Pregabalin Research Articles

Comparative efficacy of amitriptyline, duloxetine and pregabalin for treating fibromyalgia in adults: an overview with network meta-analysis.

Treatment recommendations for fibromyalgia (FM) include a range of predominantly pharmacological treatment options designed to ensure the maintenance of symptoms and improvement in the quality of life of these patients. Our aim is to identify and compare the efficacy of amitriptyline (AMT), duloxetine (DLX), and pregabalin (PGB) for reducing pain intensity by 30% (R30%) and 50% (R50%) in adult patients with fibromyalgia. The review was conducted in the Medline/PubMed, Cochrane Library, and Embase databases up to February 2022. This study included systematic reviews (SR) of randomized clinical trials (RCTs) targeting adult patients over 18years of age diagnosed with fibromyalgia according to the criteria of scientific societies, which include the basic clinical diagnosis characterized by the presence of pressure sensitivity in at least 11 of the 18 tender points, in addition to the presence of widespread musculoskeletal pain for a period longer than 3months and a general assessment of the patient's health status. Pregnant women and children or adolescents were excluded. The Rob 2.0 tool from the Cochrane Collaboration was used to assess the risk of bias in RCTs. The quality of evidence of the reviews included was assessed according to the Grading of Recommendations Assessment, Development and Evaluation-GRADE. A meta-analysis for the evidence network was performed using the Bayesian approach, which allows simultaneous comparison of all treatment options (medication and dose). The different treatments were ranked according to the response rate according to the surface under the curve (SUCRA), which was expressed as a percentage. The results were presented in tables and figures. The protocol with the detailed methods was registered in PROSPERO (CRD42021229264). Eight systematic reviews were identified, and, from these, 15 clinical trials comparing AMT (n = 273), DLX (n = 2595), and PGB (n = 3,506) against placebo were selected. For the outcome R30%, PGB 450mg was superior to DLX 30mg and PGB 150mg, while DLX 20mg and 30mg were not superior to placebo. For the outcome R50%, AMT 25mg was superior to all other alternatives evaluated. The calculation of the SUCRA indicated that PGB 450mg was the best performance option for R30% and AMT 25mg for R50%. PGB 150mg was the drug with the worst performance in the two outcomes evaluated. The drugs evaluated showed benefits for pain reduction in patients with fibromyalgia. In the absence of direct comparison studies, indirect comparison meta-analyses are an important resource for assisting in clinical decision-making. Our data only provide an indicator of the effectiveness of the three drugs evaluated, but as with other health conditions, tolerability and safety are important for the decision-making process and clinical management. In this regard, we encourage caution in interpreting our data.

Acetaminophen and pregabalin attenuate central sensitization in rodent models of nociplastic widespread pain

The “nociplastic pain,” a recently proposed novel mechanistic pain descriptor, is defined as pain occurring through altered nociception without nociceptor activation and nerve injury. Nociplastic pain is often characterized by widespread pain sensitization (WSP) in multiple body regions (Fitzcharles et al., 2021). As many patients with primary chronic pain would have nociplastic backgrounds, developing appropriate methods to evaluate drug effects against nociplastic pain in animal model is in great demand. Using two rat models with the WSP involving central amygdala (CeA) activation by orofacial inflammation or direct chemogenetic activation (Sugimoto et al., 2021), we examined whether widely used analgesics, acetaminophen (AcAph), pregabalin (PGB), and duloxetine (DLX) could attenuate the WSP. AcAph (100 or 200 mg/kg, i.p.) significantly elevated 50%-paw withdrawal threshold (PWT50), which had been lowered significantly by upper lip injection of formalin, or systemic injection of clozapine-N-oxide in the rats with excitatory designer receptors (hM3Dq) expressed in the right CeA. This effect lasted for > ∼4 h. PGB (30 mg/kg, i.p.) also significantly counteracted the lowered PWT50 in rats with orofacial formalin injection for >∼6 h. DLX was ineffective on the WSP. Based on these results, we propose that these preclinical models could be used to evaluate drug effects for primary chronic pain. We conclude that the widely used pain killers, AcAph and PGB, also relieve nociplastic widespread sensitization in the absence of ongoing nociceptor activation and nerve injury.This article is part of the Special Issue on ‘Advances in mechanisms and therapeutic targets relevant to pain’.

Eski ve Yeni Kuşak Antiepileptik İlaçların Hemogram Parametrelerine Etkileri Farklı Mı?

Aim: There are different comments related to hematological side effects caused by antiseizure drugs (ASDs). In our study, we investigated the effects of ASDs on hemogram parameters. Materials and Methods: Hemogram values of 293 patients including 156 women, who used ASDs for at least six months, were compared with the values of 36 healthy control participants group who did not. In addition, the hemogram values of the patients using old-generation antiepileptic drugs such as phenytoin (PHT), carbamazepine (CBZ), valproic acid were compared with those using new-generation antiepileptic drugs as levetiracetam, oxcarbazepine, pregabalin (PGB), gabapentin and two ASDs in combination. Results: Comparison of the patients using ASDs with the control group revealed that white blood cell (WBC) values of only PHT users were lower than the control group (p=0.045). Red cell distribution width (RDW) values were found to be higher in healthy controls than those using AEDs (p<0.001). When the groups using ASDs were compared among themselves, it was found that the WBC values of the users of old- generation ASDs as PHT and CBZ were significantly lower than those using PGB (p=0.006; P=0.005, respectively). Conclusion: As hematological side effects, ASDs may decrease WBC counts. The WBC decreasing effects of PHT and CBZ, which are older generation antiepileptics, are more pronounced than pregabalin, which is a new- generation antiepileptic drug. The effects of antiepileptic drugs on hemogram parameters of the patients should be taken into consideration while choosing appropriate ASDs and also while following the patient.

Pregabalin for Recurrent Seizures in Critical Illness: A Promising Adjunctive Therapy, Especially for cyclic Seizures.

Pregabalin (PGB) is an effective adjunctive treatment for focal epilepsy and acts by binding to the alpha2-delta subunit of voltage-gated calcium channels to reduce excitatory neurotransmitter release. Limited data exist on its use in the neurocritical care setting, including cyclic seizures-a pattern of recurrent seizures occurring at nearly regular intervals. Although the mechanism underpinning cyclic seizures remains elusive, spreading excitation linked to spreading depolarizations may play a role in seizure recurrence and periodicity. PGB has been shown to increase spreading depolarization threshold; hence,we hypothesized that the magnitude of antiseizure effect from PGB is more pronounced in patients with cyclic versus noncyclic seizures in a critically ill cohort with recurrent seizures. We conducted a retrospective case series of adults admitted to two academic neurointensive care units between January 2017 and March 2019 who received PGB for treatment of seizures. Data collected included demographics, etiology of brain injury, antiseizure medications, and outcome. Continuous electroencephalogram recordings 48hours before and after PGB administration were reviewed by electroencephalographers blinded to the administration of antiseizure medications to obtain granular data on electrographic seizure burden. Cyclic seizures were determined quantitatively (i.e., < 50% variation of interseizure intervals for at least 50% of consecutive seizures). Coprimary outcomes were decrease in hourly seizure burden in minutes and decrease in seizure frequency in the 48hours after PGB initiation. We used nonparametric tests for comparison of seizure frequency and burden and segmented linear regression to assess PGB effect. We included 16 patients; the median age was 69years, 11 (68.7%) were women, three (18.8%) had undergone a neurosurgical procedure, and five (31%) had underlying epilepsy. All seizures had focal onset; ten patients (62.5%) had cyclic seizures. The median hourly seizure burden over the 48hours prior to PGB initiation was 1.87min/hour (interquartile range 1.49-8.53), and the median seizure frequency was 1.96 seizures/hour (interquartile range 1.06-3.41). In the 48hours following PGB (median daily dose 300mg, range 75-300mg), the median number of seizures per hour was reduced by 0.80 seizures/hour (95% confidence interval 0.19-1.40), whereas the median hourly seizure burden decreased by 1.71min/hour (95% confidence interval 0.38-3.04). When we compared patients with cyclic versus noncyclic seizures, there was a relative decrease in hourly seizure frequency (- 86.7% versus - 2%, p = 0.04) and hourly seizure burden (- 89% versus - 7.8%, p = 0.03) at 48hours. PGB was associated with a relative reduction in seizure burden in neurocritically ill patients with recurrent seizures, especially those with cyclic seizures, and may be considered in the therapeutic arsenal for refractory seizures. Whether this effect is mediated via modulation of spreading depolarization requires further study.

Effect of caffeine on the anticonvulsant action of pregabalin against electroconvulsions in mice.

Experimental data indicate that caffeine (CAF) can reduce the anticonvulsant activity of antiepileptic drugs (AEDs) in animal models of seizures. The purpose of the current study was to examine the effect of CAF on the protective action of pregabalin (PGB) against electroconvulsions in mice. Maximal electroshock seizure (MES) test was used in the current study. In addition, the combined treatment with CAF and PGB was assessed in the passive avoidance task (long-term memory) and the chimney test (motor coordination). Drugs were injected intraperitoneally (ip) as single injections. CAF was administered at doses reported to compromise the anticonvulsant action of AEDs in mice. CAF at a dose of 23.1mg/kg reduced the anticonvulsant action of PGB in the MES test. The brain concentration of PGB was not significantly changed by CAF and vice versa. In the chimney test, CAF (23.1mg/kg) protected mice against PGB-induced motor coordination impairment. Regarding seizure control, it might be suggested that patients with epilepsy treated with PGB should avoid taking CAF. The estimated total brain concentration of PGB and CAF does not suggest a pharmacokinetic interaction as an explanation for these results.

Development and in vitro Characterization of Gastroretentive Formulations as Calcium Pectinate Hydrogel Pellets of Pregabalin by Ionotropic Gelation Method

Abstract: Introduction: Pregabalin (PG) is primarily prescribed for epilepsy, painful diabetic neuropathy, post-herpetic neuralgia, and fibromyalgia. Also, it is used in clinical practice to treat general anxiety disorder due to its anxiolytic properties. Pectin is a watersoluble ionic polysaccharide. As a result of the interaction of pectin with calcium ions, a hydrophilically coated insoluble carrier system is formed by complexing between surfaces, which provides a sustained release. In this direction, floating hydrogel pellets containing PG were developed and characterized in our study. This study aimed to make a sustained release of PG, reach the optimum level in characterization, and bring a new approach to widely used oral drug therapy. Materials and Methods: PG was a gift from Ilko Pharmaceuticals (Turkey) and pectin was purchased from CPKelco (USA). The ionotropic gelation technique was used to prepare pellets. To characterize the pellets, flotation/swelling degrees, yield, drug loading capacity/encapsulation efficiency, particle size/distribution, in-vitro release/kinetics, and morphological studies have been done. Also, the structural features of pellets have determined via the Fourier Transform Infrared (FT-IR), scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET), and X-ray diffraction (XRD) studies. Results: The formulations have been successfully developed without using any coating agent to prolong drug release for 24 h with an encapsulation efficiency of ~82%. Optimum results were obtained in characterization studies. As a result of BET analysis, it has been proven that the structure is porous and there is no change in the chemical and crystal structure of PG by FT-IR and XRD studies. Conclusion: We anticipate that the formulation we developed will provide an alternative to the sustained-release PG preparations in the current pharmaceutical market. Key words: Gastroretentive drug delivery, Pregabalin, Pectin, HPLC, FT-IR, BET, XRD.

Green synthesis of pregabalin-stabilized gold nanoclusters and their applications in sensing and drug release.

This is the first report on the simple preparation of gold nanoclusters stabilized with pregabalin (PREG) as a capping and reducing agent. PREG is an active pharmaceutical ingredient of the commercially available drug "Lyrica" used to treat different diseases like epilepsy and anxiety. PREG has never been used before in the synthesis of any nanoparticles or nanoclusters. The prepared gold nanoclusters (PREG-stabilized gold nanoclusters [PREG-AuNCs]) have blue fluorescence with excitation/emission at 365/425 nm, respectively. The reaction conditions were optimized for the synthesis of the as-prepared AuNCs. Different tools were used for the characterization of the synthesized nanoclusters in terms of size and surface properties. The PREG-AuNCs were exploited as a sensitive and selective fluorescent nanosensor for Cu2+ detection. The quenching of AuNC fluorescence intensity in the presence of Cu2+ is due to the aggregation-induced fluorescence quenching mechanism. The detection limit of Cu2+ ions was found to be 1.11 × 10-7 M. The selectivity of the PREG-AuNCs was studied and proved to be excellent. The drug entrapment efficacy and in vitro drug diffusion studies along with drug release kinetics helped to understand more about the pharmaceutical approaches of PREG-AuNCs. Moreover, we think that PREG-AuNCs open new opportunities as a promising candidate material for drug delivery systems and medical applications.

Effectiveness and safety of amitriptyline, duloxetine, and pregabalin in painful diabetic neuropathy: An observational study

Background: Studies comparing the real-world effectiveness, safety, and effect on quality of life (QoL) of drugs for painful diabetic peripheral neuropathy (DPN) are scarce. Aims and Objectives: The aim of the study was to compare effectiveness, safety and effect on QoL of amitriptyline (AMY), duloxetine (DUL) and pregabalin (PGN) in DPN. Materials and Methods: After ethics committee approval and informed consent, 75 outpatients (25 each) prescribed any one of above drugs were consecutively recruited in a prospective and observational study. Drug effectiveness was assessed by comparing difference in mean monthly visual analogue scale (VAS) score from baseline, obtained from pain diary. QoL was assessed by comparing total and domain-wise score on Nottingham health profile (NHP) questionnaire. Safety was assessed by comparing frequency of adverse drug reactions (ADRs). Qualitative and quantitative outcome measures were compared using Chi-square test and one-way analysis of variance, respectively. P &lt; 0.05 was considered statistically significant. Results: The difference in mean monthly VAS scores at the end of 4, 8, and 12 weeks was similar between the three drugs. Patients on PGN had smaller beneficial effects in total as well as emotional, energy, and sleep domains of NHP compared to other drugs. Sedation and dizziness occurred with all drugs but PGN had least incidence of sedation. Conclusion: AMY, DUL and PGN are equally effective and safe in DPN. Although PGN did not improve QoL unlike AMY and DUL, it had lower incidence of sedation.

Analytical Study of the Royal-Jelly Effect on Sperms Morphological Characteristics and some Liver Function Parameters and their Correlation with some Antioxidants in Male Albino Rats Treated with Pregabalin Drug

In recent years, the consideration of natural products as anti-inflammatory and antioxidative treatments has more interested worldwide. Moreover, natural products are easily obtained and are relatively safe the Royal jelly (RJ) is one of them. The current study was carried to evaluate the effects of pregabalin (PGB) on physiological activity of sperms, reproductive hormones assay and some biochemical analysis. Forty (40) male albino rats (10-weeks-old) were divided into four groups (10 rats each): G1 (treated with PGB drug, 150 mg/kg B.wt (Lyrica-Pfizer-Pharmaceutical Industries), G2 (treated with RJ 1g/kg), G3 (treated with PGB drug and RJ together), and G4 control treated with normal saline only. all groups were treated orally via stomach tube for 60 consecutive days.. PGB caused a significant reduction in sperm count, sperm viability, motility and sperm abnormality percent, serum FSH, LH and testosterone levels, the co-administration of RJ caused normal level of the previous tests near the control group level. Results of the lipid profile and some the present results of the liver function parameters showed increased concentrations in PGB-treated group, but after treated with RJ the levels were recovered to normal level. In the studied antioxidants markers, the results appeared high level in malondialdehyde (MDA) and low level in the antioxidants enzymes; superoxide dismutase (SOD) and catalase (CAT) the RJ was appeared direct effect on MDA and showed decreased concentration of MDA and increased levels in the studied antioxidants enzymes of the PGB group which treated with RJ.

Carbon quantum dots as a sensitive fluorescent probe for quantitation of pregabalin; application to real samples and content uniformity test.

A novel optical nano-sensor for the detection of pregabalin (PG) in its pharmaceutical (Lyrica®) capsules and biological samples was reported. For the fabrication of highly fluorescent carbon quantum dots (CQDts), a simple green hydrothermal approach was described, and ascorbic acid (AA) was used as a carbon source. The obtained CQDts were confirmed by spectroscopic characterization such as transmission electron microscopy (TEM) and Fourier-transform infrared (FTIR) spectra. The synthesized CQDts were capped by alcohol to form yellow emitters, showing strong fluorescent emission at 524 nm, and excitation at 356 nm. The method is based on fluorescence quenching of CQDts in the presence of PG. The proposed analytical method was validated according to ICH guidelines. PG was successively assayed in the concentration range of 4.0 to 100 μg/ml). The detection and quantitation limits were 1.12 and 3.39 μg/ml, respectively. The proposed method could be used in both quality control and pharmacokinetic research for the studied drug.

RP-HPLC QUANTIFIABLE TECHNIQUE DEVELOPMENT FOR EVALUATING PREGABALIN AND ETORICOXIB COMBINATION IN TABLET AND BULK KINDS

Objective: This evaluation study aims to initiate a relatively sensitive RP-HPLC quantifiable technique for evaluating pregabalin (PRBN) and etoricoxib (ETRB) combination in tablet and bulk kinds. Methods: PRBN and ETRB chromatographic evaluations were carried off using the “KNAUER C18 Eurospher II column (250 mm × 4.6 mm × 5 μ)”. The mobile phase (MBP) was driven into the KNAUER C18 Eurospher II column at a 1.0 ml/min run rate with an isocratic elution programme of 65% volume of 0.5 mmol sodium perchlorate 35% volume methanol, detected and evaluated the PRBN and ETRB content at 217 nm. Results: The analysis of PRBN and ETRB is executed inside a run period of 15 min. The RP-HPLC quantifiable technique was developed to separate PRBN and ETRB and likely degradants formed from stress testing by isocratic elution. The RP-HPLC quantifiable technique developed was successfully validated to existing ICH limit guidelines and was confirmed as robust, specific, accurate, selective, precise, sensitive, and linear. Conclusion: The RP-HPLC quantifiable technique developed here is more valuable and worthy for routine PRBN and ETRB analysis of tablets and bulk kinds.

Preclinical Evaluation of Polymeric Nanocomposite Containing Pregabalin for Sustained Release as Potential Therapy for Neuropathic Pain.

This study offers a novel oral pregabalin (PG)-loaded drug delivery system based on chitosan and hypromellose phthalate-based polymeric nanocomposite in order to treat neuropathic pain (PG-PN). PG-PN has a particle size of 432 ± 20 nm, a polydispersity index of 0.238 ± 0.001, a zeta potential of +19.0 ± 0.9 mV, a pH of 5.7 ± 0.06, and a spherical shape. Thermal and infrared spectroscopy confirmed nanocomposite generation. PG-PN pharmacokinetics was studied after a single oral dose in male Wistar rats. PG-PN showed greater distribution and clearance than free PG. The antinociceptive effect of PG-PN in neuropathic pain rats was tested by using the chronic constriction injury model. The parameter investigated was the mechanical nociceptive threshold measured by the von Frey filaments test; PG-PN showed a longer antinociceptive effect than free PG. The rota-rod and barbiturate sleep induction procedures were used to determine adverse effects; the criteria included motor deficit and sedative effects. PG-PN and free PG had plenty of motors. PG-PN exhibited a less sedative effect than free PG. By prolonging the antinociceptive effect and decreasing the unfavorable effects, polymeric nanocomposites with pregabalin have shown promise in treating neuropathic pain.

Development of Physiologically Based Pharmacokinetic Model for Pregabalin to Predict the Pharmacokinetics in Pediatric Patients with Renal Impairment and Adjust Dosage Regimens: PBPK Model of Pregabalin in Pediatric Patients with Renal Impairment

Pregabalin (PGB) is widely used clinically; however, its pharmacokinetics (PK) has not been studied in pediatric patients with renal impairment (RI). To design optimized PGB regimens for pediatric patients with varying degrees of RI and predict exposure to PGB, physiologically based pharmacokinetic (PBPK) models of PGB were developed and verified, and its disposition was simulated in the healthy population and adults with RI. The simulated results from the PBPK models after single-dose and multi-dose administrations of PGB were consistent with the corresponding observed data based on the fold error values of less than 2. The area under curve ratios were 1.23 ± 0.06, 2.02 ± 0.10, 3.86 ± 0.21, and 9.92 ± 0.79 in pediatric patients with mild, moderate, severe, and end-stage RI, respectively. Based on the predictions for pediatric patients with moderate, severe, and end-stage RI, the maximum dose should not exceed 7, 3.5, and 1.4 mg/kg/day, respectively, among those weighing < 30 kg, and it should not exceed 5, 2.5, and 1 mg/kg/day, respectively, among those weighing > 30 kg. In conclusion, the developed PBPK model is a valuable tool for predicting PGB dosage for pediatric patients with RI.

Comparison of loading and unloading of different small drugs on graphene and its oxide

Adsorption of drugs on graphene nanosheets can prevent enzymatic degradation. However, the mechanisms of graphene-drug complex permeating into the cell interior and the subsequent drug release remain unclear. In this work, we performed molecular dynamics simulations to investigate the drug delivery capability of pristine graphene (PG) and its oxide (graphene oxide, GO). Three drugs, namely, primidone (PRI), pregabalin (PRE) and bortezomib (BOR) were adopted as they have different molecular size and polarity. The results show that the adsorption intensity of GO is much stronger than that of PG, due to the electrostatic interactions or hydrogen bonding originated from the oxygen-containing groups on GO, which is confirmed by free energy calculations. And therefore, drug molecules are difficult to leave from GO surface after the complexes enter the membrane. Compared with PRE and BOR, PRI molecules are more suitable to be loaded and unloaded by both PG and GO. The results indicate that graphene and its oxide served as substrates to deliver particular drugs is theoretically feasible.

Neuropathic Pain Creates Systemic Ultrastructural Changes in the Nervous System Corrected by Electroacupuncture but Not by Pregabalin.

PurposeIt is unclear whether neuropathological structural changes in the peripheral nervous system and central nervous system can occur in the spared nerve injury model. In this study, we investigated the pathological changes in the nervous system in a model of neuropathic pain as well as the effects of electroacupuncture (EA) and pregabalin (PGB) administration as regards pain relief and tissue repair.Patients and MethodsForty adult male SD rats were equally and randomly divided into 4 groups: spared nerve injury group (SNI, n = 10), SNI with electroacupuncture group (EA, n = 10), SNI with pregabalin group (PGB, n =10) and sham-operated group (Sham, n=10). EA and PGB were given from postoperative day (POD) 14 to 36. EA (2 Hz and 100 Hz alternating frequencies, intensities ranging from 1–1.5–2 mA) was applied to the left “zusanli” (ST36) and “Yanglingquan” (GB34) acupoints for 30 minutes. The mechanical withdrawal thresholds (MWTs) were tested with von Frey filaments. Moreover, the organizational and structural alterations of the bilateral prefrontal cortex, hippocampus, sciatic nerves and the thoracic, lumbar spinal cords and dorsal root ganglions (DRGs) were examined via light and electron microscopy.ResultsMWTs of left hind paw demonstrated a remarkable decrease in the SNI model (P < 0.05). In the SNI model, ultrastructural changes including demyelination and damaged neurons were observed at all levels of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, EA improved MWTs and restored the normal structure of neurons. However, the effect was not found in the PGB treatment group.ConclusionChronic pain can induce extensive damage to the central and peripheral nervous systems. Meanwhile, EA and PGB can both alleviate chronic pain syndromes in rats, but EA also restores the normal cellular structures, while PGB is associated with no improvement.

Effects of Pregabalin, Nimodipine, and Their Combination in the Inhibition of Status Epilepticus and the Prevention of Death in Mice

The current study aims to evaluate the combined antiepileptic effects of pregabalin (PGB) and nimodipine (NMD) in an acute seizure model of epilepsy in mice. This study assessed the combined antiepileptic effects of PGB with NMD on death protection in mice. Pentylenetetrazole was used to induce seizures. Both drugs were used singly and in combination to judge anticonvulsant effects on an acute seizure model of epilepsy in mice. Diazepam (DZ) and valproate (VPT) were used as standard antiepileptic drugs. The death protection in mice by both these drugs was observed in percentage and deliberated as marked change when the outcome of the tested drug was equal to ED50 of PGB and measured highly marked when the result was more than ED50 for PGB. Treatment with pregabalin and nimodipine combination revealed substantial mortality protection at 30+2.5 mg/kg dose and highly marked at doses from 35+5 mg/kg to 55+15 mg/kg, these effects were superior to individual effects of PGB, showing synergism, however lesser then classic drugs valproate and diazepam. NMD showed synergistic anticonvulsant effect with PGB. However, clinical studies are required to establish the effectiveness of this combination in humans.

In Silico Screening and In Vivo Evaluation of Potential CACNA2D1 Antagonists as Intraocular Pressure-Reducing Agents in Glaucoma Therapy.

Glaucoma is a leading cause of permanent vision loss and current drugs do not halt disease progression. Thus, new therapies targeting different drug targets with novel mechanisms of action are urgently needed. Previously, we identified CACNA2D1 as a novel modulator of intraocular pressure (IOP) and demonstrated that a topically applied CACNA2D1 antagonist—pregabalin (PRG)—lowered IOP in a dose-dependent manner. To further validate this novel IOP modulator as a drug target for IOP-lowering pharmaceutics, a homology model of CACNA2D1 was built and docked against the NCI library, which is one of the world’s largest and most diverse compound libraries of natural products. Acivicin and zoledronic acid were identified using this method and together with PRG were tested for their plausible IOP-lowering effect on Dutch belted rabbits. Although they have inferior potency to PRG, both of the other compounds lower IOP, which in turn validates CACNA2D1 as a valuable drug target in treating glaucoma.

Input-dependent synaptic suppression by pregabalin in the central amygdala in male mice with inflammatory pain

Pregabalin (PGB) is a synthetic amino acid compound most widely prescribed for chronic peripheral and central neuropathic pain. PGB is a ligand for the α2δ1 subunit of voltage-dependent calcium channels, and its binding reduces neurotransmitter release and thus inhibits synaptic transmission. The central nucleus of the amygdala (CeA) is a kernel site for the enhanced nociception-emotion link in chronic pain. The nociceptive information is conveyed to the CeA via the following two pathways: 1) the pathway arising from the basolateral amygdala (BLA), which carries nociceptive information mediated by the thalamocortical system, and 2) that arising from the external part of the pontine lateral parabrachial nucleus (LPB), that forms the final route of the spino-parabrachio-amygdaloid pathway that conveys nociceptive information directly from the superficial layer of the spinal dorsal horn. We compared the effects of PGB on the excitatory postsynaptic currents of neurons in the right CeA in response to electrical stimulation of BLA and LPB pathways using the whole-cell patch-clamp technique. Inflammatory pain was induced by intraplantar injection of formalin solution at the left hind paw.At eight hours post-formalin, PGB reduced EPSCs amplitude of the BLA-to-CeA synaptic transmission, accompanied by a significant increase in the PPR, suggesting a decreased release probability from the presynaptic terminals. In addition, these effects of PGB were only seen in inflammatory conditions. PGB did not affect the synaptic transmission at the LPB-to-CeA pathway, even in formalin-treated mice. These results suggest PGB improves not simply the aberrantly enhanced nociception but also various pain-associated cognitive and affective consequences in patients with chronic nociplastic pain.

Biotransformation of pregabalin in surface water matrices and the occurrence of transformation products in the aquatic environment - comparison to the structurally related gabapentin

The biodegradability of the anticonvulsant pregabalin (PGB) was studied in laboratory incubation experiments in contact with water/sediment systems under different redox conditions. PGB was degraded by biological processes under aerobic conditions reaching half-lives of 8 to 10 d, while inactivated and anaerobic control experiments revealed no significant decrease of PGB concentrations. Within experiments spiked with elevated PGB concentrations, 12 TPs were formed and tentative chemical structures could be proposed by accurate masses and fragmentation pathways detected via measurements with high resolution mass spectrometry (LC-QToF-MS). Four of the proposed TPs were finally confirmed either by authentic reference standards (PGB-Lactam, ISA, TP 157-A (II)) or a self-synthesized standard (NA-PGB). PGB-Lactam was identified as the quantitatively most relevant TP formed via intramolecular cyclization under aerobic conditions, reaching up to 33% of the initial PGB concentration. Incubation experiments spiked with PGB-Lactam revealed three times higher half-lives compared to the parent compound, indicating that PGB-Lactam is more stable than PGB. A comparison with results gained from water/sediment incubation experiments with the structurally related compound gabapentin (GBP) revealed, that the transformation behaviour can be mainly extrapolated to PGB. Most of the observed transformation reactions found for PGB were comparable to the ones found for GBP. The TPs PGB-Lactam and NA-PGB as well as three GBP TPs (GBP-Lactam, NA-GBP and CCHA) have been detected in German wastewater treatment plants (WWTPs) effluents and the river Rhine including some of its tributaries such as Main, Neckar, Moselle and Aare. Moreover, GBP and PGB as well as some of their TPs were detected in German bank filtrates and finished drinking waters up to 260 ng L-1. For that reason these compounds should be monitored in drinking water in the future.

Chronic Pregabalin Treatment and Oxycodone Requirement after Spinal Surgery Versus Short Course Perioperative Administration: A Prospective, Nonrandomized Study

Although being controversial, pregabalin (PGB) is proposed during a short perioperative period to improve pain relief.Comparisons between chronic and short-term users during lumbar spine surgery are lacking. The purpose was to compare opioid requirements and postoperative pain among PGB chronic users and naive patients receiving a 48-hour perioperative administration. Prospective nonrandomized study. Tertiary care hospital. Chronic users (group PGB, n = 39) continued their treatment, naive patients (group C, n = 43) received a dose of 150 mg preoperatively and 75 mg/12 hours for 48 hours. Anesthesia and analgesia were standardized. The primary outcome was the cumulative oxycodone consumption at 24 hours, other outcomes included pain scores, DN4 (Douleur Neuropathique 4 Questions) scores, and side effects. Group PGB consumed less oxycodone at 24 hours (median [interquartile range] 10 mg [10-17.5] vs. 20 mg [10-20], P = 0.013], at 48 hours (15 mg [10-20] vs. 20 mg [12.5-30], P = 0.018), and required less intraoperative remifentanil (P = 0.004). Both groups showed similar pain scores during the 48-hour follow-up and at 3 months.Based on multivariate analysis, chronic users of PGB before surgery exhibited lower oxycodone requirements at 24 hours (odds ratio, 3.98; 95% confidence interval, 1.44-7.74; P = 0.008]. No differences were noted regarding side effects and DN4 scores. Nonrandomized study. Patients chronically treated with PGB required less opioid when compared with a short perioperative administration before spinal surgery. Further prospective studies are required to confirm these results in spinal surgeries.