-
American Journal of Ophthalmology Sep 2023To evaluate the safety, efficacy, and pharmacokinetics of pilocarpine hydrochloride 1.25% (Pilo hereafter) compared with vehicle when administered bilaterally, twice... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate the safety, efficacy, and pharmacokinetics of pilocarpine hydrochloride 1.25% (Pilo hereafter) compared with vehicle when administered bilaterally, twice daily (6 hours apart) for 14 days in participants with presbyopia.
DESIGN
Phase 3, randomized (1:1), controlled, double-masked, multicenter study.
METHODS
Participants (40-55 years of age) had objective and subjective evidence of presbyopia affecting daily activities with mesopic, high-contrast, binocular distance-corrected near visual acuity (DCNVA) of 20/40 to 20/100. The primary/key secondary endpoint was the proportion of participants gaining ≥3 lines in mesopic/photopic, high-contrast, binocular DCNVA on day 14 (last study visit), hour 9 (3 hours after the second dose), with no more than a 5-letter loss in mesopic/photopic corrected distance visual acuity with the same refractive correction. Key safety measures included treatment-emergent adverse events (TEAEs) and some ocular measurements. Pilocarpine plasma levels were assessed in approximately 10% of enrolled participants.
RESULTS
Overall, 230 participants were randomized to Pilo twice daily (N = 114) and vehicle (N = 116). The proportion of participants achieving the primary and key secondary efficacy endpoints was statistically significantly greater with Pilo twice daily than vehicle, with between-treatment differences of 27.3% (95% CI = 17.3, 37.4) and 26.4% (95% CI = 16.8, 36.0), respectively. The most common TEAE was headache, reported in 10 participants (8.8%, Pilo group) and 4 participants (3.4%, vehicle group). Pilocarpine's accumulation index on day 14 was ≤1.11 after the second dose.
CONCLUSIONS
Near-vision improvements were statistically greater with Pilo twice daily than with vehicle, without compromising distance acuity. The safety profile of Pilo twice daily was consistent with that of Pilo once daily, and systemic accumulation was minimal, supporting twice daily administration.
Topics: Humans; Pilocarpine; Presbyopia; Visual Acuity; Refraction, Ocular; Double-Blind Method
PubMed: 37149245
DOI: 10.1016/j.ajo.2023.05.008 -
The Journal of Physiology Dec 2020Temporal lobe epilepsy is a complex neurological disease caused by imbalance of excitation and inhibition in the brain. Growing literature implicates altered Ca...
KEY POINTS
Temporal lobe epilepsy is a complex neurological disease caused by imbalance of excitation and inhibition in the brain. Growing literature implicates altered Ca signalling in many aspects of epilepsy but the diversity of Ca channels that regulate this syndrome are not well-understood. Here, we report that mice lacking the store-operated Ca channel, Orai1, in the brain show markedly stronger seizures in response to the chemoconvulsants, kainic acid and pilocarpine. Electrophysiological analysis reveals that selective deletion of Orai1 channels in inhibitory neurons disables chemoconvulsant-induced excitation of GABAergic neurons in the CA1 hippocampus. Likewise, deletion of Orai1 in GABAergic neurons abrogates the chemoconvulsant-induced burst of spontaneous inhibitory postsynaptic currents (sIPSCs) on CA1 pyramidal neurons in the hippocampus. This loss of chemoconvulsant inhibition likely aggravates status epilepticus in Orai1 KO mice. These results identify Orai1 channels as regulators of hippocampal interneuron excitability and seizures.
ABSTRACT
Store-operated Orai1 channels are a major mechanism for Ca entry in many cells and mediate numerous functions including gene expression, cytokine production and gliotransmitter release. Orai1 is expressed in many regions of the mammalian brain; however, its role in regulating neuronal excitability, synaptic function and brain disorders has only now begun to be investigated. To investigate a potential role of Orai1 channels in status epilepticus induced by chemoconvulsants, we examined acute seizures evoked by intraperitoneal injections of kainic acid (KA) and pilocarpine in mice with a conditional deletion of Orai1 (or its activator STIM1) in the brain. Brain-specific Orai1 and STIM1 knockout (KO) mice exhibited significantly stronger seizures (P = 0.00003 and P < 0.00001), and higher chemoconvulsant-induced mortality (P = 0.02) compared with wildtype (WT) littermates. Electrophysiological recordings in hippocampal brain slices revealed that KA stimulated the activity of inhibitory interneurons in the CA1 hippocampus (P = 0.04) which failed to occur in Orai1 KO mice. Further, KA and pilocarpine increased the frequency of spontaneous IPSCs in CA1 pyramidal neurons >twofold (KA: P = 0.04; pilocarpine: P = 0.0002) which was abolished in Orai1 KO mice. Mice with selective deletion of Orai1 in GABAergic neurons alone also showed stronger seizures to KA (P = 0.001) and pilocarpine (P < 0.00001) and loss of chemoconvulsant-induced increases in sIPSC responses compared with WT controls. We conclude that Orai1 channels regulate chemoconvulsant-induced excitation in GABAergic neurons and that destabilization of the excitatory/inhibitory balance in Orai1 KO mice aggravates chemoconvulsant-mediated seizures. These results identify Orai1 channels as novel molecular regulators of hippocampal neuronal excitability and seizures.
Topics: Animals; Hippocampus; Kainic Acid; Mice; ORAI1 Protein; Pilocarpine; Pyramidal Cells; Seizures
PubMed: 32851638
DOI: 10.1113/JP280119 -
Journal of Dental Research Feb 2024Tight junction proteins play a crucial role in paracellular transport in salivary gland epithelia. It is clear that severe xerostomia in patients with HELIX syndrome is...
Tight junction proteins play a crucial role in paracellular transport in salivary gland epithelia. It is clear that severe xerostomia in patients with HELIX syndrome is caused by mutations in the claudin-10 gene. However, little is known about the expression pattern and role of claudin-10 in saliva secretion in physical and disease conditions. In the present study, we found that only claudin-10b transcript was expressed in human and mouse submandibular gland (SMG) tissues, and claudin-10 protein was dominantly distributed at the apicolateral membranes of acini in human, rat, and mouse SMGs. Overexpression of claudin-10 significantly reduced transepithelial electrical resistance and increased paracellular transport of dextran and Na in SMG-C6 cells. In C57BL/6 mice, pilocarpine stimulation promoted secretion and cation concentration in saliva in a dose-dependent increase. Assembly of claudin-10 to the most apicolateral portions in acini of SMGs was observed in the lower pilocarpine (1 mg/kg)-treated group, and this phenomenon was much obvious in the higher pilocarpine (10 mg/kg)-treated group. Furthermore, 7-, 14-, and 21-wk-old nonobese diabetic (NOD) and BALB/c mice were used to mimic the progression of hyposalivation in Sjögren syndrome. Intensity of claudin-10 protein was obviously lower in SMGs of 14- and 21-wk-old NOD mice compared with that of age-matched BALB/c mice. In the cultured mouse SMG tissues, interferon-γ (IFN-γ) downregulated claudin-10 expression. In claudin-10-overexpressed SMG-C6 cells, paracellular permeability was decreased. Furthermore, IFN-γ stimulation increased p-STAT1 level, whereas pretreatment with JAK/STAT1 antagonist significantly alleviated the IFN-γ-induced claudin-10 downregulation. These results indicate that claudin-10 functions as a pore-forming component in acinar epithelia of SMGs, assembly of claudin-10 is required for saliva secretion, and downregulation of claudin-10 induces hyposecretion. These findings may provide new clues to novel therapeutic targets on hyposalivation.
Topics: Humans; Mice; Rats; Animals; Submandibular Gland; Pilocarpine; Mice, Inbred C57BL; Claudins; Sjogren's Syndrome; Tight Junctions; Xerostomia; Claudin-4
PubMed: 38058154
DOI: 10.1177/00220345231210547 -
Cellular and Molecular Biology... Jun 2022Corneal stability is essential for contact lenses and refractive surgery. It seems that paralyzing eye drops or expansion of the ciliary muscle affect the radius of...
Corneal stability is essential for contact lenses and refractive surgery. It seems that paralyzing eye drops or expansion of the ciliary muscle affect the radius of curvature and the strength of the cornea, and this effect is to increase the strength of the cornea during muscle spasm and decrease it in the relaxed state of the muscle. On the other hand, different factors (such as contact lens wear, ocular surface disorders, trauma, dry eye, and immunosuppression) could alter the immune defense mechanisms of the outer eye and permit microorganisms to invade the cornea. Therefore, the present study compared Pilocarpine and tropicamide drop on corneal topography and their effect on IL-6 and TNF-α levels in tear. This prospective study was performed on sixty normal and healthy eyes of sixty volunteers with a mean age of 38.19 years and without any ocular pathology. Volunteers were divided into two groups of thirty. In the first group, corneal topography of both eyes was measured before and 30 minutes after instillation of topical tropicamide 1% in only one eye. The other eye was the control eye, and no drop was given. The same routine was performed in the second group, except that subject received one drop of Pilocarpine 2% in one eye. Statistical comparison between groups for the central corneal power, corneal radius, and corneal astigmatism was performed using paired t-test. IL-6 and TNF-α levels in tear were analyzed using two Luminex commercial assays with Bio-Plex 200TM System (Bio-Rad, Hercules, California, USA). In group 1, no significant changes were found in corneal radius, power, and astigmatism. However, in group 2 subjects who received pilocarpine eye drops, the mean corneal radius value decreased significantly by 0.05 mm. The mean corneal power increased by +0.32 D. There was no significant difference change in corneal astigmatism in both groups. Evaluation of IL-6 levels in tears showed a significant difference between the control and treatment groups (P = 0.041). But no significant difference was observed between the Pilocarpine and the Tropicamide groups (P = 0.761). Evaluation of TNF-α level in tears also showed no significant difference between these groups (P = 0.088). Pilocarpine induced ciliary muscle contraction, which may cause pressure on the corneal limbus and scleral spur, resulting in changes in corneal curvature. But tropicamide eye drop did not affect corneal radius and other corneal parameters, and corneal topography can be carried out after the installation of tropicamide eye drop.
Topics: Adult; Astigmatism; Cornea; Corneal Topography; Humans; Interleukin-6; Ophthalmic Solutions; Pilocarpine; Prospective Studies; Tropicamide; Tumor Necrosis Factor-alpha
PubMed: 36227674
DOI: 10.14715/cmb/2022.68.6.12 -
International Journal of Molecular... Oct 2022Epilepsy is a brain disorder characterized by recurrent epileptic seizures and neurobiological, physiological, mood, and cognitive consequences. In the last decade, the...
Epilepsy is a brain disorder characterized by recurrent epileptic seizures and neurobiological, physiological, mood, and cognitive consequences. In the last decade, the beneficial effects of regular physical exercise have been investigated in patients with neurodegenerative diseases such as epilepsy. However, data on its beneficial effects and underlying mechanisms are still insufficient. The objective of the current study was to investigate the effects of endurance training, applied before and after pilocarpine (Pilo) administration, on status epilepticus (SE) severity, and its relation to epileptogenesis deleterious consequences during the chronic epileptic phase. Long-term aerobic training, applied four weeks before SE and eight weeks after SE, elevated the threshold to induce SE and reduced spontaneous motor seizures. The protective effect of this alternative approach on seizure susceptibility resulted in improved memory responses, and alleviated comorbid depression in epileptic rats. The exercised epileptic rats had improved markers of oxidative stress by decreasing lipid peroxidation and increasing the levels of glutathione and activity of superoxide dismutase in the rat hippocampus. Aerobic training managed to ameliorate the neuroinflammation by decreasing the levels of TNF-α and IL-1β in the hippocampus. Our results suggest that regular physical training predisposes the subjects to crucial plastic changes, leading to increased resistance to SE and the development of epileptogenesis.
Topics: Animals; Rats; Humans; Pilocarpine; Endurance Training; Status Epilepticus; Seizures; Epilepsy; Hippocampus; Disease Models, Animal
PubMed: 36361978
DOI: 10.3390/ijms232113188 -
Heliyon Jul 2020The pilocarpine animal model of status epilepticus is a well-established, clinically translatable model that satisfies all of the criteria essential for an animal model... (Review)
Review
The pilocarpine animal model of status epilepticus is a well-established, clinically translatable model that satisfies all of the criteria essential for an animal model of status epilepticus: a latency period followed by spontaneous recurrent seizures, replication of behavioural, electrographic, metabolic, and neuropathological changes, as well as, pharmacoresistance to anti-epileptic drugs similar to that observed in human status epilepticus. However, this model is also characterized by high mortality rates and studies in recent years have also seen difficulties in seizure induction due to pilocarpine resistant animals. This can be attributed to differences in rodent strains, species, gender, and the presence of the multi-transporter, P-glycoprotein at the blood brain barrier. The current paper highlights the various alterations made to the original pilocarpine model over the years to combat both the high mortality and low induction rates. These range from the initial lithium-pilocarpine model to the more recent Reduced Intensity Status Epilepticus (RISE) model, which finally brought the mortality rates down to 1%. These modifications are essential to improve animal welfare and future experimental outcomes.
PubMed: 32775726
DOI: 10.1016/j.heliyon.2020.e04557 -
Neurochemical Research May 2021This study aimed to explore the effects and function of microRNA-101a-3p (miR-101a-3p) in epilepsy. Rat model of pilocarpine-induced epilepsy was established and the...
This study aimed to explore the effects and function of microRNA-101a-3p (miR-101a-3p) in epilepsy. Rat model of pilocarpine-induced epilepsy was established and the seizure frequency was recorded. Expression of miR-101a-3p and c-Fos in hippocampus tissues of Rat models were detected by qRT-PCR and western blot. Besides, we established a hippocampal neuronal culture model of acquired epilepsy using Mg free medium to evaluate the effects of miR-101a-3p and c-Fos in vitro. Cells were transfected with miR-101a-3p mimic, si-c-FOS, miR-101a-3p + c-FOS and its corresponding controls. MTT assay was used to detect cell viability upon transfection. Flow cytometry was performed to determine the apoptosis rate. Western blot was performed to measure the protein expression of apoptosis-related proteins (Bcl-2, Bax, and cleaved caspase 3), autophagy-related proteins (LC3 and Beclin1) and c-FOS. The targeting relationship between miR-101a-3p and c-FOS was predicted and verified by TargetScan software and dual-luciferase reporter assay. The role of miR-101a-3p was validated using epilepsy rat models in vivo. Another Rat models of pilocarpine-induced epilepsy with miR-NC or miR-101a-3p injection were established to evaluate the effect of miR-101a-3p overexpression on epilepsy in vivo. MiR-101a-3p was downregulated while c-FOS was increased in hippocampus tissues of Rat model of pilocarpine-induced epilepsy. Overexpression of miR-101a-3p or c-FOS depletion promoted cell viability, inhibited cell apoptosis and autophagy. C-FOS was a target of miR-101a-3p and miR-101a-3p negatively regulated c-FOS expression to function in epilepsy. Overexpression of miR-101a-3p attenuated pilocarpine-induced epilepsy in Rats in vivo. This study indicated that miR-101a-3p could attenuate pilocarpine-induced epilepsy by repressing c-Fos expression.
Topics: Animals; Apoptosis; Autophagy; Cell Survival; Down-Regulation; Epilepsy; Hippocampus; MicroRNAs; Neurons; Pilocarpine; Proto-Oncogene Proteins c-fos; Rats, Sprague-Dawley; Up-Regulation; Rats
PubMed: 33559830
DOI: 10.1007/s11064-021-03245-w -
Journal of Ophthalmology 2023To evaluate the influence of pilocarpine eyedrops on the ocular biometric parameters and whether these parameter changes affect the intraocular lens (IOL) power...
OBJECTIVE
To evaluate the influence of pilocarpine eyedrops on the ocular biometric parameters and whether these parameter changes affect the intraocular lens (IOL) power calculation in patients with primary angle-closure glaucoma (PACG).
METHODS
Twenty-two PACG patients and fifteen normal subjects were enrolled. Ocular biometric parameters including the axial length (AL), anterior chamber depth (ACD), lens thickness (LT), mean keratometry (Km), and white-to-white distance (WTW) were measured by using a Lenstar LS 900 device before and at least 30 minutes after instillation of 2% pilocarpine eyedrops. Lens position (LP) was calculated, and the IOL power prediction based on the ocular biometric parameters was performed using the Barrett Universal II, Haigis, Hoffer Q, Holladay I, or SRK/T formulas before and after pilocarpine application.
RESULTS
In both PACG and normal groups, pilocarpine eyedrops induced a slight but statistically significant increase in the mean AL (0.01 mm for both groups) and mean LT (0.02 mm and 0.03 mm, respectively) but a significant decrease in the mean ACD (0.03 mm and 0.05 mm, respectively) and mean LP (0.02 mm and 0.04 mm, respectively). No significant changes in the mean Km and WTW were noticed in both groups. In addition, the IOL power calculation revealed insignificant changes before and after the pilocarpine instillation in both groups, regardless of the formula used.
CONCLUSIONS
Pilocarpine eyedrops can induce slight changes in the ocular biometric parameters including the AL, ACD, LT, and LP. However, these parameter changes will not result in a significant difference in IOL power estimation.
PubMed: 37455794
DOI: 10.1155/2023/7680659 -
Veterinary Ophthalmology Mar 2022To describe the clinical findings, imaging features, underlying conditions, treatment, and progression of dogs presented between 2010 and 2019 with neurogenic...
OBJECTIVE
To describe the clinical findings, imaging features, underlying conditions, treatment, and progression of dogs presented between 2010 and 2019 with neurogenic keratoconjunctivitis sicca (NKCS).
METHODS
Dogs diagnosed with NKCS were searched in the clinical database. Inclusion criteria were STT-1 readings <15 mm/min, clinical signs of KCS with concurrent ipsilateral xeromycteria.
RESULTS
Thirty-four cases were identified. Mean age at presentation was 8.2 years, median 8.9 years (0.3-14.7). Twenty dogs were male, and 14 dogs were female. Concurrent neurological deficits included facial neuropathy (n = 13, 38%), peripheral vestibular syndrome (n = 10, 29%), and Horner's syndrome (n = 5, 15%). Advanced imaging was acquired in 53% of cases (n = 18). Etiologies included idiopathic (n = 18, 53%), endocrinopathy (n = 6, 18%), otitis interna (n = 4, 12%), head trauma (n = 3, 9%), iatrogenic (post-TECA-LBO, n = 1, 3%), brainstem mass (n = 1, 3%), and an area of inflammation in the pterygopalatine fossa (n = 1, 3%). Treatment for NKCS was initiated in most cases (n = 30, 88%) including: oral pilocarpine 2% and lacrimostimulant (n = 19), oral pilocarpine 2% only (n = 3), or lacrimostimulant only (n = 8). A mean time follow-up of 3.7 months, median 3 months (1-14) was available in 23 cases (68%). Eleven cases with follow-up were responsive (48%) with resolution of the clinical signs in a median time 4 months (1-10), and all of them were treated with oral pilocarpine (±lacrimostimulant).
CONCLUSIONS
Most cases presented as idiopathic NKCS; in others, an underlying cause of facial neuropathy was identified. All responsive cases were treated with oral pilocarpine 2%.
Topics: Animals; Dog Diseases; Dogs; Female; Horner Syndrome; Keratoconjunctivitis Sicca; Male; Pilocarpine
PubMed: 34870366
DOI: 10.1111/vop.12949 -
BMC Oral Health Dec 2022Pilocarpine is an accepted treatment for xerostomia, but limited research has been conducted on the oral, topical form. The present study aimed to compare the effects of... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS & BACKGROUND
Pilocarpine is an accepted treatment for xerostomia, but limited research has been conducted on the oral, topical form. The present study aimed to compare the effects of 1 and 2% pilocarpine mouthwash on xerostomic participants.
METHODS
In this double-blind clinical trial study, 48 subjects with xerostomia were randomly divided into three groups to measure the effects of 1 and 2% pilocarpine and placebo mouthwashes on saliva levels. The amount of saliva in the 1st and 14th days was measured at 0, 45, 60, and 75 mins, while participants used their mouthwash three times a day for 14 days. On the 1st and 14th days, they filled out the information forms on xerostomia and the medicine's side effects before and after the intervention.
RESULTS
On the 1st day, the mean salivary flow at 45, 60, and 75 mins in the 2 and 1% pilocarpine mouthwash were significantly higher than in the placebo mouthwash group (p < 0.05). On the 14th day, the mean salivary flow time at 45 mins in the 2% pilocarpine mouthwash group was significantly higher than in the placebo mouthwash group (p = 0.007). Furthermore, the mean salivary flow at 60 and 75 mins in the 2% (p < 0.001) and 1% pilocarpine mouthwash (p = 0.028) was significantly higher than in the placebo group. Moreover, the salivary flow in the 2% pilocarpine mouthwash group was significantly higher than the 1% pilocarpine mouthwash (p < 0.05) during these two times. No side effects were observed in any of the subjects.
CONCLUSIONS
The study showed that 5 ml of 2 and 1% pilocarpine mouthwash for 2 weeks increased salivary flow in xerostomic participants compared to placebo without any side effects.
Topics: Humans; Pilocarpine; Mouthwashes; Xerostomia; Saliva
PubMed: 36457091
DOI: 10.1186/s12903-022-02576-6