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1.
Toxins (Basel) ; 14(6)2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35737026

RESUMO

Botulinum neurotoxin type A (BoNT/A) causes muscle paralysis by blocking cholinergic signaling at neuromuscular junctions and is widely used to temporarily correct spasticity-related disorders and deformities. The paralytic effects of BoNT/A are time-limited and require repeated injections at regular intervals to achieve long-term therapeutic benefits. Differences in the level and duration of effectivity among various BoNT/A products can be attributed to their unique manufacturing processes, formulation, and noninterchangeable potency units. Herein, we compared the pharmacodynamics of three BoNT/A formulations, i.e., Botox® (onabotulinumtoxinA), Xeomin® (incobotulinumtoxinA), and Coretox®, following repeated intramuscular (IM) injections in mice. Three IM injections of BoNT/A formulations (12 U/kg per dose), 12-weeks apart, were administered at the right gastrocnemius. Local paresis and chemodenervation efficacy were evaluated over 36 weeks using the digit abduction score (DAS) and compound muscle action potential (CMAP), respectively. One week after administration, all three BoNT/A formulations induced peak DAS and maximal reduction of CMAP amplitudes. Among the three BoNT/A formulations, only Coretox® afforded a significant increase in paretic effects and chemodenervation with a prolonged duration of action after repeated injections. These findings suggest that Coretox® may offer a better overall therapeutic performance in clinical settings.


Assuntos
Toxinas Botulínicas Tipo A , Fármacos Neuromusculares , Animais , Toxinas Botulínicas Tipo A/toxicidade , Injeções Intramusculares , Camundongos , Espasticidade Muscular , Músculo Esquelético , Fármacos Neuromusculares/farmacologia , Paresia
3.
PLoS One ; 16(8): e0256869, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34449810

RESUMO

Human serum albumin (HSA) has been widely used as a pharmaceutical excipient in Botulinum toxin serotype A (BoNT/A) products that are indicated for use in therapeutics and cosmetics. However, HSA as a human-derived material has some concerns, such as the potential risk of transmission of infectious agents, an insufficient supply, and difficulty in maintaining a certain quality. For those reasons, newly developed BoNT/A products (CORETOX®, Medytox, Inc., Republic of Korea) contained polysorbate 20, a non-human-derived excipient, to replace the HSA. However, most safety studies of polysorbate 20 have been conducted with non-invasive routes of administration, and thus there are a few studies on the safety of polysorbate 20 when administered intramuscularly. To secure the in vivo safety profile of polysorbate 20, a four-week repeated intramuscular dose toxicity study (0.02, 0.1, and 0.4 mg/kg, one injection every two weeks for a total of three injections) was conducted in 66 Sprague-Dawley (SD) rats. An intradermal irritation study was further conducted with 18 New Zealand White (NZW) rabbits. The toxicological evaluation of HSA (0.06 and 0.12 mg/kg) was also carried out as a comparative substance. Systemic and local toxicities were not observed in any of the SD rats or NZW rabbits based on clinical signs, body weight, hematology, clinical biochemistry, macroscopic findings on necropsy, histopathology of the injection site, and allergic reactions. The current study suggested that intramuscular administration of polysorbate 20 was considered to be safe at a level similar to that of HSA, which has an in vivo safety profile accumulated over the years. This provided the basis for the in vivo safety profile of polysorbate 20 administered intramuscularly and the scientific reliability of the use of polysorbate 20 as an alternative to HSA, which is used as an excipient for various pharmaceuticals in terms of its safety.


Assuntos
Botulismo/tratamento farmacológico , Polissorbatos/farmacologia , Animais , Toxinas Botulínicas/antagonistas & inibidores , Excipientes , Humanos , Polissorbatos/efeitos adversos , Coelhos , Ratos , Ratos Sprague-Dawley , República da Coreia , Albumina Sérica Humana/efeitos adversos , Albumina Sérica Humana/uso terapêutico
4.
Clin Cosmet Investig Dermatol ; 14: 765-778, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239313

RESUMO

PURPOSE: Hyaluronic acid (HA)-based dermal fillers have been approved for various clinical indications, both cosmetic and medical. Previous studies that have assessed the performance of HA dermal fillers have primarily focused on evaluating filler durability, and only a few have studied their distribution within the tissues. The present study aimed to compare tissue integration of various types of HA dermal fillers having different clinical indications and varying injection depths. METHODS: To examine the local inflammatory response and distribution pattern of 14 HA dermal fillers (six Neuramis [NEU], one Belotero [BEL], three Juvéderm [JUV], and four Restylane [RES]), each product was injected intradermally and subcutaneously at the backs of two male miniature pigs. Histopathological evaluation and visual examination of the tissue sections were conducted 1 and 4 weeks after injection. RESULTS: Mean inflammatory cell infiltration scores tended to be lower in response to fillers from the NEU and BEL series than to those from the JUV and RES series after intradermal and subcutaneous injection. Furthermore, the inflammatory response to fillers with higher physicochemical properties specifically designed for injection into deeper layers of the skin tended to be slightly higher than those designated for injection into more superficial layers. There was no significant difference in tissue integration according to clinical indication and injection depth, although fillers from the NEU and BEL series exhibited better tissue integration than those from the JUV and RES series. CONCLUSION: Our findings not only suggest that the local inflammatory response and tissue integration differ across HA dermal filler products, but also that these parameters could vary according to the recommended clinical indication and injection depth of the products.

5.
Clin Cosmet Investig Dermatol ; 14: 241-248, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33727845

RESUMO

PURPOSE: Hyaluronic acid (HA) is the most common injectable dermal filler used for soft-tissue augmentation, and can be removed non-surgically by directly injecting hyaluronidase. In this study, the hyaluronidase-mediated degradation of different types of HA fillers implanted subcutaneously at the back of hairless mice having filler residence time of four days or three months were compared. METHODS: Two sites at the back of female hairless mice were subcutaneously implanted with 0.1-mL of one of the seven HA fillers (NLL, NL, NDL, NVL, and ND, JUVX+, and RESLYFT) and injected with 30 IU or 60 IU hyaluronidase per 0.1-mL filler after reaching a filler residence time of 4 or 91 days, respectively. Filler bolus projection was measured using three-dimensional optical imaging over a 72 h period, and the implantation sites were histologically examined 2 weeks after hyaluronidase injection. RESULTS: Following hyaluronidase injection, all seven HA fillers showed a rapid decrease of filler volume within 24 h, and complete degradation was confirmed by histological examination after 2 weeks. There was no significant difference in filler volume reduction rate among the seven HA fillers, and no evidence of macroscopic or microscopic adverse effects were observed at the implantation sites. CONCLUSION: All seven HA fillers show comparable susceptibility to hyaluronidase-mediated degradation. HA fillers with prolonged filler residence time may require a higher dose of hyaluronidase to achieve efficient degradation owing to tissue integration.

6.
Pharmaceutics ; 13(2)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494145

RESUMO

Dermal fillers are gel-type substances for nonsurgical medical-device use to achieve facial rejuvenation. Currently, the most widely used skin fillers are hyaluronic-acid-based dermal fillers. This study aimed to explain the change in the volume of injected dermal fillers by developing a mathematical kinetic model for various dermal fillers. The kinetics of the injected fillers were separated by a biphasic phenomenon. We attributed an increase in filler volume to the hydration of hyaluronic acid molecules and injection-site reaction and a decrease in volume to enzyme-mediated degradation. To explain these in vivo characteristics of dermal fillers, we proposed a two-compartment model, divided into a depot compartment (where the filler was injected) and a subcutaneous compartment (an observation compartment where the fillers swell and degrade), assuming that the swelling and degradation occurred in accordance with the swelling and degradation rate constants, respectively. The model was developed using five hyaluronic-acid-based dermal fillers and NONMEM. We determined that the rate-limiting step for the complete degradation of the dermal fillers in vivo was the swelling phase, as described by the swelling rate constant (Kswell). This study could enable scientists developing novel dermal fillers to predict the in vivo behavior of fillers.

7.
Dermatol Surg ; 46(12): e132-e138, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32251006

RESUMO

BACKGROUND: A new complexing protein-free botulinum toxin Type A (CBoNT) with the same mechanism of action as the botulinum toxin complex onabotulinumtoxinA (OBoNT) and complexing protein-free incobotulinumtoxinA (IBoNT) was recently developed. OBJECTIVE: To compare the local paresis and chemodenervation efficacy of 3 different botulinum toxin Type A preparations in mice. MATERIALS AND METHODS: Efficacy and duration of action of CBoNT, OBoNT, and IBoNT after a single intramuscular injection to the right gastrocnemius was evaluated by digit abduction score (DAS) and compound muscle action potential (CMAP) assays. RESULTS: Mouse DAS and CMAP responses were comparable between CBoNT and OBoNT, indicating similar paresis and chemodenervation efficacy, as well as duration of action. Both botulinum toxins showed significantly higher efficacy and longer duration of action than IBoNT. Similarly, mean DAS potency of CBoNT (ED50: 3.85 ± 0.34 U/kg) and OBoNT (ED50: 4.13 ± 0.07 U/kg) were significantly higher compared with IBoNT (ED50: 6.70 ± 0.83 U/kg). CONCLUSION: CBoNT displays the same efficacy as OBoNT as shown by their comparable chemodenervation and local paretic effects, and demonstrates superior efficacy and duration of action compared with IBoNT. Likewise, CBoNT has comparable DAS potency to OBoNT and is superior to IBoNT.


Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Músculo Esquelético/efeitos dos fármacos , Bloqueio Nervoso/métodos , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Injeções Intramusculares , Camundongos , Modelos Animais , Músculo Esquelético/inervação , Fatores de Tempo
8.
Forensic Sci Int ; 257: 513.e1-513.e9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26375427

RESUMO

OBJECTIVE: From computed tomographic images, the dentocentral synchondrosis can be identified in the second cervical vertebra. This can demarcate the border between the odontoid process and the body of the 2nd cervical vertebra and serve as a good model for the prediction of bone and forensic age. Nevertheless, until now, there has been no application of the 2nd cervical vertebra based on the dentocentral synchondrosis. METHODS: In this study, statistical shape analysis was used to build bone and forensic age estimation regression models. Following the principles of statistical shape analysis and principal components analysis, we used cone-beam computed tomography (CBCT) to evaluate a Japanese population (35 males and 45 females, from 5 to 19 years old). RESULTS: The narrowest prediction intervals among the multivariate regression models were 19.63 for bone age and 2.99 for forensic age. There was no significant difference between form space and shape space in the bone and forensic age estimation models. However, for gender comparison, the bone and forensic age estimation models for males had the higher explanatory power. CONCLUSION: This study derived an improved objective and quantitative method for bone and forensic age estimation based on only the 2nd, 3rd and 4th cervical vertebral shapes.


Assuntos
Determinação da Idade pelo Esqueleto/métodos , Vértebras Cervicais/diagnóstico por imagem , Modelos Estatísticos , Adolescente , Adulto , Povo Asiático , Vértebras Cervicais/anatomia & histologia , Criança , Pré-Escolar , Tomografia Computadorizada de Feixe Cônico , Feminino , Antropologia Forense , Humanos , Japão , Masculino , Análise Multivariada , Análise de Componente Principal , Estudos Retrospectivos , Adulto Jovem
9.
Korean J Orthod ; 45(2): 59-65, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25798411

RESUMO

OBJECTIVE: To investigate skeletal and dental changes after application of a mandibular setback surgery-first orthodontic treatment approach in cases of skeletal Class III malocclusion. METHODS: A retrospective study of 34 patients (23 men, 11 women; mean age, 26.2 ± 6.6 years) with skeletal Class III deformities, who underwent surgery-first orthodontic treatment, was conducted. Skeletal landmarks in the maxilla and mandible at three time points, pre-treatment (T0), immediate-postoperative (T1), and post-treatment (T2), were analyzed using cone-beam computed tomography (CBCT)-generated half-cephalograms. RESULTS: The significant T0 to T1 mandibular changes occurred -9.24 ± 3.97 mm horizontally. From T1 to T2, the mandible tended to move forward 1.22 ± 2.02 mm, while the condylar position (Cd to Po-perpendicular plane) shifted backward, and the coronoid process (Cp to FH plane) moved vertically. Between T1 and T2, the vertical dimension changed significantly (p < 0.05). Changes in the vertical dimension were significantly correlated to T1 to T2 changes in the Cd to Po-perpendicular plane (r = -0.671, p = 0.034), and in the Cp to FH plane (r = 0.733, p = 0.016), as well as to T0 to T1 changes in the Cp to Po-perpendicular plane (r = 0.758, p = 0.011). CONCLUSIONS: Greater alterations in the vertical dimension caused larger post-treatment (T2) stage skeletal changes. Studying the mandibular position in relation to the post-surgical vertical dimension emphasized the integral importance of vertical dimension control and proximal segment management to the success of surgery-first orthodontic treatment.

10.
Toxicon ; 60(3): 341-7, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22613167

RESUMO

PURPOSE: We performed a prevalidation of the compound muscle action potential (CMAP) assay to determine the potency of botulinum neurotoxin type A (BoNT/A) with the aim of substituting for the mouse lethality test (LD50), which is used for quality control. METHODS: Prevalidation experiments were performed to demonstrate the specificity, linearity, accuracy, precision, range, limit of quantitation (LOQ), and robustness of the assay. For specificity, toxin detection ability was determined in the presence of neutralizing antibodies (0.8 and 8 IU/mL). Linearity of this assay was determined by measuring CMAP amplitude using nine concentrations (n = 3) in the range of 1-100 U/mL (n = 3). Accuracy was assessed using five concentrations (n = 3) in the range of 4-40 U/mL. Intermediate precision was confirmed by analyzing individually prepared reagents on multiple days by one operator (n = 3). Different body weights (23-25 and 25-27 g) and measurement times (3-5 and 5-7 min) after anesthetic induction were tested to assess robustness. RESULTS: This assay might have BoNT/A specificity, based on the CMAP amplitude recovery using a concentration of neutralizing antibodies. The calibration curves were linear over the range of 2-40 U/mL (R² = 0.982). The accuracy of 14 determinations was within the range of 89.8-118.6% compared to the theoretical values among 15 determinations, except one (131.3%). Assay variability was acceptable with coefficients of variation of 4.3-14.4%. The range of quantification and the LOQ were 4-40 U/mL and 4 U/mL, respectively. Different body weights and measurement times after inducing anesthesia had no effect on CMAP amplitude. CONCLUSIONS: These results suggest that the mouse CMAP assay is an alternative method to the standard LD50 potency test and meets the requirement of the three Rs (particularly refinement and reduction).


Assuntos
Potenciais de Ação/efeitos dos fármacos , Alternativas ao Uso de Animais , Toxinas Botulínicas Tipo A/farmacologia , Química Farmacêutica/métodos , Músculo Esquelético/efeitos dos fármacos , Bloqueadores Neuromusculares/farmacologia , Animais , Anticorpos Neutralizantes/metabolismo , Blefarospasmo , Antitoxina Botulínica/farmacologia , Toxinas Botulínicas Tipo A/antagonistas & inibidores , Calibragem , Estudos de Viabilidade , Feminino , Camundongos , Camundongos Endogâmicos ICR , Músculo Esquelético/metabolismo , Bloqueadores Neuromusculares/antagonistas & inibidores , Concentração Osmolar , Músculos Psoas/efeitos dos fármacos , Músculos Psoas/metabolismo , Controle de Qualidade , Reprodutibilidade dos Testes , Fatores de Tempo
11.
Appl Biochem Biotechnol ; 135(1): 59-80, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17057256

RESUMO

The production of recombinant anti-HIV peptide, T-20, in Escherichia coli was optimized by statistical experimental designs (successive designs with multifactors) such as 2(4-1) fractional factorial, 2(3) full factorial, and 2(2) rotational central composite design in order. The effects of media compositions (glucose, NPK sources, MgSO4, and trace elements), induction level, induction timing (optical density at induction process), and induction duration (culture time after induction) on T-20 production were studied by using a statistical response surface method. A series of iterative experimental designs was employed to determine optimal fermentation conditions (media and process factors). Optimal ranges characterized by %T-20 (proportion of peptide to the total cell protein) were observed, narrowed down, and further investigated to determine the optimal combination of culture conditions, which was as follows: 9, 6, 10, and 1 mL of glucose, NPK sources, MgSO4, and trace elements, respectively, in a total of 100 mL of medium inducted at an OD of 0.55-0.75 with 0.7 mM isopropyl-beta-D-thiogalactopyranoside in an induction duration of 4 h. Under these conditions, up to 14% of T-20 was obtained. This statistical optimization allowed the production of T-20 to be increased more than twofold (from 6 to 14%) within a shorter induction duration (from 6 to 4 h) at the shake-flask scale.


Assuntos
Fármacos Anti-HIV/farmacologia , Biotecnologia/métodos , Escherichia coli/metabolismo , Peptídeos/química , Reatores Biológicos , Meios de Cultura , Desenho de Fármacos , Eletroforese em Gel de Poliacrilamida , Fermentação , Regulação Bacteriana da Expressão Gênica , Sulfato de Magnésio/química , Engenharia de Proteínas , Proteínas Recombinantes/química , Análise de Regressão , Fatores de Tempo
12.
Appl Biochem Biotechnol ; 135(1): 81-110, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17057257

RESUMO

The medium formulation and robust process modeling for anti-HIV peptide (T-20) production by recombinant Escherichia coli overexpression were studied by employing a crossed experimental design. The crossed design, a mixture design combined with process factor (induction duration), was used to find the optimal medium formulation and process time. The optimal settings for three major components (7.75 mL of NPK sources, 5.5 mL of glucose, and 11.75 mL of MgSO4) characterized by %T-20 (14.45%), the proportion of peptide to the total protein, were observed in a total of 100 mL of medium inducted at an optical density of 0.67 with 0.7 mM isopropyl-beta-D-thiogalactopyranoside) for a 3-h induction duration at shake-flask scale. These conditions were further investigated to find robust process conditions (8.2 mL of NPK sources, 5.6 mL of glucose, and 11.3 mL of MgSO4, and a 3.5-h induction duration time) for T-20 production (13.9%) by applying propagation of error.


Assuntos
Biotecnologia/métodos , Escherichia coli/metabolismo , Peptídeos/química , Engenharia de Proteínas/métodos , Fármacos Anti-HIV/química , Química Farmacêutica/métodos , Meios de Cultura , Desenho de Fármacos , Eletroforese em Gel de Poliacrilamida , Regulação Bacteriana da Expressão Gênica , Modelos Estatísticos , Plasmídeos/metabolismo , Proteínas Recombinantes , Análise de Regressão , Fatores de Tempo
13.
Biotechnol Lett ; 28(15): 1159-62, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16810450

RESUMO

The effects of glycerol and the oxygen transfer rate on the xylitol production rate by a xylitol dehydrogenase gene (XYL2)-disrupted mutant of Candida tropicalis were investigated. The mutant produced xylitol near the almost yield of 100% from D: -xylose using glycerol as a co-substrate for cell growth and NADPH regeneration: 50 g D: -xylose l(-1) was completely converted into xylitol when at least 20 g glycerol l(-1) was used as a co-substrate. The xylitol production rate increased with the O(2) transfer rate until saturation and it was not necessary to control the dissolved O(2) tension precisely. Under the optimum conditions, the volumetric productivity and xylitol yield were 3.2 g l(-1) h(-1) and 97% (w/w), respectively.


Assuntos
Candida tropicalis/enzimologia , Candida tropicalis/genética , D-Xilulose Redutase/metabolismo , Glicerol/metabolismo , Xilitol/biossíntese , Aerobiose/fisiologia , Candida tropicalis/metabolismo , Microbiologia Industrial/métodos , Cinética , Oxigênio/metabolismo
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