Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type.

A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.

New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans.

A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity and selectivity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed to be the primary D2 agonist pharmacophore. The 2-methylchroman moiety was discovered to be an entirely novel scaffold which could be used to access the D2 agonist pharmacophore. Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had significant effects on selectivity for the D2High receptor vs the 5HT1A and alpha 1 receptors. A novel DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as having the highest affinity and best selectivity for the D2High receptor vs the alpha 1 and 5HT1A receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-2-AMC moiety was identified as fulfilling the McDermed model D2 agonist pharmacophoric criteria and was proposed as the D2 receptor-bound conformation. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.

Structure-activity relationships among analogues of pemedolac, cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indo le-1-a cetic acid, a potent analgesic agent.

The syntheses of analogues of pemedolac (cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indol e-1-acetic acid), a potent analgesic, are described. They were tested for analgesic and antiinflammatory effects in vivo and for inhibition of prostaglandin production in vitro. Analysis of structure-activity relationships shows that analgesic activity in this series is associated with 1S-cis stereochemistry, the presence of a pi-system (allyl or benzyl) at position 4, and a log P value greater than 4.0.

Synthesis and analgesic activity of pemedolac (cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]ind ole-1- acetic acid).

The synthesis of cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indole -1-acetic acid, pemedolac (USAN), is described. This compound has been found to be a potent analgesic agent in primary screening. Pemedolac has been resolved and the active (+)-enantiomer assigned a 1S,4R absolute configuration on the basis of a crystallographic analysis of its (S)-(-)-borneol ester.

Thyroid carcinoma.

Differentiated thyroid carcinoma was studied with regard to mode of presentation, initial findings, treatment and survival. The classic signs, symptoms, physical and scan findings were found to be present in approximately 70% of the patients. Thirty percent of the patients had either unusual presentations or findings. Prognosis was found to be dependent on age of presentation more than any other factor. The effects of neck metastasis, extracapsular invasion and recurrent laryngeal nerve involvement on long-term survival are studied in detail. patients with prior exposure to radiation were found to have more extensive disease and require more extensive surgery but ultimately had the same prognosis for 15-year cure. Treatment for distant metastatic disease by surgery, radioactive iodine and external radiation all resulted in long-term survival in certain cases.

Evolution of the clinically negative neck.

A retrospective study was done of 602 patients with primary squamous cell carcinoma of the upper aerodigestive tract and a clinically negative neck (No) seen at the University of Illinois Hospital between 1960-1975. There was no uniform policy as to the treatment of No neck during this period; therefore in many of the patients, cervical lymph nodes were treated with elective neck dissection and others were followed until they became positive clinically. It was this difference which formed the basis for this study. All the patients were treated surgically; the patients were placed into two groups depending on whether they had radical neck dissection at the same time as resection of the primary. Group 1 consisted of 149 patients and had surgery for the primary only. The 253 patients of group 2 had surgery for the primary and also had a neck dissection. Both groups were analyzed for recurrences in the cervical region. In group 1, 12.9% of the patients developed either ipsilateral or contralateral metastases. Of the group 2 patients, 22% developed palpable nodal disease. The evolution of palpable nodal disease was analyzed by primary site, T-stage, and according to whether the tumor at the primary was controlled. Only 3% of the patients developed lymph nodes when the primary was controlled. The pathology reports of the neck specimens were studied to determine the relationship between a) positive node histology and b) number of nodes positive to the recurrence rate in the neck. Our results showed a 23% failure rate for the histologically positive group and a 21% failure rate for the negative group. The number of positive nodes did not seem to affect the recurrence rate.

Genetic counseling in chronic disease.

The counseling of those who are affected directly or indirectly by genetic disorders had traditionally been provided by physicians and geneticists. The author, using the example of hemophilia, argues that this type of counseling should be carried out not exclusively by medical personnel, but by social workers and others trained to deal with the social and psychological implications of such diseases.

Self-care is not a solipsistic trap: a reply to critics.

This paper is an answer to criticism of the self-care, self-help movement in health recently advanced by Robert Crawford and other writers. The authors review the multiple and varied origins, motivations, and ideologies associated with self-care developments. It is maintained that the self-care movement embodies a broad, popular social resistance to the ills, inequities, and iatrogenic elements in highly technological health care systems. Empirical examination of specific programs and formulations of this movement reveals that it cannot be fitted into a simplistic "victim-blaming" ideology, but instead operates to decrease dependence and heighten individual and political/social awareness of hazards to health.

Otologic complications of radiation therapy.

Radiation therapy has proved to be a valuable modality in the management of patients with nasopharyngeal tumors. Routine follow-up of patients in the tumor clinic of the University of Illinois Eye and Ear Infirmary appeared to indicate an increasing incidence of otologic pathology. For this reason, a retrospective study focusing on the otologic findings in patients whose radiation therapy for nasopharyngeal tumors included the external auditory canal, middle ear space, or eustachian tube was performed. The results of this study are discussed in relationship to total radiation dosage, time of survival after therapy, and pretreatment otologic status. The complications covered a spectrum from intermittent serous otitis media to osteoradionecrosis of the external auditory canal. Possible contributing factors are discussed, and preventive neasures are suggested.