Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC) correspondence and conflicts with DSM-IV criteria in diagnosis of autism.

Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC) are tests widely used for screening and diagnosis of autism. This study verified their correspondence and conflict with a diagnosis made with DSM-IV criteria. The sample consisted of 65 children, aged 18 months to 11 years. We found complete agreement between DSM-IV and CARS. We show that ABC does not distinguish individuals with autistic disorders from other cases of developmental disorders as well as CARS: the number of false negatives is high (46%) with ABC as opposed to 0% with CARS.

Use of the Parental Bonding Instrument to compare interpretations of the parental bond by adolescent girls with restricting and binge/purging anorexia nervosa.

The Parental Bonding Instrument (PBI) was administered to 62 adolescent female patients (mean age 14.3): 35 with restricting-type anorexia nervosa (RAN), and 27 with binge/purging-type anorexia nervosa (B/PAN) according to the DSM-IV criteria, all at onset and initial diagnosis. The PBI was also administered to a control group (55 subjects) and 22 patients with Crohn's disease or celiac disease. The three groups were matched for age and socioeconomic status. The RAN and B/PAN patients gave significantly different interpretations of the parental bond (PB): for the former, it was adequate with both parents, for the latter it was inadequate, especially with the father. The fact that these differences exist at the onset of anorexia prior to any possible effect of therapy suggests that its structure is determined by different family dynamics.

Two distinct actions of retinoid-receptor ligands.

Signalling by all-trans retinoic acid is mediated through RXR-RAR retinoid receptor heterodimers, in which RXR has been considered to act as a transcriptionally silent partner. However, we show here that in cultured NB4 (ref. 6) human acute promyelocytic leukaemia cells treated with either an RAR-alpha-selective agonist alone, or certain RAR-alpha antagonists in combination with an RXR agonist, receptor-DNA binding is induced in vivo, resulting in expression of the target genes of retinoic acid as well as acute promyelocytic leukaemia protein (PML) relocation to nuclear bodies and differentiation before apoptosis. These results indicate that RAR-alpha ligands can induce two separate events: one enables RXR-RAR-alpha heterodimers to bind to DNA in vivo and allows RXR agonists to act; the other induces transcriptional activity of RAR-alpha. The availability of receptor-specific synthetic retinoids that can induce distinct receptor functions has potential in extending the therapeutic repertoire of retinoids.

Retinoic acid receptor beta,gamma-selective ligands: synthesis and biological activity of 6-substituted 2-naphthoic acid retinoids.

In search for retinoic acid receptor (RAR) selective ligands, a series of 6-substituted 2-naphthoic acid retinoids were synthesized and evaluated in vitro in a transactivation assay and a competition binding assay for all RARs. These derivatives, in general, showed RAR beta,gamma selectivity. Among these naphthoic acids, oxime derivative 12 was identified as a potent RAR gamma-selective retinoid, while olefinic derivative 11 was found to be comparable to retinoic acid and slightly RAR beta,gamma selective. For the bioassays, a general correlation was observed between the binding affinity of the ligand to the receptors and the potency of the compounds in the transactivation assay. The structure-activity relationship of these naphthoic acids will be discussed.

Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA).

A series of phosphonate prodrugs were evaluated in an attempt to increase the oral bioavailability of the anti-HIV agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; 1). The majority of the bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol or amine displacement of dichlorophosphonate 2. Basic hydrolysis of the bis(esters) or bis(amides) provided the corresponding monoesters or monoamides. Synthesis of bis[(acyloxy)alkyl] phosphonates 10a-c was accomplished by alkylation of PMEA with the appropriate chloromethyl ether in the presence of N,N'-dicyclohexylmorpholinecarboxamidine. The systemic levels of PMEA following oral administration of a PMEA prodrug to rats were determined by measuring the concentration of PMEA in the urine for 48 h after administration of the prodrug. The oral bioavailability of PMEA employing this method was determined to be 7.8%. Oral dosing with bis(alkyl) phosphonates 3a,b resulted in apparent absorption of the prodrugs (> or = 40%), although neither of the esters were completely cleaved to liberate the parent phosphonate PMEA. The mono(alkyl esters) 7a-e and 8a,b exhibited poor oral bioavailability (< or = 5%). Phosphonamides 5, 6, and 9 were unstable under acidic conditions and provided levels of PMEA comparable to the parent compound after oral administration. Bis[(acyloxy)alkyl] phosphonates 10a-c demonstrated significantly improved oral bioavailabilities of 17.6%, 14.6%, and 15.4%, respectively. When evaluated in vitro against HSV-2, (acyloxy)alkyl phosphonates 10a-c were greater than 200-fold more active than PMEA.

Prodrugs of 2',3'-didehydro-3'-deoxythymidine (D4T): synthesis, antiviral activity, and rapid pharmacokinetic evaluation.

A series of 5'-derivatives and modified pyrimidine analogues of 2',3'-didehydro-3'-deoxythymidine (d4T, stavudine, 1) were synthesized to determine their potential as oral prodrugs of d4T. Utilizing a screen developed for the rapid evaluation of a variety of prodrugs in mice, it was determined that 5'-acetate 2 provided comparable plasma levels of d4T after oral administration of the prodrug to that when d4T was administered alone. The relative oral bioavailability of methoxy acetate 3 and cyclohexyl carbonate 5 was 79 and 41%, respectively. Dihydropyridine ester 6 did not provide detectable levels of d4T up to 1 h after oral administration of 6. Thiopyrimidines 8 and 9, as well as aminopyrimidine 10 also failed to provide measurable levels of d4T after oral administration. 5'-Derivatives 3, 5, and 6 showed similar activity to that of d4T against HIV and MuLV, as did 5'-benzoyl-4-thio derivative 8. However, the corresponding 4-thio 5'-alcohol 9 was inactive.

Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine.

9-(2-Phosphonylmethoxyethyl)adenine (PMEA; 1) was acylated with chloromethyl pivalate to afford bis(pivaloyloxymethyl) PMEA (2). The ester prodrug demonstrated enhanced in vitro potency against HSV-2 greater than 150-fold higher than the parent compound. The antiviral activity of 2 was 50-fold better than PMEA against HSV-1, and equipotent against HIV and HCMV. The toxicity of 2 was studied in both resting and growing cells.

Systemic research on chronicity factors in infantile asthma.

This work is the result of research into chronicity factors in infantile asthma. The research had two main goals. The first, using a sample of 100 asthmatic children, was to reconstruct the therapeutic history of the individual patients on the hypothesis that the therapeutic intervention they had undergone in fact conditioned the quality of the cure demand. The second was to evaluate the influence of family dynamics on the chronic development of infantile asthma. A comparison was made between two interactive models using a sample of 10 families with asthmatic children with chronic tendencies and a sample of 10 normal families. The results show that typical dysfunctional interactive patterns exist in the experimental sample and that they are correlated with the perpetuation of the asthmatic symptom. The paper concludes that every therapeutic intervention that is limited to dealing with the biological component of the asthmatic symptom and ignores the influence of family dynamics becomes itself a major chronicity factor. Thus a "systemic" intervention is considered necessary to prevent chronicity.