New antagonists of LHRH II. Inhibition and potentiation of LHRH by closely related analogues

Modifications of the previously described LHRH antagonists, [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Trp³, d -Cit⁶, d -Ala¹⁰]LHRH and the corresponding d -Hci⁶ analogue, have been made to alter the hydrophobicity of the N-terminal acetyl-tripeptide portion. Substitution of d -Trp³ with the less hydrophobic d -Pal(3) had only marginal effects on the antagonistic activities and receptor binding potencies of the d -Cit/d -Hci⁶ analogues, but it appeared to further improve the toxicity lowering effect of d -Cit/d -Hci⁶ substitution. Antagonists containing d -Pal(3)³ and d -Cit/d -Hci⁶ residues, i.e. [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Pal(3)³d -Cit⁶, d -Ala¹⁰]LHRH (SB-75) and [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Pal(3)³, d -Hci⁶, d -Ala¹⁰]LHRH (SB-88), were completely free of the toxic effects, such as cyanosis and respiratory depression leading to death, which have been observed in rats with the d -Trp³, d -Arg⁶ antagonist and related antagonists. Replacement of the N-acetyl group with the hydrophilic carbamoyl group caused a slight decrease in antagonistic activities, particularly in vitro. Introduction of urethane type acyl group such as methoxycarbonyl (Moc) or t-butoxycarbonyl (Boc) led to analogues that showed LHRH-potentiating effect. The increase in potency induced by these analogues, e.g. [Moc-d -Nal(2)¹, d -Phe(4Cl)², d -Trp³, d -Cit⁶, d -Ala¹⁰]LHRH and [Boc-d -Phe¹, d -Phe(4Cl)², d -Pal(3)³, d -Cit⁶, d -Ala¹⁰]LHRH, was 170-260% and persisted for more than 2 h when studied in a superfused rat pituitary system.     

Understanding disability in Tourette syndrome

The aim of this study was to understand how children with Tourette syndrome (TS), with or without attention-deficit-hyperactivity disorder (ADHD) and/or obsessive-compulsive disorder (OCD), experience disability. Children seen at two TS centres were eligible for participation. Clinicians compiled baseline information and symptom severity rating scales. Parents completed the Child Health Questionnaire, a measure of physical and psychosocial health. Seventy-one children (56 males, 15 females); mean age 11y 2mo [SD 3y 1mo], range 7−17y) were analyzed in the subgroups: TS only ( n =20), TS+ADHD ( n =22), TS+ADHD+OCD ( n =18), and TS+OCD ( n =11). Almost all psychosocial domain scores were significantly lower than national norms for the TS+ADHD and TS+ADHD+OCD subgroups ( p <0.001). For the TS only subgroup, only the family activities domain was significantly affected. Psychosocial summary scores were 53.2 for norms, 54.4 for the TS only subgroup ( ns ), 41.4 for the TS+ADHD subgroup ( p <0.001), 35.3 for the TS+ADHD+OCD subgroup ( p <0.001), and 35.5 for the TS+OCD group ( p =0.003). A multiple linear regression model including diagnosis, age, sex, and TS, OCD, and ADHD symptom severity found that the most significant predictor of the psychosocial summary score was ADHD symptom severity (R²=0.55, p <0.001). Children with TS+ADHD±OCD experience impairment in all aspects of psychosocial health. For children with TS only, psychosocial health was not different from that of the normative population in the majority of domains tested. This suggests treatment of ADHD and OCD should be the priority in children with multiple diagnoses.