Characterization of anti-inflammatory properties and evidence for no sedation liability for the novel antihistamine SUN-1334H.
BACKGROUND
The anti-inflammatory potential of antihistamines has significant clinical utility. Long-term pharmacotherapy of so-called 'safe' antihistamines may be hampered by side effects in the central nervous system. In the present study, the new potential antihistamine SUN-1334H was compared with different antihistamines for anti-inflammatory effects, sedation potential and interaction with alcohol.


METHODS
Nasal and skin allergy were induced in guinea pig and mice by ovalbumin sensitization and challenge. Neurogenic nasal inflammation was induced by capsaicin. Sedation potential and interaction with alcohol were assessed by i.v. and intracerebroventricular pentobarbital-induced sedation and alcohol-induced ataxia models.


RESULTS
Ovalbumin sensitization and challenge caused rhinitis pathology including inflammatory cell infiltration, IL-4, and protein leakage in the nasal lavage fluid (NLF) and presence of inflammatory cells in nasal epithelium. A 5-day treatment of antihistamines reduced these markers of inflammation. SUN-1334H, cetirizine and hydroxyzine caused comparable inhibition of NLF leukocytes, IL-4 and total protein concentrations. Fexofenadine and desloratadine showed moderate inhibition of NLF leukocytes and had no significant effect on IL-4 concentration. While fexofenadine had no effect on total protein concentration, the effect of desloratadine was comparable with the other antihistamines. In neurogenic nasal inflammation induced by capsaicin, SUN-1334H and fexofenadine caused better inhibition at lower and middle dose levels than the other antihistamines. In skin allergy models, SUN-1334H showed potent reduction of passive and active cutaneous anaphylactic reactions. In central nervous system side effects models, SUN-1334H, desloratadine and fexofenadine were devoid of any significant effects.


CONCLUSIONS
The results are suggestive of a high anti-inflammatory to sedation index of SUN-1334H among leading antihistamines.
Mandhane
Sanjay N
SN
Pharmacology Division, Sun Pharma Advanced Research Company Limited, Vadodara, India. sanjay.mandhane@sunpharma.com
Shah
Jigar H
JH
Bahekar
Prashant C
PC
Mehetre
Sameer V
SV
Pawar
Chandrashekhar A
CA
Bagad
Ashish S
AS
Chidrewar
Gajanan U
GU
Rao
Chitturi Trinadha
CT
Rajamannar
Thennati
T
D000085:Acetates / Q000009:adverse effects* / Q000627:therapeutic use; D000438:Alcohols / Q000008:administration & dosage*; D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D001259:Ataxia / Q000139:chemically induced / Q000188:drug therapy; D017332:Cetirizine / Q000009:adverse effects / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D039563:Histamine H1 Antagonists, Non-Sedating / Q000009:adverse effects* / Q000627:therapeutic use; D006919:Hydroxyzine / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D006967:Hypersensitivity / Q000188:drug therapy*; D007074:Immunoglobulin G / Q000097:blood; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D017336:Loratadine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017817:Nasal Lavage Fluid / Q000737:chemistry / Q000276:immunology; D009297:Nasal Mucosa / Q000276:immunology / Q000473:pathology; D010424:Pentobarbital / Q000494:pharmacology; D010879:Piperazines / Q000009:adverse effects* / Q000627:therapeutic use; D012912:Sneezing / Q000187:drug effects / Q000276:immunology; D016593:Terfenadine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use
C528564:4-(4-(bis(4-fluorophenyl)methyl)piperazin-1-ylbut-2-enyloxy)acetic acid; D000085:Acetates; D000438:Alcohols; D000894:Anti-Inflammatory Agents, Non-Steroidal; D039563:Histamine H1 Antagonists, Non-Sedating; D007074:Immunoglobulin G; D010879:Piperazines; D015847:Interleukin-4; D006919:Hydroxyzine; D017336:Loratadine; D016593:Terfenadine; C093230:fexofenadine; C121345:desloratadine; D010424:Pentobarbital; D017332:Cetirizine