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PURPOSE: AlzeCure Pharma AB is developing novel positive allosteric modulators of Trk-receptors for treatment of Alzheimer's disease, depression, other psychiatric conditions and other disorders where cognition is impaired. The preceding candidate drug ACD855 was shown to have a too long half-life in humans to allow further development. To de-risk the development of the follow-up compound ACD856, the oral single ascending dose study of ACD856 in humans was preceded by an intravenous microdose study, assessing the elimination half-life in plasma. METHODS: A phase 0 study with a microdose of ACD856 (0.100 mg), was conducted in six healthy male subjects all receiving ACD856. Sequentially, a randomized, placebo-controlled, double-blind Phase I single ascending oral dose study (1 - 150 mg) was conducted, including 56 healthy subjects. Both studies assessed the safety and tolerability, as well as the PK properties of ACD856 after single dose intravenous and oral administration. RESULTS: ACD856 was well tolerated with no treatment emergent, or dose related adverse events or other safety assessments. In the microdose study, ACD856 exhibited a bi-exponential plasma decline, low distribution volume, low plasma clearance with a half-life of approximately 20 hours. Orally, ACD856 exhibited rapid absorption, an almost complete bioavailability and a dose proportional increase in exposure. While the Cmax was lowered and delayed by food intake, the effect on plasma half-life and the overall bioavailability was low. No renal elimination of ACD856 was detected. CONCLUSION: The prediction proved accurate demonstrating the value of conducting a microdose study prior to ascending dose studies. TRIAL REGISTRATION: NCT05783830 March 24, 2023 (microdose study, retrospectively registered) and NCT05077631 October 14, 2021 (single ascending dose study).
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Voluntarios Sanos , Humanos , Masculino , Disponibilidad Biológica , Área Bajo la Curva , Administración Oral , Semivida , Método Doble Ciego , Relación Dosis-Respuesta a DrogaRESUMEN
Galvanic vestibular stimulation (GVS) has increasingly been used to stimulate the vestibular system in health and disease. While perceptible supra-threshold GVS destabilizes postural control in healthy control (HC) subjects, imperceptible 'noisy' GVS (nGVS) is reported to improve postural control in patients with bilateral vestibulopathy (BV) and therapeutic devices using nGVS are currently under development. We questioned (1) whether perceptible GVS destabilizes postural control of BV patients, expecting any effect to be smaller than in healthy subjects due to the patients' vestibulopathy, and (2) whether imperceptible nGVS improves postural control in comparison to an active sham stimulus in context-dependent conditions, hypothesizing that it fades off once postural control becomes more challenging with respect to its sensory (standing on foam) or cognitive (dual task) complexity. We tested postural responses of 30 BV patients to bimastoidal perceptible (lowGVS, highGVS) or imperceptible (nGVS, sham, noGVS) GVS in comparison to 24 age-matched HC. Perceptible GVS intensities were applied according to the participants' individual motion perception thresholds. Postural sway speed (PSS) was analyzed in a 4-factorial experimental design with the factors group (BV, HC), vision (eyes open/closed), condition (baseline, proprioception, cognition) and stimulation (noGVS, sham, nGVS, lowGVS, highGVS). With eyes open (EO), there were no group-related PSS differences in the baseline and cognition condition in response to either stimulations. With EO on foam and with eye closed (EC) in all conditions, patients showed larger PSS than HC, irrespective of the stimulation type. PSS differed with GVS intensities within each group but not between the groups. PSS under nGVS on EC was only smaller in patients when compared to perceptible GVS, but it was not different from noGVS or sham stimulation. Moreover, this nGVS effect was only found in the baseline but not in the more challenging dual task and foam condition. Almost half of the patients showed higher individual thresholds of motion perception of GVS compared to HC. Interestingly, this high-threshold subgroup showed significantly larger PSS with EC as compared to HC and the low-threshold patient subgroup, although both patient subgroups did not differ in vestibular parameters. We conclude, first, that perceptible GVS is able to destabilize BV patients similarly to HC subjects, suggesting sufficient vestibular afferent processing of GVS during vestibulo-spinal postural control. Second, the effect of the hitherto observed improved postural control by nGVS appears to be small during more demanding postural control conditions (foam, cognitive distraction) that are closer to the patients' everyday life, when active sham stimuli are used as control stimuli. These findings underline the meaning of active control conditions when the efficacy of nGVS is tested, e.g. in portable GVS devices in the attempt to improve postural control in BV patients. However, differential GVS effects on vestibulo-perceptional and vestibulo-spinal thresholds should be taken into account. Finally, our data suggest that individual motion perception thresholds for GVS could potentially serve as a predictor of postural control safety and falling risk in BV.
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Vestibulopatía Bilateral , Percepción de Movimiento , Vestíbulo del Laberinto , Vestibulopatía Bilateral/terapia , Estimulación Eléctrica , Humanos , Equilibrio PosturalRESUMEN
We examined the effect of galvanic vestibular stimulation (GVS) on resting state brain activity using fMRI (rs-fMRI) in patients with bilateral vestibulopathy. Based on our previous findings, we hypothesized that GVS, which excites the vestibular nerve fibers, (a) increases functional connectivity in temporoparietal regions processing vestibular signals, and (b) alleviates abnormal visual-vestibular interaction. Rs-fMRI of 26 patients and 26 age-matched healthy control subjects was compared before and after GVS. The stimulation elicited a motion percept in all participants. Using different analyses (degree centrality, DC; fractional amplitude of low frequency fluctuations [fALFF] and seed-based functional connectivity, FC), group comparisons revealed smaller rs-fMRI in the right Rolandic operculum of patients. After GVS, rs-fMRI increased in the right Rolandic operculum in both groups and in the patients' cerebellar Crus 1 which was related to vestibular hypofunction. GVS elicited a fALFF increase in the visual cortex of patients that was inversely correlated with the patients' rating of perceived dizziness. After GVS, FC between parietoinsular cortex and higher visual areas increased in healthy controls but not in patients. In conclusion, short-term GVS is able to modulate rs-fMRI in healthy controls and BV patients. GVS elicits an increase of the reduced rs-fMRI in the patients' right Rolandic operculum, which may be an important contribution to restore the disturbed visual-vestibular interaction. The GVS-induced changes in the cerebellum and the visual cortex were associated with lower dizziness-related handicaps in patients, possibly reflecting beneficial neural plasticity that might subserve visual-vestibular compensation of deficient self-motion perception.
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Vestibulopatía Bilateral/fisiopatología , Cerebelo/fisiopatología , Corteza Cerebral/fisiopatología , Conectoma/métodos , Mareo/fisiopatología , Cinestesia/fisiología , Red Nerviosa/fisiopatología , Plasticidad Neuronal/fisiología , Anciano , Vestibulopatía Bilateral/complicaciones , Vestibulopatía Bilateral/diagnóstico por imagen , Cerebelo/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Mareo/diagnóstico por imagen , Mareo/etiología , Estimulación Eléctrica , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagenRESUMEN
In this event-related functional magnetic resonance imaging (fMRI) study we investigated how the brain of patients with bilateral vestibular failure (BVF) responds to vestibular stimuli. We used imperceptible noisy galvanic vestibular stimulation (GVS) and perceptible bi-mastoidal GVS intensities and related the corresponding brain activity to the evoked motion perception. In contrast to caloric irrigation, GVS stimulates the vestibular organ at its potentially intact afferent nerve site. Motion perception thresholds and cortical responses were compared between 26 BVF patients to 27 age-matched healthy control participants. To identify the specificity of vestibular cortical responses we used a parametric design with different stimulus intensities (noisy imperceptible, low perceptible, high perceptible) allowing region-specific stimulus response functions. In a 2â¯×â¯3 flexible factorial design all GVS-related brain activities were contrasted with a sham condition that did not evoke perceived motion. Patients had a higher motion perception threshold and rated the vestibular stimuli higher than the healthy participants. There was a stimulus intensity related and region-specific increase of activity with steep stimulus response functions in parietal operculum (e.g. OP2), insula, superior temporal gyrus, early visual cortices (V3) and cerebellum while activity in the hippocampus and intraparietal sulcus did not correlate with vestibular stimulus intensity. Using whole brain analysis, group comparisons revealed increased brain activity in early visual cortices (V3) and superior temporal gyrus of patients but there was no significant interaction, i.e. stimulus-response function in these regions were still similar in both groups. Brain activity in these regions during (high)GVS increased with higher dizziness-related handicap scores but was not related to the degree of vestibular impairment or disease duration. nGVS did not evoke cortical responses in any group. Our data indicate that perceptible GVS-related cortical responsivity is not diminished but increased in multisensory (visual-vestibular) cortical regions despite bilateral failure of the peripheral vestibular organ. The increased activity in early visual cortices (V3) and superior temporal gyrus of BVF patients has several potential implications: (i) their cortical reciprocal inhibitory visuo-vestibular interaction is dysfunctional, (ii) it may contribute to the visual dependency of BVF patients, and (iii) it needs to be considered when BVF patients receive peripheral vestibular stimulation devices, e.g. vestibular implants or portable GVS devices. Imperceptible nGVS did not elicit cortical brain responses making it unlikely that the reported balance improvement of BVF by nGVS is mediated by cortical mechanisms.
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Vestibulopatía Bilateral/diagnóstico por imagen , Vestibulopatía Bilateral/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Vestíbulo del Laberinto/diagnóstico por imagen , Vestíbulo del Laberinto/fisiopatología , Anciano , Estimulación Eléctrica/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Percepción de Movimiento/fisiología , Equilibrio Postural/fisiologíaRESUMEN
We compared the effectiveness of topical ketoprofen in Transfersome(®) gel (IDEA-033) with oral ketoprofen and drug-free Sequessome™ vesicles (FLEXISEQ(®) Sport; TDT 064) in reducing calf muscle soreness. One hundred and sixty eight healthy individuals with a pain score ≥ 3 (10-point scale) 12-16 h post-exercise (walking down stairs with an altitude of 300-400 m) were randomised to receive IDEA-033 plus oral placebo (two dose groups), oral ketoprofen plus TDT 064, or TDT 064 plus oral placebo. The primary endpoint was muscle soreness reduction from pre-dosing to Day 7. Higher pain scores were recorded with oral ketoprofen plus TDT 064 (mean ± s 462.4 ± 160.4) versus IDEA-033 plus oral placebo (434.7 ± 190.8; P = 0.2931) or TDT 064 plus oral placebo (376.2 ± 159.1; P = 0.0240) in the 7 days post-exercise. Recovery from muscle soreness was longer with oral ketoprofen plus TDT 064 (mean 91.0 ± 19.5 h) versus IDEA-033 plus placebo (mean 81.4 ± 22.9 h; P = 0.5964) or TDT 064 plus placebo (mean 78.9 ± 22.8 h; P = 0.0262). In conclusion, ultradeformable phospholipid vesicles ± ketoprofen did not retard recovery from muscle soreness. TDT 064 improves osteoarthritis-related pain and could be of interest as a treatment for joint pain during and post-exercise.
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Antiinflamatorios no Esteroideos/administración & dosificación , Ejercicio Físico/fisiología , Cetoprofeno/administración & dosificación , Mialgia/tratamiento farmacológico , Vehículos Farmacéuticos/administración & dosificación , Fosfolípidos/administración & dosificación , Administración Oral , Administración Tópica , Adolescente , Adulto , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacocinética , Área Bajo la Curva , Método Doble Ciego , Femenino , Geles , Humanos , Cetoprofeno/efectos adversos , Cetoprofeno/farmacocinética , Masculino , Persona de Mediana Edad , Mialgia/etiología , Vehículos Farmacéuticos/efectos adversos , Vehículos Farmacéuticos/farmacocinética , Fosfolípidos/efectos adversos , Fosfolípidos/farmacocinética , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Many patients with osteoarthritis (OA) experience side effects with available systemic therapies, some of which can be life threatening. The widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs), often without prescription, is concerning given their potential risks. New treatments for OA are therefore required. This review discusses evidence supporting the use of TDT 064, a drug-free, topical gel containing ultra-deformable phospholipid vesicles (Sequessome * vesicles), for OA-associated pain. SCOPE: Preclinical and clinical studies investigating TDT 064 in patients with OA-associated knee pain were identified in searches of PubMed and congress abstracts. FINDINGS: The ultra-deformable phospholipid vesicles (sequessome vesicles) in TDT 064 pass through the skin intact to reach the synovial space within the joint. The mechanism of action is not yet certain, but the phospholipid-based structure of these ultra-deformable phospholipid vesicles, and the observation that they localize to the cartilage surface, support biolubrication as a possible mechanism of action of TDT 064. Data from randomized, phase III studies in OA knee pain in which TDT 064 was used as the drug-free vehicle control for IDEA-033 (ketoprofen in ultra-deformable phospholipid vesicles) demonstrate a marked and consistent response to TDT 064 in terms of pain, stiffness, and function. In a 12 week study of >1300 patients, the effects of TDT 064 on pain and function were statistically noninferior to those of oral celecoxib, and superior to oral placebo. TDT 064 was well tolerated in all studies, and adverse events were typically mild-to-moderate effects on the skin. CONCLUSIONS: Evidence from clinical studies supports the use of TDT 064 as a drug-free topical treatment for patients with OA. Further experience with TDT 064, particularly among patients with comorbidities or NSAID contraindications, will provide more information on its potential use.
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Osteoartritis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Vehículos Farmacéuticos/administración & dosificación , Fosfolípidos/administración & dosificación , Administración Tópica , Antiinflamatorios no Esteroideos/administración & dosificación , Geles , Humanos , Cetoprofeno/administración & dosificación , Membrana Dobles de Lípidos , Vehículos Farmacéuticos/efectos adversos , Vehículos Farmacéuticos/farmacología , Fosfolípidos/efectos adversos , Fosfolípidos/farmacologíaRESUMEN
OBJECTIVE: To evaluate the safety and efficacy of ketoprofen in Transfersome® gel (IDEA-033) in comparison with a ketoprofen-free vehicle (TDT 064) for the treatment of osteoarthritis (OA) of the knee. METHODS: Patients with knee OA (N = 866) were randomly assigned to receive topical IDEA-033 containing 100, 50, or 25 mg ketoprofen, or TDT 064 twice daily for 12 weeks, in a double-blind trial. The primary efficacy endpoint was the change in the Western Ontario and McMaster Universities (WOMAC®) Osteoarthritis Index pain subscale score. The coprimary efficacy endpoints were the WOMAC function subscale score and the patient global assessment of response to therapy. The secondary endpoints included the numeric pain rating for the first 14 days of treatment and the Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) responder rates. RESULTS: The WOMAC pain scores were reduced by approximately 50% or more in all four groups. The 100 and 50 mg ketoprofen groups, but not the 25 mg group, showed a superior reduction in the WOMAC pain score versus the TDT 064 group (100 mg: -57.4% [P = 0.0383]; 50 mg: -57.1% [P = 0.0204]; and 25 mg: -53.4% [P = 0.3616] versus TDT 064: -49.5%). The superiority of the ketoprofen-containing formulations was not demonstrated for the WOMAC function subscale score, whereas the patient global assessment of 50 mg ketoprofen group, but not the 100 or 25 mg group, was superior to that of the TDT 064 group (P = 0.0283). Responder rates were significantly higher for all the IDEA-033 groups versus the TDT 064 group, but were high in all groups (100 mg: 88.6%; 50 mg: 86.8%; 25 mg: 88.6%; and TDT 064: 77.5%). Dermal reactions were the only relevant drug-related adverse events in all four groups. CONCLUSION: The 50 and 100 mg ketoprofen doses of IDEA-033 were only marginally superior to TDT 064 for reducing pain associated with knee OA. The study indicates a high treatment response to the topical ketoprofen-free vehicle TDT 064.
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OBJECTIVE: This randomized, double-blind, phase III study evaluated the efficacy and safety of ketoprofen in an ultradeformable vesicle gel compared with ketoprofen-free gel in osteoarthritis (OA) knee pain. METHODS: Patients with American College of Rheumatology-defined OA of the knee and moderate pain were randomized to receive 100 mg ketoprofen in 4.4 g transfersome gel (IDEA-033) or 4.4 g ketoprofen-free vehicle (TDT 064) topically, twice daily, for 12 weeks. The primary endpoint was mean change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score from baseline to Week 12. RESULTS: Patients (n = 555) were randomized and treated. Mean baseline WOMAC pain scores were 5.2 (SD 1.0) for IDEA-033 and 5.3 (SD 1.0) for TDT 064. Mean change in WOMAC pain scores from baseline to Week 12 was 38.6% for IDEA-033 and 44.6% for TDT 064 (Mann-Whitney estimator 0.4505; p = 0.022). Both groups reported progressive decreases in pain and improvements in function and stiffness. Mean baseline WOMAC function scores decreased from 5.4 to 3.4 with IDEA-033 and 3.1 with TDT 064 at Week 12. The proportion of patients achieving ≥ 50% decrease in WOMAC pain score from baseline at Week 12 was 41.2% (95% CI 0.35-0.47) with IDEA-033 and 50.5% (95% CI 0.45-0.57) with TDT 064. Mild skin and subcutaneous tissue disorders were the most frequently reported treatment-related adverse events (AE). CONCLUSIONS: IDEA-033 was inferior to drug-free gel (TDT 064) in relieving moderate OA knee pain and improving joint function.
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Antiinflamatorios no Esteroideos/uso terapéutico , Cetoprofeno/análogos & derivados , Articulación de la Rodilla/efectos de los fármacos , Osteoartritis de la Rodilla/tratamiento farmacológico , Dolor/tratamiento farmacológico , Administración Cutánea , Anciano , Antiinflamatorios no Esteroideos/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Cetoprofeno/administración & dosificación , Cetoprofeno/uso terapéutico , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/complicaciones , Dolor/etiología , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess the efficacy and safety of 12-week treatment with ketoprofen in ultradeformable phospholipid vesicles in patients with OA knee pain and to compare the efficacy with that of ketoprofen-free vehicle and celecoxib. METHODS; A multicentre, double-blind controlled study in which patients with knee OA and moderate pain were randomized to one of the six arms: topical ketoprofen 50 or 100 mg in ultradeformable vesicles (IDEA-033), 2.2 or 4.4 g ketoprofen-free vehicle (TDT 064), oral celecoxib 100 mg or matching oral placebo, all bd. The primary outcome was change from baseline in the WOMAC pain subscale at week 12. RESULTS: A total of 1395 patients received treatment. Baseline mean WOMAC pain scores ranged from 4.7 to 4.8 across groups. The mean reduction in WOMAC pain score at week 12 was -1.9 (-40.8%) for ketoprofen 50 mg, -1.9 (-40.9%) for ketoprofen 100 mg, -1.9 (-39.8%) for 2.2 g TDT 064, -1.8 (-37.8%) for 4.4 g TDT 064, -1.9 (-40.4%) for celecoxib and -1.4 (-29.3%) for oral placebo. IDEA-033 was not statistically superior to TDT 064. All topical treatments were statistically superior to oral placebo and non-inferior to celecoxib. The most frequent types of treatment-related adverse events reported were gastrointestinal for oral (15.9% for celecoxib) and dermal for topical applications (12.2% for ketoprofen 100 mg). CONCLUSION: IDEA-033 was not superior to ketoprofen-free vehicle, but both formulations were superior to oral placebo and non-inferior to celecoxib in reducing OA knee pain. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00716547.
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Antiinflamatorios no Esteroideos/administración & dosificación , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Cetoprofeno/administración & dosificación , Osteoartritis de la Rodilla/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Administración Oral , Administración Tópica , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/efectos adversos , Celecoxib , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Método Doble Ciego , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/efectos adversos , Femenino , Geles , Humanos , Cetoprofeno/efectos adversos , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/fisiopatología , Dimensión del Dolor , Pirazoles/efectos adversos , Sulfonamidas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Pain related to ultraviolet B radiation (UVR) induced sunburn is an established, simple, acute pain model. One of the major criticisms is related to the potential dermal adverse events caused by the UVR exposure. This study tried to validate the model for oral and topical drugs and to define the minimum required UVR exposure. METHODS: This subject- and observer-blinded, placebo-controlled, crossover study evaluated 600 mg oral ibuprofen (IB) and topical hydrocortisone-21-acetate (HC) twice daily (bid) in 24 healthy volunteers. Treatment started immediately after irradiation and again at 12 hours, 24 hours, and 36 hours post-UVR. Assessment of hyperalgesia to heat and signs of inflammation (erythema, skin temperature) for all areas was performed after UVR and again at 6, 12, 24, 36, and 48 hours. Subjects returned within 4-11 days to the study site for the second period of the study. As in the first period, subjects received HC at one side and topical placebo on the other side, but oral treatment was crossed-over. RESULTS: The primary analysis failed to show the expected superiority of the IB-group vs the placebo group in period 1 of the study. Evaluating period 2 alone clearly showed the expected treatment effects of IB for erythema and heat pain threshold. The results were less pronounced for skin temperature. In contrast to IB vs oral placebo, there were no differences in treatment response between HC and topical placebo. UVR at all dosages induced profound erythema and reduction of heat pain threshold without causing blisters or other unexpected discomfort to the subjects. The changes were almost linear between 1 and 2 minimal erythema doses (MED), whereas the change from 2 to 3 MED was less pronounced. CONCLUSION: Use of 2 MED in upcoming studies seems to be reasonable to limit subjects' UVB exposure. The following procedural changes are suggested: Intensified training sessions before randomization to treatmentIncrease in sample size if they are crossover studiesSimplification in design (either oral or topical treatment).
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OBJECTIVE: To investigate the effect of epicutaneously applied Diractin (ketoprofen in Transfersome gel) on pain induced by eccentric muscle contractions. METHODS: Three pilot studies which were subsequently pooled for a meta-analysis compared the efficacy of a single application of 25 mg ketoprofen in Diractin to 25 mg oral ketoprofen and placebo for the treatment of pain induced by 50 eccentric contractions of the elbow flexor muscles. In addition, the effect of multiple usage of up to 100 mg ketoprofen in Diractin bid over seven days on pain induced by walking down stairs with a total altitude of 200 meters was investigated. RESULTS: A single dose of 25 mg ketoprofen in Diractin after the elbow flexion exercise was significantly superior to placebo from 5 to 12 hours after treatment and also to oral ketoprofen at some time points after treatment. In contrast, oral ketoprofen was not different to placebo at any time after treatment. Multiple doses of up to 100 mg ketoprofen Diractin provided significant more pain relief than placebo on muscle pain induced by walking down stairs. CONCLUSIONS: Eccentric exercise-induced muscle soreness was shown to be an appropriate acute pain model to evaluate the efficacy of nonsteroidal anti-inflammatory drugs applied epicutaneously with Transfersome carriers. Diractin proved to be efficacious in relieving pain from eccentric muscle contractions and muscle over-exercise, respectively. The effect needs to be confirmed in a larger prospective clinical trial.
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The risk of oral NSAID including Cox-2 inhibitors to cause gastrointestinal, renal or cardiovascular adverse events related to systemic drug exposure could be reduced by local application. But only few long-term studies have been published to show safety and efficacy for long-term use of topical NSAID s. Diractin (formerly IDEA-033) is a viscous, aqueous formulation for epicutaneous application of ketoprofen based on ultra-deformable, self-regulating carrier (Transfersome). This multiple-dose, open label study with treatment periods up to 18 months included 402 patients with joint pain, musculoskeletal pain, stiffness or soft tissue inflammation (age of 61.4+/-11.5 years). Most of the patients suffered from osteoarthritis (OA) of the knee (68.9%). Diractin was applied epicutaneously up to twice daily with a maximum dose of 220 mg ketoprofen per a maximum of 2 application sites. The mean pain score at baseline was 5.4+/-.4 on a 10 point categorical scale. During the study the pain score progressively improved up to week 36 (3.5+/-1.9) without a substantial further change during the rest of observation period of up to 18 months. The reduction of pain scores between week 0 (baseline) and at all later visits was statistically significant (P<0.0001). Patients also reported an improvement of quality of life on the EUROQoL. The majority of treatment related adverse events were skin and subcutaneous tissue disorders with the highest frequency reported for erythema (16.7%) and pruritus (2.0%). Systemic ketoprofen exposure remained low throughout the study period with plasma concentrations of less than 1% of what was reported for a single, standard oral dose of 200 mg ketoprofen. There were no occurrences of treatment related serious adverse events and no remarkable changes in laboratory values or vital signs. In summary, Diractin provided adequate pain relief with a good safety and tolerability profile when used for up to 18 months (72 weeks).
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Antiinflamatorios no Esteroideos/administración & dosificación , Inflamación/tratamiento farmacológico , Cetoprofeno/administración & dosificación , Dolor/tratamiento farmacológico , Administración Cutánea , Anciano , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacocinética , Artralgia/tratamiento farmacológico , Portadores de Fármacos , Femenino , Humanos , Cetoprofeno/efectos adversos , Cetoprofeno/farmacocinética , Estudios Longitudinales , Masculino , Cumplimiento de la Medicación/estadística & datos numéricos , Persona de Mediana Edad , Enfermedades Musculoesqueléticas , Dimensión del Dolor , Calidad de Vida , Traumatismos de los Tejidos Blandos/tratamiento farmacológicoRESUMEN
We studied skin occlusion effects in vitro and in vivo on local and systemic delivery of ketoprofen across the organ, using the drug in a conventional non-occlusive topical gel (Togal Mobil-Gel), an occlusive tape (Mohrus), and the new targeted analgesic (Diractin), comprising ultradeformable, hydrophilic carriers in the form of a Transfersome vesicle. In vitro occluded skin permeability to ketoprofen from the tape (0.086cmh(-1)) marginally exceeds the value for the drug from carriers in a gel (0.058cmh(-1)), which resembles conventional gel on open excised skin (0.057cmh(-1)); smallness of occlusion-induced permeation enhancement ( approximately 1.5x) may be due to the high tested applied dose. In contrast, open skin permeability to the drug from the carriers in vitro is approximately 15xlower (0.004cmh(-1)). The benefit of ketoprofen association with the carriers for targeted transcutaneous delivery only shows-up in vivo after an non-occlusive epicutaneous application: the area under the curve (AUC) in peripheral deep muscle for the carrier-based gel then exceeds AUC for conventional gel approximately 35-fold. The AUC for occluded ultradeformable, hydrophilic carriers measured in living pigs is conversely approximately 10x lower, being 1.4-2.2x below that of the tape that is inferior to non-occluded carriers formulation (normalised cmax: approximately 200x). Occlusion thus disables ultradeformable, hydrophilic carriers by eliminating transcutaneous hydration gradient that normally drives the carriers across the skin. Compared with other non-steroidal anti-inflammatory agents (NSAIDs) for local usage, Diractin is thus evidently well differentiated and innovative.
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Antiinflamatorios no Esteroideos/farmacocinética , Portadores de Fármacos/química , Cetoprofeno/farmacocinética , Absorción Cutánea , Administración Cutánea , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Área Bajo la Curva , Transporte Biológico , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos , Geles , Interacciones Hidrofóbicas e Hidrofílicas , Cetoprofeno/administración & dosificación , Permeabilidad , PorcinosRESUMEN
We compared in vivo transport and biodistribution of ketoprofen applied on the skin in ultradeformable carriers (Diractin) or a conventional topical gel (Gabrilen) with oral drug (Oruvail); for reference we used in vitro study data. The drug from Gabrilen diffuses into body with low bioavailability (<10%) and limited regio-selectivity (AUC(deep muscle/plasma) approximately 45/0.8 (t=0-8h), reaching maximum concentration in subcutaneous tissues and plasma at similar time (t(max) approximately 3-4h). The apparent drug elimination half-life is then similar to oral ketoprofen (t1/2,a) approximately 2 h). In contrast, Diractin containing ultradeformable carriers (Transfersome vesicles) delivers the drug more efficiently (>50%) and more directly into peripheral muscles (AUC(deep muscle/plasma) approximately 447/0.7 (652/1.4) for t=0-8 (0-24)h; tmax approximately 1 h), arguably in non-diffusive fashion. Ketoprofen from Diractin moreover disappears from body periphery slower (t1/2,a) approximately 4-6 h), owing to sustained drug release from the carriers in target tissue. Final clearance always proceeds via plasma (tmax approximately 4 h). Epicutaneous application of ketoprofen in conventional gels or the carrier-based formulation thus leads to different local accumulations and clearances. Ketoprofen from Diractin achieves more desirable biodistribution and clearance, arguably due to spontaneous carrier-mediated drug transport across the skin, which ensures local and relatively long-lasting drug deposition into peripheral target tissues.
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Antiinflamatorios no Esteroideos/administración & dosificación , Cetoprofeno/administración & dosificación , Administración Oral , Administración Tópica , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Difusión , Cámaras de Difusión de Cultivos , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Excipientes , Geles , Humanos , Técnicas In Vitro , Cetoprofeno/farmacocinética , Masculino , Espectrofotometría Ultravioleta , Porcinos , Porcinos Enanos , Distribución TisularRESUMEN
OBJECTIVE: To compare epicutaneous ketoprofen in Transfersome (ultra-deformable vesicles, IDEA-033) versus oral celecoxib and placebo for relief of signs and symptoms in knee osteoarthritis. METHODS: This was a multicentre, randomised, double-blind, controlled trial; 397 patients with knee osteoarthritis participated and 324 completed the trial. They were randomly assigned 110 mg epicutaneous ketoprofen in 4.8 g Transfersome plus oral placebo (n = 138), 100 mg oral celecoxib plus placebo gel (n = 132), or both placebo formulations (n = 127) twice daily for 6 weeks. Primary efficacy outcome measures were the changes from baseline to end of the study on the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain subscale, physical function subscale and patient global assessment (PGA) of response. RESULTS: The mean WOMAC pain subscale scores in the intent to treat population were reduced by 18.2 (95% confidence interval -22.1 to -14.3), 20.3 (-24.3 to -16.2) and 9.9 (-13.9 to -5.8) in the IDEA-033, celecoxib and placebo groups, respectively, and the physical function subscale score by 14.6 (-18.1 to -11.0), 16.6 (-20.2 to -13.0) and 10.2 (-13.8 to -6.6), respectively. The mean PGA of response scores were 1.8 (1.6 to 2.1), 1.7 (1.5 to 1.9) and 1.3 (1.1 to 1.5), respectively. The differences in change between IDEA-033 and placebo were statistically significant for pain subscale (p<0.01) and PGA of response (p<0.01). Gastrointestinal adverse events for IDEA-033 were similar to placebo. CONCLUSION: IDEA-033 is superior to placebo and comparable with celecoxib in relieving pain associated with an acute flare of knee osteoarthritis.