ABSTRACT
BACKGROUND: Pruritus is a leading cause of reduced health-related quality of life (QoL) in atopic dermatitis (AD). Crisaborole ointment is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. In identical Phase 3 studies (NCT02118766, NCT02118792), crisaborole reduced disease and pruritus severity versus vehicle. OBJECTIVE: Quantify the relationship between pruritus and QoL using data from these studies. METHODS: Patients aged ≥2 years were randomly assigned 2 : 1 to receive crisaborole:vehicle twice daily for 28 days. QoL was measured at baseline and day 29 using the Dermatology Life Quality Index (DLQI; patients aged ≥16 years), the Children's Dermatology Life Quality Index (CDLQI; patients aged 2-15 years) and the Dermatitis Family Impact (DFI; caregivers of patients aged 2-17 years). Pruritus was measured using the Severity of Pruritus Scale (SPS), a 4-point scale from 0 ('no itching') to 3 ('bothersome itching/scratching that disturbs sleep'), and captured morning and evening via electronic diary. Data from crisaborole and vehicle arms were pooled for this analysis. A repeated-measures longitudinal model was used to estimate relationships between pruritus (SPS) and QoL (DLQI, CDLQI and DFI in separate analyses). RESULTS: One thousand five hundred and twenty two patients received crisaborole or vehicle. A linearity assumption for the relationship between SPS and DLQI (n = 294), CDLQI (n = 1200), and DFI (n = 1293) was appropriate. For DLQI, SPS score of 0 was associated with 'no negative effect on patient QoL'; SPS score of 1 was associated with 'small effect on patient QoL'; SPS score of 2 was associated with 'moderate effect on patient QoL'; and SPS score of 3 was associated with 'very large effect on patient QoL'. The pattern of relationships between SPS and CDLQI and DFI was similar. CONCLUSIONS: The relationships between SPS and DLQI, CDLQI and DFI substantiate the significant link between pruritus and patient/caregiver QoL in AD.
Subject(s)
Boron Compounds/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Dermatitis, Atopic/drug therapy , Pruritus/drug therapy , Quality of Life , Adolescent , Adult , Aged , Child , Child, Preschool , Double-Blind Method , Female , Humans , Infant , Male , Middle Aged , Ointments , Severity of Illness IndexABSTRACT
WHAT IS KNOWN AND BACKGROUND: Although paracetamol (acetaminophen), N-(4-Hydroxyphenyl)acetamide, is one of the world's most widely used analgesics, the mechanism by which it produces its analgesic effect is largely unknown. This lack is relevant because: (i) optimal pain treatment matches the analgesic mechanism to the (patho)physiology of the pain and (ii) modern drug discovery relies on an appropriate screening assay. OBJECTIVE: To review the clinical profile and preclinical studies of paracetamol as means of gaining insight into its mechanism of analgesic action. METHODS: A literature search was conducted of clinical and preclinical literature and the information obtained was organized and reviewed from the perspective of its contribution to an understanding of the mechanism of analgesic action of paracetamol. RESULTS: Paracetamol's broad spectrum of analgesic and other pharmacological actions is presented, along with its multiple postulated mechanism(s) of action. No one mechanism has been definitively shown to account for its analgesic activity. WHAT IS NEW AND CONCLUSION: Further research is needed to uncover the mechanism of analgesic action of paracetamol. The lack of this knowledge affects optimal clinical use and impedes drug discovery efforts.
Subject(s)
Acetaminophen/pharmacology , Analgesia , Analgesics, Non-Narcotic/pharmacology , Pain/drug therapy , Pain/physiopathology , Acetaminophen/administration & dosage , Acetaminophen/adverse effects , Acetaminophen/pharmacokinetics , Acetanilides/adverse effects , Acetanilides/therapeutic use , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/adverse effects , Analgesics, Non-Narcotic/pharmacokinetics , Analgesics, Opioid/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antipyretics/adverse effects , Antipyretics/therapeutic use , Drug Discovery , Humans , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Pain MeasurementABSTRACT
Photosensitive seizures occur most commonly in childhood and adolescence, usually as a manifestation of complex idiopathic generalized epilepsies (IGEs). Molecular mechanisms underlying this condition are yet to be determined because no susceptibility genes have been identified. The NEDD4-2 (Neuronally Expressed Developmentally Downregulated 4) gene encodes a ubiquitin protein ligase proposed to regulate cell surface levels of several ion channels, receptors and transporters involved in regulating neuronal excitability, including voltage-gated sodium channels (VGSCs), the most clinically relevant of the epilepsy genes. The regulation of NEDD4-2 in vivo involves complex interactions with accessory proteins in a cell type specific manner. We screened NEDD4-2 for mutations in a cohort of 253 families with IGEs. We identified three NEDD4-2 missense changes in highly conserved residues; S233L, E271A and H515P in families with photosensitive generalized epilepsy. The NEDD4-2 variants were as effective as wild-type NEDD4-2 in downregulating the VGSC subtype Na(v)1.2 when assessed in the Xenopus oocyte heterologous expression system showing that the direct interaction with the ion channel was not altered by these variants. These data raise the possibility that photosensitive epilepsy may arise from defective interaction of NEDD4-2 with as yet unidentified accessory or target proteins.
