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PubMed2002

Combined therapy of pilocarpine or latanoprost with timolol versus latanoprost monotherapy.

Adjunctive intraocular pressure (IOP)-lowering therapy is widely used today, as one-third of all patients being treated for glaucoma need additional therapy to reach and maintain healthy IOPs. Timolol, latanoprost, and pilocarpine are three potent drugs that have been used in combination to reduce IOP. Timolol reduces the production rate of aqueous humor to achieve the IOP decrease. Latanoprost and pilocarpine both affect aqueous outflow, although by different mechanisms. The IOP efficacy of combined therapy with timolol and pilocarpine compared with timolol and latanoprost or with latanoprost alone has been investigated in three multicenter, randomized, clinical trials in Europe. This is a review of those published trials. In 2 of the 3 studies, the additional IOP lowering effect of latanoprost 0.005% administered once daily was compared with pilocarpine 2% administered 3 times daily in patients with primary open-angle glaucoma (POAG) or ocular hypertension currently on monotherapy with timolol 0.5% twice daily. These 6-month studies found that the timolol and latanoprost combination reduced IOP more and was better tolerated with fewer side-effects than the timolol and pilocarpine combination. At 6 months, there was no evidence of long-term drift in IOP with timolol and latanoprost. This combined therapy provides an effective and safe option for lowering IOP in glaucoma patients. These results suggest that the timolol/latanoprost combination is preferable to the timolol/pilocarpine combination not only with regard to side effects but also to the magnitude of IOP reduction. Two of the 3 studies compared latanoprost monotherapy with timolol and pilocarpine combined therapy in patients with POAG, various other glaucomas, or ocular hypertension. Treatment was for 6 weeks or 6 months. In both studies, latanoprost was more effective and better tolerated than the combination of timolol and pilocarpine. These results suggest that latanoprost alone should be tried before the addition of pilocarpine to timolol therapy is considered. The convenience of daily administration of a single drop of latanoprost versus multiple drops of timolol and pilocarpine should improve patient compliance.

Adrenergic beta-Antagonists↗

PubMed2000

Behavioral and neurochemical alterations after lithium-pilocarpine administration in young and adult rats: a comparative study.

Pilocarpine and lithium-pilocarpine can induce seizures and brain damage in adult rats. However, manifestation of cerebral lesions seems to be an age-related phenomenon suggesting that maturational states of neurocircuitry may be involved. We have studied behavior changes, cerebral histopathology, and muscarinic and dopaminergic receptors density in rodents subjected to lithium-pilocarpine treatment. Wistar rats, at two different ages (21 days and 2 months), were treated with pilocarpine (15 mg/kg, SC), lithium (3 mEq/kg, IP), atropine (50 mg/kg, IP) and the combination of lithium to pilocarpine. Histopathologic studies showed that younger animals were more resistant to the development of cerebral changes and there was a preferential involvement of the striatum (Wilcoxon p = 0.02) as opposed to more generalized areas in adult animals such as hippocampus and neocortex. Lithium treatment induced an upregulation of muscarinic receptors at both ages, and this effect was reversed in younger animals after pilocarpine administration. Lithium also induced an upregulation of dopaminergic receptors in the striatum at both ages (p < 0.05), and this effect was not reversed after pilocarpine administration. Our data confirm that young animals show less brain damage after lithium-pilocarpine, and main alterations in dopaminergic receptors density occur in young and older animals after treatment with lithium and lithium combined to a low dose of pilocarpine.

Age Factors↗

PubMed1997

MK-801 augments pilocarpine-induced electrographic seizure but protects against brain damage in rats.

1. The authors examined the anticonvulsant effects of MK-801 on the pilocarpine-induced seizure model. Intraperitoneal injection of pilocarpine (400 mg/kg) induced tonic and clonic seizure. Scopolamine (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of pilocarpine-induced behavioral seizure but MK-801 (0.5 mg/kg) did not. 2. An electrical seizure measured with hippocampal EEG appeared in the pilocarpine-treated group. Scopolamine and pentobarbital blocked the pilocarpine-induced electrographic seizure, MK-801 treatment augmented the electrographic seizure induced by pilocarpine. 3. Brain damage was assessed by examining the hippocampus microscopically. Pilocarpine produced neuronal death in the hippocampus, which showed pyknotic changes. Pentobarbital, scopolamine and MK-801 protected the brain damage by pilocarpine, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by pilocarpine is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause brain damage through an excitatory NMDA receptor-mediated mechanism.

Animals↗

PubMed2001

Twenty-four hour intraocular pressure reduction with latanoprost compared with pilocarpine as third-line therapy in exfoliation glaucoma.

PURPOSE: To compare the 24 hour efficacy of latanoprost 0.005% given every evening with that of pilocarpine 4% given four times daily as third-line therapy in patients with exfoliation glaucoma receiving timolol 0.5% and dorzolamide 2% each given twice daily. METHOD: We enrolled 30 patients with exfoliation glaucoma not adequately controlled on timolol maleate 0.5% and dorzolamide 2%. Each patient underwent a baseline 24 hour intraocular pressure curve testing at 06:00, 10:00, 14:00, 18:00, 22:00 and 02:00 hours. Patients were randomised to receive either latanoprost 0.005% or pilocarpine 4% for a minimum of 8 weeks and were then crossed over to the opposite therapy. Diurnal curve testing was repeated at the end of each treatment. RESULTS: There was a significant decrease from baseline in intraocular pressure at each timepoint for both study medicines (p < 0.016). Latanoprost provided better intraocular pressure control than pilocarpine at daytime measuresments (17.4 vs 19.7 mmHg at 06:00 hours, p < 0.001; 17.8 vs 19.1 mmHg at 10:00 hours, p = 0.04). However, pilocarpine reduced the pressure more than latanoprost at 22:00 hours (18.4 vs 19.5 mmHg, p = 0.016). Overall, the diurnal intraocular pressure was reduced from a baseline of 21.5 +/- 3.7 mmHg to 18.8 +/- 3.1 mmHg on pilocarpine and to 18.0 +/- 3.0 mmHg on latanoprost (p = 0.06). In addition, mean peak pressure was similar between pilocarpine (21.0 +/- 2.9 mmHg) and latanoprost (20.5 +/- 3.8 mmHg) (p = 0.20). Side-effects were similar with the exception of blurred vision, which was only found with pilocarpine (10%). Compliance was more difficult with pilocarpine. CONCLUSION: In exfoliation glaucoma, as a third-line adjunctive therapy added to timolol and dorzolamide, latanoprost and pilocarpine have similar diurnal efficacy. However, latanoprost provides a greater morning pressure reduction.

Aged↗

PubMed1995

Effect of pilocarpine on anterior chamber angles.

Pilocarpine is widely used in the treatment of glaucoma, especially for the acute form of angle-closure glaucoma. Previous studies have shown that pilocarpine decreases central anterior chamber depth. In the present study, a quantitative measurement method, applying Scheimpflug photography, was used to report whether pilocarpine also affected the anterior chamber angles. Twenty-nine normal Chinese subjects, 17 female and 12 male with an age range from 11 to 63 years old, were enrolled. One eye of each subject was treated with one drop of 2% pilocarpine. Photographs of each of four quadrants were taken prior to, and after, pilocarpine treatment in both eyes, using a rotating slit-lamp video camera based on the Scheimpflug principle. The slit beams were set at 0 degrees and 90 degrees. The eyes which did not receive pilocarpine treatment served as control. The angles of the four quadrants were calculated for both eyes both prior to, and after, pilocarpine treatment, and results were compared by Student's paired t-test. The comparison of angles between the eyes prior to, and after, pilocarpine treatment indicated that there is a significant narrowing of angles in all quadrants. The complex factors involved in the change of anterior chamber angle are reviewed in the light of muscarinic action of pilocarpine.

Adolescent↗

PubMed2002

Usefulness of basal and pilocarpine-stimulated salivary flow in primary Sjögren's syndrome. Correlation with clinical, immunological and histological features.

OBJECTIVES: To examine salivary function in patients with primary Sjögren's syndrome (SS) by assessing unstimulated and stimulated flows using 5 mg of pilocarpine in a 5% solution, in order to define their clinical usefulness in the evaluation of xerostomia in patients with primary SS as well as to identify those factors related to the increase in salivary flow after pilocarpine stimulation. METHODS: We investigated the clinical and immunological characteristics of 60 consecutive patients with primary SS. All patients fulfilled four or more of the preliminary diagnostic European criteria for SS. We measured unstimulated (basal) salivary flow (BSF) in all patients. In patients with BSF </=1.5 ml, stimulated salivary flows (SSF) were also measured after stimulation with an ophthalmic 5% pilocarpine solution (0.1 ml=5 mg, administered sublingually). SSF was also measured after oral administration of 50 mg anetholetrithione (ANTT) in the same patients. These stimulated salivary flows were measured 1, 2 and 3 h after the stimulus. RESULTS: Of the 60 patients, 55 were women and five men, with a mean age at the SS onset of 61 yr (range 18-82 yr). The mean BSF for SS patients was 1.40+/-0.17 ml. Fifty (83%) patients showed a BSF less than 1.5 ml. The stimulated salivary flow after 1 h was 3.23 ml in the pilocarpine group and 0.57 in the ANTT group (P<0.001); after 2 h it was 1.32 ml in the pilocarpine group and 0.52 in the ANTT group (P=0.02) and after 3 h it was 0.80 ml in the pilocarpine group and 0.41 in the ANTT group (P=0.046). No clinical or immunological differences were found between SS patients with BSF more or less than 1.5 ml, although patients with a BSF less than 1.5 ml showed a parotid scintigraphy class III or IV more frequently (42 vs 0%, P=0.01). SS patients with a pilocarpine SSF less than 1.5 ml had a longer duration of SS (73.3 vs 31.3 months, P=0.03) and a higher prevalence of positive anti-Ro/SS-A (70 vs 36%, P=0.038), anti-La/SS-B (65 vs 32%, P=0.038), parotid scintigraphy class III-IV (79 vs 9%, P<0.001) and positive salivary gland biopsy (90 vs 43%, P<0.001). CONCLUSION: The study of xerostomia using basal and pilocarpine SSF is simple to perform, acceptable to patients and needs no special equipment. We describe a significant increase in SSF using a solution of 5% pilocarpine in comparison with salivary flow obtained after stimulation with ANTT. Twenty-two of the 46 patients with low BSF had stimulated flows over 1.5 ml. These 'responder' patients showed a shorter duration of sicca symptoms, a lower frequency of positive immunological markers and milder grades of scintigraphic patterns and lymphocytic infiltrates in salivary gland biopsies. This subset of patients probably maintain a residual capacity of their salivary glands, as opposed to the 'non-responder' patients, who had a longer duration of sicca syndrome evolution with more severe involvement of the salivary glands.

Adolescent↗

PubMed2001

Salivary scintigraphy for assessing the protective effect of pilocarpine in head and neck irradiated tumours.

Patients with head and neck cancers can develop salivary hypofunction after radiotherapy. The use of pilocarpine during radiotherapy treatment has been shown to be an effective treatment, although its usefulness is being discussed. The aim of this study was: (1) to determine the value of a semiquantitative scintigraphy method for measuring the uptake and excretory salivary function of patients with head and neck irradiated tumours; and (2) to study the usefulness of pilocarpine as a salivary gland protector during radiotherapy. We prospectively studied 49 patients (mean age 61 years, range 29-87 years) with head and neck cancer in need of radiotherapy. Patients were divided into two groups consecutively: group P (26 patients) received 5 mg of pilocarpine three times per day starting the day before radiation therapy, and group NP (23 patients) received radiotherapy without pilocarpine and were used as the control group. Salivary gland scintigraphy and a visual analogue scale (VAS) of mouth dryness were obtained from each patient before radiotherapy and during the first year after treatment. The most frequent finding after radiotherapy was a quick impairment in parotid and submaxillary excretion (P < 0.001). There were no statistical differences comparing the pilocarpine group against the non-pilocarpine group. Parotid and submaxillary uptake significantly decreased after radiotherapy in both groups (P < 0.001). However, a tendency to recover within the pilocarpine group was observed in both the parotids and the submaxillary glands at 12 months. No differences were found comparing the VAS results in both groups. Strikingly, VAS data did not correlate with salivary gland dysfunction observed by means of scintigraphy. In conclusion, salivary scintigraphy is a useful technique to evaluate objectively the salivary gland function of patients with head and neck irradiated tumours as well as to test the response to pilocarpine. However, despite better results on the salivary uptake at 12 months, pilocarpine did not significantly improve salivary gland function.

Adult↗

PubMed2005

Additivity of pilocarpine to bimatoprost in ocular hypertension and early glaucoma.

PURPOSE: To determine if the intraocular pressure (IOP) effect of pilocarpine at various concentrations is additive to that of bimatoprost and to assess the tolerability of this combination. METHODS: This was a randomized, prospective trial of patients with IOP > 21 mm Hg following appropriate medication washout. For all visits IOP was measured at 9:00 AM and 11:00 AM. Following baseline visit (#1), bimatoprost 0.03% was instilled qhs OU through visit 6. Following visits 2, 3, and 4 pilocarpine (2%, 4%, 6%) was instilled qid in one randomly selected eye. Pilocarpine was discontinued after visit 5 and bimatoprost after visit 6. Two-tailed, paired t test was used to compare treated and contralateral eyes for their IOP, IOP change, percentage IOP change from baseline, and to compare IOP in the same eye at 9:00 AM and 11:00 AM (before and after pilocarpine administration). IOPs using bimatoprost alone or in combination with various pilocarpine concentrations were compared using single variant Analysis of Variance (ANOVA). RESULTS: Seventeen patients were enrolled and 13 patients completed the study. Bimatoprost reduced IOP 28.7% to 30.5% (P < 0.0001) from baseline to visit 2. IOPs in eyes treated with bimatoprost alone or with bimatoprost and various pilocarpine concentrations were similar (P > 0.81, ANOVA). The IOP (P > 0.17) and percentage IOP change from baseline (P > 0.10) was similar in treated and contralateral eyes with all three strengths of pilocarpine. IOP values at 9:00 AM and 11:00 AM, before and after pilocarpine administration, were similar (P > 0.22). CONCLUSION: Bimatoprost alone reduces IOP substantially. Pilocarpine added to bimatoprost at concentrations of 2%, 4%, or 6% was neither additive nor antagonistic to the ocular hypotensive efficacy of bimatoprost.

Amides↗

PubMed1995

Competitive inhibition of coumarin 7-hydroxylation by pilocarpine and its interaction with mouse CYP 2A5 and human CYP 2A6.

1. We have shown earlier that pilocarpine strongly inhibits mouse and human liver coumarin 7-hydroxylase activity of CYP 2A and pentoxyresorufin O-deethylase activity of CYP 2B in vitro. Since pilocarpine, like coumarin, contains a lactone structure we have studied in more detail its inhibitory potency on mouse and human liver coumarin 7-hydroxylation. 2. Pilocarpine was a competitive inhibitor of coumarin 7-hydroxylase in vitro both in mouse and human liver microsomes although it was not a substrate for CYP 2A5. Ki values were similar, 0.52 +/- 0.22 microM in mice and 1.21 +/- 0.51 microM in human liver microsomes. 3. Pilocarpine induced a type II difference spectrum in mouse, human and recombinant CYP 2A5 yeast cell microsomes, with Ka values of 3.7 +/- 1.6, 1.6 +/- 1.1 and 1.5 +/- 0.1 microM, respectively. 4. Increase in pH of the incubation medium from pH 6 to 7.5 increased the potency of inhibition of coumarin 7-hydroxylation by pilocarpine. 5. Superimposition of pilocarpine and coumarin in such a way that their carbonyls, ring oxygens and the H-7' of coumarin and N-3 of pilocarpine overlap yielded a common molecular volume of 82%. 6. The results indicate that pilocarpine is a competitive inhibitor and has a high affinity for mouse CYP 2A5 and human CYP 2A6. In addition the immunotype nitrogen of pilocarpine is coordinated towards the haem iron in these P450s.

Animals↗

PubMed2002

Allosteric modulation of muscarinic receptor signaling: alcuronium-induced conversion of pilocarpine from an agonist into an antagonist.

Previous studies on allosteric interactions at muscarinic receptors have often focused on ligand-receptor binding interactions, because ligand binding seemed to reflect functional consequences. The prototypal allosteric agent alcuronium is known to bind with similar affinity to the M(2) subtype of muscarinic acetylcholine receptors whether or not the receptors are occupied by the agonist pilocarpine. To determine allosteric modulation of receptor signaling by alcuronium, the effects of pilocarpine were measured in contracting guinea pig left atria and on G-protein coupling in M(2)-transfected Chinese hamster ovary (CHO) cell membranes. Alcuronium dose-dependently suppressed pilocarpine-induced reduction of isometric contraction force in atria (pIC(50, Alc) = 5.63) without any effect on the EC(50) of pilocarpine, consistent with an allosteric mechanism. In contrast, alcuronium shifted the concentration-effect curve of the agonist oxotremorine M to the right without affecting the maximal effect, in a formally competitive manner (pK(A, Alc) = 5.54). If pilocarpine remained receptor bound in the presence of alcuronium, this indicates that pilocarpine can no longer act as an agonist. In support of this hypothesis, pilocarpine acted as a competitive antagonist against oxotremorine M in the presence of 10 microM alcuronium. Measuring guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in CHO-M(2) membranes yielded similar results. Alcuronium suppressed pilocarpine-induced stimulation of [(35)S]GTPgammaS binding (pIC(50, Alc) = 5.47) without shift in EC(50), whereas it competitively shifted the response to oxotremorine M (pK(A, Alc) = 5.97). [(3)H]Oxotremorine M binding data corresponded with the functional findings. In conclusion, alcuronium converted the agonist pilocarpine into an antagonist-a novel type of functional allosteric interaction.

Alcuronium↗

PubMed2006

Development of a rat pilocarpine model of seizure/status epilepticus that mimics chemical warfare nerve agent exposure.

We developed a rat pilocarpine seizure/status epilepticus (SE) model, which closely resembles 1.6-2.0 x LD50 soman exposure, to analyse the molecular mechanism of neuronal damage and to screen effective neuroprotectants against cholinergic agonist and chemical warfare nerve agent (CWNA) exposure. Rats implanted with radiotelemetry probes capable of recording electroencephalogram (EEG), electrocardiogram (ECG), temperature, and physical activity were treated with lithium chloride (5 mEq/kg, im), followed 24 h later by (ip) doses of pilocarpine hydrochloride. Based on radiotelemetry analysis, a dose of 240 mg/kg (ip) pilocarpine generated seizure/SE analogous to 1.6-2.0 x LD50 of soman. The model was refined by reducing the peripheral convulsions without affecting the central nervous system (CNS) by administering methylscopolamine bromide (1 mg/kg, ip), an anti-cholinergic that does not cross the blood-brain barrier. However, when methylscopolamine bromide was administered, a higher dose of pilocarpine (320 mg/kg, ip) was required to generate the equivalent seizure/SE. Histopathology data indicated that pilocarpine induces significant damage to the hippocampal region of the brain, with similar neuropathology to that of 1.6-2.0 x LD50 soman exposure. There was a reduction in body temperature after the administration of pilocarpine, as observed in organophosphate (OP) nerve agents exposure. The heart-rate of pilocarpine-treated animals increased compared to the normal range. The pilocarpine seizure/SE model was also reproducible in the absence of lithium chloride. These results support that pilocarpine seizure/SE model is useful in studying the molecular mechanisms of neuropathology and screening neuroprotectants following cholinergic agonist and CWNA exposure.

Animals↗

PubMed1982

Effect of pilocarpine on behavior of mucus glycoproteins of canine tracheal secretory cells.

Behavior of mucus glycoproteins in tracheal secretory cells after treatment with pilocarpine was investigated histologically and histochemically using the isolated canine trachea. Following pilocarpine treatment, the number of total and neutral glycoprotein-containing goblet cells was reduced concentration-dependently. The number of acid glycoprotein (AGP)-containing goblet cells was not altered with 10(-7) and 10(-6) M pilocarpine, but significantly decreased with 10(-5) and 10(-4) M pilocarpine. The thickness of the acini of submucosal glands significantly decreased, and the ratio of acinar inner diameter to tracheal wall thickness increased in 10(-5) and 10(-4) M pilocarpine. AGP content in glandular cells increased in 10(-7) and 10(-6) M pilocarpine, but markedly decreased at concentrations of 10(-5) and 10(-4) M. Pilocarpine treatment caused an increase in N-acetylhexosamine concentration in the incubation fluid. Total saccharide concentration in the incubation fluid decreased in 10(-7) and 10(-6) M pilocarpine, but was not apparently altered at concentrations of 10(-5) and 10(-4) M. These findings suggest that lower concentrations of pilocarpine stimulate synthesis of AGP in goblet and glandular cells much more preferentially than it stimulates discharge of AGP from the cells. While at higher concentrations, the AGP-discharge effect overcomes the stimulation in synthesis.

Animals↗

PubMed2002

Effect of pilocarpine mouthwash on salivary flow.

Pilocarpine is a cholinergic agonist that increases salivary flow and has been used to treat xerostomia. Oral intake is the most frequent route of administration. Adverse effects are dose-dependent and include sudoresis, facial blushing and increased urinary frequency. The objective of the present study was to evaluate the effects of topical pilocarpine solutions as mouthwashes on salivary flow and their adverse effects on healthy subjects. Forty volunteers received 10 ml 0.5, 1 and 2% pilocarpine solutions or 0.9% saline in a randomized, double-blind, placebo-controlled manner. Salivation was measured before and 45, 60 and 75 min after mouth rinsing for 1 min with 10 ml of saline or pilocarpine solutions. Vital signs were measured and ocular, gastrointestinal and cardiovascular symptoms, anxiety and flushing were estimated using visual analog scales. There was a dose-dependent increase in salivation. Salivation measured after 1 and 2% pilocarpine (1.4 +/- 0.36 and 2.22 +/- 0.42 g, respectively) was significantly (P<0.001) higher than before (0.70 +/- 0.15 and 0.64 +/- 0.1 g), with a plateau between 45 and 75 min. Cardiovascular, visual, gastrointestinal and behavioral symptoms and signs were not changed by topical pilocarpine. Mouth rinsing with pilocarpine solutions at concentrations of 1 to 2% induced a significant objective and subjective dose-dependent increase in salivary flow, similar to the results reported by others studying the effect of oral 5 mg pilocarpine. The present study revealed the efficacy of pilocarpine mouthwash solutions in increasing salivary flow in healthy volunteers, with no adverse effects. Additional studies on patients with xerostomia are needed.

Adolescent↗

PubMed1995

Oral pilocarpine: a review of its pharmacological properties and clinical potential in xerostomia.

Pilocarpine is a cholinergic agonist which stimulates salivary secretion both in individuals with normal salivary gland function and in those with impaired salivary flow (xerostomia or oral dryness). A rapid increase in salivary flow rate is observed following oral pilocarpine administration and peak levels are maintained for at least 1 to 2 hours. Mean salivary flow rates after administration of pilocarpine are 2- to 10-fold higher than after placebo, and no evidence of tolerance to the pharmacological effects of the drug has been observed during prolonged administration for up to 5 months. The clinical efficacy of oral pilocarpine in relieving symptoms of xerostomia (resulting from radiation therapy to the head and neck region or salivary gland dysfunction), including oral dryness and difficulty in chewing, swallowing and speaking, has been demonstrated in double-blind placebo-controlled clinical trials. In these studies, pilocarpine 5 to 10mg 3 times daily increased salivary flow and improved symptoms of xerostomia in a significantly higher percentage of patients than did placebo (54 versus 25% in one study). Preliminary findings indicate that administration of pilocarpine during radiation therapy may reduce the severity of xerostomia; however, this requires further investigation. The majority of patients receiving oral pilocarpine therapy for xerostomia experience adverse events (most commonly sweating); however, these are generally mild and tolerable in nature. Thus, pilocarpine is an effective agent for the treatment of xerostomia, increasing salivary flow and reducing symptom severity to a significantly greater extent than placebo. Further clinical trials should evaluate the potential beneficial effects of pilocarpine on the incidence of dental caries and oral candidiasis during prolonged therapy, its prophylactic efficacy during radiation therapy and its efficacy relative to that of other salivary stimulants.

Controlled Clinical Trials as Topic↗

PubMed1996

A new transdermal delivery system for pilocarpine in glaucoma treatment.

We studied the intraocular pressure (IOP)-lowering effect and the side effects of a new transdermal delivery system (TDS) containing pilocarpine. After giving their written informed consent, patients were randomly assigned to receive a pilocarpine TDS or a placebo TDS. Two patches, each containing 30 mg of pilocarpine or placebo, were applied to the supraclavicular skin of 24 patients. The IOP was recorded before and at +12, 16, and 20 h after application. Plasma samples were analyzed for pilocarpine before treatment and 12 and 20 h later via high-performance liquid chromatography. The amount of drug remaining on the dermal patches was analyzed at 20 h. The mean IOP recorded before application was 22.7 +/- 5.8 mmHg. As compared with the placebo TDS, the pilocarpine TDS did not significantly reduce IOP at 12, 16, or 20 h after application (P = 0.42). The mean plasma concentrations were 2.9 ng/ml at 12 h and 1.3 ng/ml at 20 h. The verum TDS showed a residual mean drug concentration of 35.3 mg pilocarpine on the TDS. A substantial amount of pilocarpine was released from the TDS to the dermis, causing detectable plasma levels of pilocarpine at 12 and 20 h after administration. The pilocarpine TDS is a new nonocular pharmaceutical device that should avoid the side effects well known in glaucoma treatment when conventional eye drops are used.

Absorption↗

PubMed1977

Vehicle effects on ocular drug bioavailability II: Evaluation of pilocarpine.

The influence of vehicle composition on ocular penetration of pilocarpine was studied in the albino rabbit. Increasing the pH of a vehicle promoted increased corneal penetration for pilocarpine, in accordance with the pH-partition hypothesis, but a similar series of experiments with a nonionizable drug, glycerin, gave similar results. The extent of pH-induced lacrimation by the vehicle and its effect on precorneal drug concentration also was determined. Increased pilocarpine absorption at neutral to slightly alkaline pH was due primarily to its peculiar solubility characteristics coupled with less irritation and lacrimation rather than a direct pH effect on the molecule. Incorporation of pilocarpine into a petrolatum-based ointment vehicle resulted in increased aqueous humor pilocarpine levels above those provided by an equivalent dose of aqueous solution. The mechanism of this increase was determined to be a higher effective concentration of pilocarpine in the ointment vehicle coupled with an increase in contact time of the dose. The ointment system also exerted an unusual form of vehicle control in that it promoted the corneal penetration of pilocarpine while impeding uniform mixing of the dose with tears and thereby imposed a restriction on the amount of pilocarpine available to the ocular tissues.

Animals↗

PubMed1988

Mechanism of transcorneal permeation of pilocarpine.

The mechanism of transcorneal permeation of pilocarpine has been investigated in relation to the physicochemical properties of the permeating species and its interaction with the membrane biophase. In vitro corneal transport experiments suggested the transport of un-ionized as well as ionized pilocarpine species across the corneal membrane. However, the permeability of the ionized pilocarpine species was 4.818 x 10(-6) cm s-1, a value only one-half of that obtained for the un-ionized pilocarpine species (9.744 x 10(-6) cm s-1). Further evidence of ion transport across the cornea was obtained by examining the transport of the quaternized pilocarpine compound (i.e., pilocarpinium methyl iodide). The quaternized compound had a corneal permeability of 4.66 x 10(-6) cm s-1, similar to that obtained for the ionized pilocarpine species. The lipoidal epithelial layer of the corneal membrane appears to be the predominant barrier to the transport of polar species. Therefore, the transport of pilocarpinium cations across the lipoidal epithelium might have occurred as tightly bound ion pairs with dihydrogen phosphate and/or nitrate counter ions. Excellent linear correlation has been obtained between pilocarpine corneal permeability and the 1-octanol-water partition coefficient as a function of the state of ionization of pilocarpine. The ratio of un-ionized to ionized drug permeability across the cornea is expected to be much higher for drugs with higher 1-octanol-water partition coefficients.

Animals↗

PubMed1997

Ultrasound biomicroscopic analysis of the effect of pilocarpine on the anterior chamber angle.

BACKGROUND: This study was carried out to determine the effects of pilocarpine on the anterior chamber angle in healthy volunteers. METHODS: We measured changes in anterior chamber depth (ACD), trabecular-iris angle (TIA), angle opening distance at 250 and 500 microns from the scleral spur (AOD250 and AOD500), and iris thickness using ultrasound biomicroscopy in 48 eyes of 48 normal volunteers (ages 18-57 years, mean 34.8 years) before and 1 h after instillation of 2% pilocarpine. RESULTS: Pilocarpine altered the TIA by -18.6 degrees to +10.5 degrees (mean -4.16 degrees), and change in the TIA increased significantly and linearly in relation with decrease in the pretreatment TIA (r = 0.929). Pilocarpine altered AOD250 change by -136 to +94 microns (mean -38 microns) and AOD500 by -151 to +157 microns (mean -42 microns); changes in the AOD250 and AOD500 were significantly correlated to the pretreatment AOD250 and AOD500 values, respectively (r = 0.923 and r = 0.896, respectively). The pilocarpine-induced change in the ACD showed a linear relationship to the pretreatment ACD (r = 0.887). The changes in the TIA, AOD250 and AOD500 showed greater increases in association with lower pretreatment ACD (r = 0.848, r = 0.891, r = 0.842) and smaller change in the ACD (r = 0.834, r = 0.839, r = 0.812). CONCLUSIONS: The response of the anterior chamber angle to pilocarpine, narrowing or widening, depended on its pretreatment state. The ability to predict the pilocarpine-induced change in the angle before the instillation of pilocarpine would be helpful in treating patients with glaucoma.

Adolescent↗