Objective: To determine the efficacy of Sativex (USAN: nabiximols) in the alleviation of spastici... more Objective: To determine the efficacy of Sativex (USAN: nabiximols) in the alleviation of spasticity in people with multiple sclerosis. Methods: The results from three randomized, placebo-controlled, double-blind parallel group studies were combined for analysis. Patients: 666 patients with multiple sclerosis and spasticity. Measures: A 0–100 mm Visual Analogue Scale (VAS, transformed to a 0–10 scale) or a 0–10 Numerical Rating Scale (0–10 NRS) was used to measure spasticity. Patients achieving a 30% improvement from baseline in their spasticity score were defined as ‘responders’. Global impression of change (GIC) at the end of treatment was also recorded. Results: The patient populations were similar. The adjusted mean change of the numerical rating scale from baseline in the treated group was 1.30 compared with 0.97 for placebo. Using a linear model, the treatment difference was 0.32 (95% CI 0.61, 0.04, p1⁄4 0.026). A statistically significant greater proportion of treated patients...
The floral development and potencies [Δ(9) -tetrahydrocannabinol (THC) contents] of cannabis plan... more The floral development and potencies [Δ(9) -tetrahydrocannabinol (THC) contents] of cannabis plants were compared when grown indoors under high-pressure sodium lamps consuming electrical power at three densities (270, 400, and 600 W/m(2)). After a 3-week vegetative phase, plants were grown for 8 weeks, with lamps maintaining an artificial day length of 12 h. Foliar and floral yields were measured. Gas chromatography was used to measure the content of the psychoactive cannabinoid THC. Mean yields per unit of electrical power in each lighting regime ranged from 0.9 to 1.6 g/W, the highest being achieved in the lowest irradiance regime. The individual potencies of the separated leaf and flower materials were not affected by increasing irradiance. However, there was a corresponding increase in the overall potency of the aerial plant tissue. This was because of the plants in brighter conditions producing a higher proportion of floral material.
Maintenance of the blind-to-treatment allocation is one of the most important means of avoiding b... more Maintenance of the blind-to-treatment allocation is one of the most important means of avoiding bias in randomised controlled clinical trials. Commonly used methodologies to determine whether patients have become unblinded to treatment allocation are imperfect. This may be of particular concern in studies where outcomes are patient-reported, and with products which have a characteristic adverse event profile. We report the results of an evidence-based statistical approach to exploring the possible impact of unblinding to a cannabis-based medicine (Sativex®) in people with muscle spasticity due to multiple sclerosis. All 666 patients included in three Phase III placebo-controlled studies were included in this analysis. The relationship between factors that might permit patients to identify their treatment allocation and the effect of treatment on the self-reported primary outcome measure was investigated using a general linear model where the dependent variable was the change from ba...
Topical decongestants are available over the counter and provide rapid relief of nasal obstructio... more Topical decongestants are available over the counter and provide rapid relief of nasal obstruction for conditions of short duration, for example the common cold. Manufacturers' recommendations are that topical decongestants should not be used regularly for more than 1 week in view of the risk of rebound mucosal hyperaemia with persistent nasal obstruction and refractoriness to further effects of decongestants. For this reason we performed a randomised double-blind placebo-controlled trial in 30 normal adult subjects with 0.05% oxymetazoline nasal spray 2 sprays (0.1 ml/spray) to each nostril 3 times daily over an extended period of 4 weeks. Degree of nasal blockage was assessed before and after 4 weeks treatment and for 2 weeks following discontinuation of treatment. Outcome measures included diary symptom scores and measurements of nasal peak inspiratory flow, airway resistance (using posterior active rhinomanometry) and volume (using acoustic rhinometry). Nasal patency was ass...
Background: Maintenance of the blind-to-treatment allocation is one of the most important means o... more Background: Maintenance of the blind-to-treatment allocation is one of the most important means of avoiding bias in randomised controlled clinical trials. Commonly used methodologies to determine whether patients have become unblinded to treatment allocation are imperfect. This may be of particular concern in studies where outcomes are patient-reported, and with products which have a characteristic adverse event profile. We report the results of an evidence-based statistical approach to exploring the possible impact of unblinding to a cannabis-based medicine (Sativex W) in people with muscle spasticity due to multiple sclerosis. Methods: All 666 patients included in three Phase III placebo-controlled studies were included in this analysis. The relationship between factors that might permit patients to identify their treatment allocation and the effect of treatment on the self-reported primary outcome measure was investigated using a general linear model where the dependent variable was the change from baseline in patient self-reported spasticity severity, and the various possible explanatory factors were regarded as fixed factors in the model. Results: There was no significant relationship between the effect of Sativex W on spasticity and the prior use of cannabis or the incidence of 'typical' adverse events. Nor was there any significant relationship between the prior use of cannabis and the incidence of 'typical' adverse events, nor between prior use of cannabis and dose of Sativex W. Conclusions: There is no evidence to suggest that there was widespread unblinding to treatment allocation in these three studies. If any patients did become unblinded, then there is no evidence that this led to bias in the assessment of the treatment difference between Sativex W and Placebo for efficacy, adverse events or study drug dosing. This methodology may be suitable for assessment of the integrity of the blind in other randomized clinical trials
The floral development and potencies [Δ(9) -tetrahydrocannabinol (THC) contents] of cannabis plan... more The floral development and potencies [Δ(9) -tetrahydrocannabinol (THC) contents] of cannabis plants were compared when grown indoors under high-pressure sodium lamps consuming electrical power at three densities (270, 400, and 600 W/m(2)). After a 3-week vegetative phase, plants were grown for 8 weeks, with lamps maintaining an artificial day length of 12 h. Foliar and floral yields were measured. Gas chromatography was used to measure the content of the psychoactive cannabinoid THC. Mean yields per unit of electrical power in each lighting regime ranged from 0.9 to 1.6 g/W, the highest being achieved in the lowest irradiance regime. The individual potencies of the separated leaf and flower materials were not affected by increasing irradiance. However, there was a corresponding increase in the overall potency of the aerial plant tissue. This was because of the plants in brighter conditions producing a higher proportion of floral material.
Anthralin is a widely used topical therapy for psoriasis. While antiproliferative and anti-inflam... more Anthralin is a widely used topical therapy for psoriasis. While antiproliferative and anti-inflammatory proparties of anthralin have been reported, the specific mechanism of action remains undefined. We demonstrate that anthralin may preferentially exert its effect on mononuclear cells through rapid induction of lipid peroxidation (LPO) and c-jun-N-terminal protein kinase (JNK) activation, a stress-induced signal transducbon pathway associated with apoptosis and cell death. LPO was observed Immediately after anthralin exposure es measured by loss of fluorescence of cis-parinaric acid using laser scanning confocal microscopy and flow cytometry. Half-maximal LPO was reached at a ?&fold lower dose for peripheral blood mononuclear cells (PBMC) than in normal keratinocytes. JNK activation was observed at a ZO-fold lower dose in PBMC as comoared to keratinocvtes. JNK activation for both cell tvoes was doseend time-dependent. LD50 was d&ted at 30-fold lower concentra&s of anthralin for PBMC vs. keratinocutes. For both cell tvoes. selected inhibitors of LPO orevented JNK activation, and ceil death. Similar r&ults~ were observed in HaCaT 'cells that stably overexpress bcl-2, an endogenous inhibitor of LPO. These findings demonstrate that JNK activation and the coupled response of cell death may be mediated by LPO which represents one of the earliest responses to anthralin PBMC are 20-50 fold more sensitive to anthralin-induced LPO, JNK activation and cell death than keratinocytes and suggests that mononuclear cells may be the primary target of the pharmacologic action of anthralin.
Background: The measurement of spasticity as a symptom of neurologic disease is an area of growin... more Background: The measurement of spasticity as a symptom of neurologic disease is an area of growing interest. Clinician-rated measures of spasticity purport to be objective but do not measure the patient's experience and may not be sensitive to changes that are meaningful to the patient. In a patient with clinical spasticity, the best judge of the perceived severity of the symptom is the patient. Objectives: The aim of this study was to assess the validity and reliability, and determine the clinical importance, of change on a 0-10 numeric rating scale (NRS) as a patient-rated measure of the perceived severity of spasticity. Methods: Using data from a large, randomized, doubleblind, placebo-controlled study of an endocannabinoid system modulator in patients with multiple sclerosisrelated spasticity, we evaluated the test-retest reliability and comparison-based validity of a patient-reported 0-10 NRS measure of spasticity severity with the Ashworth Scale and Spasm Frequency Scale. We estimated the level of change from baseline on the 0-10 NRS spasticity scale that constituted a clinically important difference (CID) and a minimal CID (MCID) as anchored to the patient's global impression of change (PGIC). Results: Data from a total of 189 patients were included in this assessment (114 women, 75 men; mean age, 49.1 years). The test-retest reliability analysis found an interclass correlation coefficient of 0.83 (P < 0.001) between 2 measures of the 0-10 NRS spasticity scores recorded over a 7-to 14-day period before randomization. A significant correlation was found between change on 0-10 NRS and change in the Spasm Frequency Scale (r = 0.63; P < 0.001), and a moderate correlation was found between the change on 0-10 NRS and the PGIC (r = 0.47; P < 0.001). A reduction of ~30% in the spasticity 0-10 NRS score best represented the CID and a change of 18% the MCID. Conclusions: The measurement of the symptom of spasticity using a patient-rated 0-10 NRS was found to be both reliable and valid. The definitions of CID and MCID will facilitate the use of appropriate responder analyses and help clinicians interpret the significance of future results.
Objective: To determine the efficacy of Sativex (USAN: nabiximols) in the alleviation of spastici... more Objective: To determine the efficacy of Sativex (USAN: nabiximols) in the alleviation of spasticity in people with multiple sclerosis. Methods: The results from three randomized, placebo-controlled, double-blind parallel group studies were combined for analysis. Patients: 666 patients with multiple sclerosis and spasticity. Measures: A 0–100 mm Visual Analogue Scale (VAS, transformed to a 0–10 scale) or a 0–10 Numerical Rating Scale (0–10 NRS) was used to measure spasticity. Patients achieving a 30% improvement from baseline in their spasticity score were defined as ‘responders’. Global impression of change (GIC) at the end of treatment was also recorded. Results: The patient populations were similar. The adjusted mean change of the numerical rating scale from baseline in the treated group was 1.30 compared with 0.97 for placebo. Using a linear model, the treatment difference was 0.32 (95% CI 0.61, 0.04, p1⁄4 0.026). A statistically significant greater proportion of treated patients...
The floral development and potencies [Δ(9) -tetrahydrocannabinol (THC) contents] of cannabis plan... more The floral development and potencies [Δ(9) -tetrahydrocannabinol (THC) contents] of cannabis plants were compared when grown indoors under high-pressure sodium lamps consuming electrical power at three densities (270, 400, and 600 W/m(2)). After a 3-week vegetative phase, plants were grown for 8 weeks, with lamps maintaining an artificial day length of 12 h. Foliar and floral yields were measured. Gas chromatography was used to measure the content of the psychoactive cannabinoid THC. Mean yields per unit of electrical power in each lighting regime ranged from 0.9 to 1.6 g/W, the highest being achieved in the lowest irradiance regime. The individual potencies of the separated leaf and flower materials were not affected by increasing irradiance. However, there was a corresponding increase in the overall potency of the aerial plant tissue. This was because of the plants in brighter conditions producing a higher proportion of floral material.
Maintenance of the blind-to-treatment allocation is one of the most important means of avoiding b... more Maintenance of the blind-to-treatment allocation is one of the most important means of avoiding bias in randomised controlled clinical trials. Commonly used methodologies to determine whether patients have become unblinded to treatment allocation are imperfect. This may be of particular concern in studies where outcomes are patient-reported, and with products which have a characteristic adverse event profile. We report the results of an evidence-based statistical approach to exploring the possible impact of unblinding to a cannabis-based medicine (Sativex®) in people with muscle spasticity due to multiple sclerosis. All 666 patients included in three Phase III placebo-controlled studies were included in this analysis. The relationship between factors that might permit patients to identify their treatment allocation and the effect of treatment on the self-reported primary outcome measure was investigated using a general linear model where the dependent variable was the change from ba...
Topical decongestants are available over the counter and provide rapid relief of nasal obstructio... more Topical decongestants are available over the counter and provide rapid relief of nasal obstruction for conditions of short duration, for example the common cold. Manufacturers' recommendations are that topical decongestants should not be used regularly for more than 1 week in view of the risk of rebound mucosal hyperaemia with persistent nasal obstruction and refractoriness to further effects of decongestants. For this reason we performed a randomised double-blind placebo-controlled trial in 30 normal adult subjects with 0.05% oxymetazoline nasal spray 2 sprays (0.1 ml/spray) to each nostril 3 times daily over an extended period of 4 weeks. Degree of nasal blockage was assessed before and after 4 weeks treatment and for 2 weeks following discontinuation of treatment. Outcome measures included diary symptom scores and measurements of nasal peak inspiratory flow, airway resistance (using posterior active rhinomanometry) and volume (using acoustic rhinometry). Nasal patency was ass...
Background: Maintenance of the blind-to-treatment allocation is one of the most important means o... more Background: Maintenance of the blind-to-treatment allocation is one of the most important means of avoiding bias in randomised controlled clinical trials. Commonly used methodologies to determine whether patients have become unblinded to treatment allocation are imperfect. This may be of particular concern in studies where outcomes are patient-reported, and with products which have a characteristic adverse event profile. We report the results of an evidence-based statistical approach to exploring the possible impact of unblinding to a cannabis-based medicine (Sativex W) in people with muscle spasticity due to multiple sclerosis. Methods: All 666 patients included in three Phase III placebo-controlled studies were included in this analysis. The relationship between factors that might permit patients to identify their treatment allocation and the effect of treatment on the self-reported primary outcome measure was investigated using a general linear model where the dependent variable was the change from baseline in patient self-reported spasticity severity, and the various possible explanatory factors were regarded as fixed factors in the model. Results: There was no significant relationship between the effect of Sativex W on spasticity and the prior use of cannabis or the incidence of 'typical' adverse events. Nor was there any significant relationship between the prior use of cannabis and the incidence of 'typical' adverse events, nor between prior use of cannabis and dose of Sativex W. Conclusions: There is no evidence to suggest that there was widespread unblinding to treatment allocation in these three studies. If any patients did become unblinded, then there is no evidence that this led to bias in the assessment of the treatment difference between Sativex W and Placebo for efficacy, adverse events or study drug dosing. This methodology may be suitable for assessment of the integrity of the blind in other randomized clinical trials
The floral development and potencies [Δ(9) -tetrahydrocannabinol (THC) contents] of cannabis plan... more The floral development and potencies [Δ(9) -tetrahydrocannabinol (THC) contents] of cannabis plants were compared when grown indoors under high-pressure sodium lamps consuming electrical power at three densities (270, 400, and 600 W/m(2)). After a 3-week vegetative phase, plants were grown for 8 weeks, with lamps maintaining an artificial day length of 12 h. Foliar and floral yields were measured. Gas chromatography was used to measure the content of the psychoactive cannabinoid THC. Mean yields per unit of electrical power in each lighting regime ranged from 0.9 to 1.6 g/W, the highest being achieved in the lowest irradiance regime. The individual potencies of the separated leaf and flower materials were not affected by increasing irradiance. However, there was a corresponding increase in the overall potency of the aerial plant tissue. This was because of the plants in brighter conditions producing a higher proportion of floral material.
Anthralin is a widely used topical therapy for psoriasis. While antiproliferative and anti-inflam... more Anthralin is a widely used topical therapy for psoriasis. While antiproliferative and anti-inflammatory proparties of anthralin have been reported, the specific mechanism of action remains undefined. We demonstrate that anthralin may preferentially exert its effect on mononuclear cells through rapid induction of lipid peroxidation (LPO) and c-jun-N-terminal protein kinase (JNK) activation, a stress-induced signal transducbon pathway associated with apoptosis and cell death. LPO was observed Immediately after anthralin exposure es measured by loss of fluorescence of cis-parinaric acid using laser scanning confocal microscopy and flow cytometry. Half-maximal LPO was reached at a ?&fold lower dose for peripheral blood mononuclear cells (PBMC) than in normal keratinocytes. JNK activation was observed at a ZO-fold lower dose in PBMC as comoared to keratinocvtes. JNK activation for both cell tvoes was doseend time-dependent. LD50 was d&ted at 30-fold lower concentra&s of anthralin for PBMC vs. keratinocutes. For both cell tvoes. selected inhibitors of LPO orevented JNK activation, and ceil death. Similar r&ults~ were observed in HaCaT 'cells that stably overexpress bcl-2, an endogenous inhibitor of LPO. These findings demonstrate that JNK activation and the coupled response of cell death may be mediated by LPO which represents one of the earliest responses to anthralin PBMC are 20-50 fold more sensitive to anthralin-induced LPO, JNK activation and cell death than keratinocytes and suggests that mononuclear cells may be the primary target of the pharmacologic action of anthralin.
Background: The measurement of spasticity as a symptom of neurologic disease is an area of growin... more Background: The measurement of spasticity as a symptom of neurologic disease is an area of growing interest. Clinician-rated measures of spasticity purport to be objective but do not measure the patient's experience and may not be sensitive to changes that are meaningful to the patient. In a patient with clinical spasticity, the best judge of the perceived severity of the symptom is the patient. Objectives: The aim of this study was to assess the validity and reliability, and determine the clinical importance, of change on a 0-10 numeric rating scale (NRS) as a patient-rated measure of the perceived severity of spasticity. Methods: Using data from a large, randomized, doubleblind, placebo-controlled study of an endocannabinoid system modulator in patients with multiple sclerosisrelated spasticity, we evaluated the test-retest reliability and comparison-based validity of a patient-reported 0-10 NRS measure of spasticity severity with the Ashworth Scale and Spasm Frequency Scale. We estimated the level of change from baseline on the 0-10 NRS spasticity scale that constituted a clinically important difference (CID) and a minimal CID (MCID) as anchored to the patient's global impression of change (PGIC). Results: Data from a total of 189 patients were included in this assessment (114 women, 75 men; mean age, 49.1 years). The test-retest reliability analysis found an interclass correlation coefficient of 0.83 (P < 0.001) between 2 measures of the 0-10 NRS spasticity scores recorded over a 7-to 14-day period before randomization. A significant correlation was found between change on 0-10 NRS and change in the Spasm Frequency Scale (r = 0.63; P < 0.001), and a moderate correlation was found between the change on 0-10 NRS and the PGIC (r = 0.47; P < 0.001). A reduction of ~30% in the spasticity 0-10 NRS score best represented the CID and a change of 18% the MCID. Conclusions: The measurement of the symptom of spasticity using a patient-rated 0-10 NRS was found to be both reliable and valid. The definitions of CID and MCID will facilitate the use of appropriate responder analyses and help clinicians interpret the significance of future results.
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Papers by Paul Duncombe