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S Iyengar

Publications and source records attributed to S Iyengar.

At least 19 recordsLinked to original sources
PubMed1997

Improving the design of muscle relaxant studies. Stabilization period and tetanic recruitment.

BACKGROUND: The results from studies of muscle relaxants show wide variations among institutions. The authors hypothesized that some of this variability could be explained by differences in duration of nerve stimulation before drug administration (stabilization period). METHODS: Train-of-four stimulation was applied every 12 s to both ulnar nerves and adductor pollicis twitch tension was measured in anesthetized participants given 30 micrograms/kg vecuronium. In phase 1, the stabilization period was > 30 min for both extremities. In phase 2-4, stabilization period was 20 min for one extremity and 2 min for the other. In addition, in phase 3, a 2-s 50-Hz tetanus initiated the 2-min stimulation period; in phase 4, duration of tetanus was 5 s. Twitch recovery was recorded until stable for more than 15 min. Time to 25% recovery (clinical duration) was calculated based on two indices: predrug and final (recovery) twitch tension. Values for onset and clinical duration were compared by paired parametric and nonparametric tests. RESULTS: In phase 1, predrug and recovery twitch tension were similar in each extremity, and onset and clinical duration did not differ between extremities, permitting paired comparisons in remaining studies. In phase 2, onset was more rapid with 20-min of prestimulation. With 20-min prestimulation, predrug and recovery twitch tension were similar; with 2-min prestimulation, recovery twitch tension exceeded predrug values. When referenced to predrug twitch tension, clinical duration was shorter with 2-min, that with 20-min prestimulation. Initiating stimulation with 2-s or 5-s 50-Hz tetani (phases 3, 4) abolished differences between extremities in onset and recovery. CONCLUSIONS: With only train-of-four stimulation (no tetani), onset and clinical duration vary with duration of prestimulation, suggesting that a brief period of predrug stimulation is inadequate. However, lengthy prestimulation may be impractical in clinical studies. Tetanic stimulation for 2 or 5 s obviates the need for prolonged stabilization during studies of muscle relaxants.

Adult↗
PubMed1997

LY303870, a centrally active neurokinin-1 antagonist with a long duration of action.

The selective neurokinin (NK)-1 antagonist LY303870 has high affinity and specificity for human and guinea pig brain NK-1 receptors labeled with 125I-substance P. It has approximately 15- to 30-fold lower affinity for rat and mouse brain NK-1 receptors, consistent with previously reported species differences in the affinities of nonpeptide antagonists for NK-1 receptors. In vivo, LY303870 blocked the characteristic, caudally directed, biting and scratching response elicited by intrathecal administration of the selective NK-1 agonist Ac-[Arg6,Sar9,Met(O2)11]substance P6-11 in conscious mice. The potentiation of the tail-flick response elicited by intrathecal administration of the NK-1 agonist [Sar9,Met(O2)11]substance P in rats was also selectively blocked by LY303870. When tested in a model of persistent nociceptive activation induced by tissue injury (the formalin test), LY303870 blocked licking behavior in the late phase of the formalin test, in a dose-dependent manner. After oral administration of 10 mg/kg, the blockade of the late-phase licking behavior was evident for at least 24 hr. Ex vivo binding studies in guinea pigs showed that orally administered LY303870 potently inhibited binding to central and peripheral NK-1 receptors labeled with 125I-substance P. This inhibition was long-lasting, consistent with other in vivo activities. LY306155, the opposite enantiomer of LY303870, was less active in all of the functional assays. In rodents, LY303870 did not exhibit any neurological, motor, cardiovascular, gastrointestinal or autonomic side effects at doses of < or = 50 mg/kg p.o. Thus, LY303870 is a potent, centrally active, NK-1 antagonist in vivo, with long-lasting oral activity.

Animals↗
PubMed1996

Peripheral effects of three novel non-peptide tachykinin NK1 receptor antagonists in the anaesthetized rat.

Three novel non-peptide tachykinin NK1 receptor antagonists were assessed on the transient fall in mean arterial blood pressure and the salivation induced by i.v. substance P (0.65 nmol/kg) in the urethane-anaesthetized rat. LY303241 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- phenylpiperazin-1-yl)acetyl)amino]propane), LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(++ +piperidin-1 -yl)piperidin-1-yl)acetyl)amino]propane) and LY306740 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4 -cyclohexylpiperazin-1-yl)acetyl)amino]propane) (65 nmol-9 micromol/kg i.v.; 5 min earlier) inhibited both the vasodepressor and salivary responses to substance P in a dose-dependent manner. LY303241 and LY306740 were more potent in inhibiting the vascular response to substance P while LY303870 was more potent in inhibiting the salivary response. LY303870 and LY306740 were devoid of direct effects while LY303241 decreased blood pressure and heart rate for 1 and 10 min, respectively. The antagonists act in a stereoselective and specific manner since the opposite (S) enantiomers of LY303870 (LY306155) and LY306740 (LY307679) failed to block the effects of substance P. In addition, LY303241, LY303870 and LY306740 neither affected the hypotension and the salivation induced by carbachol nor the increases in mean arterial pressure and heart rate induced by the tachykinin NK2 receptor agonist [beta-Ala8]neurokinin A-(4-10). Only LY303241 attenuated the decreases in mean arterial pressure and heart rate evoked by the tachykinin NK3 receptor agonist senktide. LY303870 and LY306740 appear to be the most interesting antagonists since they act in a specific and selective manner at the tachykinin NK1 receptor. The difference in the order of potency of the three antagonists to inhibit the hypotension and salivation elicited by substance P could be ascribed to their pharmacodynamic features or to the existence of different signal transduction mechanisms or receptor subtypes.

Anesthesia↗
PubMed1996

Bayesian inference on prevalence using a missing-data approach with simulation-based techniques: applications to HIV screening.

Health departments and other health-related authorities seek accurate assessment of the spread of human immunodeficiency virus (HIV) among populations. Although screening for HIV provides a direct means for estimating its prevalence, it is complicated by the heterogeneity of available diagnostic tests and the degree to which they can diagnose HIV accurately. To integrate the limited precision of screening tests with prior results, Bayesian inference becomes a method of choice. Current Bayesian methods, however, have limited applications and do not readily generalize for complicated sampling designs and for modelling needs, particularly those that relate to HIV screening. By utilizing recent developments in the theories of missing-data analysis and simulation-based techniques, we develop an approach to Bayesian analysis of prevalence. This methodology is quite general for a variety of sampling schemes and sufficiently flexible to accommodate various practical considerations that arise from HIV screening. We illustrate the methodology with real as well as simulated data sets. Further, by utilizing the methodology, we performed simulations to demonstrate that pooled testing provides a cost-effective means to improve the precision of estimates of prevalence under the currently limited screening technology.

Algorithms↗
PubMed1996

3-Aryl-1,2-diacetamidopropane derivatives as novel and potent NK-1 receptor antagonists.

Early structure-activity studies on racemic tryptophan ester and amide NK-1 antagonists 5-7 led to the discovery that the potency of the series could be markedly increased by moving the carbonyl function in these molecules to an off-chain position as in the 3-aryl-1,2-diacetamidopropane 9. Further medicinal chemistry incorporating this change resulted in the discovery of a novel series of highly potent aryl amino acid derived NK-1 antagonists of the R stereoisomeric series (IC50's = 100 pM to > 5 microM). Compounds in this series were shown to be competitive antagonists using an in vitro NK-1 smooth muscle assay, and this data correlated well with observed human NK-1 binding affinities. Two of these agents, (R)-25 and (R)-32, blocked intrathecal NK-1 agonist-driven [Ac-[Arg6,Sar9,Met(O2)11]- substance P 6-11 (Ac-Sar9)] nociceptive behavior in mice. Both compounds potently blocked the neurogenic dural inflammation following trigeminal ganglion stimulation in the guinea pig after intravenous administration. Further, upon oral administration in this model, (R)-32 was observed to be very potent (ID50 = 91 ng/kg) and have a long duration of action (> 8 h at 1 micrograms/kg). Compound (R)-32, designated LY303870, is currently under clinical development as an NK-1 antagonist with a long duration of action.

Amides↗
PubMed1996

Early presentation of metastatic medullary carcinoma in multiple endocrine neoplasia, type IIA: implications for therapy.

A girl 5 years 11 months of age, belonging to an extensive kindred with multiple endocrine neoplasia, type IIA (MEN IIA), was found to have multifocal medullary thyroid carcinoma with metastasis in one paraglandular lymph node after positive findings on a calcium-pentagastrin stimulation test. Her sister, 3 years 8 months of age, also had an elevated calcitonin level, and thyroidectomy revealed C-cell hyperplasia and a focus of medullary thyroid carcinoma. These two cases underscore the need for prophylactic thyroidectomies in MEN IIA patients as young as 5 years of age and strict yearly provocative screening beginning at age 1 year.

Carcinoma, Medullary↗
PubMed1996

A randomized, controlled trial of amitriptyline in the acute treatment of adolescent major depression.

OBJECTIVE: To determine amitriptyline's (AMI) efficacy in the acute treatment of adolescent major depressive disorder (MDD). METHOD: Subjects aged 12 through 17 years meeting Research Diagnostic Criteria for MDD, diagnosed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS), participated in a 2-week placebo-washout followed by an 8-week, randomized, double-blind, parallel-design, placebo-controlled trial of AMI, 5 mg/kg per day. The K-SADS nine-item scale, the Hamilton Depression Rating Scale, and the Clinical Global Impressions rating scale were used as outcome measures. RESULTS: Thirty-one subjects were randomized (18 AMI, 13 placebo). Twenty-two subjects were study completers (12 AMI, 10 placebo). AMI's efficacy was suggested by the Clinical Global Impressions but not the K-SADS-derived data. Perhaps the primary limitation of the current study is its small sample size. CONCLUSION: No definitive recommendation can be made regarding the efficacy of tricyclic antidepressants in the treatment of adolescent MDD.

Adolescent↗
PubMed1996

Psychiatric disorder and metabolic control among youths with IDDM. A longitudinal study.

OBJECTIVE: To investigate the longitudinal relationship between psychiatric diagnostic variables and metabolic control among youths with IDDM. RESEARCH DESIGN AND METHODS: A group of 88 youths, 8 to 13 years old at onset of IDDM, were evaluated repeatedly during a 9-year follow-up period, on average, using a standardized psychiatric protocol. Levels of HbA1 were also assessed repeatedly. Psychiatric diagnoses were derived independently of HbA1 values. RESULTS: In univariate longitudinal analyses, the psychiatric diagnosis of noncompliance with medical treatment was significantly related to HbA1 level. There was a trend of an association between any major psychiatric disorder, as well as nondepressive disorder, and HbA1. Interaction terms between IDDM duration (or age) and psychiatric variables were also significantly related to metabolic control. According to the final multivariate model of repeatedly assessed HbA1, noncompliance with medical treatment (irrespective of IDDM duration) and the interaction between nondepressive psychiatric disorder and IDDM duration contributed to worse metabolic control. CONCLUSIONS: We found some support for the hypothesis that psychiatric morbidity negatively affects blood glucose regulation and that its consequences are more marked the longer young patients have had IDDM. We did not confirm the hypothesis that depressive illness has particularly deleterious consequences on metabolic control. Noncompliance with medical treatment and having had nondepressive psychiatric illness in interaction with IDDM duration account for a statistically significant but clinically modest amount of variability in HbA1 over time. The weak relationship among these variables may explain the inconsistent findings in the literature regarding psychiatric morbidity and metabolic control.

Adolescent↗
PubMed1995

A longitudinal study of life events and metabolic control among youths with insulin-dependent diabetes mellitus.

In a study of school-age children with new-onset insulin-dependent diabetes mellitus (IDDM), life stress, metabolic control (glycosylated hemoglobin), and psychiatric and psychosocial variables were assessed repeatedly for up to 6 years. Life stress was defined as the number of undesirable life events and extent of life change necessitated by all life events. In univariate longitudinal analyses, total life change units were related to metabolic control, with a trend for number of undesirable events to be associated with metabolic control. In multivariate analyses, metabolic control was related to life change units, whether the glycosylated hemoglobin was in the 1st year of IDDM, IDDM duration, and the diagnosis of pervasive noncompliance with medical regimen. The relationship of life stress to metabolic control among youths with diabetes in significant but clinically modest and may be partially mediated by serious noncompliance with the medical regimen.

Adaptation, Psychological↗
PubMed1995

Biomedical and psychiatric risk factors for retinopathy among children with IDDM.

OBJECTIVE: Illness duration and glycemic control influence the development of retinopathy in childhood-onset insulin-dependent diabetes mellitus (IDDM). Psychiatric disorders and sociodemographic factors also affect diabetes-related outcomes. However, biomedical and psychosocial factors have not been examined together in modeling the risk of retinopathy. RESEARCH DESIGN AND METHODS: We conducted a single-site prospective longitudinal study of 66 children (aged 8-13 years) newly diagnosed with IDDM. Repeated assessments served to derive psychiatric diagnoses. Poor glycemic control was defined as the upper 15th percentile of all HbA1 values. After a median follow-up of 10 years, severity of retinopathy was determined. It was modeled with a stepwise polychotomous regression procedure using antecedent biomedical and psychosocial variables. RESULTS: Young adults with childhood-onset IDDM were found to be at increased risk of retinopathy the longer they had IDDM, the more persistently they evidenced poor antecedent glycemic control, and the longer they suffered from depressive illness. These three factors operated individually and additively, with duration of IDDM conferring a baseline level of risk. In depressed patients (27%), depression onset antedated the detection of retinopathy generally by 7 years. CONCLUSIONS: Duration of childhood-onset IDDM confers a baseline level of risk of retinopathy irrespective of glycemic control; antecedent clinical depression is also a risk factor. Depression therefore may serve as a marker of vulnerability and help to identify a subgroup of patients at risk for complications. The findings raise the question whether timely treatment of depression could forestall diabetic retinopathy.

Adolescent↗
PubMed1994

Different genomic fragments encode for two human herpesvirus 6 early proteins that share a cross-reactive antigen.

A monoclonal antibody was previously described which precipitated two human herpesvirus 6 early proteins. The experiments reported in this paper were designed to determine the relationship of these two proteins. This was determined by probing enzymatically digested viral DNA with a cloned p41 cDNA construct and with a synthetic p38 oligonucleotide. These probes reacted with genomic fragments of different sizes following enzymatic digestion. In addition, the p38 synthetic probe reacted with uninfected cell DNA. These results indicated that p41 and p38 share an antigenic epitope but are encoded by different genomic fragments.

Amino Acid Sequence↗
PubMed1993

Indole-2-carboxylates, novel antagonists of the N-methyl-D-aspartate (NMDA)-associated glycine recognition sites: in vivo characterization.

Recent in vitro receptor binding studies have indicated that indole-2-carboxylates with halogen substitutions at the position 5 or 6 are potent competitive antagonists of the NMDA (N-methyl-D-aspartate)-associated strychnine-insensitive glycine receptor (Gray N. M., Dappen M. S., Cheng B. K., Cordi A. A., Biesterfeldt J. P., Hood W. F. and Monahan J. B. (1992) J. med. Chem. 34: 1283-1292; Hood W. F., Gray N. M., Dappen M. S., Watson G. B., Compton R. P., Cordi A. A., Larthorn T. H. and Monahan J. B. (1992) J. Pharmac. exp. Ther. 262: 654-660). In the present investigation, a series of indole-2-carboxylates and two putative antagonists of glycine receptor HA-966 (3-amino-l-hydroxypyrrolidin-2-one) and 7-chlorokynurenic acid were examined for their effects on cGMP responses, mediated by the NMDA receptor complex, in vivo. Both SC-49648 (6-chloro-2-carboxyindole-3-acetic acid, intracerebellar injection, i.c.b.) and HA-966 (i.c.b. or intraperitoneal, i.p.) antagonized increases in levels of cyclic GMP in the cerebellum of the mouse, induced by the intracerebellar administration of NMDA and D-serine, agonists of the NMDA and the NMDA-associated glycine recognition sites, respectively. The drugs SC-49648 and 7-chlorokynurenic acid (i.p.) did not affect cGMP responses, suggesting poor bioavailability in brain. Following direct intracerebellar injection, SC-49648 was eliminated with a half-life of 12 min from the brain. Following intraperitoneal administration, SC-50132, the 3-ethylester analog of SC-49648, was eliminated from the brain with a half-life of 35 min and was found to be metabolized to SC-49648, in vivo. Some lipophilic analogs of SC-49648, designed as its prodrugs, were minimally active as glycine antagonists, in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Identification of a DNA-binding protein of human herpesvirus 6, a putative DNA polymerase stimulatory factor.

A 41K early nuclear antigen (p41), expressed in human herpesvirus type 6 (HHV-6)-infected T cells, was cloned by screening a cDNA expression library with the anti-p41 monoclonal antibody (MAb) C5. When expressed in mammalian cells, the cloned p41 protein comigrated with the authentic p41 protein from HHV-6-infected cells and localized to the nucleus. HHV-6 p41 shares 44% sequence identity with the human cytomegalovirus (HCMV) DNA-binding protein, ICP36 (UL44 gene product); p41 binds to ssDNA with the same apparent affinity as ICP36. Since ICP36 has recently been shown to be an HCMV DNA polymerase-associated stimulatory factor, a similar function is suggested for p41.

Amino Acid Sequence↗
PubMed1992

Characterization of 3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a potent competitive N-methy-D-aspartate (NMDA) receptor antagonist, in vitro and in vivo.

(+/-)-3-Carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a conformationally restricted analog of the potent competitive N-methyl-D-aspartate (NMDA) antagonist, 2-amino-5-phosphonopentanoate (AP-5), potently inhibited the binding of [3H]glutamate to the N-methyl-D-aspartate (NMDA) receptors with a Ki of 1.6 mcM, but with minimal affinity for kaininate and quisqualate receptors (Ki greater than 50 mcM), in vitro. Consistent with its ability to antagonize the NMDA receptor, SC-48981 decreased the binding of [3H]glycine and [3H]TCP [1-(2-thienyl)cyclohexylpiperidine] to the NMDA-associated glycine and phencyclidine (PCP) recognition sites, in vitro. SC-48981 attenuated levels of basal cGMP and harmaline-induced increases in levels of cGMP in the mouse cerebellum, in vivo, in a competitive manner, with ED50 values of 5.5 and 8.7 mg/kg, i.p. Direct intracerebellar injection of SC-48981 (0.5 microgram) attenuated increases in levels of cGMP induced by central injection of the NMDA-associated glycine receptor agonist, D-serine and by NMDA itself. Parenteral administration of SC-48981 (25 mg/kg, s.c.) decreased basal levels of cGMP for up to 3 h. These results indicate that SC-48981 represents a novel bioavailable competitive NMDA antagonist with a long duration of action.

Animals↗
PubMed1992

Neuroendocrine response to L-5-hydroxytryptophan challenge in prepubertal major depression. Depressed vs normal children.

The neuroendocrine response to L-5-hydroxytryptophan was compared in 37 prepubertal children who met the Research Diagnostic Criteria for major depressive disorder with that in 23 normal children with no lifetime history of any psychiatric disorder and very low rates of depression in both first- and second-degree relatives. Intravenous L-5-hydroxytryptophan (0.8 mg/kg) was given over a 1-hour interval after preloading with oral carbidopa, an inhibitor of peripheral but not central L-5-hydroxytryptophan metabolism. L-5-Hydroxytryptophan, a precursor of serotonin, increases serotonin turnover in the central nervous system when given after carbidopa. Seven (19%) of the 37 children with major depressive disorder and two (9%) of the 23 normal children had nausea or vomiting and therefore did not complete the full infusion. They were subsequently excluded from data analysis. After this stimulation, prolactin, cortisol, and growth hormone secretion were compared between diagnostic groups. The depressed children secreted significantly less cortisol (effect size, 0.70) and significantly more prolactin (effect size, 0.83). There was a sex-by-diagnosis interaction in prolactin response to L-5-hydroxytryptophan and, on examination, the prolactin hypersecretion was seen in depressed girls but not in depressed boys compared with same-sex controls. There was no significant stimulation of growth hormone in either group. These findings are consistent with dysregulation of central serotonergic systems in childhood major depression.

Adult↗
PubMed1992

Comparison of exposure assessment guidelines for pesticides.

The field of exposure assessment of pesticides has become well established in the past decade. Consequently, government agencies and industry groups have identified the need for guidelines for conducting studies that assess mixer/loader/applicator exposure to pesticides, as well as the exposure of individuals to residues. This paper reviews guidelines on mixer/loader/applicator exposure studies issued by the International Group of National Associations of Manufacturers of Agrochemical Products, the National Agricultural Chemicals Association, the U.S. EPA, and the World Health Organization. Mention is also made of Canadian exposure guidelines in preparation. Also reviewed are two guidelines for conducting indoor occupant exposure studies, one by the National Agricultural Chemicals Association and one by Health and Welfare Canada. The only available guideline (EPA) on assessing pesticide exposure to workers upon reentry into treated fields is also reviewed. These guidelines are reviewed and compared as to criteria for requirements of exposure studies, methodologies recommended for dermal, inhalation, and biological monitoring, quality assurance and quality control, the use of surrogate data, data reporting, and exposure calculations. From this comparison, it is evident that there has been little significant progress in the area of methodologies used for dermal exposure monitoring. The use of patches as suggested by Durham and Wolfe (1962) is still accepted and widely used, despite its limitations. However, relatively recent research in this area has shown that the fluorescent tracer technique (Fenske et al. 1986a,b) and use of full-body dosimeters may help in overcoming some of these limitations. The tracer technique is mentioned in the EPA guidelines and full-body dosimeters are addressed by EPA, WHO, and NACA. Biological monitoring can also overcome many of the limitations of passive dosimetry, but all guidelines stress the need for extensive knowledge of the pharmacokinetics and metabolism of the pesticide before this approach can be used. Rapid advancement has been made in quality assurance/quality control and analytical techniques. This has increased the level of confidence placed in exposure estimates and is evidenced by the detailed requirements of quality assurance and quality control in most of the guidelines reviewed. Guidelines on conducting indoor occupant exposure studies deal extensively with methodologies for collecting residue samples, but do not make concrete recommendations for estimating human exposure based on these residues. More research is required before the subject can be adequately dealt with in guidelines. It is encouraging that this research is being coordinated among industry, academia, and government. Further research is also needed in determining exposure to pesticides during reentry into treated areas in order to develop further guidelines.(ABSTRACT TRUNCATED AT 400 WORDS)

Air Pollution, Indoor↗
PubMed1992

A secular increase in child and adolescent onset affective disorder.

Both longitudinal and cross-sectional studies utilizing population and family study samples have found evidence for a secular increase in major affective disorders in adults. Applying techniques used in cross-sectional studies in adults to family study data of children and adolescents, the authors demonstrate evidence of a parallel secular increase for child and adolescent onset affective disorders. Normal and depressed prepubertal probands were identified. All full siblings were directly interviewed for lifetime episodes of affective disorder. Analysis of the siblings (probands not further analyzed in this article) by the Cox proportional hazards model demonstrates that the risk for affective disorder is higher in siblings born more recently.

Bias↗