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The Journal of Urology Sep 2019We evaluated the efficacy and safety of a combination of 2 mg tolterodine and 9 mg pilocarpine, vs tolterodine monotherapy in patients with overactive bladder. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We evaluated the efficacy and safety of a combination of 2 mg tolterodine and 9 mg pilocarpine, vs tolterodine monotherapy in patients with overactive bladder.
MATERIALS AND METHODS
We enrolled patients with overactive bladder symptoms in a multicenter, randomized, double-blind, parallel, active control study. Patients were randomized to the combination or 2 mg tolterodine twice daily for 12 weeks. After the double-blind period finished all patients were started on the combination for 12 weeks. Study co-primary end points were the change from baseline in the mean number of daily micturitions and cumulative incidence of dry mouth at the end of 12 weeks. Secondary end points were other overactive bladder symptoms, the total xerostomia inventory score and results of a visual analogue scale for dry mouth at the end of 12 and 24 weeks.
RESULTS
The mean change in the number of daily micturitions from baseline to 12 weeks was -1.49 and -1.74 in the combination and tolterodine monotherapy groups, respectively. The mean difference was -0.26 (95% CI -0.79-0.27), confirming noninferiority. At 12 weeks the incidence of dry mouth was lower in the combination group than in the tolterodine monotherapy group (30.0% vs 42.9%, p = 0.009). All secondary and other efficacy outcomes related to overactive bladder symptoms improved in each group with no significant differences between the groups at 12 weeks. Changes from baseline in the total xerostomia inventory score and the visual analogue scale for dry mouth were significantly lower in the combination group than in the tolterodine monotherapy group.
CONCLUSIONS
Tolterodine and pilocarpine alleviated dry mouth in patients with overactive bladder while maintaining anticholinergic efficacy similar to that of tolterodine.
Topics: Aged; Cholinergic Antagonists; Double-Blind Method; Drug Combinations; Female; Humans; Incidence; Male; Middle Aged; Muscarinic Agonists; Pilocarpine; Tolterodine Tartrate; Treatment Outcome; Urinary Bladder, Overactive; Urination; Xerostomia
PubMed: 31009289
DOI: 10.1097/JU.0000000000000281 -
Epilepsy & Behavior : E&B Mar 20232-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of... (Review)
Review
2-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of glucose-6-phosphate to fructose-6-phosphate, and thereby reversibly inhibits glycolysis. PET studies of regional brain glucose utilization positron-emitting 18F-2DG demonstrate that brain regions generating seizures have diminished glucose utilization during interictal conditions, but rapidly transition to markedly increased glucose delivery and utilization during seizures, particularly in status epilepticus (SE). 2-deoxy-D-glucose has acute antiseizure actions in multiple in vivo and in vitro seizure models, including models of SE induced by the chemo convulsants pilocarpine and kainic acid, suggesting that focal enhanced delivery of 2DG to ictal brain circuits is a potential novel anticonvulsant intervention for the treatment of SE.
Topics: Humans; Deoxyglucose; Status Epilepticus; Seizures; Glucose; Glycolysis; Pilocarpine
PubMed: 36804714
DOI: 10.1016/j.yebeh.2023.109108 -
Current Opinion in Ophthalmology Jul 2022Despite affecting approximately 1.8 billion individuals worldwide, until recently, a pharmacologic treatment for presbyopia was not available. This special commentary... (Review)
Review
PURPOSE OF REVIEW
Despite affecting approximately 1.8 billion individuals worldwide, until recently, a pharmacologic treatment for presbyopia was not available. This special commentary reviews the treatment of presbyopia with a focus on the recently approved medication Vuity (pilocarpine 1.25%, Allergan, an AbbVie Company).
RECENT FINDINGS
Vuity is a re-engineered formulation of pilocarpine 1.25% specifically designed for the treatment of presbyopia. Recently published results from the GEMINI 1 Phase 3 clinical trial reported improvement in distance corrected near vision without significant compromise in distance vision. No unexpected safety findings were reported with mild headache being the most common adverse event. Notably, there were no reported cases of retinal detachment or angle closure during the 30-day phase 3 clinical trials.
SUMMARY
Vuity is the first treatment designed and FDA approved to treat the growing presbyopia market. Phase 3 clinical trials demonstrated its ability to improve near vision without significant compromise in distance vision. We recognize this paradigm shift in the treatment of presbyopia and anxiously await additional treatment options for this ubiquitous condition.
Topics: Humans; Myopia; Pilocarpine; Presbyopia; Vision, Ocular
PubMed: 35779051
DOI: 10.1097/ICU.0000000000000864 -
Neurobiology of Disease May 2023Interictal activity and seizures are the hallmarks of focal epileptic disorders (which include mesial temporal lobe epilepsy, MTLE) in humans and in animal models.... (Review)
Review
Interictal activity and seizures are the hallmarks of focal epileptic disorders (which include mesial temporal lobe epilepsy, MTLE) in humans and in animal models. Interictal activity, which is recorded with cortical and intracerebral EEG recordings, comprises spikes, sharp waves and high-frequency oscillations, and has been used in clinical practice to identify the epileptic zone. However, its relation with seizures remains debated. Moreover, it is unclear whether specific EEG changes in interictal activity occur during the time preceding the appearance of spontaneous seizures. This period, which is termed "latent", has been studied in rodent models of MTLE in which spontaneous seizures start to occur following an initial insult (most often a status epilepticus induced by convulsive drugs such as kainic acid or pilocarpine) and may mirror epileptogenesis, i.e., the process leading the brain to develop an enduring predisposition to seizure generation. Here, we will address this topic by reviewing experimental studies performed in MTLE models. Specifically, we will review data highlighting the dynamic changes in interictal spiking activity and high-frequency oscillations occurring during the latent period, and how optogenetic stimulation of specific cell populations can modulate them in the pilocarpine model. These findings indicate that interictal activity: (i) is heterogeneous in its EEG patterns and thus, presumably, in its underlying neuronal mechanisms; and (ii) can pinpoint to the epileptogenic processes occurring in focal epileptic disorders in animal models and, perhaps, in epileptic patients.
Topics: Animals; Humans; Epilepsy, Temporal Lobe; Pilocarpine; Seizures; Epilepsies, Partial; Epilepsy; Electroencephalography
PubMed: 36907521
DOI: 10.1016/j.nbd.2023.106065 -
Synapse (New York, N.Y.) Jul 2023SLIT and NTRK-like protein-5 (SLITRK5) is one of the six members of SLITRK protein family, which is widely expressed in central nervous system (CNS). In brain, SLITRK5...
SLIT and NTRK-like protein-5 (SLITRK5) is one of the six members of SLITRK protein family, which is widely expressed in central nervous system (CNS). In brain, SLITRK5 plays important roles in neurite outgrowth, dendritic branching, neuron differentiation, synaptogenesis, and signal transmission of neurons. Epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. The pathophysiological mechanism of epilepsy remains unclear. Neuronal apoptosis, abnormal nerve excitatory transmission, and synaptic remodeling are thought to be involved in the development of epilepsy. To explore whether there is a potential relationship between SLITRK5 and epilepsy, we investigated the expression and distribution of SLITRK5 in patients with temporal lobe epilepsy (TLE) and a rat model of epilepsy. We collected cerebral cortex samples from patients with drug-refractory temporal lobe epilepsy, and a rat model of epilepsy induced by lithium chloride/pilocarpine was established. The ways of immunohistochemistry, double-immunofluorescence labeling and western blot have been used in our study to research the expression and distribution of SLITRK5 in the temporal lobe epilepsy patients and epilepsy animal model. All of the results have shown that SLITRK5 is mainly localized in the cell cytoplasm of neurons both in patients with TLE and in epilepsy model. In addition, compared with nonepileptic controls, the expression of SLITRK5 was upregulated in the temporal neocortex of TLE patients. And both in the temporal neocortex and hippocampus of pilocarpine-induced epilepsy rats, the expression of SLITRK5 was increased at 24 h after status epilepticus (SE), with a relatively high level within 30 days, and reached the peak on the 7th day after SE. Our preliminary results revealed that SLITRK5 may have a potential relationship with epilepsy, which may be a foundation for the further study of the underlying mechanism between SLITRK5 and epilepsy and the therapeutic targets of antiepileptic drugs.
Topics: Animals; Rats; Disease Models, Animal; Epilepsy; Epilepsy, Temporal Lobe; Hippocampus; Neocortex; Pilocarpine; Rats, Sprague-Dawley; Seizures; Up-Regulation
PubMed: 36811190
DOI: 10.1002/syn.22266 -
Turkish Journal of Medical Sciences 2023Propofol is a positive allosteric modulator of GABAA receptor (GABAAR) and has potent antioxidant activity. The aim of this study was to investigate the effect of...
Propofol mitigates brain injury and oxidative stress, and enhances GABAA receptor α1 subunit expression in a rat model of lithium chloride-pilocarpine induced status epilepticus.
BACKGROUND/AIM
Propofol is a positive allosteric modulator of GABAA receptor (GABAAR) and has potent antioxidant activity. The aim of this study was to investigate the effect of propofol on damage to the cerebral cortex and hippocampus in a lithium chloride (LiCl)-pilocarpine animal model of status epilepticus (SE).
MATERIALS AND METHODS
Adult male Sprague Dawley rats were injected with LiCl-pilocarpine to induce SE. They were then randomized and injected 30 min later with vehicle saline (SE+saline), propofol (SE+PPF, 50 mg/kg), Diazepam (SE+DZP, 10 mg/kg), Scopolamine (SE+SCOP, 10 mg/kg), or MK-801 (SE+MK-801, 2 mg/kg). Another group of rats received saline only and served as the naïve control (BLK). The levels of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) in the serum, cortex and hippocampus were analyzed 2 and 24 h posttreatment. The degree of tissue damage in the cortex and hippocampus of individual rats was assessed 24 h posttreatment, together with expression of the GABAAR α1 subunit.
RESULTS
The propofol group showed reduced levels of tissue damage in the cerebral cortex and hippocampus, decreased levels of MDA, and increased levels of GSH compared to the SE+saline group. No changes in SOD level were observed in serum and tissue samples from the cortex and hippocampus of SE+saline rats. Immunohistochemistry and Western blot assays showed that propofol treatment significantly increased the expression of GABAR α1 subunit in the cortical and hippocampal tissues of SE rats.
CONCLUSION
Propofol treatment protected against SE-induced tissue injury in the cortex and hippocampus of rats. This was due at least in part to its antioxidant activity and to its induction of GABAAR α1 subunit expression in the brain.
Topics: Animals; Propofol; Receptors, GABA-A; Status Epilepticus; Pilocarpine; Male; Rats, Sprague-Dawley; Lithium Chloride; Oxidative Stress; Rats; Disease Models, Animal; Hippocampus; Brain Injuries; Malondialdehyde; Cerebral Cortex
PubMed: 38813010
DOI: 10.55730/1300-0144.5670 -
Neurobiology of Disease Jan 2020The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABA and glutamate receptors. The... (Review)
Review
The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soman-induced SE to test this hypothesis. Treatment of RSE with combinations of the GABAR agonists midazolam or diazepam and the NMDAR antagonists MK-801 or ketamine terminated RSE unresponsive to high-dose monotherapy with benzodiazepines, ketamine or other antiepileptic drugs (AEDs). It also reduced RSE-associated neuronal injury, spatial memory deficits and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of sc soman-induced SE similarly showed much greater reduction of EEG power by a combination of midazolam with ketamine, compared to midazolam monotherapy. When treating late (40 min after seizure onset), there may not be enough synaptic GABAR left to be able to restore inhibition with maximal GABAR stimulation, and further benefit is derived from the addition of an AED which increases inhibition or reduces excitation by a non-GABAergic mechanism. The midazolam-ketamine-valproate combination is effective in terminating RSE. 3-D isobolograms demonstrate positive cooperativity between midazolam, ketamine and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index is increased by combination therapy between GABAR agonist, NMDAR antagonist and selective AEDs. We compared this drug combination based on the receptor trafficking hypothesis to treatments based on clinical practice. The midazolam-ketamine-valproate combination is far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines. Furthermore, sequential administration of midazolam, ketamine and valproate is far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that we should re-evaluate our traditional treatment of RSE, and that treatment should be based on pathophysiology. The search for a better drug has to deal with the fact that most monotherapy leaves half the problem untreated. The search for a better benzodiazepine should acknowledge the main cause of pharmacoresistance, which is loss of synaptic GABAR. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm.
Topics: Animals; Anticonvulsants; Cholinesterase Inhibitors; Drug Therapy, Combination; Ketamine; Male; Midazolam; Muscarinic Agonists; Nerve Agents; Pilocarpine; Rats; Rats, Sprague-Dawley; Soman; Status Epilepticus; Valproic Acid
PubMed: 31454548
DOI: 10.1016/j.nbd.2019.104537 -
PloS One 2022Inflammation of brain structures, in particular the hippocampal formation, can induce neuronal degeneration and be associated with increased excitability manifesting as...
OBJECTIVE
Inflammation of brain structures, in particular the hippocampal formation, can induce neuronal degeneration and be associated with increased excitability manifesting as propensity for repetitive seizures. An increase in the abundance of individual proinflammatory molecules including interleukin 1 beta has been observed in brain tissue samples of patients with pharmacoresistant temporal lobe epilepsy (TLE) and corresponding animal models. The NLRP3-inflammasome, a cytosolic protein complex, acts as a key regulator in proinflammatory innate immune signalling. Upon activation, it leads to the release of interleukin 1 beta and inflammation-mediated neurodegeneration. Transient brain insults, like status epilepticus (SE), can render hippocampi chronically hyperexcitable and induce segmental neurodegeneration. The underlying mechanisms are referred to as epileptogenesis. Here, we have tested the hypothesis that distinct NLRP3-dependent transcript and protein signalling dynamics are induced by SE and whether they differ between two classical SE models. We further correlated the association of NLRP3-related transcript abundance with convulsive activity in human TLE hippocampi of patients with and without associated neurodegenerative damage.
METHODS
Hippocampal mRNA- and protein-expression of NLRP3 and associated signalling molecules were analysed longitudinally in pilocarpine- and kainic acid-induced SE TLE mouse models. Complementarily, we studied NLRP3 inflammasome-associated transcript patterns in epileptogenic hippocampi with different damage patterns of pharmacoresistant TLE patients that had undergone epilepsy surgery for seizure relief.
RESULTS
Pilocarpine- and kainic acid-induced SE elicit distinct hippocampal Nlrp3-associated molecular signalling. Transcriptional activation of NLRP3 pathway elements is associated with seizure activity but independent of the particular neuronal damage phenotype in KA-induced and in human TLE hippocampi.
SIGNIFICANCE
These data suggest highly dynamic inflammasome signalling in SE-induced TLE and highlight a vicious cycle associated with seizure activity. Our results provide promising perspectives for the inflammasome signalling pathway as a target for anti-epileptogenic and -convulsive therapeutic strategies. The latter may even applicable to a particularly broad spectrum of TLE patients with currently pharmacoresistant disease.
Topics: Animals; Disease Models, Animal; Epilepsy, Temporal Lobe; Hippocampus; Humans; Inflammasomes; Interleukin-1beta; Kainic Acid; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Neuroinflammatory Diseases; Pilocarpine; Seizures; Status Epilepticus
PubMed: 35972937
DOI: 10.1371/journal.pone.0271995