Patient listening on social media for patient-focused drug development: a synthesis of considerations from patients, industry and regulators.

Patients, life science industry and regulatory authorities are united in their goal to reduce the disease burden of patients by closing remaining unmet needs. Patients have, however, not always been systematically and consistently involved in the drug development process. Recognizing this gap, regulatory bodies worldwide have initiated patient-focused drug development (PFDD) initiatives to foster a more systematic involvement of patients in the drug development process and to ensure that outcomes measured in clinical trials are truly relevant to patients and represent significant improvements to their quality of life. As a source of real-world evidence (RWE), social media has been consistently shown to capture the first-hand, spontaneous and unfiltered disease and treatment experience of patients and is acknowledged as a valid method for generating patient experience data by the Food and Drug Administration (FDA). While social media listening (SML) methods are increasingly applied to many diseases and use cases, a significant piece of uncertainty remains on how evidence derived from social media can be used in the drug development process and how it can impact regulatory decision making, including legal and ethical aspects. In this policy paper, we review the perspectives of three key stakeholder groups on the role of SML in drug development, namely patients, life science companies and regulators. We also carry out a systematic review of current practices and use cases for SML and, in particular, highlight benefits and drawbacks for the use of SML as a way to identify unmet needs of patients. While we find that the stakeholders are strongly aligned regarding the potential of social media for PFDD, we identify key areas in which regulatory guidance is needed to reduce uncertainty regarding the impact of SML as a source of patient experience data that has impact on regulatory decision making.

Serotonin 5-HT6 Receptor Ligands and Butyrylcholinesterase Inhibitors Displaying Antioxidant Activity-Design, Synthesis and Biological Evaluation of Multifunctional Agents against Alzheimer's Disease.

Neurodegeneration leading to Alzheimer's disease results from a complex interplay of a variety of processes including misfolding and aggregation of amyloid beta and tau proteins, neuroinflammation or oxidative stress. Therefore, to address more than one of these, drug discovery programmes focus on the development of multifunctional ligands, preferably with disease-modifying and symptoms-reducing potential. Following this idea, herein we present the design and synthesis of multifunctional ligands and biological evaluation of their 5-HT6 receptor affinity (radioligand binding assay), cholinesterase inhibitory activity (spectroscopic Ellman's assay), antioxidant activity (ABTS assay) and metal-chelating properties, as well as a preliminary ADMET properties evaluation. Based on the results we selected compound 14 as a well-balanced and potent 5-HT6 receptor ligand (Ki = 22 nM) and human BuChE inhibitor (IC50 = 16 nM) with antioxidant potential expressed as a reduction of ABTS radicals by 35% (150 µM). The study also revealed additional metal-chelating properties of compounds 15 and 18. The presented compounds modulating Alzheimer's disease-related processes might be further developed as multifunctional ligands against the disease.

Reply to Papageorgopoulou et al. The Aftermath of Bariatric Surgery: Can the Average Emergency Surgeon Deal with Its Complications? Comment on "Zawadzka et al. Current Knowledge and Perceptions of Bariatric Surgery among Diabetologists and Internists in Poland. J. Clin. Med. 2022, 11, 2028".

The World Health Organization (WHO) has identified obesity and overweight as an epidemic of the 21st century [...].

Current Knowledge and Perceptions of Bariatric Surgery among Diabetologists and Internists in Poland.

Perioperative care and follow-up after bariatric surgery (BS) engage various medical professionals. It is key for them to be well informed about these procedures. However, knowledge and attitudes may be not satisfactory enough to provide proper care. We aimed to assess knowledge and perceptions of BS among diabetologists and internists. A total of 34 diabetologists and 30 internists completed the electronic questionnaire. There were no differences in self-estimated knowledge between them, except regarding items related to the treatment of diabetes and metabolic control. Several misconceptions were identified in the questions testing the understanding of key issues in BS. Most participants considered BS effective in weight loss and metabolic control. A total of 75% highlighted the lack of appropriate equipment for dealing with morbidly obese patients. Interestingly, in a multivariable linear regression model, self-estimated knowledge was the only variable associated with frequency of referrals to bariatric surgeons. A total of 92% of respondents were interested in broadening their knowledge. Guidelines for long-term follow-up and funding were the most frequently chosen topics to explore. The study showed a positive attitude of diabetologists and internists towards surgical treatment of obesity and identified some significant gaps in knowledge. The results may be helpful in planning trainings to provide the best care for patients suffering from morbid obesity.

Higher milk consumption is not associated with fracture risk reduction: systematic review and meta-analysis.

INTRODUCTION: Osteoporosis affects over 200 million people worldwide causing nearly 9 million fractures annually, with more than half in America and Europe. OBJECTIVES: This meta-analysis was conducted to investigate whether low milk intake is associated with an increased risk of fractures by summarizing all the available evidence. METHODS: Relevant studies were identified by searching the PubMed and EMBASE databases up to June 2020. The pooled relative risks with 95% confidence intervals were calculated. RESULTS: In a meta-regression analysis of 20 included studies (11 cohort and 9 case-control studies), a higher milk intake was not associated with a reduction in the total fracture risk in both sexes (OR 0.95, 95% CI: 0.84- 1.08), either in cohort (OR 0.91; 95% CI: 0.79-1.05) or case-control studies (OR 1.09; 95% CI: 0.82-1.44), as well as separately in men (OR 0.87; 95% CI: 0.71-1.07) and women (OR 0.95; 95% CI: 0.80-1.13). CONCLUSION: Higher milk consumption is not associated with fracture risk reduction and should not be recommended for fracture prevention.

Diagonal Earlobe Crease (Frank's Sign) for Diagnosis of Coronary Artery Disease: A Systematic Review of Diagnostic Test Accuracy Studies.

Coronary artery disease is a global challenge for healthcare systems. Early diagnosis is a key issue to improve quality of life and reduce morbidity and mortality. Diagonal earlobe crease, a wrinkle extending obliquely across the earlobe, was linked by many authors to various atherosclerotic diseases. This systematic review aimed at summarizing the diagnostic accuracy of diagonal earlobe crease for diagnosis of chronic and acute coronary syndromes in adults. Cochrane's recommendations for systematic reviews of diagnostic test accuracy studies were followed. The protocol was registered on PROSPERO. Seven electronic databases were searched up to April 2021. The risk of bias and applicability were assessed using the QUADAS-2 tool. Meta-analysis was not performed. Finally, 13 cross-sectional studies evaluating 3951 patients were analyzed, all of which focused on chronic coronary syndromes defined as anatomically significant coronary stenosis. Invasive coronary angiography was used as a reference in most studies, except one which utilized computed tomography angiography. Sensitivity ranged from 26% to 90%, and specificity from 32% to 96%. Positive likelihood ratios varied from 1.11 to 7.03, but most results were below 2. Negative likelihood ratios were from 0.84 to 0.30, but most values exceeded 0.5. Diagnostic accuracy of diagonal earlobe crease for the detection of chronic coronary syndromes is insufficient. It only slightly changes pre-test probability, and its mere presence or absence should not affect the clinical management of the patients. However, for its feasibility and easy interpretation, Frank's sign could be considered as a part of physical examination.

Risk factors for hemodynamic instability during laparoscopic pheochromocytoma resection: a retrospective cohort study.

BACKGROUND: Adrenalectomy for pheochromocytoma, a rare catecholamine-secreting tumour, is a challenging procedure because of the high risk of intraoperative hemodynamic instability, which can cause life-threatening complications. Our study aimed to identify predictive factors for hemodynamic instability during pheochromocytoma resection as well as to assess the risk factors for postoperative morbidity. METHODS: Data of 96 patients, who underwent laparoscopic adrenalectomy were analysed retrospectively. Hemodynamic instability was defined as an occurrence of both intraoperative episodes of systolic blood pressure above 160 mmHg and vasoactive (vasodilators or vasoconstrictors) drug administration. Patients were divided into two groups: one which met both criteria, and another one without hemodynamic instability-42 (43.8%) and 54 (56.2%) respectively. RESULTS: The mean tumour size was 4.5±2.0 cm. 86 patients had a sporadic pheochromocytoma and 10 (10.4%) had a familial disease. Sixty-three patients were preoperatively treated with nonselective blockers and 33 patients with selective blockers. Mean operative time was 98.7±41.7 min. and mean intraoperative blood loss was 165.7±381.2 mL. In 26% of patients, postoperative complications occurred. The median length of hospital stay was 3 days. The multivariate logistic regression model showed that the size of adrenal tumour and diabetes were significant factors of hemodynamic instability. Intraoperative use of vasopressors was an independent risk factor for both all-cause and cardiovascular morbidity. CONCLUSIONS: Adrenal tumour size and diabetes were associated with hemodynamic instability during pheochromocytoma resection. The only risk factor for complications in our group was intraoperative necessity to use vasopressors.

Selective vs non-selective alpha-blockade prior to adrenalectomy for pheochromocytoma: systematic review and meta-analysis.

OBJECTIVE: Alpha-adrenergic blockade is currently the first choice of preoperative treatment in patients with functional pheochromocytoma and sympathetic paraganglioma. Nevertheless, there is no consensus whether selective or non-selective alpha-blockade is superior for preventing both perioperative hemodynamic instability and complications. DESIGN: Our study aimed to compare selective and non-selective alpha-blockade through a systematic review with meta-analysis. METHODS: MEDLINE, Embase, Web of Science and Cochrane Library were searched for eligible studies. Randomized and observational studies comparing selective and non-selective alpha-blockade in pheochromocytoma and sympathetic paraganglioma surgery in adults were included. Data on perioperative hemodynamic parameters and postoperative outcomes were extracted. RESULTS: Eleven studies with 1344 patients were enrolled. Patients receiving selective alpha-blockade had higher maximum intraoperative systolic blood pressure (WMD: 12.14 mmHg, 95% CI: 6.06-18.21, P < 0.0001) compared to those treated with non-selective alpha-blockade. Additionally, in the group pretreated with selective alpha-blockers, intraoperative vasodilators were used more frequently (OR: 2.46, 95% CI 1.44-4.20, P = 0.001). Patients treated with selective alpha-blockers had lower minimum intraoperative systolic blood pressure (WMD: -2.03 mmHg, 95% CI: -4.06 to -0.01, P = 0.05) and shorter length of hospital stay (WMD: -0.58 days, 95% CI: -1.12 to -0.04, P = 0.04). Operative time, overall morbidity and mortality did not differ between the groups. CONCLUSIONS: This meta-analysis shows non-selective alpha-blockade was more effective in preventing intraoperative blood pressure fluctuations while maintaining comparable risk of both intraoperative and postoperative hypotension and overall morbidity.

Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer's disease.

Effective therapy of Alzheimer's disease (AD) requires treatment with a combination of drugs that modulate various pathomechanisms contributing to the disease. In our research, we have focused on the development of multi-target-directed ligands - 5-HT6 receptor antagonists and cholinesterase inhibitors - with disease-modifying properties. We have performed extended in vitro (FRET assay) and in cellulo (Escherichia coli model of protein aggregation) studies on their ß-secretase, tau, and amyloid ß aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound 17 with inhibitory potency against tau and amyloid ß aggregation in in cellulo assay of 59% and 56% at 10 µM, respectively, hBACE IC50=4 µM, h5TH6 K i=94 nM, hAChE IC50=26 nM, and eqBuChE IC50=5 nM. This study led to the development of multifunctional ligands with a broad range of biological activities crucial not only for the symptomatic but also for the disease-modifying treatment of AD.

Correction to: Comparative Assessment of the New PDE7 Inhibitor - GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach.

There was a mistake in the unit of clearance (Cl) in Table II. In addition, the descriptions of V1(ROL) and V1(GRMS-55) were imprecise and the reference number in the footnote below this table should be (9). The corrected Table appears below.

Comparative Assessment of the New PDE7 Inhibitor - GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach.

PURPOSE: This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders. METHODS: Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling. RESULTS: GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis. CONCLUSIONS: PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immune-related diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.

1-Benzylpyrrolidine-3-amine-based BuChE inhibitors with anti-aggregating, antioxidant and metal-chelating properties as multifunctional agents against Alzheimer's disease.

Complex pathomechanism of Alzheimer's disease (AD) prompts researchers to develop multifunctional molecules in order to find effective therapy against AD. We designed and synthesized novel multifunctional ligands for which we assessed their activities towards butyrylcholinesterase, beta secretase, amyloid beta (Aß) and tau protein aggregation as well as antioxidant and metal-chelating properties. All compounds showed dual anti-aggregating properties towards Aß and tau protein in the in cellulo assay in Escherichia coli. Of particular interest are compounds 24b and 25b, which efficiently inhibit aggregation of Aß and tau protein at 10 µM (24b: 45% for Aß, 53% for tau; 25b: 49% for Aß, 54% for tau). They display free radical scavenging capacity and antioxidant activity in ABTS and FRAP assays, respectively, and selectively chelate copper ions. Compounds 24b and 25b are also the most potent inhibitors of BuChE with IC50 of 2.39 µM and 1.94 µM, respectively. Promising in vitro activities of the presented multifunctional ligands as well as their original scaffold are a very interesting starting point for further research towards effective anti-AD treatment.

Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease.

Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid ß antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors ( Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50 hAChE = 14 nM, IC50 eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid ß antiaggregation activity (IC50 = 1.27 µM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.

Novel 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole-Based Multifunctional Ligands with Antipsychotic-Like, Mood-Modulating, and Procognitive Activity.

The most troublesome aspects of behavioral and psychological symptoms of dementia (BPSD) are nowadays addressed by antidepressant, anxiolytic, and antipsychotic drugs, often administered off-label. Considering their modest effectiveness in dementia patients, the increased risk of adverse events and cognitive decline, there is an unmet need for well-tolerated and effective therapy of BPSD. We designed and synthesized multifunctional ligands characterized in vitro as high-affinity partial agonists of D2R, antagonists of 5-HT6R, and blockers of SERT. Moreover, the molecules activated 5-HT1AR and blocked 5-HT7R while having no relevant affinity for off-target M1R and hERG channel. Compound 16 (N-{2-[4-(5-chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl}-3-methylbenzene-1-sulfonamide) exhibited a broad antipsychotic-, antidepressant-, and anxiolytic-like activity, not eliciting motor impairments in mice. Most importantly, 16 showed memory-enhancing properties and it ameliorated memory deficits induced by scopolamine. The molecule outperformed most important comparators in selected tests, indicating its potential in the treatment of both cognitive and noncognitive (behavioral and psychological) symptoms of dementia.

Lipophilic properties of anti-Alzheimer's agents determined by micellar electrokinetic chromatography and reversed-phase thin-layer chromatography.

Lipophilicity as one of the most important physicochemical properties of the biologically active compounds is closely related to their pharmacokinetic parameters and therefore, it is taken into account at the design stage of new drugs. Among the novel, fast, and reliable methods for determination of the lipophilicity of compounds micellar electrokinetic chromatography (MEKC) is considered to be an appropriate one for bioactive molecules, as it closely mimics the physiological conditions. In this paper MEKC was used for the estimation of log P values for 49 derivatives of phthalimide, tetrahydroisochinoline and indole, designed and synthesized as potential anti-Alzheimer's agents with cholinesterase inhibitory activity. RP-TLC method was applied for determination of another lipophilicity descriptor - RM0 . The results of both experimental methods were compared with each other giving satisfactory correlation (R = 0.784), and with computational methods (Marvin, ChemOffice Software) resulting in weaker correlation (R = 0.466-0.687). The lipophilicity-activity relationship was finally established, showing significant influence of lipophilicity on cholinesterase inhibition in some subgroups of phthalimide derivatives.

Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation.

As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT6 receptor (Kb = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC50hAChE = 12 nM, IC50hBuChE = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD.

3-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one and pregabalin attenuate tactile allodynia in the mouse model of chronic constriction injury.

PURPOSE: There is a strong medical demand to search for novel, more efficacious and safer than available, analgesics for the treatment of neuropathic pain. This study investigated antinociceptive activity of intraperitoneally administered 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one (LPP1) and pregabalin in the chronic constriction injury (CCI) model of neuropathic pain in mice and evaluated these drugs' influence on motor coordination. In addition, microscopic examinations of the sciatic nerve were performed to assess, if a surgical method or drug treatment caused changes in the structure of this nerve. Moreover, the alterations of nerve growth factor (NGF) content after drug treatment were assessed. METHODS: Antiallodynic and antihyperalgesic activities of LPP1 and pregabalin were assessed in the von Frey and hot plate tests. Motor-impairing properties were evaluated in the rotarod test. Microscopic examinations of the sciatic nerve were performed using electron microscope. In immunohistochemical assays the content of NGF in the sciatic nerve after single or repeated administration of test drugs was assessed. RESULTS: Microscopic examinations of the sciatic nerve revealed ultrastructural changes in nerve fibers indicating for neurodegenerative processes induced by CCI. Seven days after CCI surgery LPP1 and pregabalin reduced tactile allodynia in von Frey test (ED50 values were 1.5 and 15.4 mg/kg, respectively). None of the test drugs at dose range 0.5-100 mg/kg induced motor deficits in the rotarod test. In immunohistochemical assays repeated doses of pregabalin and LPP1 elevated NGF content. CONCLUSIONS: LPP1 has antiallodynic properties and is an interesting lead structure in the search for novel analgesics used in neuropathic pain.

Synthesis of new N-benzylpiperidine derivatives as cholinesterase inhibitors with ß-amyloid anti-aggregation properties and beneficial effects on memory in vivo.

Due to the complex nature of Alzheimer's disease, multi-target-directed ligand approaches are one of the most promising strategies in the search for effective treatments. Acetylcholinesterase, butyrylcholinesterase and ß-amyloid are the predominant biological targets in the search for new anti-Alzheimer's agents. Our aim was to combine both anticholinesterase and ß-amyloid anti-aggregation activities in one molecule, and to determine the therapeutic potential in vivo. We designed and synthesized 28 new compounds as derivatives of donepezil that contain the N-benzylpiperidine moiety combined with the phthalimide or indole moieties. Most of these test compounds showed micromolar activities against cholinesterases and aggregation of ß-amyloid, combined with positive results in blood-brain barrier permeability assays. The most promising compound 23 (2-(8-(1-(3-chlorobenzyl)piperidin-4-ylamino)octyl)isoindoline-1,3-dione) is an inhibitor of butyrylcholinesterase (IC50=0.72 µM) that has ß-amyloid anti-aggregation activity (72.5% inhibition at 10 µM) and can cross the blood-brain barrier. Moreover, in an animal model of memory impairment induced by scopolamine, the activity of 23 was comparable to that of donepezil. The selected compound 23 is an excellent lead structure in the further search for new anti-Alzheimer's agents.

A microwave-assisted multicomponent synthesis of substituted 3,4-dihydroquinazolinones.

A microwave-assisted, multicomponent protocol for the synthesis of substituted 3,4-dihydroquinazolinones via a novel cascade imine/cyclization/aza-Henry reaction sequence is reported. Starting from o-formyl carbamates, a series of structurally diverse 3,4-dihydroquinazolinones was synthesized via a cyclic iminium ion intermediate in moderate to excellent yields. Notably, the reaction is fast, flexible, simple to perform and tolerates a variety of functional groups.

Antiallodynic and antihyperalgesic activity of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one compared to pregabalin in chemotherapy-induced neuropathic pain in mice.

BACKGROUND: Anticancer drugs - oxaliplatin (OXPT) and paclitaxel (PACLI) cause painful peripheral neuropathy activating Transient Receptor Potential (TRP) channels. Here we investigated the influence of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one (LPP1) and pregabalin on nociceptive thresholds in neuropathic pain models elicited by these drugs. Pharmacokinetics of LPP1 and its ability to attenuate neurogenic pain caused by TRP agonists: capsaicin and allyl isothiocyanate (AITC) were also investigated. METHODS: Antiallodynic and antihyperalgesic effects of intraperitoneally administered LPP1 and pregabalin were tested in the von Frey, hot plate and cold water tests. The influence of LPP1 on locomotor activity and motor coordination was assessed using actimeters and rotarod. Serum and tissue concentrations of LPP1 were measured using the HPLC method with fluorimetric detection. RESULTS: In OXPT-treated mice LPP1 and pregabalin dose-dependently reduced tactile allodynia (41-106% and 6-122%, respectively, p<0.01). At the dose of 10mg/kg LPP1 attenuated cold allodynia. In PACLI-treated mice LPP1 and pregabalin reduced tactile allodynia by 12-63% and 8-50%, respectively (p<0.01). Both drugs did not affect cold allodynia, whereas pregabalin (30 mg/kg) attenuated heat hyperalgesia (80% vs. baseline latency time; p<0.01). No motor impairments were observed in LPP1 or pregabalin-treated neuropathic mice in the rotarod test, while severe sedation was noted in the locomotor activity test. LPP1 reduced pain induced by capsaicin (51%; p<0.01) and AITC (41%; p<0.05). The mean serum concentration of LPP1 measured 30 min following i.p. administration was 7904.6 ± 1066.1 ng/ml. Similar levels were attained in muscles, whereas brain concentrations were 62% lower. Relatively high concentrations of LPP1 were also determined in the cerebrospinal fluid and the sciatic nerve. CONCLUSIONS: LPP1 and pregabalin reduce pain in OXPT and PACLI-treated mice. This activity of LPP1 might be in part attributed to the inhibition of TRPV1 and TRPA1 channels, but also central mechanisms of action cannot be ruled out.