A Focus on the Synthesis and Pharmacokinetics of Tocainide and its Analogues.

Tocainide is an antiarrhythmic agent belonging to class IB that was primarily used for suppression of symptomatic ventricular arrhythmias. Tocainide was also reported to relieve pain such as tic douloureux, trigemina neuralgia in humans and tinnitus. Significant antinociception, as assayed on the hot-plate test, was observed after intraperitoneal injection of tocainide, too. By the mid-1980s tocainide was emerging as a more consistently effective treatment for myotonic disorders. Numerous reports of serious adverse reactions led to the use of tocainide being discontinued, even though research on tocainide and its analogues, endowed with a better pharmacological profile, is still in progress for their potential usefulness in the treatment of myotonias. This review is focused on the description of the different synthetic routes to racemic and optically active tocainide developed in the last decades, as well as analytical studies regarding enantioseparation methods. Finally, some analogues of tocainide reported in the literature, most of which with pharmacological studies, have been mentioned.

Increased sodium channel use-dependent inhibition by a new potent analogue of tocainide greatly enhances in vivo antimyotonic activity.

Although the sodium channel blocker, mexiletine, is the first choice drug in myotonia, some myotonic patients remain unsatisfied due to contraindications, lack of tolerability, or incomplete response. More therapeutic options are thus needed for myotonic patients, which require clinical trials based on solid preclinical data. In previous structure-activity relationship studies, we identified two newly-synthesized derivatives of tocainide, To040 and To042, with greatly enhanced potency and use-dependent behavior in inhibiting sodium currents in frog skeletal muscle fibers. The current study was performed to verify their potential as antimyotonic agents. Patch-clamp experiments show that both compounds, especially To042, are greatly more potent and use-dependent blockers of human skeletal muscle hNav1.4 channels compared to tocainide and mexiletine. Reduced effects on F1586C hNav1.4 mutant suggest that the compounds bind to the local anesthetic receptor, but that the increased hindrance and lipophilia of the N-substituent may further strengthen drug-receptor interaction and use-dependence. Compared to mexiletine, To042 was 120 times more potent to block hNav1.4 channels in a myotonia-like cellular condition and 100 times more potent to improve muscle stiffness in vivo in a previously-validated rat model of myotonia. To explore toxicological profile, To042 was tested on hERG potassium currents, motor coordination using rotarod, and C2C12 cell line for cytotoxicity. All these experiments suggest a satisfactory therapeutic index for To042. This study shows that, owing to a huge use-dependent block of sodium channels, To042 is a promising candidate drug for myotonia and possibly other membrane excitability disorders, warranting further preclinical and human studies.

N-aryl-2,6-dimethylbenzamides, a new generation of tocainide analogues as blockers of skeletal muscle voltage-gated sodium channels.

On the basis of a 3D-QSAR study, a new generation of tocainide analogues were designed and synthesized as voltage-gated skeletal muscle sodium channel blockers. Data obtained by screening new compounds by means of Hille-Campbell Vaseline gap voltage-clamp recordings showed that the elongation of the alkyl chain and the introduction of lipophilic and sterically hindered groups on the amino function enhance both potency and use-dependent block. The results provide additional indications about the structural requirement of pharmacophores for further increasing potency and state-dependent block and allowed us to identify a new tocainide analogue (6f) with a favorable pharmacodynamic profile to be proposed as a valid candidate for studies aimed at evaluating its usefulness in the treatment of myotonias.

Species-dependent binding of tocainide analogues to albumin: affinity chromatography and circular dichroism study.

A series of novel tocainide analogues were characterized for their HSA and RSA binding, by using high-performance liquid affinity chromatography (HPLAC) and circular dichroism (CD). In this HPLAC study, HSA and RSA were covalently immobilized to the silica matrix of HPLC columns, with a procedure that maintained unaltered the binding properties of the proteins. The tocainide analogues were ranked for their affinity to HSA and RSA on the basis of their bound fractions measured by the two albumin-based columns. This technique was also applied to characterize the high affinity binding sites of these tocainide analogues to the protein. For this purpose displacement experiments were carried out by means of increasing concentrations in the mobile phase of competitors known to bind selectively to the main binding sites of HSA. The results obtained with the immobilized proteins were confirmed by investigating the same drug-protein systems in solution by circular dichroism. The comparison of the data collected with both methodologies highlighted the dramatic effect of small differences in the amino acidic sequences of the two proteins. In fact, despite their similar primary and secondary structures, a small difference in the amino acidic sequence leads to significant differences in their three-dimensional structure reflecting their different binding capacity and their stereoselectivity. Therefore, this study confirms how it is crucial to consider the significant differences among the animal models when performing pharmacokinetic studies. It is also clear that the knowledge of serum carrier binding parameters at an early stage of drug discovery represents a great advantage that may help to save time and efforts.

Non-antiepileptic drugs for trigeminal neuralgia.

BACKGROUND: Trigeminal neuralgia was defined by the International Association for the Study of Pain as a sudden, usually unilateral, severe, brief, stabbing recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Standard treatment is with anti-epileptic drugs. Non-antiepileptic drugs have been used in the management of trigeminal neuralgia since the 1970s. This is an update of a review first published in 2006 and previously updated in 2011. OBJECTIVES: To systematically review the efficacy and tolerability of non-antiepileptic drugs for trigeminal neuralgia. SEARCH METHODS: On 20 May 2013, for this updated review, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2013, Issue 4), MEDLINE (January 1966 to May 2013), EMBASE (January 1980 to May 2013), LILACS (January 1982 to May 2013) and the Chinese Biomedical Retrieval System (1978 to May 2013). We searched clinical trials registries for ongoing trials. SELECTION CRITERIA: We included double-blind, randomised controlled trials in which the active drug was used either alone or in combination with other non-antiepileptic drugs for at least two weeks. DATA COLLECTION AND ANALYSIS: Two authors decided which trials fitted the inclusion criteria and independently graded risk of bias. We assessed the quality of the evidence according to the GRADE criteria for this update. MAIN RESULTS: In this 2013 update, we updated the searches, but identified only two new ongoing studies. The review includes four trials involving 139 participants. The primary outcome measure in each was pain relief. Three trials compared one of the oral non-antiepileptic drugs tizanidine, tocainide or pimozide with carbamazepine. The quality of evidence for all outcomes for which data were available was low. In a trial of tizanidine involving 12 participants (one dropped out due to unrelated disease), one of five participants treated with tizanidine and four of six treated with carbamazepine improved (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.05 to 1.89). Few side effects were noted with tizanidine. For pimozide, there was evidence of greater efficacy than carbamazepine at six weeks. Up to 83% of participants reported adverse effects but these did not lead to withdrawal; the report did not provide comparable data for carbamazepine. Limited data meant that we could not assess the effects of tocainide; however, data from non-randomised studies (not included in this review) indicate that serious haematological adverse events can occur. A trial involving 47 participants compared 0.5% proparacaine hydrochloride eyedrops with placebo but did not show any significant benefits, again according to low-quality evidence. The report did not mention adverse events. The proparacaine trial was at low risk of bias; the other trials were at unclear risk of bias overall. AUTHORS' CONCLUSIONS: There is low-quality evidence that the effect of tizanidine is not significantly different than that of carbamazepine in treating trigeminal neuralgia. Pimozide is more effective than carbamazepine, although the evidence is of low quality and the data did not allow comparison of adverse event rates. There is also low-quality evidence that 0.5% proparacaine hydrochloride eye drops have no benefit over placebo. Limitations in the data for tocainide prevent any conclusions being drawn. There is insufficient evidence from randomised controlled trials to show significant benefit from non-antiepileptic drugs in trigeminal neuralgia. More research is needed.

Searching for novel anti-myotonic agents: pharmacophore requirement for use-dependent block of skeletal muscle sodium channels by N-benzylated cyclic derivatives of tocainide.

Drug screening on sodium currents of native myofibers by means of voltage-clamp recordings is predictive of pre-clinical anti-myotonic activity in vivo and ex vivo. By this approach we identified the N-benzylated beta-proline derivative of tocainide (To10) as the most potent use-dependent blocker of Nav1.4 so far. We tested novel analogs with modifications on the pharmacophore groups of To10. The substitution of the proline cycle with less planar piperidine or piperazine rings disclosed the importance of a two carbon atom distance and/or an additional nitrogen atom for potency. Structural changes on the xylididic group corroborated the role of a proper electronic cloud for hydrophobic interactions with the binding site. The N-benzylated moiety lead to a stereoselective behavior only in the rigid alpha-proline analog To11 vs. To10 and N-benzylated tocainide (To12). The results confirm the strict structural requirements of Nav1.4 blockers and allow to refine the drug design toward novel anti-myotonic drugs.

The efficacy of anticonvulsants on orofacial pain: a systematic review.

OBJECTIVE: Controversy exists about the effectiveness of anticonvulsants for the management of orofacial pain disorders. To ascertain appropriate therapies, a systematic review was conducted of existing randomized controlled trials. STUDY DESIGN: Trials were identified from PubMed, Cochrane, and Ovid Medline databases from 1962 through March 2010, from references in retrieved reports, and from references in review articles. Eight useful trials were identified for this review. Six studies were randomized placebo-controlled trials and 2 studies were randomized active-controlled. Two independent investigators reviewed these articles by using a 15-item checklist. RESULTS: Four studies were classified as "high quality." However, heterogeneity of the trials and the small sample sizes precluded the drawing of firm conclusions about the efficacy of the interventions studied on orofacial pain patients. CONCLUSIONS: There is limited to moderate evidence supporting the efficacy of commonly used anticonvulsants for treatment of patients with orofacial pain disorders. More randomized controlled trials are needed on the efficacy of anticonvulsants.

Non-antiepileptic drugs for trigeminal neuralgia.

BACKGROUND: Non-antiepileptic drugs have been used in the management of trigeminal neuralgia since the 1970s. OBJECTIVES: The objective was to systematically review the efficacy and tolerability of non-antiepileptic drugs for trigeminal neuralgia. SEARCH STRATEGY: For this updated review we searched the Cochrane Neuromuscular Disease Group Specialized Register (30 April 2010). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), MEDLINE (January 1966 to April 2010), EMBASE (January 1980 to April 2010), LILACS (January 1982 to April 2010) and the Chinese Biomedical Retrieval System (1978 to April 2010). We handsearched 10 Chinese journals. SELECTION CRITERIA: We searched for double-blind randomized or quasi-randomized controlled trials in which the active drug was used for at least two weeks. DATA COLLECTION AND ANALYSIS: Two authors decided which trials fitted the inclusion criteria and independently graded risk of bias. MAIN RESULTS: Four trials involving 139 participants were included. The primary outcome measure in each was pain relief. Three trials with an unclear risk of bias compared one of the non-antiepileptic drugs tizanidine, tocainide or pimozide with carbamazepine. In a trial of tizanidine involving 12 participants (one dropped out due to unrelated disease) one of five treated with tizanidine and four of six treated with carbamazepine improved, risk ratio 0.30 (95% CI 0.05 to 1.89). Few side effects were noted with tizanidine. In a study involving 12 participants there was an improvement in mean pain scores with tocainide similar to that with carbamazepine, but significant side effects limited its use. In the pimozide study more participants improved on pimozide (48/48) than with carbamazepine (27/48) (risk ratio 1.76, 95% CI 1.37 to 2.26). Up to 83% of participants reported adverse effects but these did not lead to withdrawal from the study. A trial with low risk of bias involving 47 participants compared 0.5% proparacaine hydrochloride eyedrops with placebo but did not show any significant benefits or side effects. AUTHORS' CONCLUSIONS: Of the four studies identified, one had low and three an unclear risk of bias. There is insufficient evidence from randomized controlled trials to show significant benefit from non-antiepileptic drugs in trigeminal neuralgia. More research is needed.

Effects of a new potent analog of tocainide on hNav1.7 sodium channels and in vivo neuropathic pain models.

The role of voltage-gated sodium channels in the transmission of neuropathic pain is well recognized. For instance, genetic evidence recently indicate that the human Nav1.7 sodium channel subtype plays a crucial role in the ability to perceive pain sensation and may represent an important target for analgesic/anti-hyperalgesic drugs. In this study a newly synthesized tocainide congener, named NeP1, was tested in vitro on recombinant hNav1.4 and hNav1.7 channels using patch-clamp technique and, in vivo, in two rat models of persistent neuropathic pain obtained either by chronic constriction injury of the sciatic nerve or by oxaliplatin treatment. NeP1 efficiently blocked hNav1.4 and hNav1.7 channels in a dose- and use-dependent manner, being by far more potent than tocainide. Importantly, the new compound displayed a remarkable use-dependent effect, which likely resulted from a very high affinity for inactivated compared to closed channels. In both models of neuropathic pain, NeP1 was greatly more potent than tocainide in reverting the reduction of pain threshold in vivo. In oxaliplatin-treated rats, NeP1 even produced greater and more durable anti-hyperalgesia than the reference drug tramadol. In addition, in vivo and in vitro studies suggest a better toxicological and pharmacokinetic profile for NeP1 compared to tocainide. Overall, these results indicate NeP1 as a new promising lead compound for further development in the treatment of chronic pain of neuropathic origin.

Tocainide analogues binding to human serum albumin: a HPLAC and circular dichroism study.

A series of synthesised tocainide analogues were characterized for their human serum albumin (HSA) binding, using high-performance liquid affinity chromatography (HPLAC) and circular dichroism (CD). The synthesis and physico-chemical characterization of compounds 7a-7d is reported here. For the HPLAC investigation HSA was covalently immobilized to the silica matrix of the HPLC column, using an anchoring procedure, which allows the binding properties of the protein to be maintained. The HSA-based column was used for getting information on the high affinity binding sites of the tocainide analogues to HSA. According to the displacement chromatography approach, the retentions of the analytes were determined in the absence and in the presence of increasing concentrations of competitors known to bind to specific binding sites on the protein. The same system, drug/protein, was investigated in solution by CD. The analysed compounds, proved active as sodium channel blockers, showed a much higher affinity to the serum carrier with respect to the parent compound, tocainide. Further, a non-cooperative interaction at sites I and II, and an almost independent binding at the bilirubin binding site on HSA were hypothesised on the bases of the competition experiments.

2D- and 3D-QSAR of tocainide and mexiletine analogues acting as Na(v)1.4 channel blockers.

Enantiomeric forms of Tocainide, Mexiletine, and structurally related local anaesthetic compounds, were analyzed with respect to their potency in blocking Na(v)1.4 channel. Structure-activity relationships based on in vitro pharmacological assays, suggested that an increase in terms of lipophilicity and/or molecular surface as well as the presence of specific polar spacers might be determinant for receptor interactions. QSAR and pharmacophore models were then used to support at 3D level this hypothesis.

Constrained analogues of tocainide as potent skeletal muscle sodium channel blockers towards the development of antimyotonic agents.

1-Benzyl-N-(2,6-dimethylphenyl)piperidine-3-carboxamide and 4-benzyl-N-(2,6-dimethylphenyl)piperazine-2-carboxamide, two conformationally restricted analogues of tocainide, were designed and synthesized as voltage-gated skeletal muscle sodium channel blockers. They showed, with respect to tocainide, a marked increase in both potency and use-dependent block.

Cyclic metabolites: chemical and biological considerations.

Metabolism of xenobiotics can sometimes generate cyclic metabolites. Such metabolites are usually the result of intramolecular reactions occurring within a primary or secondary metabolite and this chemistry may lead to unexpected structures. Intramolecular chemistry is often driven by nucleophilic groups reacting with electrophilic atoms, often carbon, although radical processes also occur. Conjugation of xenobiotics or their metabolites with endogenous thiols, such as glutathione or cysteine, introduce a reactive amino group that can lead to the formation of cyclic structures. Less common than chemically driven cyclizations are enzymatically mediated ring-closures, although this may reflect our incomplete recognition of enzymatic involvement in this step of cyclic metabolite formation. While some cyclic metabolites are biologically inactive, others are biologically active. Thus, a cyclic metabolite may display desirable pharmacology, or, contribute to toxicology. When a cyclic metabolite is identified, it is important to consider the possibility that it is an artifact, i.e. metabonate, that was formed during processing of the sample, for example, through degradation or by chemical reactions with other components present in the matrix. From a medicinal chemistry perspective, a cyclic metabolite with a different chemical scaffold from the parent structure may lead to a new series of structurally novel, biologically active molecules with the same, or different, pharmacology from the parent. This review will cover a selection of cyclic metabolites from a mechanistic point of view, and when possible, discuss their biological relevance.

Preparation of two new liquid chromatographic chiral stationary phases based on diastereomeric chiral crown ethers incorporating two different chiral units and their applications.

Two new liquid chromatographic chiral stationary phases based on diastereomeric chiral crown ethers incorporating two different chiral units such as optically active 3,3'-diphenyl-1,1'-binaphthyl and tartaric acid unit were prepared. Between the two CSPs, one was much superior to the other especially in the resolution of tocainide and its analogues (for example, in the resolution of tocainide the separation factor, alpha, was 4.26 vs. 1.00 on the two CSPs). From these results, the two chiral units composing the two diastereomeric chiral crown ether moieties of the stationary phases were expected to show "matched" or "mismatched" effect on the chiral recognition according to their stereochemistry. The different chiral recognition abilities of the two CSPs were rationalized by the different three-dimensional structures of the two diastereomeric chiral crown ethers.

Non-antiepileptic drugs for trigeminal neuralgia.

BACKGROUND: Non-antiepileptic drugs have been used in trigeminal neuralgia management since the 1970s. OBJECTIVES: The objective was to review systematically the efficacy of non-antiepileptic drugs for trigeminal neuralgia. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register, MEDLINE, EMBASE, and LILACS (all to August 2005) and the Chinese Biomedical Retrieval System, the database of the Chinese Cochrane Center (The Cochrane Library, Issue 1 2005), conference paper databases and checked bibliographies. We handsearched ten Chinese journals. SELECTION CRITERIA: We searched for randomized or quasi-randomized controlled trials. DATA COLLECTION AND ANALYSIS: Two authors decided which trials fitted the inclusion criteria and graded methodological quality independently. MAIN RESULTS: Nine trials of different non-antiepileptic drugs involving 223 participants were included. Each trial investigated one non-antiepileptic drug. Two trials tested baclofen. In one, more people gained 50% reduction from baseline than with placebo (relative risk 15.00, 95% CI 0.97 to 231.84, P value = 0.05). In the other, slightly more participants on baclofen had a 75% reduction in attacks on the 10th day compared with carbamazepine (relative risk 2.38, 95% CI 0.83 to 6.85, P value = 0.11). One trial showed no significant difference in reduction in average daily frequency of attacks with L-Baclofen compared with racemic baclofen. Tizanidine was investigated in two trials. In one, the proportion of people with reduction in the average number of paroxysms per day increased with tizanidine compared with placebo (relative risk 8.00, 95% CI 1.21 to 52.69, P value = 0.03). In the other, one of five participants improved in visual analog scale score with tizanidine and four of six with carbamazepine (relative risk 0.30, 95% CI 0.05 to 1.89, P value = 0.20). One study showed that the improvement in mean values of pain scores with tocainide was similar to that of carbamazepine. In one study more participants improved during the pimozide than the carbamazepine period (relative risk 1.78, 95% CI 1.39 to 2.28). In one study, proparacaine hydrochloride 0.5% instillation into the eyes was not significantly different from placebo (relative risk 1.06, 95% CI 0.37 to 2.99, P value = 0.92). In another, there was moderate or marked improvement in seven of nine participants treated with clomipramine and three of nine with amitriptyline after a 12-week treatment (RR 2.33, 95% CI 0.87 to 6.27). AUTHORS' CONCLUSIONS: There is insufficient evidence from randomized controlled trials to show significant benefit from non-antiepileptic drugs in trigeminal neuralgia. More research is needed.

Quantitative structure-pharmacokinetic relationships for drug clearance by using statistical learning methods.

Quantitative structure-pharmacokinetic relationships (QSPkR) have increasingly been used for the prediction of the pharmacokinetic properties of drug leads. Several QSPkR models have been developed to predict the total clearance (CL(tot)) of a compound. These models give good prediction accuracy but they are primarily based on a limited number of related compounds which are significantly lesser in number and diversity than the 503 compounds with known CL(tot) described in the literature. It is desirable to examine whether these and other statistical learning methods can be used for predicting the CL(tot) of a more diverse set of compounds. In this work, three statistical learning methods, general regression neural network (GRNN), support vector regression (SVR) and k-nearest neighbour (KNN) were explored for modeling the CL(tot) of all of the 503 known compounds. Six different sets of molecular descriptors, DS-MIXED, DS-3DMoRSE, DS-ATS, DS-GETAWAY, DS-RDF and DS-WHIM, were evaluated for their usefulness in the prediction of CL(tot). GRNN-, SVR- and KNN-developed models have average-fold errors in the range of 1.63 to 1.96, 1.66-1.95 and 1.90-2.23, respectively. For the best GRNN-, SVR- and KNN-developed models, the percentage of compounds with predicted CL(tot) within two-fold error of actual values are in the range of 61.9-74.3% and are comparable or slightly better than those of earlier studies. QSPkR models developed by using DS-MIXED, which is a collection of constitutional, geometrical, topological and electrotopological descriptors, generally give better prediction accuracies than those developed by using other descriptor sets. These results suggest that GRNN, SVR, and their consensus model are potentially useful for predicting QSPkR properties of drug leads.

Chiral separations on multichannel microfluidic chips.

Chiral separations of FITC-labeled basic drugs on multichannel microfluidic chips with LIF detector were investigated. A preliminary screening procedure for seven neutral CDs was performed under optimized conditions for chiral separations of three FITC-labeled drugs (baclofen, norfenefrine, and tocainide) on a mono-channel microfluidic chip. According to the results of screening, FITC-baclofen and FITC-norfenefrine as well as two chiral selectors including gamma-CD and dimethyl-beta-CD (DM-beta-CD) were selected as models to perform chiral separations on a two-channel chip. FITC-baclofen enantiomers were separated completely by gamma-CD in one channel, while resolution of FITC-norfenefrine enantiomers was achieved by DM-beta-CD in the other channel in the same run. Furthermore, the feasibility of using one chiral selector to separate multiple chiral samples was studied on a four-channel chip. These results show that multichannel chip has a potential for chiral high-throughput screening.

Systemic administration of local anesthetic agents to relieve neuropathic pain.

BACKGROUND: Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain (Keats 1951; Gilbert 1951; De Clive-Lowe 1958; Bartlett 1961). Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients (Boas 1982; Lindblom 1984; Petersen 1986; Dunlop 1988; Bach 1990; Awerbuch 1990). With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy. OBJECTIVES: To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions. SEARCH STRATEGY: We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews. SELECTION CRITERIA: We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause. DATA COLLECTION AND ANALYSIS: We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively. MAIN RESULTS: Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P <0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias. AUTHORS' CONCLUSIONS: Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.

Tratamento famacológico da neuralgia do trigêmeo: revisão sistemática e metanálise / Pharmacological treatment of trigeminal neuralgia: systematic review and metanalysis

JUSTIFICATIVA E OBJETIVOS: A neuralgia do trigêmeo é uma síndrome de dor crônica, caracterizada por paroxismos de dor excruciante que afeta de maneira dramática a qualidade de vida dos pacientes acometidos. A terapia medicamentosa sistêmica é considerada o tratamento de primeira linha para esta doença. Este estudo teve como objetivo avaliar a eficácia, a segurança e a tolerabilidade dos diversos tratamentos farmacológicos oferecidos aos pacientes com neuralgia do trigêmeo, visando fornecer evidências para as recomendações da prática clínica e identificar as necessidades de pesquisas adicionais. MÉTODO: Foram analisados ensaios clínicos aleatórios e controlados, publicados até julho de 2003, sobre o efeito analgésico das drogas prescritas no tratamento da neuralgia do trigêmeo. A análise estatística foi realizada com o auxilio do programa Review Manager 4.2.2 (Colaboração Cochrane, 2003). RESULTADOS: Os resultados da metanálise sugerem que a carbamazepina é mais eficaz que o placebo. Em três estudos controlados comparando a lamotrigina, o topiramato e o cloridrato de proparacaína ao placebo, somente a lamotrigina mostrou-se superior a ele. O dextrometafano foi comparado ao lorazepam em baixas doses, havendo aumento da dor com o uso daquele fármaco. Três estudos compararam a carbamazepina com a tizanidina, a tocainida e a pimozida, mostrando-se apenas a pimozida superior à carbamazepina. CONCLUSÕES: A carbamazepina continua como droga de escolha para o tratamento da neuralgia do trigêmeo, estando a lamotrigina e a pimozida indicadas em casos refratários à terapia convencional. Além disso, estudos adicionais são necessários para o estabelecimento de futuras opções terapêuticas.

Synthesis, structure and pharmacology of acyl-2,6-xylidines.

L-2-perhydroheterocyclicalkyl acids were condensed with 2,6-xylidine. 8 new optically active acyl-2,6-xylidines were obtained. Absolute configuration of acyl-2,6-xylidines were selected for pharmacological examinations.