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AIM: Determine the potential for cheek pouch buccal mucosa irritation in hamsters following administration of apomorphine hydrochloride film (APL-130277). METHODS: Three studies were conducted with Syrian golden hamsters. (First study, four hamsters received APL-130277 three times a day [TID] for 7 days. Second study, four hamsters received APL-130277 once a day [QD] for days 1-3, twice a day [BID] for days 4-7 and TID for days 8-21. Third study, 32 hamsters received either a placebo strip or APL-130277-dosed TID for 28 days). For all the studies, the macroscopic appearance of the buccal cavities was evaluated throughout the study. In the third study, all animals were necropsied on day 29, and macroscopic and histopathological examinations were performed. RESULTS: In the first and second studies, the buccal mucosa of the cheek pouch did not show any signs of irritation. In the third study, administration of APL-130277-dosed TID for 28 consecutive days did not result in observable local irritation of the buccal mucosa. CONCLUSION: In all the studies, APL-130277 produced no irritation of the cheek pouch buccal mucosa.
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Apomorfina/administração & dosagem , Bochecha , Mucosa Bucal/efeitos dos fármacos , Administração Sublingual , Animais , Apomorfina/efeitos adversos , Cricetinae , MesocricetusRESUMO
The first-line treatment for cervical dystonia (CD) is botulinum toxin type A (BoNT-A), which has been established as a highly effective and well-tolerated therapy. However, this treatment is also complex and challenging to apply in clinical practice. Approximately 20% of patients discontinue therapy due to treatment failure, adverse effects, and other reasons. In addition, expert consensus recommendations are lacking to guide physicians in the optimal use of BoNT-A for CD. Among the issues still to be clarified is the optimal dosing frequency. The generally accepted standard for intervals between BoNT-A injections is ≥12 weeks; however, this standard is based primarily on the methodology of pivotal trials for the BoNT-A products, rather than on evidence that it is optimal in comparison to other intervals. While some retrospective, observational studies of BoNT-A used in clinical practice appear to support the use of ≥12-week dosing intervals, it is often unclear in these studies how the need for reinjection was determined. In contrast, a prospective dose-ranging trial in which patients were allowed to request reinjection as early as 8 weeks showed that about half of patients receiving abobotulinumtoxinA, at the currently recommended initial dose of 500â U, requested reinjection at 8 weeks. Moreover, results from an open-label, 68-week extension phase of the pivotal trial of incobotulinumtoxinA showed that 47.1% of patients had received reinjection at ≤12 weeks. Ongoing studies, such as the Cervical Dystonia Patient Registry for Observation of BOTOX® Efficacy (CD PROBE), may help clarify this question of optimal dosing intervals for BoNT-A in CD.
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BACKGROUND: XCiDaBLE is a large, prospective, observational "naturalistic" study evaluating Xeomin® for Cervical Dystonia or BLEpharospasm in the United States. We report the interim results from the blepharospasm cohort of XCiDaBLE. METHODS: Subjects (â§18 years old) with blepharospasm were followed for two treatment cycles of incobotulinumtoxinA and monitored for 4 weeks after injection via interactive voice/web response system (IVRS/IWRS). The investigator-reported scale includes the Clinical Global Impression Scale-Severity subscale (CGI-S). Patient-reported outcome measures include the Patient Global Impression Scale-Severity (PGI-S) and -Improvement (PGI-I) subscales, Jankovic Rating Scale (JRS), SF-12v2® health survey, and Work Productivity and Activity Impairment questionnaire. Subjects are seen by the investigator at baseline (including the first injection), during the second injection, and at a final study visit (12 weeks after the second injection). RESULTS: One hundred seventy subjects were included in this interim analysis. The majority of subjects were female (77.1%) and white (91.8%), and had previously been treated with botulinum toxins (96.5%). The mean total dose (both eyes) was 71.5â U of incobotulinumtoxinA for the first injection. PGI-S, PGI-I, and JRS scores were significantly improved 4 weeks after treatment (all p<0.0001). No differences were noted in either quality of life (QoL) or work productivity in this short assessment period. No unexpected adverse events occurred. DISCUSSION: This is an interim study and assessment method based on an IVRS/IWRS. In this predominantly toxin-experienced cohort, significant benefits in specific and global measures of disease severity were seen in the immediate post-incobotulinumtoxinA injection period. It will be interesting to see if there are improvements in QoL with consistent individualized injections over a longer period.
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BACKGROUND: We report the interim results from XCiDaBLE, a large, prospective, observational "naturalistic" study evaluating Xeomin® (incobotulinumtoxinA) for Cervical Dystonia or BLEpharospasm in the United States. METHODS: Subjects (≥ 18 years old) with cervical dystonia (CD) are followed for two treatment cycles and monitored via Interactive Voice/Web Response. The subject's physician must have chosen to treat with incobotulinumtoxinA prior to and independent of enrollment in this study. Subject-reported scales include the Subject Global Impression-Severity and Improvement and Cervical Dystonia Impact Profile (CDIP-58), and Work Productivity and Quality of Life (QoL) are assessed by means of an employment questionnaire and work history and the SF-12v2 Health Survey (SF-12v2). Subjects are seen by the investigator for three visits, which include a baseline visit (including the first injection), a second injection visit, and a final study visit (12 weeks after the second injection). RESULTS: This ongoing study includes 145 subjects with a diagnosis of CD. The majority were female (82.3%) and white (91.0%) and had previously been treated with botulinum toxins (77.2%). There were 106 employed at the time of disease onset, but 12.6 years later only 44% were still employed at the time of enrolment into the study, and 20% were either receiving or seeking disability benefits. The mean total dose/treatment of CD was 225.2 units for the first injection. The CDIP-58 total score was significantly improved 4 weeks after the first injection compared to baseline (p≤0.0001). Most subjects noted improvement in their global impression assessment. No new or unexpected adverse events occurred. DISCUSSION: The results from these interim analyses confirm previous controlled, single-dose studies of incobotulinumtoxinA in terms of efficacy and safety.
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BACKGROUND: To determine whether botulinum toxin treatment history affected the outcomes of a study comparing the safety and efficacy of incobotulinumtoxinA with placebo in subjects with cervical dystonia (CD). METHODS: This was a prospective, double-blind, randomized, placebo-controlled, multicenter trial in botulinum toxin-treated or toxin-naïve CD subjects. Subjects received a fixed dose of either 120 U or 240 U of incobotulinumtoxinA or placebo. The primary outcome measure was change from baseline to Week 4 in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score. Treatment-emergent adverse events (TEAEs) were also evaluated. This report represents a subgroup analysis of botulinum toxin-treated or toxin-naïve subjects. RESULTS: Participants (Nâ=â233; 38.6% toxin-naïve) had a mean age of 52.8 years. IncobotulinumtoxinA significantly improved TWSTRS total scores from baseline to Week 4 in both dose groups versus placebo, and the improvement persisted through the end of the study (≤20 weeks). Both the previously toxin-treated and toxin-naïve subjects demonstrated significant improvements in TWSTRS total scores at Week 4 compared to baseline. The most frequent TEAEs in the incobotulinumtoxinA groups were dysphagia, neck pain, and muscular weakness, which were generally mild. TEAEs were more common in the 240 U group and toxin-naïve subjects. DISCUSSION: Overall, incobotulinumtoxinA was safe and effective in CD, regardless of toxin therapy history. A lower starting dose may be better tolerated among toxin-naïve subjects without sacrificing efficacy.
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Tinea versicolor (TV) is a superficial cutaneous fungal infection characterized by cutaneous pigment changes, pruritus, scaling, and erythema. This open-label, single-center pilot study evaluated the efficacy and safety of naftifine 1% gel applied twice daily for 2 weeks in 10 men and women (median age 38 years) with TV. Baseline mycology status was determined by potassium hydroxide (KOH) and microscopy and clinical symptom severity (CSS) scored by the investigator using a 0 to 9 scale (0=absent, 9=worst). Patients applied naftifine HCI 1% gel to the affected area twice daily for 14 days. They returned for follow-up efficacy and safety assessments at the end of treatment (week 2), 2 weeks after treatment (week 4), and 6 weeks after treatment (week 8). All patients had a positive mycology at baseline; one was KOH negative at week 2, two were negative at week 4, and five (50%) were negative at week 8. Mean investigator total CSS score decreased from a baseline value of 4.7 to 3.2 at week 2 (32% improvement), 2.6 at week 4 (45% improvement), and 2.7 at week 8 (43% improvement). The patients rated their symptoms to be improved at all follow-up visits. There were no treatment-related adverse events during the study. These results suggest that naftifine 1% gel is a safe and efficacious topical treatment for TV.
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Alilamina/análogos & derivados , Antifúngicos/uso terapêutico , Tinha Versicolor/tratamento farmacológico , Administração Cutânea , Adulto , Alilamina/administração & dosagem , Alilamina/efeitos adversos , Alilamina/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Feminino , Seguimentos , Géis , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Índice de Gravidade de Doença , Tinha Versicolor/patologia , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Naftifine HCl 2% cream (NAFT-2%) is a topical allylamine antifungal preparation under development in the U.S. The objective of this randomized, double-blind, vehicle-controlled study was to evaluate the efficacy and safety of a two-week course of once-daily NAFT-2% vs. vehicle in the treatment of Tinea cruris ("jock itch"). METHODS: A total of 334 subjects with T. cruris were enrolled and randomly assigned to NAFT-2% (n=166) or vehicle (n=168), which was applied once daily for 14 days. Efficacy and safety were evaluated at week 2 (end of treatment) and week 4. Efficacy measures included complete cure, treatment effectiveness, mycological cure, clinical cure, and clinical success and were analyzed only in subjects with a positive potassium hydroxide (KOH) and dermatophyte culture at baseline (n=75, naftifine; n=71, vehicle). Safety was assessed by adverse events and changes from baseline in clinical status and laboratory studies. RESULTS: At week 4, 25 percent of naftifine-treated subjects achieved complete cure vs. three percent of vehicle subjects and 72 percent achieved mycological cure vs. 16 percent of vehicle treated subjects (one-sided, P<0.001). Treatment effectiveness was achieved in 60 percent of NAFT-2% subjects vs. 10 percent of vehicle subjects (one-sided, P<0.001). Clinical cure rate and clinical success rate were 33 percent and 84 percent in NAFT-2% subjects, respectively vs. 10 percent and 46 percent in vehicle subjects (both P is less than 0.001, 2-sided). Week 2 efficacy response rates in NAFT-2% subjects were all lower than at week 4 but were significantly higher than week 2 vehicle-treated counterparts (P<0.025). Treatment-related AE occurred in 11 subjects (7 NAFT-2%, 4 vehicle) during the study. The most common AE in both groups were contact dermatitis (2 NAFT-2%), pruritus (2 vehicle), and application site reaction (1 per group). CONCLUSION: NAFT-2% applied once daily for two weeks (one-half the treatment duration for naftifine 1% cream) is efficacious and safe for the treatment of T. cruris.
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Alilamina/análogos & derivados , Antifúngicos/uso terapêutico , Tinha/tratamento farmacológico , Administração Cutânea , Adulto , Alilamina/administração & dosagem , Alilamina/efeitos adversos , Alilamina/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Repeat treatments of nonpermanent dermal fillers are used in the long-term treatment of wrinkles and folds and to volumize. OBJECTIVE To determine the safety and effectiveness of a nonanimal-sourced hyaluronic acid (HA) (which uses a cohesive polydensified matrix (CPM) technology [CPMHA]) for the treatment of nasolabial folds (NLFs) during an 18-month open-label extension trial. METHODS AND MATERIALS: Ninety-five of 118 subjects continued with this optional open-label extension of a split-face, double-blind trial. All subjects received CPMHA in both NLFs at 24 weeks after treatment in this study and were assessed at weeks 32, 48, 72, and 96. Touch-ups were allowed for optimal correction. Safety was assessed according to reported adverse events (AEs) and serum antibody measurement. RESULTS: At all four post-week 24 time points, the severity of the NLFs showed a decrease from baseline on the Wrinkle Severity Rating Scale. The effects persisted in the majority (â¼80%) of subjects without repeat treatment for at least one interval of 48 weeks. The study filler was well tolerated, with only one related AE (injection site bruising) reported. Little potential for immunogenic reactions was identified. CONCLUSION: This CPMHA is a well-tolerated and effective treatment for at least 48 weeks in the majority of subjects for the correction of moderate to severe NLFs with repeat injections given over an 18-month period.
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Técnicas Cosméticas , Ácido Hialurônico/administração & dosagem , Ritidoplastia/métodos , Envelhecimento da Pele , Viscossuplementos/administração & dosagem , Adulto , Idoso , Método Duplo-Cego , Face , Feminino , Seguimentos , Humanos , Injeções Intradérmicas/métodos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: Evaluate the safety and efficacy of a sequential dose escalation of rimabotulinumtoxinB (BoNT-B) in cervical dystonia (CD) subjects. METHODS: This multicenter, open-label, within-subject, sequential dose-escalation study (BoNT-B dosed at 10,000, 12,500, and 15,000 Units) evaluated subjects over each phase of treatment at preinjection and at periodic intervals postinjection. Adverse events, vital signs, and laboratory results were recorded. Efficacy measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and three visual analog scales (VASs). RESULTS: 119 out of 145 CD subjects received all three doses in sequence. Dry mouth and dysphagia were the most common adverse events, and both decreased in frequency by the final injection, despite the increasing doses of the escalation. TWSTRS-Total and subscale scores demonstrated significant improvements following all doses at the week 2, 4, 8, and 12 assessments, with the exception of disability and pain at week 12 with the lowest dose. All VAS scores demonstrated similar improvements following all doses. The mean number of weeks in each phase of the study was 12.1 weeks (10,000 Units), 12.9 weeks (12,500 Units), and 13.9 weeks (15,000 Units). CONCLUSION: BoNT-B was well tolerated and efficacious at 10,000, 12,500, and 15,000 Units in this within-subject, sequential dose-escalation study in CD subjects.
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Antidiscinéticos , Toxinas Botulínicas , Torcicolo/tratamento farmacológico , Antidiscinéticos/administração & dosagem , Antidiscinéticos/efeitos adversos , Toxinas Botulínicas/administração & dosagem , Toxinas Botulínicas/efeitos adversos , Toxinas Botulínicas Tipo A , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Medição da Dor , Torcicolo/fisiopatologia , Resultado do TratamentoRESUMO
This study evaluated the effect of an onion extract cream with Centella asiatica and hyaluronic acid in improving the appearance of striae rubra (SR). Women participants with bilateral, outer aspect of the thigh SR were randomized to apply a quarter-sized amount of the onion extract cream twice daily for 12 weeks to the randomized left or right, outer aspect of the thigh. No treatment was administered to the contralateral side. Participants were evaluated at weeks 2, 4, 8, and 12. Primary efficacy endpoints included color, texture, softness, and overall appearance of SR by the participant and investigator at week 12. The treated thigh demonstrated a statistically significant difference in the mean change in participant and investigator evaluations in overall appearance, texture, color, and softness compared with the untreated thigh at week 12. No adverse events occurred during the study. The onion extract cream was well tolerated and significantly improved the appearance of SR in women.
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Tecido Elástico/patologia , Fitoterapia , Extratos Vegetais/administração & dosagem , Triterpenos/administração & dosagem , Administração Cutânea , Adolescente , Adulto , Centella , Feminino , Humanos , Ácido Hialurônico , Pessoa de Meia-Idade , Pomadas/administração & dosagem , Adulto JovemRESUMO
The objective of this study was to compare efficacy, safety, and duration of botulinum toxin type A (BoNT-A) and type B (BoNT-B) in toxin-naïve cervical dystonia (CD) subjects. BoNT-naïve CD subjects were randomized to BoNT-A or BoNT-B and evaluated in a double-blind trial at baseline and every 4-weeks following one treatment. The primary measure was the change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to week 4 post-injection. Secondary measures included change in TWSTRS-subscale scores, pain, global impressions, and duration of response and safety assessments. The study was designed as a noninferiority trial of BoNT-B to BoNT-A. 111 subjects were randomized (55 BoNT-A; 56 BoNT-B). Improvement in TWSTRS-total scores 4 weeks after BoNT-B was noninferior to BoNT-A (adjusted means 11.0 (SE 1.2) and 8.8 (SE 1.2), respectively; per-protocol-population (PPP)). The median duration of effect of BoNT-A and BoNT-B was not different (13.1 vs. 13.7 weeks, respectively; P-value = 0.833; PPP). There were no significant differences in the occurrence of injection site pain and dysphagia. Mild dry mouth was more frequent with BoNT-B but there were no differences for moderate/severe dry mouth. In this study, both BoNT-A and B were shown to be effective and safe for the treatment of toxin-naive CD subjects.
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Toxinas Botulínicas Tipo A/uso terapêutico , Toxinas Botulínicas/uso terapêutico , Fármacos Neuromusculares/uso terapêutico , Torcicolo/tratamento farmacológico , Toxinas Botulínicas/efeitos adversos , Toxinas Botulínicas Tipo A/efeitos adversos , Avaliação da Deficiência , Método Duplo-Cego , Feminino , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/efeitos adversos , Dor/etiologia , Medição da Dor , Índice de Gravidade de Doença , Torcicolo/complicações , Torcicolo/diagnóstico , Resultado do Tratamento , Xerostomia/induzido quimicamente , Xerostomia/epidemiologiaRESUMO
OBJECTIVE: Evaluate the safety of botulinum toxin type B (BoNT-B) in subjects with hemifacial spasm (HFS). METHODS: This open-label, sequential dose-escalation study evaluated BoNT-B in subjects with HFS. Eligible subjects were enrolled and received a single injection of one of four sequential BoNT-B doses (100, 200, 400, or 800 U). Following injection, subjects were evaluated in person at Weeks 2 and 8 and by phone at Weeks 1, 4, and 10 and every 2 weeks thereafter until benefit was lost. Safety was assessed by adverse events (AEs), vital signs and clinical laboratory evaluation. The severity of HFS was assessed using a patient social impairment visual analog scale (VAS), subject severity of contraction VAS, the HFS physician assessment, and subject HFS frequency and severity assessment. RESULTS: Nineteen predominately Caucasian (92%) and female (67%) subjects (aged 36-80 years) with HFS participated in this study. Subjects remained in the study an average of 88 days (range of 41-332 days) after receiving a single dose of BoNT-B. No deaths, serious AEs or AEs leading to trial discontinuation occurred during the study period. Two subjects in the 400 U dose group requested early withdrawal, whereas all other subjects completed the study. A reduction in HFS severity was observed in subjects treated with doses of 200 U or more. Improvements in subject HFS assessments tended to return to baseline values by 8 weeks following injection. CONCLUSION: BoNT-B was well-tolerated and reduced HFS severity in subjects who received injections of 200 to 800 U. Additional investigation is necessary to confirm the findings from this open-label study.
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Antidiscinéticos/uso terapêutico , Toxinas Botulínicas/uso terapêutico , Avaliação de Medicamentos , Espasmo Hemifacial/tratamento farmacológico , Adulto , Idoso , Toxinas Botulínicas Tipo A , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Fatores de Tempo , Resultado do TratamentoRESUMO
Toxins can be cited as a cause of several movement disorders, but this association is rare and the resultant syndromes usually include additional signs that are not typical for the idiopathic movement disorders. Most instances of confirmed toxin-induced movement disorders show lesions on CT and MRI scans of cortical or subcortical structures. A common underlying element in these toxin-induced syndromes is the development of lesions primarily in the pallidum and striatum. Because many toxins result in lesions affecting these structures, a selective vulnerability to hypoxic or metabolic insults has long been postulated. The susceptibility of these structures may relate to a number of factors, including the pattern of oxidative metabolism, heavy metal concentration, vascular perfusion, and neuronal innervation. Finally, in addition to causing disability, certain neurotoxins have led to a better understanding of human disease through the development of research models. As an example, the MPTP model has not only provided an animal model to study therapeutic strategies in PD but has also contributed important insights into the mechanism of neuronal degeneration.