Cenobamate (XCOPRI): Can preclinical and clinical evidence provide insight into its mechanism of action?

Approximately one-third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic seizures, the precise mechanism(s) through which CBM exerts its broad-spectrum antiseizure effects is not known. Experimental evidence suggests that CBM differentiates itself from other ASMs in that it appears to possess dual modes of action (MOAs); that is, it predominately blocks persistent sodium currents and increases both phasic and tonic γ-aminobutyric acid (GABA) inhibition. In this review, we analyze the preclinical efficacy of CBM alongside ASMs with similar MOAs to better understand the mechanism(s) through which CBM achieves such broad-spectrum seizure protection. CBM's preclinical performance in tests, including the mouse 6-Hz model of treatment-resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage-gated sodium channel blockers and GABAA modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy-resistant epilepsy.

[Clinical observation on the inflammatory indexes in septic gastrointestinal dysfunction treated with acupuncture at Jiaji (EX-B 2)].

OBJECTIVE: To evaluate the effect on the inflammatory indexes of septic gastrointestinal dysfunction treated with acupuncture at Jiaji (EX-B 2). METHODS: A total of 118 patients of septic gastrointestinal dysfunction were randomized into an observation group and a control group, 59 cases in each one. In the control group, mosapride citrate was prescribed for oral administration, 5 mg each time, 3 times a day, bifidobacterium triple viable capsules, 420 mg each time, twice a day, intravenous drip with omeprazole, 40 mg, twice a day. Additionally, the antibiotics and the symptomatic treatment were selected rationally for maintaining the functions of the important organs, e.g. heart, lung, brain and kidney, and water-electrolyte balance. In the observation group, on the routine management as the control group, acupuncture at Jiaji (EX-B 2, T6-T12) was added, the needles were retained for 30 min in each treatment, once a day, 10 days as one course and 1 course was required. Separately, on the 1st, 3rd, 6th and 10th days of treatment, the white blood cell (WBC) count, the levels of hypersensitive C-reactive protein (hs-CRP) and procalcitonin (PCT) were observed, the enteral nutrition feeding dose and gastrointestinal dysfunction score before and after treatment as well as the clinical effect were assessed in the two groups. RESULTS: The differences were not significant in the indexes mentioned above on 1st and 3rd days of treatment between the two groups (P>0.05). On the 6th and 10th days of treatment, regarding the gastrointestinal dysfunction score and inflammatory indexes count, the results in the observation group were lower than the control group (all P<0.05), and feeding dose in the observation group was higher than the control group (P<0.05). After treatment, the gastrointestinal dysfunction scores and inflammatory indexes count were all reduced and feeding dose was increased as compared with those before treatment in the patients of the two groups (all P<0.05). After treatment, the total effective rate was 91.5% (54/59) in the observation group, higher than 76.3% (45/59) in the control group (P<0.05). CONCLUSION: Acupuncture at Jiaji (EX-B 2) points achieves the satisfactory effect on septic gastrointestinal dysfunction and reduces the inflammatory indexes count.

Complestatin exerts antibacterial activity by the inhibition of fatty acid synthesis.

Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In the screening of inhibitors of Staphylococcus aureus enoyl-ACP reductase (FabI), complestatin was isolated as a potent inhibitor of S. aureus FabI together with neuroprotectin A and chloropeptin I from Streptomyces chartreusis AN1542. Complestatin and related compounds inhibited S. aureus FabI with IC50 of 0.3-0.6 µM. They also prevented the growth of S. aureus as well as methicillin-resistance S. aureus (MRSA) and quinolone-resistant S. aureus (QRSA), with minimum inhibitory concentrations (MICs) of 2-4 µg/mL. Consistent with its FabI-inhibition, complestatin selectively inhibited the intracellular fatty acid synthesis in S. aureus, whereas it did not affect the macromolecular biosynthesis of other cellular components, such as DNA, RNA, proteins, and the cell wall. Additionally, supplementation with exogenous fatty acids reversed the antibacterial effect of complestatin, demonstrating that it targets fatty acid synthesis. In this study, we reported that complestatin and related compounds showed potent antibacterial activity via inhibiting fatty acid synthesis.

In vivo antimicrobial effects of endodontic treatment procedures as assessed by molecular microbiologic techniques.

INTRODUCTION: This culture-independent molecular microbiology study evaluated the antimicrobial effects of chemomechanical preparation supplemented by intracanal medication during treatment of teeth with apical periodontitis. METHODS: Samples were taken from 24 necrotic root canals at the baseline (S1), after chemomechanical preparation by using 2.5% NaOCl as the irrigant (S2), and after a 7-day interappointment medication with calcium hydroxide paste in either glycerin (CHG) or camphorated paramonochlorophenol/glycerin (CHPG) (S3). Bacterial, archaeal, and fungal presence was evaluated by polymerase chain reaction (PCR), and bacterial identifications were performed by a closed-ended reverse-capture checkerboard approach targeting 28 candidate endodontic pathogens. RESULTS: All S1 samples were positive for bacteria but negative for both archaea and fungi. Treatment procedures were highly effective in reducing the bacterial levels and number of taxa. Overall, 46% of S2 samples and 62.5% of S3 samples were PCR-negative for bacteria. Specifically, S2 and S3 samples yielded negative PCR results in 50% and 58% of the canals in the CHG group and in 42% and 67% of the canals in the CHPG group, respectively. Except for comparisons with S1 samples, no other statistically significant differences were observed for intragroup and intergroup comparisons involving S2 and S3. Several taxa were still found in S2 and S3 samples, and the most prevalent were Propionibacterium acnes and Streptococcus species. CONCLUSIONS: Bacterial levels and number of taxa were substantially reduced after chemomechanical preparation and intracanal medication. However, presence of detectable levels of persisting bacteria in many cases indicates that the search for more effective antimicrobial treatment strategies should be stimulated.

Periradicular repair after two-visit endodontic treatment using two different intracanal medications compared to single-visit endodontic treatment.

The number of appointments necessary to treat infected root canals is one of the most controversial issues in endodontics. This study evaluated, in dogs, the response of the periradicular tissues to the endodontic treatment of infected root canals performed in a single visit or in two visits, using different interappointment dressings. Periradicular lesions were induced by inoculating Enterococcus faecalis in the root canals. After confirming that a periradicular lesion developed, the root canals were treated within one or two visits, using either ozonized oil or calcium hydroxide in camphorated paramonochlorophenol (CMCP) as an intracanal medication. After 6 months, the animals were sacrificed and the specimens were processed for histological and histobacteriological analysis. The root canals treated in a single visit showed a success rate of 46%. When a calcium hydroxide/CMCP-based interappointment intracanal medication was used, 74% of the cases were categorized as success. In cases where ozonized oil was used as the intracanal medication, a success rate of 77% was observed. These results of the present study demonstrated that the two-visit treatment offered a higher success rate compared to one-visit therapy. In addition, ozonized oil may potentially be used as an intracanal medication.

Periradicular repair after two-visit endodontic treatment using two different intracanal medications compared to single-visit endodontic treatment

The number of appointments necessary to treat infected root canals is one of the most controversial issues in endodontics. This study evaluated, in dogs, the response of the periradicular tissues to the endodontic treatment of infected root canals performed in a single visit or in two visits, using different interappointment dressings. Periradicular lesions were induced by inoculating Enterococcus faecalis in the root canals. After confirming that a periradicular lesion developed, the root canals were treated within one or two visits, using either ozonized oil or calcium hydroxide in camphorated paramonochlorophenol (CMCP) as an intracanal medication. After 6 months, the animals were sacrificed and the specimens were processed for histological and histobacteriological analysis. The root canals treated in a single visit showed a success rate of 46 percent. When a calcium hydroxide/CMCP-based interappointment intracanal medication was used, 74 percent of the cases were categorized as success. In cases where ozonized oil was used as the intracanal medication, a success rate of 77 percent was observed. These results of the present study demonstrated that the two-visit treatment offered a higher success rate compared to one-visit therapy. In addition, ozonized oil may potentially be used as an intracanal medication.

O número de sessões necessárias para tratar um canal radicular infectado é um dos assuntos mais controversos da endodontia. O objetivo deste estudo foi analisar, em cães, a resposta dos tecidos perirradiculares ao tratamento endodôntico de canais infectados em uma ou duas consultas, usando diferentes medicamentos entre as sessões. Lesões perirradiculares foram induzidas pela inoculação de Enterococcus faecalis nos canais. Após a confirmação do desenvolvimento de uma lesão perirradicular, os canais foram tratados em uma ou duas sessões, usando óleo ozonizado ou hidróxido de cálcio associado ao paramonoclorofenol canforado (PMCC) como medicação intracanal. Após 6 meses, os animais foram sacrificados e os espécimes processados para análise histológica e histobacteriológica. Os canais tratados em sessão única apresentaram uma taxa de sucesso de 46 por cento dos casos. Quando a medicação usada entre as sessões foi o hidróxido de cálcio associado com o PMCC, 74 por cento dos casos resultaram em sucesso. Nos casos em que o óleo ozonizado foi usado, uma taxa de sucesso de 77 por cento foi observada. Esses achados demonstraram que o tratamento em duas sessões oferece uma taxa de sucesso mais alta quando comparado à terapia em uma sessão. Além disso, o óleo ozonizado mostrou potencial para ser usado como medicação intracanal.

Bacterial leakage in roots filled with different medicaments and sealed with Cavit.

The aim of this study was to evaluate the time required by four different root canal medications coupled with the temporary filling material Cavit (ESPE, Seefeld, Germany) to prevent penetration of bacteria into the root canal. There were 145 roots prepared in a standardized manner. Four groups with 15 samples each were dressed with calcium hydroxide (Ca(OH)(2)), a 5% chlorhexidine gel (CHX), a chloromono-campherphenolic compound (ChKM), and Ledermix (LM), respectively, and sealed with Cavit. Four control groups contained identical medications but the roots were left unsealed. The 25 remaining roots served as additional controls. A standard setup for bacterial leakage studies was chosen with Staphylococcus epidermidis as test strain. Cavit application resulted in a significantly better seal compared with the unsealed groups. In the Cavit-sealed groups, all groups differed significantly from one another except for the CHX and the ChKM groups. The Ca(OH)(2) medicated roots provided the longest protection (median of 36 days), followed by the Ledermix-group (27 days) and the CHX (18 days) or ChKM groups (19 days). It may be concluded that Cavit-sealed and medicated root canals do not provide adequate protection against bacterial leakage for more than 1 month.

Efficacy of camphorated paramonochlorophenol to a mixture of honey and mustard oil as a root canal medicament.

OBJECTIVE: To compare the efficacy of camphorated paramonochlorophenol to a mixture of honey and mustard oil as a root canal medicament. DESIGN: An in vitro comparative study. PLACE AND DURATION OF STUDY: This study was carried out in collaboration with microbiology department of Armed Forces Institute of Pathology, Rawalpindi and was conducted from Aug-2001 to Nov-2001. MATERIALS AND METHODS: A sample of 90 infected root canal contents of decayed teeth was collected from Operative Dentistry Department of Armed Forces Institute of Dentistry, Rawalpindi. Each sample was inoculated aerobically as well as an-aerobically. Organisms were identified and isolates were preserved and refrigerated for experiments. Medicaments were procured and prepared in comparable dilutions. Minimum inhibitory concentration of both medicaments was compared by susceptibility testing against already preserved isolates. RESULTS: The tested mixture (honey and mustard oil equal v/v ) demonstrated antibacterial activity against all isolates at concentration of 12.5%(mean of effective conc.17.11%) while that of camphorated paramonochlorophenol was comparably at higher concentration 3.1%(mean of effective conc. 3.35%). However the mixture revealed better results than that of individual agents, which was 12.5% to 25% respectively. CONCLUSION: Mixture (honey and mustard oil) was effective, viable alternate endodontic medicament.

[Activity of the anthelmintic agent trichlorophen on the models of human helminthiasis]. / Aktivnost' otechestvennogo antigel'mintika trikhlofena na modeliakh gel'mintozov cheloveka.

Trials of trichlorophen have shown its high efficacy on models of cestode infections: hymenolepiasis (at the adult and cysticercoid stages of development on three types of animals: outbred albino mice, albino rats and golden hamsters), preimaginal echinococciasis alveolaris, larval alveolar echinococciasis (at the early stage of development of the parasite in experiments on cotton rats). The high nematodical activity of trichlorophen was first found on models of trichocephaliasis in DBA/2y mice, nippostrongyloidiasis (in in vitro experiments), and aspiculuriasis in outbred mice. The agent proved to be ineffective at the tissue developmental stage of Hymenolepsis nana (H. nana), the dwarf tapeworm, in albino mice, during experimental opisthorchiasis in golden hamsters. It showed a low efficacy in treating trichinosis in outbred albino mice. Unlike carbamatebenzimidazoles, trichlorophen was inactive at the tissue stage of H. nana; it exerted no effects on the eggs of a dwarf tapeworm in trichinosis. Trichlorophen was also inactive in treating experimental opisthorchiasis in golden hamsters.

[Efficacy of the Russian anthelmintic agent trichlorophen]. / Potentsiruiushchie effecty otechestvennogo antigel'mintika trikhlofena.

Experiments have established the high efficacy of combinations of the micronized dosage form of trichlorophen, with albendazole or medamine in treating trichocephaliasis (its causative agent being Trichocephalus muris) in DBA/2st mice and that of trichlorophen in combination with azinox or fenasal in outbred albino mice with hymenolepiasis (its causative agent being Hymenolepis nana). These combinations are promising in treating patients with cestodosis and nemadosis, respectively.

[The effect of treatment on the course of invasion by Hymenolepis nana and the state of its population in white mice]. / Vliianie lecheniia na techenie invazii i sostoianie populiatsii Hymenolepis nana u belykh myshei.

Leukinferon administered before infection affects the development of a Hymenolepis nana population in the murine intestine: in rodents, its defective forms predominate over mature ones. Leukinferon caused cell prestimulation in the immune system and activation of nonspecific defense factors. The cytokine properties of the agent appear to have an impact on parasitic growth and development by leading to formation of defective Hymenolepis forms directly and indirectly through the host's body due to the prestimulation and enhancement of nonspecific defense. There may be a concurrent influence of these factors on H. nana embryos in the murine intestine.

[Approaches to the combined therapy of helminthiases with leukinferon and etiotropic preparations]. / Podkhody k kombinirovannoi terapii gel'mintozov leikinferonom i étiotropnymi preparatami.

The results of therapy with anthelmintics in combination with leukinferon show either higher efficiency of anthelmintics (medamin) or their same efficiency (albendazole). The outcomes of combined treatment of infected animals with anthelmintics and leukinferon are different and associated with the time of leukinferon administration as to the tissue stages of parasitic development, with the host's sensitivity and susceptibility to helminth.

Recontamination of coronally unsealed root canals medicated with camphorated paramonochlorophenol or calcium hydroxide pastes after saliva challenge.

This in vitro study evaluated the ability of some medications to prevent recontamination of coronally unsealed root canals by bacteria from saliva. The medications tested were camphorated paramonochlorophenol (CPMC) applied in cotton pellets in the pulp chamber; calcium hydroxide/saline solution paste filling the root canal; and calcium hydroxide/CPMC/glycerin paste also filling the root canal. Medicated canals were exposed to saliva, and the number of days required for total recontamination to occur was recorded. Canals medicated with CPMC in cotton pellets were thoroughly recontaminated within an average of 6.9 days. Canals filled with calcium hydroxide/saline solution and calcium hydroxide/CPMC/glycerin showed entire recontamination within an average of 14.7 and 16.5 days, respectively. Calcium hydroxide pastes were significantly more effective than CPMC (p < 0.05).

Estudo histomorfológico do tecido conjuntivo subcutâneo do rato ao implante de pastas à base de hidróxido de cálcio, contidas em tubos de dentina humana / Histomorphologic study of the subcutaneous connective tissue reactions of rat, due to the implantation of calcium hydroxide pastes contained in human dentin tubes

Foram utilizados 36 ratos, albinos, machos, adultos jovens, divididos em 3 grupos, de 12 animais cada, agrupados inicialmente em gaiolas para 3 indivíduos. Os animais receberam implantes de tubos de dentina humana contendo as seguintes pastas: Grupo I - Hidróxido de cálcio + Polietileno glicol 400; Grupo II - Hidróxido de cálcio + Lipiodol (ultrafluido) e Grupo III - Hidróxido de cálcio + Paramonoclorofenol canforado 2,5:7,5. Decorridos os períodos de 30, 60, 90 e 120 dias, os animais foram recuperados e as áreas circunjacentes aos implantes, removidas e preparadas para estudo histológico. Os resultados microscópicos mostraram que as misturas correspondentes aos Grupos I, II e III, comportaram-se como irritantes de tecido conjuntivo subcutâneo do rato, possibilitando no entanto cápsula em colagenizaçäo progressiva no decorrer dos períodos