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Aim: Amitriptyline (AMI) has been used to treat neuropathic pain. However, the clinical outcomes remain unsatisfactory, presumably due to a limited understanding of the underlying molecular mechanisms. Here, we investigated a drug repositioning strategy using a low-dose of AMI encapsulated in poly (D, L lactic-co-glycolic acid) (PLGA) nanoparticles (AMI NPs) for neuropathic pain, since PLGA nanoparticles are known to enhance delivery to microglia. Methods: We evaluated the anti-allodynic effects of AMI and AMI NPs on neuropathic pain by assessing behaviors and inflammatory responses in a rat model of spinal nerve ligation (SNL). While the anti-allodynic effect of AMI (30 μg) drug injection on SNL-induced neuropathic pain persisted for 12 h, AMI NPs significantly alleviated mechanical allodynia for 3 days. Results: Histological and cytokine analyses showed AMI NPs facilitated the reduction of microglial activation and pro-inflammatory mediators in the spinal dorsal horn. This study suggests that AMI NPs can provide a sustained anti-allodynic effect by enhancing the targeting of microglia and regulating the release of pro-inflammatory cytokines from activated microglia. Conclusion: Our findings suggest that the use of microglial-targeted NPs continuously releasing AMI (2 μg) as a drug repositioning strategy offers long-term anti-allodynic effects. Graphical Abstract Article highlights This study investigated a drug repositioning strategy using a low-dose of AMI encapsulated in poly (D, L lactic-co-glycolic acid) (PLGA) nanoparticles (AMI NPs) for neuropathic pain, since PLGA nanoparticles are known to enhance delivery to microglia. While the anti-allodynic effect of AMI (30 μg) drug injection on SNL-induced neuropathic pain persisted for 12 h, AMI NPs significantly alleviated mechanical allodynia for 3 days. This study suggests that AMI NPs can provide a sustained anti-allodynic effect by enhancing the targeting of microglia and regulating the release of pro-inflammatory cytokines from activated microglia. [ABSTRACT FROM AUTHOR]

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and is prescribed off-label for several neurological conditions like neuropathic pain, migraines and anxiety. Besides their action on the reuptake of monoaminergic neurotransmitters, tricyclic antidepressants interact with several additional targets that may contribute to either therapeutic or adverse effects. Here, we investigated the effects of amitriptyline on proliferation and autophagy (i.e., an evolutionarily conserved catabolic pathway responsible for the degradation and recycling of cytoplasmic material) in human SH-SY5Y neuroblastoma cell cultures. The dose and time-dependent upregulation of the autophagy marker LC3II and the autophagy receptor p62, with the accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to the amitriptyline. These effects were accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5−/− MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine, suggesting that they were independent from autophagy modulation. Our findings demonstrate that amitriptyline acts on pathways crucial for cell and tissue homeostasis (i.e., autophagy and proliferation) and pose the basis for further studies on the potential therapeutic application of amitriptyline, as well as the consequences of its use for long-term treatments. [ABSTRACT FROM AUTHOR]

Afferent synapses between inner hair cells (IHCs) and the type I spiral ganglion neurons (SGNs) in the cochlea provide over 95% of sensory signals for auditory perception in the brain. However, these afferent synapses are particularly vulnerable to damage, for example from excitotoxicity, and exposure to noise in the environment which often leads to noise‐induced cochlear synaptopathy (NICS). In this study, we simulated excitotoxic trauma by incubating kainic acid, a non‐desensitizing agonist for AMPA type glutamate receptors on cultured cochleae. The possible protective effects of amitriptyline against NICS were examined. We found that, in IHCs, amitriptyline reversed the decrease of Ca2+ current and exocytosis caused by excitotoxic trauma. In SGNs, amitriptyline promoted the recovery of neurite loss caused by excitotoxic trauma. Furthermore, we found that the protective effects of amitriptyline are likely mediated by suppressing apoptosis factors that were upregulated during excitotoxic trauma. In conclusion, our results suggest that amitriptyline could protect afferent synapses in the cochlea from NICS, making it a potential drug candidate for hearing protection. [ABSTRACT FROM AUTHOR]

Background: Active drugs and nutraceutical supplements commonly induce various gastrointestinal illnesses, and constipation is a major gastrointestinal symptom accompanied with functional gastrointestinal disorders. Drug-induced imbalance in gut microbiota may play critical role in such physiological disturbances. Probiotics have been known for resuming normal and healthy gut microbiome. Objective: To investigate the clinical efficacy and safety of Bacillus coagulans LBSC in the treatment of drug induced constipation associated with functional gastrointestinal disorder (FGID) symptoms. Methods: A prospective, interventional, randomized, double-blind, parallel, multi-arm, controlled trial with 168 patients experiencing drug induced constipation associated with FGID symptoms (DICAWFGID) screened through Rome IV criteria were randomized into 2 arms, i.e. placebo arm (n = 28) and atorvastatin, atenolol, metformin, amitriptyline, and calcium in test arm (n = 28/arm). Patients in both arms received similar dosages (1 g sachet, 3 times a day) for 35 days. The occurrence of constipation using Bristol Stool Form Scale, assessment of degree of constipation on 4-point Likert scale, occurrence of hard stool and degree of stool expulsion on 3-point scale, and defecation frequency were primary endpoints. While, secondary outcomes consisted of the changes in severity of FGID symptoms, visual analogue scale and tolerance to IP, along with reports of adverse events (AEs) and severe adverse events (SAEs). Results: There was a significant reduction in occurrence of constipation (≥98.6% and P -value <0.05) in test arm over the placebo arm. Assessment of co-primary endpoints showed significant improvements in degree of stool consistency (P -value 0.0232; CI: 0.1870, 1.1629), borderline significantly superior in degree of stool expulsion (P -value 0.0553; CI: 0.0378, −0.4939), while the other co-primary efficacy endpoints displayed considerably improved advancement (non-significant, P -value ≥0.05). The intra group analysis of symptoms at start of treatment (SOT) and end of treatment (EOT) revealed a significant reduction in scores for occurrence of constipation and degree of constipation, whereas significant improvement in the scores for degree of stool consistency and degree of stool expulsion (P -value <0.001) after the intervention period. In secondary endpoints, the processed responses clearly signified a considerable positive improvement (non-significant, P -value ≥0.05) in other symptoms of constipation associated with FGIDs as determined by the changes in the EOT-SOT score. The study data also highlighted the safety o f Bacillus coagulans LBSC at the studied dose. No AEs and/or SAEs were documented during the investigation. Conclusion: At the studied dose, Bacillus coagulans LBSC was safe for oral consumption and effective in the management of the drug induced constipation associated with FGIDs symptoms. [ABSTRACT FROM AUTHOR]

Tan Thanh Nguyen,1 Lac Duy Le,1 Thanh Tri Vu,2 Anh Thai Nguyen,1 Duc Binh Doan,1 Duyen Thi Pham,1 Tung Thanh Pham,1 Chuc Ngoc Vu,3 Minh Hoang Nguyen Vo4 1Cardiac Intensive Department, Thu Duc City Hospital, Ho Chi Minh City, Vietnam; 2Board of Directors, Thu Duc City Hospital, Ho Chi Minh City, Vietnam; 3Emergency Department, Thu Duc City Hospital, Ho Chi Minh City, Vietnam; 4Office of Science Management and International Affairs, Thu Duc City Hospital, Ho Chi Minh City, VietnamCorrespondence: Minh Hoang Nguyen Vo, Office of Science Management and International Affairs, Thu Duc City Hospital, No. 29 Phu Chau Street, Tam Phu ward, Thu Duc, Ho Chi Minh City, 700000, Vietnam, Tel +84 389135014, Email minhhoangytcc87@gmail.comIntroduction: Tricyclic antidepressants (TCAs) were once commonly used to treat major depressive disorder (MDD), but are now considered second-line options after SSRIs and SNRIs. Additionally, TCAs are used to treat other conditions such as chronic pain and enuresis in children. Due to their numerous side effects and potential for drug interactions, cases of poisoning and death from TCA overdose, particularly amitriptyline, are on the rise. Therefore, this article revisits the overview and describes the clinical progression regarding blood gases, ECG, and electrolytes of the patient, as well as the use of 4.2% sodium bicarbonate and 2% lidocaine to treat cases of amitriptyline overdose poisoning.Case Presentation: A 49-year-old female patient was admitted to the hospital due to cardiac and respiratory arrest. The patient had a past medical history of untreated cervical cancer and sleep disorders. Prior to admission, the patient had taken about 20 tablets of amitriptyline 25mg and was in a drowsy state with gasping breaths. During transportation to the hospital, the patient experienced cardiac arrest once and was successfully resuscitated, with a total arrest and resuscitation time of approximately 10 minutes.Results: The use of 4.2% Sodium Bicarbonate and 2% Lidocaine, the patient was not used plasma exchange in this case, proved effective in this case. Continuous monitoring of blood gas levels, ECG, and electrolytes was maintained. The patient was able to walk independently and was discharged after 12 days of treatment.Conclusion: The key factor was the healthcare staff’s quick recognition and timely management of TCA poisoning, in this case, amitriptyline.Keywords: tricyclic antidepressants, amitriptyline, cardiac arrhythmia

Abstract Burning mouth syndrome (BMS) is characterized by burning sensations in the oral region without corresponding abnormalities and is often accompanied by uncomfortable sensations. Herein, we present cases of BMS in which the remaining uncomfortable sensations improved with perospirone augmentation with clonazepam. Case 1: A 61‐year‐old man complained of a burning pain in his tongue, a sensation of dryness and discomfort as if his tongue was sticking to a palatal plate. With the diagnosis of BMS, psychopharmacotherapy was initiated with amitriptyline. At the dose of amitriptyline 50 mg, the pain lessened but uncomfortable sensations persisted. Further attempts to alleviate symptoms by combining aripiprazole with amitriptyline, aripiprazole with mirtazapine, or aripiprazole with clonazepam were limited; however, nearly all symptoms were relieved by a combination of perospirone 8.0 mg with clonazepam 1.5 mg. Case 2: A 51‐year‐old woman complained of a burning sensation along with oral dryness and crumb‐like feeling on her tongue. She was diagnosed with BMS and began treatment with amitriptyline. Her burning sensation improved at the dose of 25 mg, but uncomfortable sensations persisted. Augmentation of amitriptyline with aripiprazole, aripiprazole either with valproate, mirtazapine, or clonazepam failed to produce a significant improvement. However, a regimen of perospirone 6.0 mg and clonazepam 1.5 mg relieved the crumb‐like sensation and pain and culminated in a stabilized condition. The reported cases suggested that multiple approaches targeting the dopaminergic circuit in basal ganglia involving the serotoninergic and GABA systems, through the administration of perospirone with clonazepam is an effective adjunctive treatment for the remaining uncomfortable sensations in patients with BMS.

The open-channel block of N-methyl-D-aspartate receptors (NMDARs) and their calcium-dependent desensitization (CDD) represent conventional mechanisms of glutamatergic synapse regulation. In neurotrauma, neurodegeneration, and neuropathic pain the clinical benefits of cure with memantine, ketamine, Mg2+, and some tricyclic antidepressants are often attributed to NMDAR open-channel block, while possible involvement of NMDAR CDD in the therapy is not well established. Here the effects of selective high-affinity sodium-calcium exchanger (NCX) isoform 1 inhibitor, SEA0400, on NMDA-activated whole-cell currents and their block by amitriptyline, desipramine and clomipramine recorded by patchclamp technique in cortical neurons of primary culture were studied. We demonstrated that in the presence of extracellular Ca2+, 50 nM SEA0400 caused a reversible decrease of the steady-state amplitude of NMDAR currents, whereas loading neurons with BAPTA or the removal of extracellular Ca2+ abolished the effect. The decrease did not exceed 30% of the amplitude and did not depend on membrane voltage. The external Mg2+ block and 50 nM SEA0400 inhibition of currents were additive, suggesting their independent modes of action. In the presence of Ca2+ SEA0400 speeded up the decay of NMDAR currents to the steady state determined by CDD. The measured IC50 value of 27 nM for SEA0400-induced inhibition coincides with that for NCX1. Presumably, SEA0400 effects are induced by an enhancement of NMDAR CDD through the inhibition of Ca2+ extrusion by NCX1. SEA0400, in addition, at nanomolar concentrations could interfere with Ca2+-dependent effect of tricyclic antidepressants. In the presence of 50 nM SEA0400, the IC50s for NMDAR inhibition by amitriptyline and desipramine increased by about 20 folds, as the Ca2+-dependent NMDAR inhibition disappeared. This observation highlights NCX1 involvement in amitriptyline and desipramine effects on NMDARs and unmasks competitive relationships between SEA0400 and these antidepressants. Neither amitriptyline nor desipramine could affect NCX3. The open-channel block of NMDARs by these substances was not affected by SEA0400. In agreement, SEA0400 did not change the IC50 for clomipramine, which acts as a pure NMDAR open-channel blocker. Thus, NCX seems to represent a promising molecular target to treat neurological disorders, because of the ability to modulate NMDARs by decreasing the open probability through the enhancement of their CDD. [ABSTRACT FROM AUTHOR]

Background Postherpetic neuralgia (PHN) is a chronic painful condition of neuronal origin lasting more than 3 months in the previously involved dermatome by herpes zoster. PHN remains the most common and debilitating complication of herpes zoster affecting the quality of life of such patients. A variety of symptoms have been reported including pain, allodynia, hyperalgesia, paresthesia, and dysesthesia, in the absence of active herpes lesions. Although there are several therapeutic options for PHN, there is little information available regarding its prevention. This study aimed to fill this research gap and explore the role of amitriptyline in preventing PHN. Objective To evaluate the efficacy of Amitriptyline in the prevention of Post Herpetic Neuralgia (PHN). Methods A total of 120 herpes zoster patients, presenting within 3 days were selected. Patients were split into two groups. Group A received 25 mg amitriptyline along with famciclovir, while group B used only oral famciclovir. Both groups were given other analgesics like Gabapentin, topical analgesics, and NSAIDs on a need basis. Patients were evaluated at monthly intervals and the final pain scores were calculated after 3 months. Results At the baseline, patients in the significant pain category were comparable in both groups. After 3 months the number of such patients in Group B was higher. Similarly, there was clear disparity between the two groups regarding the number of patients achieving good/excellent pain reduction (p valve<0.05). Conclusion This study showed that oral Amitriptyline started concomitantly with antivirals significantly reduced the incidence of post-herpetic neuralgia. [ABSTRACT FROM AUTHOR]

To describe the need and effectiveness of acute and preventive medications in a series of 100 consecutive patients referred due to COVID-19-related headaches. Patients were aged 48.0 (standard deviation (SD): 12.4), 84% were female, and 56% had a prior history of headache. The most common headache phenotype was holocranial (63%), frontal (48%), pressing (75%), of moderate intensity (7 out of 10), and accompanied by photophobia (58%). Acute medication was required by 93%, with paracetamol (46%) being the most frequently used drug, followed by ibuprofen (44%). The drugs with the highest proportion of a 2 h pain-freedom response were dexketoprofen (58.8%), triptans (57.7%), and ibuprofen (54.3%). Preventive treatment was required by 75% of patients. The most frequently used drugs were amitriptyline (66%), anesthetic blockades (18%), and onabotulinumtoxinA (11%). The drugs with the highest 50% responder rate were amitriptyline (45.5%), mirtazapine (50%), and anesthetic blockades (38.9%). The highest 75% responder rate was experienced following onabotulinumtoxinA (18.2%). In conclusion, most patients required acute medication, with triptans and non-steroidal anti-inflammatory drugs achieving the best responses. Three-quarters of patients required preventive medication. The most frequently used drug was amitriptyline, which obtained the best results. In some treatment-resistant patients, anesthetic blockades and onabotulinumtoxinA were also beneficial. [ABSTRACT FROM AUTHOR]

Patients with mutations that alter the function of the sodium channel SCN8A present with a range of clinical features, including mild to severe seizures, developmental delay, intellectual disability, autism, feeding dysfunction, motor impairment, and hypotonia. In an effort to identify compounds that could be potentially beneficial in SCN8A-associated epilepsy, Atkin et al. conducted an in vitro screen which resulted in the identification of 90 compounds that effectively reduced sodium influx into the cells expressing the human SCN8A R1872Q mutation. The top compounds that emerged from this screen included amitriptyline, carvedilol, and nilvadipine. In the current study, we evaluated the ability of these three compounds to increase resistance to 6 Hz or pentylenetetrazole (PTZ)-induced seizures in wild-type CF1 mice and in a mouse line expressing the human SCN8A R1620L mutation. We also evaluated the effects of fenfluramine administration, which was recently associated with a 60%–90% decrease in seizure frequency in three patients with SCN8Aassociated epilepsy. While amitriptyline, carvedilol, and fenfluramine provided robust protection against induced seizures in CF1 mice, only carvedilol was able to significantly increase resistance to 6 Hz- and PTZ-induced seizures in RL/+ mutants. These results provide support for further evaluation of carvedilol as a potential treatment for patients with SCN8A mutations. [ABSTRACT FROM AUTHOR]

A method for the determination of amitriptyline, a tricyclic antidepressant, in human urine by immunosensors has been developed using supramolecular systems based on hexamolybdenum cluster complexes. These complexes have electrochemical activity and give a stable analytical signal, which was used in the development of amperometric immunosensors. Luminescence and dynamic light scattering methods were used to demonstrate the formation of a supramolecular system of self-organized hexamolybdenum nanoparticles and chitosan molecules. A composite material based on hexamolybdenum cluster complexes in combination with reduced graphene oxide has been developed. The working range of amitriptyline concentrations to be determined by an amperometric immunosensor was 1 × 10–9–1 × 10–4 M, the limit of determination was at a level of 5 × 10–10 M, and the amitriptyline content of urine samples was at a level of (n – 7) × 10–8 M. A comparison of the results of analysis performed using an amperometric immunosensor and a fluorescence polarization immunoassay showed the absence of significant systematic errors. The ability to determine amitriptyline in biological fluids makes it possible to select an optimal therapeutic dose of the drug, that is, to develop approaches to creating personalized medicine. [ABSTRACT FROM AUTHOR]

Burning mouth syndrome (BMS) is characterized by burning sensations in the oral region without corresponding abnormalities and is often accompanied by uncomfortable sensations. Herein, we present cases of BMS in which the remaining uncomfortable sensations improved with perospirone augmentation with clonazepam. Case 1: A 61‐year‐old man complained of a burning pain in his tongue, a sensation of dryness and discomfort as if his tongue was sticking to a palatal plate. With the diagnosis of BMS, psychopharmacotherapy was initiated with amitriptyline. At the dose of amitriptyline 50 mg, the pain lessened but uncomfortable sensations persisted. Further attempts to alleviate symptoms by combining aripiprazole with amitriptyline, aripiprazole with mirtazapine, or aripiprazole with clonazepam were limited; however, nearly all symptoms were relieved by a combination of perospirone 8.0 mg with clonazepam 1.5 mg. Case 2: A 51‐year‐old woman complained of a burning sensation along with oral dryness and crumb‐like feeling on her tongue. She was diagnosed with BMS and began treatment with amitriptyline. Her burning sensation improved at the dose of 25 mg, but uncomfortable sensations persisted. Augmentation of amitriptyline with aripiprazole, aripiprazole either with valproate, mirtazapine, or clonazepam failed to produce a significant improvement. However, a regimen of perospirone 6.0 mg and clonazepam 1.5 mg relieved the crumb‐like sensation and pain and culminated in a stabilized condition. The reported cases suggested that multiple approaches targeting the dopaminergic circuit in basal ganglia involving the serotoninergic and GABA systems, through the administration of perospirone with clonazepam is an effective adjunctive treatment for the remaining uncomfortable sensations in patients with BMS. This is the first report introduced cases of BMS where patients' remained discomfort was ameliorated by perospirone augmentation with clonazepam, which approaches multiply to dopaminergic circuit in basal ganglia involving serotoninergic and GABA system. It may be as effective adjunctive treatment for the remaining uncomfortable sensations in the patients with BMS. [ABSTRACT FROM AUTHOR]

Background Irritable bowel syndrome, characterised by abdominal pain and a change in stool form or frequency, is most often managed in primary care. When first-line therapies are ineffective, National Institute for Health and Care Excellence guidelines suggest considering low-dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown and they are infrequently prescribed by general practitioners. Objective To evaluate the clinical and cost-effectiveness of low-dose titrated amitriptyline as a second-line treatment for irritable bowel syndrome in primary care. Design A pragmatic, randomised, multicentre, two-arm, double-blind, placebo-controlled trial. A nested, qualitative study explored participant and general practitioner experiences of treatments and trial participation, and implications for wider use of amitriptyline for irritable bowel syndrome in primary care. Participants, clinicians, investigators and analysts were masked to allocation. Setting Fifty-five general practices in three regions in England (Wessex, West of England, West Yorkshire). Participants Patients aged ≥ 18 years meeting Rome IV criteria for irritable bowel syndrome with ongoing symptoms after trying first-line treatments and no contraindications to TCAs. Intervention Amitriptyline 10 mg once-daily, self-titrated by participants to a maximum of 30 mg once-daily or matched placebo for 6 months. Participants randomised 1 : 1 with most having the option to continue blinded treatment for a further 6 months. Main outcome measures The primary participant-reported outcome was the effect of amitriptyline on global irritable bowel syndrome symptoms at 6 months, measured using the irritable bowel syndrome Severity Scoring System, with a 35-point between-group difference defined as the minimum clinically important difference. The key secondary outcome was the proportion of participants reporting subjective global assessment of relief at 6 months, defined as somewhat, considerable, or complete relief of symptoms. Other secondary outcomes included: effect on global symptoms, via the irritable bowel syndrome Severity Scoring System, and subjective global assessment of relief of irritable bowel syndrome symptoms at 3 and 12 months; effect on somatic symptom-reporting at 6 months; anxiety an–d depression scores; ability to work and participate in other activities at 3, 6 and 12 months; acceptability, tolerability and adherence to trial medication. Results Four hundred and sixty-three participants were randomised to amitriptyline (232) or placebo (231). An intention-to-treat analysis of the primary outcome showed a significant difference in favour of amitriptyline for irritable bowel syndrome Severity Scoring System score between arms at 6 months [−27.0, 95% confidence interval (CI) −46.9 to −7.10; p = 0.008]. For the key secondary outcome of subjective global assessment of relief of irritable bowel syndrome symptoms, amitriptyline was superior to placebo at 6 months (odds ratio 1.78, 95% CI 1.19 to 2.66; p = 0.005). Amitriptyline was superior to placebo across a range of other irritable bowel syndrome symptom measures but had no impact on somatoform symptom-reporting, anxiety, depression, or work and social adjustment scores. Adverse event trial withdrawals were more common with amitriptyline (12.9% vs. 8.7% for placebo) but most adverse events were mild. The qualitative study thematically analysed 77 semistructured interviews with 42 participants and 16 GPs. Most participants found the self-titration process acceptable and empowering. Conclusions General practitioners should offer low-dose amitriptyline to patients with irritable bowel syndrome whose symptoms do not improve with first-line therapies. Guidance and resources should support GP–patient communication to distinguish amitriptyline for irritable bowel syndrome from use as an antidepressant and to support patients managing their own dose titration. Study registration This trial is registered as ISRCTN48075063. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/162/01) and is published in full in Health Technology Assessment Vol. 28, No. 66. See the NIHR Funding and Awards website for further award information. Plain language summary Background People with irritable bowel syndrome experience stomach (abdominal) pain and changes to their bowel movements. Irritable bowel syndrome can have a serious impact on people’s lives. Previous small trials suggest that a drug called amitriptyline used at a low dose may help irritable bowel syndrome. Amitriptyline is already used to treat other conditions. It is available for irritable bowel syndrome but is not used much by general practitioners. Methods We recruited adults aged ≥ 18 years with irritable bowel syndrome from UK general practices who did not have any issues preventing the use of amitriptyline. Patients received either low-dose amitriptyline or placebo (a dummy tablet) for 6 months. Patients could adjust the dose according to symptoms and side effects. Neither the researchers nor the patients knew which treatment they were getting. Participants recorded symptoms using a questionnaire containing an irritable bowel syndrome severity score. We looked at the difference in average irritable bowel syndrome severity score between patients receiving amitriptyline and placebo. We also looked at effects of amitriptyline on mood, ability to work, and non-gut symptoms related to irritable bowel syndrome, as well as safety and acceptability. Some patients and general practitioners were interviewed about their experiences. Results Four hundred and sixty-three patients took part. Participants receiving amitriptyline reported a bigger improvement in their irritable bowel syndrome severity scores at 6 months, compared with patients on placebo. Amitriptyline was better across a range of irritable bowel syndrome symptom measures but did not impact anxiety, depression or ability to work. Forty-six people (19.8%) stopped taking amitriptyline and 59 (25.5%) stopped the placebo before 6 months. Patients liked being able to adjust their dose and valued contact with the research team. Conclusion This study showed that amitriptyline is more effective than a placebo and is safe. General practitioners should offer low-dose amitriptyline to people with irritable bowel syndrome if symptoms do not improve with other standard treatments. Patients should be supported and helped to adjust their dose as needed. The dose adjustment sheet used in this trial will be made available. Scientific summary Background Irritable bowel syndrome (IBS) affects 5% of the population, accounting for > 3% of all consultations in primary care in England and Wales. Symptoms include abdominal pain in association with a change in stool form or frequency. The condition impacts on quality of life and ability to work and limits social activities. The medical management of IBS is unsatisfactory, with no therapy proven to alter the long-term natural history and, at best, modest symptom reduction. Previous meta-analyses of trials conducted in secondary and tertiary care suggest low-dose tricyclic antidepressants (TCAs) may be efficacious, probably because of their pain-modifying properties, as well as their influence on gut motility, rather than any effects on mood. Although National Institute for Health and Care Excellence guidelines for the management of IBS in primary care suggest considering low-dose TCAs as second-line treatment, their effectiveness in this setting is unknown and they are infrequently prescribed by general practitioners (GPs). Objectives Our objective was to determine the clinical and cost-effectiveness of low-dose titrated amitriptyline compared with placebo for 6 months as a second-line treatment in adults with IBS in primary care. Methods ATLANTIS was a pragmatic, randomised, multicentre, parallel-group, two-arm, double-blind, placebo-controlled trial. A nested, qualitative study explored participant and GP experiences of treatments and trial participation. A within-study cost-effectiveness analysis was planned but, due to the coronavirus disease discovered in 2019 (COVID-19) pandemic, health economic analyses were removed after obtaining additional funding to complete the trial to prioritise funds for participant recruitment. These will be subject to further funding. Participants, their GPs, investigators, the research team, and the analysis team were all masked to treatment allocation throughout the trial. Patients meeting Rome IV criteria for IBS who had tried first-line treatments and with ongoing IBS symptoms [score of ≥ 75 on the IBS Severity Scoring System (IBS-SSS)] were recruited via mail-out from 55 general practices in three regions in England. Participants were randomised 1 : 1 to receive either low-dose titrated amitriptyline or placebo. Both treatments were supplied for 6 months, with the dose commenced at 10 mg o.d. and titrated to a maximum of 30 mg o.d. or a minimum of 10 mg alternate days. Dose titration was participant-led according to IBS symptoms and side effects, with support from the trial team and a dose titration document developed with input via patient and public involvement. Participants recruited earlier to the trial had the option to continue blinded treatment for an additional 6 months. The primary outcome was the effect of amitriptyline on global IBS symptom scores at 6 months. The key secondary outcome was the proportion of participants with relief of IBS symptoms at 6 months. Other secondary outcomes included effect on global IBS symptoms and relief of IBS symptoms at 3 and 12 months, effect on IBS-associated somatic symptoms at 6 months, effect on quality of life, anxiety, and depression scores, and ability to work and participate in other activities at 3, 6 and 12 months, as well as acceptability and tolerability of, and adherence to, treatment. Patient-reported questionnaires at baseline and 3, 6 and 12 months post randomisation (unless otherwise indicated) were used to assess IBS symptom severity (measured via the IBS-SSS), relief of IBS symptoms [measured by subjective global assessment (SGA) of relief], adequate relief of IBS symptoms (measured by a weekly response to the question ‘Have you had adequate relief of your IBS symptoms?’), IBS-associated somatic symptoms [using the Patient Health Questionnaire-12 (PHQ-12)], mood [using the Hospital Anxiety and Depression Scale (HADS)], ability to work and participate in other activities [using the Work and Social Adjustment Scale (WSAS)], quality of life (using the EQ-5D-3L), healthcare use (using a bespoke health resource use questionnaire), and tolerability [using the Antidepressant Side-Effect Checklist (ASEC)]. Numbers of participants reporting serious adverse events (SAEs), including serious adverse reactions (SARs), were reported for each treatment group. An evaluable sample size of 414 participants would provide 90% power to detect a minimum clinically important difference of 35 points between amitriptyline and placebo at 6 months on the IBS-SSS. This sample size provided at least 85% power to detect a 15% absolute difference in the key secondary outcome of SGA of relief of IBS symptoms at 6 months. We planned to recruit 518 participants, allowing for 20% loss to follow-up. Effectiveness outcomes were analysed in the intention-to-treat population, defined as all participants randomised, regardless of adherence. All statistical testing used two-sided 5% significance levels. The primary outcome was analysed using a linear regression model, adjusted for minimisation variables and baseline IBS-SSS score. Missing data were imputed by treatment arm, via multiple imputation, and results were expressed as point estimates with 95% confidence intervals (CIs). Secondary binary outcomes were analysed in logistic or ordinal regression models, with results expressed as odds ratios (ORs) with 95% CIs. Continuous secondary outcomes, including PHQ-12, HADS and WSAS scores, were analysed as for the primary outcome, adjusted for the respective baseline score. All participants receiving at least one dose of trial medication, according to medication received, were included in the safety analysis. The nested, qualitative study aimed to identify factors that would facilitate or impede prescribing of, acceptability of, and adherence to, low-dose amitriptyline in IBS, to identify participants’ and GPs’ perspectives on the broader impact of the trial, and to explore psychosocial and contextual factors that might shape wider use of amitriptyline for IBS. Familiarity with amitriptyline may both hinder uptake, given its association with depression, and facilitate it, given that it is a known drug, taken in a low dose distinct from the antidepressant dose, already used for a range of other painful conditions and has comparatively mild, and in some cases potentially beneficial, side effects such as on sleep. Semi-structured audio-recorded telephone interviews were conducted with a diverse sub-sample of trial participants and GPs involved in the trial and transcribed verbatim. The final sample size was dependent on saturation, to achieve a rigorous, credible analysis in relation to the aims. Topic guides allowed flexible exploration of all required topics, while remaining open to participants’ individual experiences and perspectives. To enhance trustworthiness of the analysis, all qualitative study team members contributed to avoid producing idiosyncratic interpretations, a negative case analysis was undertaken, and an audit trail was produced to enhance transparency, including detailed coding manuals and interviewer field notes. Reflexive thematic analysis, incorporating techniques from grounded theory, was used to analyse the qualitative data. Data collection and initial analyses proceeded iteratively, and informed subsequent interviews. Analysis was primarily inductive, with researchers identifying themes in the data rather than imposing any pre-existing interpretive framework. Qualitative findings were related to the main trial findings by comparing themes across subgroups and against the quantitative data. Clinical results In total, 15,672 potentially eligible patients were invited to take part, of whom 1253 were interested and were screened. Of those screened, 463 (37.0%) were randomised {mean age 48.5 years [standard deviation (SD) 16.1 years], 315 (68.0%) female}, to amitriptyline (n = 232) or placebo (n = 231). Six-month follow-up was achieved for 401 (86.6%) participants, 204 (87.9%) in the amitriptyline arm, and 197 (85.3%) in the placebo arm. Participants were well balanced between treatment arms according to demographics and baseline characteristics, IBS symptom severity, PHQ-12 scores, HADS-depression and HADS-anxiety scores, and previous first-line treatments. Among participants, 80.4% had IBS-D or IBS-M, 84.2% had a normal HADS-depression score, and 84.7% had moderate to severe scores on the IBS-SSS, with a mean IBS-SSS score in all participants of 272.8 (SD 90.3). The median duration of IBS was 10 years. In total, 338 (73.0%) participants completed 6 months of treatment, 173 (74.6%) randomised to amitriptyline and 165 (71.4%) to placebo. Discontinuation of trial medication before 6 months occurred in 105 (22.7%) participants, 46 (19.8%) allocated to amitriptyline and 59 (25.5%) to placebo. The most common reason for discontinuing trial medication was adverse events (AEs) in 30 (12.9%) participants allocated to amitriptyline and 20 (8.7%) to placebo, followed by lack of benefit in 7 (3.0%) randomised to amitriptyline and 18 (7.8%) to placebo. There were a further 17 (3.7%) participants lost to follow-up and 3 (0.6%) who did not commence trial medication. By 3 months, similar proportions of participants randomised to amitriptyline had titrated their dose to 20 mg o.d. (35.2%) or 30 mg o.d. (37.8%), although by 6 months this had increased to 42.8% taking 30 mg o.d. However, in the placebo arm, 57.0% of participants titrated their dose to 30 mg o.d. within 3 months and this proportion was similar at 6 months. For the primary outcome, amitriptyline was superior to placebo at 6 months in the intention-to-treat analysis, with a significant difference in mean IBS-SSS score between arms (−27.0, 95% CI −46.9 to −7.1; p = 0.008). For the key secondary outcome, SGA of relief of IBS symptoms, amitriptyline was also superior to placebo (OR for relief of IBS symptoms = 1.78, 95% CI 1.19 to 2.66; p = 0.005). At 3 months, the difference in mean change in IBS-SSS score also favoured amitriptyline (−23.3, 95% CI −42.0 to −4.6; p = 0.014), as did the SGA of relief of IBS symptoms (OR = 1.70, 95% CI 1.15 to 2.53; p = 0.008). In a sensitivity analysis using an alternative definition of SGA of relief of IBS symptoms, where only those reporting considerable or complete relief of IBS symptoms at 3 or 6 months were classed as responders, the effect size in the amitriptyline arm increased at both 3 (OR = 1.81, 95% CI 1.17 to 2.79) and 6 months (OR = 1.88, 95% CI 1.20 to 2.95). Other sensitivity analyses on the per-protocol population for the primary outcome and on participants with complete data for the primary and key secondary outcomes gave consistent results, albeit with larger estimated treatment effects. In terms of adequate relief of IBS symptoms, amitriptyline was also superior to placebo with increased odds of adequate relief across all 25 weeks (OR = 1.56, 95% CI 1.20 to 2.03; p < 0.001), and a higher proportion of participants reporting adequate relief for ≥ 13 of 25 weeks [90/222 (40.5%) vs. 67/221 (30.3%)]. Significantly higher numbers of participants taking amitriptyline reported the drug to be acceptable and would have been willing to continue taking it at 6 months (OR = 1.60, 95% CI 1.08 to 2.35; p = 0.018). Adherence at 3 months was identical in the two treatment arms, but it was higher in the amitriptyline arm at 6 months [172/232 (74.1%) vs. 155/228 (68.0%)]. Amitriptyline had no significant effect on PHQ-12 scores at 6 months, or HADS-anxiety, HADS-depression or WSAS scores at either 3 or 6 months. In terms of treatment-emergent AEs, there was a statistically significant increase in the total ASEC score in those receiving amitriptyline compared with placebo at 3 months (1.39, 95% CI 0.29 to 2.50; p = 0.013) but not at 6 months (0.26, 95% CI −0.98 to 1.51; p = 0.681). The AEs reported in participants receiving amitriptyline in excess of those reported by the placebo arm mainly related to its known anticholinergic effects, including dry mouth, drowsiness, blurred vision and problems with urination. However, rates of treatment-emergent AEs fell between 3 and 6 months and few were severe. The commonest AEs leading to discontinuation in the amitriptyline arm were drowsiness and deterioration of mood. In total, there were five SARs, two in the amitriptyline arm and three in the placebo arm. There were five SAEs unrelated to trial medication, of which four occurred in the amitriptyline arm and one in the placebo arm. In the subset of participants recruited to 12 months’ follow-up and with the choice to continue treatment beyond 6 months, 44% of participants completed 12 months’ treatment. Despite the mixed sample, in the 12-month ITT population, weak evidence of a significant effect in favour of low-dose amitriptyline remained on the mean IBS-SSS (−22.6, 95% CI −49.35 to −4.16; p = 0.098) and the SGA of relief of global IBS symptoms (OR = 1.58, 95% CI 0.94 to 2.64; p = 0.083). In contrast to 6-month results, there was a statistically significant effect on the HADS-depression (−0.88, 95% CI −1.71 to 0.06; p = 0.036) and WSAS (−2.14, 95% CI −3.80 to −0.49; p = 0.011) scores in favour of low-dose amitriptyline. Qualitative results The qualitative study conducted and thematically analysed 77 semistructured interviews with 42 participants and 16 GPs. A multidisciplinary team including patient collaborators explored multiple aspects of participants’ and GPs’ experiences of treatments and participating in the ATLANTIS trial. The qualitative analysis of barriers and facilitators suggests that low-dose amitriptyline for IBS is acceptable to, and is often welcomed by, GPs and patients as an additional treatment option. Addressing concerns and promoting facilitators could facilitate wider use of low-dose amitriptyline for IBS which may be achieved through: Clear communication to clinicians, for example in clinical guidelines, that distinguishes low-dose amitriptyline for IBS from amitriptyline use for other conditions (especially depression). Resources to support GP–patient communication to distinguish low-dose amitriptyline for IBS from amitriptyline for other conditions (especially depression). This might include, for example, tips for GPs when discussing amitriptyline for IBS with patients, online materials to support or reinforce messages given during consultations, tailored packaging and patient inserts, and education for pharmacists. Clear guidance about low-dose amitriptyline for IBS and anticholinergic burden. This should highlight that low-dose amitriptyline has lower potential risk and that currently anticholinergic burden risk scores do not account for dose, so can overinterpret risk with low-dose amitriptyline. Guidance and resources for GPs and patients to support patients managing their own dose titration. The dose-titration document used in ATLANTIS was well received by GPs and patients. Conclusions In the largest trial of a TCA in IBS ever conducted, titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes and was safe. The results of ATLANTIS strongly support use of titrated low-dose amitriptyline in this setting. GPs should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial. Trial registration This trial is registered as ISRCTN48075063. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/162/01) and is published in full in Health Technology Assessment; Vol. 28, No. 66. See the NIHR Funding and Awards website for further award information.

Abstract Background Chronic post-penile prosthesis pain is de novo pain persisting > 2 months post-operatively. This pain is inadequately reported, poorly understood and undermanaged. The purpose of this current pilot study was to improvise a medical approach to alleviate the condition and assess the combination of Pregabalin and Amitriptyline in its management. Results The study enrolled 9 patients complaining of idiopathic penile, pelvic, or scrotal pain persisting > 2 months after penile prosthesis implantation. Patients were prescribed pregabalin 75mg/12h (escalated after 1 week to 150mg/12h upon demand) and Amitriptyline 25mg once daily for 3 months. The pain was reassessed after 10, 30 and 100 days. The dose of pregabalin required and the side effects of the medication were noted. Findings revealed a significant decrease in pain duration (p = 0.007), frequency (p

Psychiatric drugs do not vanish after being carried to wastewater treatment plants by the urine or feces of patients and, a variable portion of their dose and also unused or expired drugs are lost to the environment. This is because the technology of plants is not intended to eradicate pharmaceuticals and their metabolites. Above all, psychotropics can change population dynamics and behavior at lower doses. We believe that antipsychotics have not gotten enough attention when it comes to drug pollution and that their importance as environmental pollutants has been underestimated. An innovative approach to eliminating pharmaceutical pollutants from water is the application of advanced oxidation methods. Among these oxidation methods are photocatalysis, ozonation, UV/hydrogen peroxide oxidation, and photo-Fenton oxidation. Photocatalytic degradation of pharmaceuticals is now the most widely used method since it is affordable and ecologically beneficial due to the reusable nature of the photocatalyst. When light is absorbed during photocatalytic degradation, electrons in the valence band (VB) get excited and migrate into the conduction band (CB). Consequently, hydroxyl radicals (•OH) are produced by VB's holes carrying out oxidation processes on photocatalyst surfaces. The charge difference between the two bands encourages reduction reactions by CB electrons at the surface. To perform successfully, a photocatalyst has to have enough surface-active sites, a favorable band edge location, modest bandgap energy, increased charge separation, and charge transfer. Due to the above-mentioned concerns, the investigation and analysis of the photocatalytic degradation of six psychiatric drugs—carbamazepine, sertraline, amisulpride, amitriptyline, diazepam, and alprazolam—are the main objectives of this review. [ABSTRACT FROM AUTHOR]

Practical relevance: Chronic pain is a significant welfare concern in cats, and neuropathic pain, which arises from aberrant processing of sensory signals within the nervous system, is a subcategory of this type of pain. To comprehend this condition and how multimodal pharmacotherapy plays a central role in alleviating discomfort, it is crucial to delve into the anatomy of nociception and pain perception. In addition, there is an intricate interplay between emotional health and chronic pain in cats, and understanding and addressing the emotional factors that contribute to pain perception, and vice versa, is essential for comprehensive care. Clinical approach: Neuropathic pain is suspected if there is abnormal sensation in the area of the distribution of pain, together with a positive response to trial treatment with drugs effective for neuropathic pain. Ideally, this clinical suspicion would be supported by confirmation of a lesion at this neurolocalisation using diagnostic modalities such as MRI and neuroelectrophysiology. Alternatively, there may be a history of known trauma at that site. A variety of therapies, including analgesic, anti-inflammatory and adjuvant drugs, and neuromodulation (eg, TENS or acupuncture), can be employed to address different facets of pain pathways. Aim: This review article, aimed at primary care/ general practitioners, focuses on the identification and management of neuropathic pain in cats. Three case vignettes are included and a structured treatment algorithm is presented to guide veterinarians in tailoring interventions. Evidence base: The review draws on current literature, where available, along with the author's extensive experience and research. [ABSTRACT FROM AUTHOR]

Background: Acupuncture showed better improvement than sham acupuncture in reducing attack frequency of tension-type headache (TTH), but its effectiveness relative to first-line drugs for TTH is unknown, which impedes the recommendation of acupuncture for patients who are intolerant to drugs for TTH. We aimed to estimate the relative effectiveness between acupuncture and tricyclic antidepressants (TCAs) through indirect treatment comparison (ITC) meta-analysis. Methods: We searched Ovid Medline, Embase, and Cochrane Library from database inception until April 13, 2023. Randomized controlled trials of TCAs or acupuncture in the prevention of TTH in adults were included. The primary outcome was headache frequency. The secondary outcomes were headache intensity, responder rate, and adverse event rate. Bayesian random-effect models were used to perform ITC meta-analysis, and confidence of evidence was evaluated by using the GRADE approach. Results: A total of 34 trials involving 4426 participants were included. Acupuncture had similar effect with TCAs in decreasing TTH frequency (amitriptyline: mean difference [MD] -1.29, 95% CI -5.28 to 3.02; amitriptylinoxide: MD -0.05, 95% CI -6.86 to 7.06) and reducing TTH intensity (amitriptyline: MD 2.35, 95% CI -1.20 to 5.78; clomipramine: MD 1.83, 95% CI -4.23 to 8.20). Amitriptyline had a higher rate of adverse events than acupuncture (OR 4.73, 95% CI 1.42 to 14.23). Conclusion: Acupuncture had similar effect as TCAs in reducing headache frequency of TTH, and acupuncture had a lower adverse events rate than amitriptyline, as shown by very low certainty of evidence. Highlights: Acupuncture showed better improvement than sham acupuncture in reducing headache frequency of tension-type headache (TTH), but the lack of comparisons between acupuncture and first-line drugs impedes recommendation of acupuncture for TTH. Our indirect treatment comparison meta-analysis found similar effect between acupuncture and tricyclic antidepressants (TCAs) in reducing TTH frequency with very low certainty of evidence. Similar effect between acupuncture and TCAs were also observed in reducing headache intensity with very low certainty of evidence. Acupuncture had a lower rate of adverse events than amitriptyline with very low certainty of evidence. [ABSTRACT FROM AUTHOR]

Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact. [ABSTRACT FROM AUTHOR]

Introduction: In the DELIVER study, eptinezumab reduced monthly migraine days (MMDs) more than placebo in patients with 2–4 prior preventive migraine treatment failures. This post hoc analysis evaluated the efficacy of eptinezumab across the 24-week placebo-controlled period of the DELIVER study in subgroups defined by prior treatment failure type. Methods: DELIVER (NCT04418765) randomized adults with migraine to eptinezumab 100 mg, 300 mg, or placebo, administered intravenously every 12 weeks. Changes from baseline in MMDs and percentages of patients with ≥ 50% reduction from baseline in MMDs (≥ 50% migraine responder rates [MRRs]) were summarized in subgroups of patients defined by prior treatment failure type. Subgroups were not mutually exclusive and included patients for whom topiramate, beta blockers (metoprolol, propranolol), amitriptyline, and/or flunarizine had failed. Results: Across Weeks 1–12 in all subgroups, patients treated with eptinezumab experienced greater reductions from baseline in MMDs than those receiving placebo (reductions ranged from 4.5–5.5 vs 1.6–2.4, respectively), with larger reductions over Weeks 13–24. Similarly, ≥ 50% MRRs were consistently higher with eptinezumab than placebo and increased following a second infusion. Conclusion: In all subgroups, regardless of prior preventive treatment failure type, eptinezumab demonstrated greater reductions in MMDs and higher MRRs compared with placebo. Trial Registration: ClinicalTrials.gov (Identifier: NCT04418765). [ABSTRACT FROM AUTHOR]

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This study aimed to compare the effectiveness of adsorption and photocatalysis techniques at removing the herbicide clomazone (CLO) and the antidepressant known as amitriptyline (AMI) from water. This study employed kinetic models to analyze the removal processes and assess the potential toxicity of the treated water. The structure and morphology of the prepared multi-walled carbon nanotubes were characterized as adsorbents by transmission electron microscopy, X-ray diffraction, Fourier transform infrared techniques, and Raman spectroscopy. The adsorption kinetics of CLO and AMI were studied on the pristine and functionalized multi-walled carbon nanotubes. Kinetic studies were performed by modeling the obtained experimental data using three kinetic models: pseudo-first-order, pseudo-second-order, and Elovich kinetic models. On the other hand, the efficiency of CLO and AMI photodegradation was examined as a function of the type of irradiation (UV and simulated solar irradiation) and type of TiO2 photocatalyst (Aeroxide and Kronos). Under the experimental conditions employed, the reaction followed pseudo-first-order kinetics. Additionally, in order to assess the toxicity of water containing CLO, AMI, and their intermediates, toxicity assessments were conducted using human fetal lung fibroblast cells. The results obtained indicate the effectiveness of both methods and provide valuable insights into their removal mechanisms, contributing to the advancement of sustainable water treatment strategies. [ABSTRACT FROM AUTHOR]

The open-channel block of N-methyl-D-aspartate receptors (NMDARs) and their calcium-dependent desensitization (CDD) represent conventional mechanisms of glutamatergic synapse regulation. In neurotrauma, neurodegeneration, and neuropathic pain the clinical benefits of cure with memantine, ketamine, Mg2+, and some tricyclic antidepressants are often attributed to NMDAR open-channel block, while possible involvement of NMDAR CDD in the therapy is not well established. Here the effects of selective high-affinity sodium-calcium exchanger (NCX) isoform 1 inhibitor, SEA0400, on NMDA-activated whole-cell currents and their block by amitriptyline, desipramine and clomipramine recorded by patch-clamp technique in cortical neurons of primary culture were studied. We demonstrated that in the presence of extracellular Ca2+, 50 nM SEA0400 caused a reversible decrease of the steady-state amplitude of NMDAR currents, whereas loading neurons with BAPTA or the removal of extracellular Ca2+ abolished the effect. The decrease did not exceed 30% of the amplitude and did not depend on membrane voltage. The external Mg2+ block and 50 nM SEA0400 inhibition of currents were additive, suggesting their independent modes of action. In the presence of Ca2+ SEA0400 speeded up the decay of NMDAR currents to the steady state determined by CDD. The measured IC50 value of 27 nM for SEA0400-induced inhibition coincides with that for NCX1. Presumably, SEA0400 effects are induced by an enhancement of NMDAR CDD through the inhibition of Ca2+ extrusion by NCX1. SEA0400, in addition, at nanomolar concentrations could interfere with Ca2+-dependent effect of tricyclic antidepressants. In the presence of 50 nM SEA0400, the IC50s for NMDAR inhibition by amitriptyline and desipramine increased by about 20 folds, as the Ca2+-dependent NMDAR inhibition disappeared. This observation highlights NCX1 involvement in amitriptyline and desipramine effects on NMDARs and unmasks competitive relationships between SEA0400 and these antidepressants. Neither amitriptyline nor desipramine could affect NCX3. The open-channel block of NMDARs by these substances was not affected by SEA0400. In agreement, SEA0400 did not change the IC50 for clomipramine, which acts as a pure NMDAR open-channel blocker. Thus, NCX seems to represent a promising molecular target to treat neurological disorders, because of the ability to modulate NMDARs by decreasing the open probability through the enhancement of their CDD.

Patients with mutations that alter the function of the sodium channel SCN8A present with a range of clinical features, including mild to severe seizures, developmental delay, intellectual disability, autism, feeding dysfunction, motor impairment, and hypotonia. In an effort to identify compounds that could be potentially beneficial in SCN8A-associated epilepsy, Atkin et al. conducted an in vitro screen which resulted in the identification of 90 compounds that effectively reduced sodium influx into the cells expressing the human SCN8A R1872Q mutation. The top compounds that emerged from this screen included amitriptyline, carvedilol, and nilvadipine. In the current study, we evaluated the ability of these three compounds to increase resistance to 6 Hz or pentylenetetrazole (PTZ)-induced seizures in wild-type CF1 mice and in a mouse line expressing the human SCN8A R1620L mutation. We also evaluated the effects of fenfluramine administration, which was recently associated with a 60%–90% decrease in seizure frequency in three patients with SCN8A-associated epilepsy. While amitriptyline, carvedilol, and fenfluramine provided robust protection against induced seizures in CF1 mice, only carvedilol was able to significantly increase resistance to 6 Hz- and PTZ-induced seizures in RL/+ mutants. These results provide support for further evaluation of carvedilol as a potential treatment for patients with SCN8A mutations.