supported by the finding that propranolol (2.5 mg/100 g b.w., i.p.) pretreatment applied 30 min prior to the pilocarpine stimulus prevented the appearance of the characteristic amylase peak. These data support that the beta-adrenergic side effect triggering the periodical synthesis of export proteins during the course of pilocarpine treatment accounts for the selative efficiency of pilocarpine in the therapy of xerostomia.

Amylases↗