Pregabalin versus gabapentin in partial epilepsy: a meta-analysis of dose-response relationships

Background

To compare the efficacy of pregabalin and gabapentin at comparable effective dose levels in patients with refractory partial epilepsy.

Methods

Eight randomized placebo controlled trials investigating the efficacy of pregabalin (4 studies) and gabapentin (4 studies) over 12 weeks were identified with a systematic literature search. The endpoints of interest were "responder rate" (where response was defined as at least a 50% reduction from baseline in the number of seizures) and "change from baseline in seizure-free days over the last 28 days (SFD)". Results of all trials were analyzed using an indirect comparison approach with placebo as the common comparator. The base-case analysis used the intention-to-treat last observation carried forward method. Two sensitivity analyses were conducted among completer and responder populations.

Results

The base-case analysis revealed statistically significant differences in response rate in favor of pregabalin 300 mg versus gabapentin 1200 mg (odds ratio, 1.82; 95% confidence interval, 1.02, 3.25) and pregabalin 600 mg versus gabapentin 1800 mg (odds ratio, 2.52; 95% confidence interval, 1.21, 5.27). Both sensitivity analyses supported the findings of the base-case analysis, although statistical significance was not demonstrated. All dose levels of pregabalin (150 mg to 600 mg) were more efficacious than corresponding dosages of gabapentin (900 mg to 2400 mg) in terms of SFD over the last 28 days.

Conclusion

In patients with refractory partial epilepsy, pregabalin is likely to be more effective than gabapentin at comparable effective doses, based on clinical response and the number of SFD.

     

Reductively activated disulfide prodrugs of paclitaxel

A series of unsymmetrical polar disulfide prodrugs 2–5 of paclitaxel were designed and synthesized as reductively activated prodrugs. These compounds behaved as prodrugs in vitro on L2987 lung carcinoma cells. In vivo evaluation in mice demonstrated that the mutual prodrug 5 with captopril exhibited significant regressions and cures.     

普瑞巴林、加巴喷丁联合神经阻滞治疗带状疱疹后神经痛的临床疗效比较

目的:比较普瑞巴林、加巴喷丁联合神经阻滞治疗带状疱疹后神经痛(PHN)的临床疗效。方法:选择2014年8月至2016年11月我院门诊收治的带状疱疹后神经痛患者80例,并将其随机分为两组,每组40例。A组患者接受普瑞巴林联合神经阻滞治疗,B组患者接受加巴喷丁联合神经阻滞治疗,比较两组患者治疗前后的视觉疼痛模拟(VAS)评分、失眠严重程度指数(ISI)评分、生活质量满意指数(LSIB)评分及治疗期间不良反应的发生情况。结果:A组患者治疗后4、7、14 d的VAS评分均显著低于B组(P0.05),LSIB评分显著高于B组(P0.05),A组患者治疗后4、7 d的ISI评分均显著低于B组(P0.05);A组发生不良反应的总发生率显著低于B组(P0.05)。结论:普瑞巴林联合神经阻滞治疗PHN缓解疼痛和失眠的效果显著优于巴喷丁联合神经阻滞治疗,其可显著提高患者的生活质量,并减少不良反应。     

Pregabalin and gabapentin inhibit substance P-induced NF-kappaB activation in neuroblastoma and glioma cells

Pregabalin and gabapentin are lipophilic amino acid derivatives of gamma-amino butyric acid that show anticonvulsant and analgesic activity against neuropathic pain. In this study, we investigated their actions on substance P-induced NF-kappaB activation in human neuroblastoma and rat glioma cells. Pregabalin and gabapentin decreased substance P-induced NF-kappaB activation in these cells. These drugs also inhibited NF-kappaB activation in rat spinal dorsal root ganglia cells pre-treated in vitro with substance P. These results suggest a previously undefined role of pregabalin and gabapentin in the regulation of inflammation-related intracellular signaling in both neuronal and glial cells.     

Gabapentin hybrid peptides and bioconjugates

Synthetic approaches to gabapentin bioconjugates that overcome the tendency of gabapentin to cyclize into its γ-lactam are studied. Gabapentin was converted by N-acylation at its N-terminus into di-, tri-, and tetrapeptides (l-Ala-Gbp, l-Val-Gbp, l-Ala-l-Phe-Gbp, Gly-l-Ala-β-Ala-Gbp). Carboxyl-activated Boc-protected gabapentin was used to N-, O-, and S-acylate small peptides and hormones to give conjugates that could also provide prodrugs containing conformationally constrained gabapentin units.     

Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study

Amide- and ester-linked kinase inhibitor-cytotoxin conjugates were rationally designed and synthesised as prototype hypoxia-activated anticancer mutual prodrugs. Chemical reduction of an aryl nitro trigger moiety was shown to initiate a spontaneous cyclisation/fragmentation reaction that simultaneously released the kinase inhibitor semaxanib (SU5416) and the amine- or alcohol-linked cytotoxin from the prodrugs. Preliminary cell testing and reduction potential measurements support optimisation of the compounds towards tumour-selective mutual prodrugs.     

Carboxylate bioisosteres of pregabalin

Several beta-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the alpha(2)-delta protein examined. Two select compounds with potent affinity for alpha(2)-delta, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.     

A comparison of the glutamate release inhibition and anti-allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain

The effects of treatment with the anti-convulsant agents, lamotrigine and riluzole were compared with gabapentin in a rat experimental model of neuropathic pain. Rats were treated intraperitoneally, with gabapentin (30, 100 and 300 mg/kg), lamotrigine (2, 10 and 50 mg/kg) or riluzole (6 and 12 mg/kg) prior to, and every 12 h for 4 days following chronic constriction injury (CCI) of the sciatic nerve. Mechanical and cold sensitivity were assessed prior to surgery (baseline) and then at 4, 8 and 12 days following CCI. The four-day treatment with each of the agents was effective at producing reductions in the development of mechanical and cold hypersensitivity for periods ranging from the fourth to 12th day. The highest doses of each of the agents were also assessed on formalin-induced nociceptive behaviors and on formalin-induced increases in extracellular glutamate (Glu) and aspartate (Asp) in the spinal cord dorsal horn (SCDH) of awake behaving rats using in vivo microdialysis. Nociceptive scores in formalin test were significantly decreased by gabapentin (300 mg/kg i.p.) and riluzole (12 mg/kg i.p.), but not by lamotrigine (50 mg/kg i.p.). Formalin-induced increases in glutamate levels in SCDH were lowered significantly, as compared with the controls, with all drugs both in the first phase and second phases, with the greatest effects for riluzole and gabapentin. Similar suppressive effects of the drugs were observed on formalin-induced increases in spinal aspartate, except that gabapentin and lamotrigine produced effects only during the second phase. Riluzole produced profound and prolonged reductions in the spinal levels of glutamate and aspartate both for basal and formalin-stimulated release. In conclusion, the results suggest that the anti-convulsant agents gabapentin, lamotrigine and riluzole may reduce the development of hyperalgesia in a rat model of neuropathic pain by reducing the spinal release of glutamate. Riluzole's pronounced suppressive effects on spinal EAA levels is attributed to its established role as a glutamate release inhibitor and an enhancer of glutamate transporter activity.     

Mutual prodrugs containing bio-cleavable and drug releasable disulfide linkers

We report herein the design and synthesis of several representative examples of novel mutual prodrugs containing nine distinct types of self-immolative drug-releasable disulfide linkers with urethane, ester, carbonate, or imide linkages between the linker and any two amine/amide/urea (primary or secondary) or carboxyl or hydroxyl (including phenolic)-containing drugs. We also report drug release profiles of a few representative mutual prodrugs in biological fluids such as simulated gastric fluid and human plasma. We also propose plausible mechanisms of drug release from these mutual prodrugs. We have also conducted a few mechanistic studies based on suggested sulfhydryl-assisted cleavage of mutual prodrugs and characterized a few important metabolites to give support to the proposed mechanism of drug release from the reported mutual prodrugs.     

Mechanical Conflict System: A Novel Operant Method for the Assessment of Nociceptive Behavior

A new operant test for preclinical pain research, termed the Mechanical Conflict System (MCS), is presented. Rats were given a choice either to remain in a brightly lit compartment or to escape to a dark compartment by crossing an array of height-adjustable nociceptive probes. Latency to escape the light compartment was evaluated with varying probe heights (0, .5, 1, 2, 3, and 4 mm above compartment floor) in rats with neuropathic pain induced by constriction nerve injury (CCI) and in naive control rats. Escape responses in CCI rats were assessed following intraperitoneal administration of pregabalin (10 and 30 mg/kg), morphine (2.5 and 5 mg/kg), and the tachykinin NK1 receptor antagonist, RP 67580 (1 and 10 mg/kg). Results indicate that escape latency increased as a function of probe height in both naive and CCI rats. Pregabalin (10 and 30 mg/kg) and morphine (5 mg/kg), but not RP 67580, decreased latency to escape in CCI rats suggesting an antinociceptive effect. In contrast, morphine (10 mg/kg) but not pregabalin (30 mg/kg) increased escape latency in naive rats suggesting a possible anxiolytic action of morphine in response to light-induced fear. No order effects following multiple test sessions were observed. We conclude that the MCS is a valid method to assess behavioral signs of affective pain in rodents.     

Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: Design,synthesis, pharmacological investigations and docking studies

The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6–8) of some acidic NSAIDs (1–3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6–8) were confirmed by IR, ¹H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6–8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t_1/2 ≈ 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6–8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4 days. In addition, docking of the mutual ester prodrugs (6–8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.     

Oxadiazolone bioisosteres of pregabalin and gabapentin

A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the α₂-δ subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.     

(R)- and (S)-4-Amino-3-(trimethylsilyl)methylbutanoic acids ameliorate neuropathic pain without central nervous system-related side effects

Neuropathic pain is a chronic pain condition resulting from neuronal damage, and is usually treated with pregabalin or gabapentin, which are structurally related to γ-aminobutyric acid (GABA) and are originally developed as anticonvulsant drugs. Here, we report the synthesis and pharmacology of (R)- and (S)-4-amino-3-(trimethylsilyl)methylbutanoic acids (1a and 1b), which showed analgesic activity as potent as that of pregabalin in the Chung spinal nerve ligation model. However, unlike pregabalin, 1a and 1b do not have antiepileptic effects, and they are therefore promising candidates for selective therapeutic agents to treat neuropathic pain without central nervous system-related side effects.     

Drugging the undruggable: gabapentin,pregabalin and the calcium channel α2δ subunit

In the post-genomic era, the idea of using the sequence of a protein to determine its potential role as a drug target has gained currency. The goal of this approach to drug discovery is to use the sequence of a protein that is known to bind a specific ligand or drug, along with the known structure of the ligand binding site, to predict other similar proteins that are also “druggable”. Gabapentin (Neurontin) and pregabalin (Lyrica) are drugs currently in the clinic that were developed based on the hypothesis that generating non-hydrolyzable analogs of GABA would lead to the development of antiepileptic agents. While these compounds are indeed good anticonvulsants, their activity is surprisingly not due to activity in the GABAergic system. By purifying the protein to which gabapentin bound, and determining its identity as the α₂δ₁ subunit of voltage gated calcium channels, it was possible to make progress in developing new compounds with similar activities to gabapentin, including pregabalin. The recognition of the α₂δ₁ subunit as the receptor for these drugs also meant that related proteins, such as α₂δ₃, may be interesting targets for novel pain therapeutics.     

Synthesis and SAR development of novel P2X7 receptor antagonists for the treatment of pain: part 2

Novel P2X₇ antagonists were developed using a purine scaffold. These compounds were potent and selective at the P2X₇ receptor in human and rodent as well as efficacious in rodent pain models. Compound 15a was identified to have oral potency in several pain models in rodent similar to naproxen, gabapentin and pregabalin. Structure–activity relationship (SAR) development and results of pain models are presented.     

Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain

Background  

Few direct head-to-head comparisons have been conducted between drugs for the treatment of diabetic peripheral neuropathic pain (DPNP). Approved or recommended drugs in this indication include duloxetine (DLX), pregabalin (PGB), gabapentin (GBP) and amitriptyline (AMT). We conducted an indirect meta-analysis to compare the efficacy and tolerability of DLX with PGB and GBP in DPNP, using placebo as a common comparator.     

Solid Phase and Solution Phase Synthesis of Gamma Amino Acid Homo-Oligomers and Mixed Oligomers

Abstract  

An efficient stepwise synthesis of homo-oligomers and mixed oligomers of gabapentin and pregabalin on solid support using Fmoc-protected derivatives and HBTU/HOBt/DIEA as coupling agent is described. The synthesis was also carried out using solution phase methodology. The Gpn/Pgn homo oligomers and mixed oligomers forms C₉ helix in solution as determined by NMR study. Chiral as well as achiral gamma amino acids were used for the synthesis of oligomers in order to investigate the secondary structural preferences.     

Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer

A promising agent for use in prostate cancer therapy is the Hedgehog (Hh) signaling pathway inhibitor, cyclopamine. This compound, however, has the potential for causing serious side effects in non-tumor tissues. To minimize these bystander toxicities, we have designed and synthesized two novel peptide-cyclopamine conjugates as prostate-specific antigen (PSA)-activated prodrugs for use against prostate cancer. These prodrugs were composed of cyclopamine coupled to one of two peptides (either HSSKLQ or SSKYQ) that can be selectively cleaved by PSA, converting the mature prodrug into an active Hedgehog inhibitor within the malignant cells. Of the two prodrugs, Mu-SSKYQ-Cyclopamine was rapidly hydrolyzed, with a half-life of 3.2h, upon incubation with the PSA enzyme. Thus, modulating cyclopamine at the secondary amine with PSA-cleavable peptides is a promising strategy for developing prodrugs to target prostate cancer.     

Pharmacological characteristics of the hind paw weight bearing difference induced by chronic constriction injury of the sciatic nerve in rats

AimsWe examined the possible involvement of spontaneous on-going pain in the rat chronic constriction injury (CCI) model of neuropathic pain.Main methodsThe development of weight bearing deficit, as an index of spontaneous on-going pain, was investigated in comparison to that of mechanical allodynia in CCI rats. We also examined the effects of morphine and a gabapentin analogue (1S, 3R)-3-methyl-gabapentin (3-M-gabapentin) on both the CCI-induced weight bearing deficit and mechanical allodynia.Key findingsRats with CCI demonstrated a significant reduction in weight bearing of the injured limb with a peak at a week post-operation, which was followed by a gradual recovery for over 7 weeks. The time course of development and recovery of CCI-induced weight bearing deficit appeared to follow that of foot deformation of the affected hind limb. CCI also evoked mechanical allodynia that was fully developed on a week post-operation, but showed no recovery for at least 8 weeks. 3-M-gabapentin significantly inhibited CCI-induced mechanical allodynia, but not weight bearing deficit, at 100 mg/kg p.o. Likewise, morphine was without significant effect on CCI-induced weight bearing deficit at the dose (3 mg/kg, s.c.) that could almost completely inhibit mechanical allodynia, whereas it inhibited both mechanical allodynia and weight bearing deficit at 6 mg/kg, s.c.SignificanceThe present findings suggest that CCI-induced weight bearing deficit is not a consequence of mechanical allodynia, but is attributable to spontaneous on-going pain. The rat CCI model of neuropathic pain thus represents both spontaneous on-going pain and mechanical allodynia.