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Biomedical subjects

B Subramanyam

Publications and source records attributed to B Subramanyam.

At least 19 recordsLinked to original sources
PubMed2006

Miglustat has no apparent effect on spermatogenesis in normal men.

BACKGROUND: In mice, administration of the glycosphingolipid biosynthesis inhibitor miglustat results in reversible infertility, characterized by impaired sperm motility and markedly abnormal sperm morphology. This observation suggested that miglustat might have utility for fertility control in man. To ascertain the impact of miglustat on human spermatogenesis, we conducted a pilot study of miglustat administration in normal men. METHODS: After a 2-week baseline period, seven normal men were administered miglustat 100 mg, orally, twice daily for 6 weeks. During treatment, subjects had frequent seminal fluid analyses to assess the impact of treatment on sperm concentration, motility and morphology and the ability to undergo the acrosome reaction by in vitro assays. RESULTS: Five subjects completed all aspects of the study. In these subjects, there was no apparent effect of miglustat on sperm concentration, motility or sperm morphology after 6 weeks of therapy. In addition, no changes in acrosome structure or function were observed with treatment, despite therapeutic concentrations of miglustat in the serum and seminal plasma. All subjects experienced gastrointestinal upset, diarrhoea and mild weight loss during treatment. No other abnormalities in blood counts, serum chemistries, vision or overall health were observed. CONCLUSION: In contrast to the observations in mice, the oral administration of miglustat does not appear to affect human spermatogenesis. Further elucidation of the mechanism underlying the species specificity of miglustat may improve our understanding of the role of glycosphingolipids in spermatogenesis and result in alternative approaches to male fertility control.

1-Deoxynojirimycin↗
PubMed2006

Susceptibility of Plodia interpunctella (Lepidoptera: Pyralidae) developmental stages to high temperatures used during structural heat treatments.

Heating the ambient air of a whole, or a portion of a food-processing facility to 50 to 60 degrees C and maintaining these elevated temperatures for 24 to 36 h, is an old technology, referred to as heat treatment. There is renewed interest in adopting heat treatments around the world as a viable insect control alternative to fumigation with methyl bromide. There is limited published information on responses of the Indian meal moth, Plodia interpunctella (Hübner), exposed to elevated temperatures typically used during heat treatments. Time-mortality relationships were determined for eggs, fifth-instars (wandering-phase larvae), pupae, and adults of P. interpunctella exposed to five constant temperatures between 44 and 52 degrees C. Mortality of each stage increased with increasing temperature and exposure time. In general, fifth-instars were the most heat-tolerant stage at all temperatures tested. Exposure for a minimum of 34 min at 50 degrees C was required to kill 99% of the fifth-instars. It is proposed that heat treatments aimed at controlling fifth-instars should be able to control all other stages of P. interpunctella.

Animals↗
PubMed2000

Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1.

The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl ]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471). Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K(i) ranged from 1 nm to 5.5 nm). BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca(2+) mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis. This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases.

Administration, Oral↗
PubMed1995

Prevalence of diabetes in the young in south India.

Students from nine schools and one college in Madras city, were screened for diabetes by oral glucose tolerance test. The criteria recommended by the World Health Organization was adopted to classify glucose tolerance. Among 3,515 students, between 5 and 19 years of age, participated in this survey, 1982 (56.4%) were males and 1.533 were (43.6%) females. Family history of diabetes was positive in 302 (8.6%) students. There was no overt case of diabetes of any type. Three (0.09%) males had renal glycosuria. It is therefore concluded that insulin-dependent diabetes, non-insulin dependent diabetes or any other type of diabetes in the young is rare in South India.

Adolescent↗
PubMed1993

Alkylamides as inducers of human leukemia cell differentiation: a quantitative structure-activity relationship study using comparative molecular field analysis.

Computer assisted quantitative structure-activity studies using comparative molecular field analysis (CoMFA) were performed on a series of alkylamides that induce cell differentiation. The series included alkylformamides, alkylacetamides, alkylureas, and substituted hexyl analogues of acetamide. The biological activity studied for correlation with structure was the ability of each compound to induce differentiation of the human promyelocytic leukemia cell line, HL-60, to granulocyte-like cells. In the CoMFA study, both steric and electrostatic fields were used along with molecular weight to determine a correlation between biological activity of the compounds and their structural features. The CoMFA results indicated a linear structure-activity correlation with a high predictive value. There was almost an even contribution towards activity from steric interactions, electrostatic potential, and molecular weight. These findings confirm a previous report by Langdon and Hickman (S. P. Langdon and J. A. Hickman, Cancer Res., 47: 140-144, 1987) that the ability to induce cell differentiation is highly dependent on molecular weight. Additionally, CoMFA contour maps provided information about regions of the molecule that are favorable to increased steric bulk and electrostatic charge. CoMFA was used to predict the activities of six hexamethylene acetamide analogues: ethyl 6-acetamidohexanoate; 6-acetamidohexanol; 1,5-bis(acetamido)hexane; 6-acetamidohexanonitrile; 6-acetamidohexanoic acid; and caprolactam. Although the model incorrectly predicted high activity for 6-acetamidohexanoic acid, the predicted activities for the remaining compounds were 0.3 to 1.5 times that of the corresponding experimental activities, which is comparable to the results obtained from other published CoMFA studies.

Cell Differentiation↗
PubMed1992

Isotopically sensitive regioselectivity in the oxidative deamination of a homologous series of diamines catalyzed by diamine oxidase.

The equivalence of aminomethylene groups in selected diamine substrates of diamine oxidase was exploited for the determination of intramolecular isotope effects. In the series of substrates, [1,1-2H2]-1,3-diaminopropane, [1,1-2H2]-1,5-diaminopentane, [1,1-2H2]-1,6-diaminohexane, [1,1-2H2]-1,7-diaminoheptane and [alpha,alpha-2H2]-4-(aminomethyl)benzylamine, the preference of the enzyme for reaction at the unlabeled methylene was found to vary from 1.45 to 10.5-fold. The observed partitioning ratios go through a minimum value with 1,5-diaminopentane, the best substrate of diamine oxidase of the compounds tested. The results suggest that fast substrates have less opportunity to reorient into alternate binding conformations while bound to the active site of the enzyme. On the other hand, diamine substrates tested that cannot exist in energetically favorable conformations with internitrogen distances of about 7-8 A showed larger intramolecular isotope effects.

Amine Oxidase (Copper-Containing)↗
PubMed1991

Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol.

Evidence that the parkinsonian inducing agent MPTP is biotransformed to a pyridinium species that selectively destroys nigrostriatal neurons in humans and subhuman primates has prompted studies to evaluate the metabolic fate of the structurally related neuroleptic agent haloperidol. With the aid of a highly sophisticated atmospheric pressure ionspray HPLC/MS/MS assay, unambiguous evidence has been obtained for the presence of the haloperidol pyridinium species in extracts of urine obtained from haloperidol-treated patients and in extracts of NADPH-supplemented human liver microsomal incubation mixtures containing haloperidol. The potential significance of the formation of this putative neurotoxic pyridinium species is considered.

Adult↗
PubMed1991

The effect of the monoamine oxidase inhibitor isocarboxazid on the canine metabolism of the cell-differentiating agent hexamethylene bisacetamide.

The acute toxicities of the cellular differentiating agent hexamethylene bisacetamide (HMBA) in humans and animals include CNS toxicity (agitation, somnolence, seizures, hallucinations) and an anion-gap metabolic acidosis. N-Acetyl-1,6-diaminohexane (NADAH), the first metabolite of HMBA, is as active as the parent compound in causing differentiation of leukemic cells in vitro, whereas 6-acetamidohexanoic acid (6AcHA), which is formed by the oxidation of NADAH in the presence of monoamine oxidase (MAO) and aldehyde dehydrogenase, is inactive. To test whether the inhibition of MAO blocks the production of an inactive and possibly toxic HMBA metabolite (6AcHA) or increases the amount of active compounds (HMBA + NADAH) in vivo, we investigated the effect of the MAO inhibitor isocarboxazid on the metabolism and toxicity of HMBA in beagle dogs. Two groups of dogs, composed of one male and one female dog per group, were used in the study. One group received isocarboxazid (3.3 mg/kg p.o. q8h x 9) beginning at 24 h before the initiation of a 48-h i.v. infusion of HMBA (40 mg kg-1 h-1), whereas the other received placebo in an identical fashion prior to the start of an identical HMBA infusion. The mean plasma steady-state concentration (css) of HMBA was 0.91 mM in dogs given HMBA and isocarboxazid as opposed to 0.78 mM in those given HMBA and placebo. As measured spectrophotometrically, plasma MAO activity was inhibited by 86% +/- 3% in dogs receiving isocarboxazid. Gas chromatography/mass spectrometry detected 6AcHA in the plasma of animals that were given placebo but not in the plasma of dogs that received isocarboxazid. Gas chromatographic analysis of urine samples revealed that the total amount of 6AcHA and of NADAH excreted in urine was 8 times less and 3 times greater, respectively, in isocarboxazid-treated dogs than in animals that received HMBA and placebo. One dog was excitable after the initial two doses of isocarboxazid and developed seizures at the end of the HMBA infusion. Another dog was agitated during treatment with HMBA and isocarboxazid. No CNS toxicity occurred in animals that were treated with HMBA and placebo. We conclude that isocarboxazid inhibits the production of 6AcHA in vivo, thus supporting the involvement of MAO in HMBA metabolism. Because the combination of HMBA and isocarboxazid produces CNS toxicity, 6AcHA is probably not the neurotoxic agent in dogs.

Acetamides↗
PubMed1990

Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats.

In vivo metabolic studies have revealed that haloperidol is converted to the corresponding pyridinium metabolite which has been characterized in both urine and brain tissues isolated from haloperidol treated rats. Unlike the corresponding conversion of the structurally related Parkinsonian inducing agent MPTP to the ultimate neurotoxic pyridinium metabolite MPP+, the oxidative biotransformation of haloperidol is not catalyzed by MAO-B. Microdialysis studies in the rat indicate that intrastriatal administration of this pyridinium metabolite is about 10% as effective as MPP+ in causing the irreversible depletion of striatal nerve terminal dopamine. The results point to the possibility that some of the neurological disorders observed in experimental animals and man during the course of chronic haloperidol treatment may be mediated by this pyridinium metabolite.

Animals↗
PubMed1989

A cyclic imine intermediate in the in vitro metabolic conversion of 1,6-diaminohexane to 6-aminohexanoic acid and caprolactam.

1. 3,4,5,6-Tetrahydro-2H-azepine is an intermediate in the enzyme-catalyzed conversion of 1,6-diaminohexane to 6-aminohexanoic acid and its corresponding lactam, caprolactam, by mammalian liver aldehyde oxidase. 2. Identification of metabolites was based on analysis by gas chromatography-mass spectrometry and confirmed by comparison with the properties of authentic standards. 3. The results indicate that the cell differentiating agent hexamethylene bisacetamide is converted into 1,6-diaminohexane, and its metabolism therefore involves diamine oxidase. 4. The metabolic fate of 1,6-diaminohexane is similar to that of putrescine and cadaverine in that a cyclic imine is an intermediate in the formation of metabolites with ring (lactam) and chain (amino acid) structures.

Aldehyde Oxidase↗
PubMed1989

Spondylothoracic dysplasia. Clinical and sonographic diagnosis.

Spondylothoracic dysplasia, also known as short-trunk dwarfism or Jarcho-Levin syndrome, is a fatal autosomal recessive disorder characterized by vertebral and spinal defects with a short thorax. Until recently, in utero diagnosis could only be made radiographically. Sonographic criteria for antenatal diagnosis are discussed in conjunction with a review of the literature.

Abnormalities, Multiple↗
PubMed1989

The postmenopausal cystic adnexal mass: the potential role of ultrasound in conservative management.

Often ovarian cancer does not present clinically until the advanced stages. In the past, the presence of any cystic adnexal enlargement in postmenopausal women was an indication for surgical exploration. The ultrasound scans of 42 postmenopausal women with simple adnexal cysts were reviewed. We included only patients who were available for follow-up and who had cysts that were less than or equal to 5 cm in maximum diameter, unilocular (ie, without septations or solid components), and without ascites. Of these patients, 26 underwent prompt surgical exploration. All exhibited benign histopathology. In 16 patients, serial sonographic surveillance was performed every 3-6 months. Two of these patients had exploratory laparotomy at 6 and 9 months of observation; the first operation, for increasing size and septation, demonstrated a cystadenofibroma, and the second, for increasing pain, demonstrated a degenerating myoma. The remaining 14 patients were followed from 10-73 months without any change in size or character of the cyst. Small (less than 5 cm), unilocular postmenopausal cysts had a low incidence of malignant disease (0%) in this series of 28 surgical specimens. Therefore, serial ultrasound follow-up without surgical intervention may play a role in the clinical management of such patients.

Adnexal Diseases↗
PubMed1988

Metabolism of hexamethylene bisacetamide and its metabolites in leukemic cells.

We investigated whether leukemic cell lines could convert hexamethylene bisacetamide (HMBA) to any of the metabolites previously identified and quantified in the urine and plasma of patients treated with HMBA. After 5-7 days of incubation with 1-2 mM HMBA, HL60 human promyelocytic leukemic cells, L1210 and P388 murine lymphoblastic leukemic cells, and Friend murine erythroleukemia cells contained 4 of the previously identified metabolites of HMBA. Gas chromatography/mass spectrometry confirmed the presence of N-acetyl-1,6-diaminohexane (NADAH), 1,6-diaminohexane (DAH), 6-acetamidohexanoic acid (AcHA), and 6-aminohexanoic acid (AmHA). Gas chromatography with nitrogen-phosphorus selective detection was used to quantify cellular concentrations of each metabolite. Cellular concentrations of AmHA and DAH were greater than those of NADAH and AcHA but no concentration of a metabolite exceeded that of HMBA. Metabolites were not detected in media from cells incubated with HMBA. Friend murine erythroleukemia cells that were resistant to HMBA contained only HMBA and NADAH. Moreover, the concentrations of NADAH in Friend murine erythroleukemia cells that were resistant to HMBA were less than those in the other cell lines studied. HL60 cells accumulated HMBA rapidly. NADAH, DAH, AcHA, and AmHA appeared sequentially in HL60 cells that were incubated with HMBA. NADAH appeared very rapidly, but concentrations of DAH were greater than or equal to those of NADAH by 8 h. AcHA and AmHA were not detected in cells before 24-48 h of incubation with HMBA. HL60 cells incubated with individual HMBA metabolites were able to accumulate each compound and to interconvert some: cells incubated with NADAH also contained DAH, AcHA, and AmHA; cells incubated with AcHA also contained low concentrations of AmHA; cells incubated with DAH also contained AmHA; and cells incubated with AmHA contained no other HMBA metabolites. HMBA was not present in cells incubated with any of its known metabolites. These results document the ability of various leukemic cells to metabolize HMBA, indicate the unidirectional catabolism of that compound, and may have implications as to its mechanism of action.

Acetamides↗
PubMed1988

Involvement of monoamine oxidase and diamine oxidase in the metabolism of the cell differentiating agent hexamethylene bisacetamide (HMBA).

We have previously demonstrated a number of metabolites of hexamethylene bisacetamide (HMBA) in the urine of patients treated with HMBA. These include N-acetyl-1,6-diaminohexane (NADAH), 6-acetamidohexanoic acid (6AcHA), 1,6-diaminohexane (DAH) and 6-aminohexanoic acid (6AmHA). Because these compounds have potential roles in the dose-limiting metabolic acidosis and neurotoxicity associated with HMBA therapy, and are similar in structure to known substrates of monoamine oxidase (MAO) and diamine oxidase (DAO), we investigated the activities of these enzymes in the metabolic interconversion of HMBA metabolites. NADAH (5 mM) was incubated with MAO and aldehyde dehydrogenase. 6AcHA production was verified by gas chromatography-mass spectrometry and quantified by gas chromatography. 6AcHA production was linear for up to 4 hr. Complete inhibition of MAO activity was observed with 2 mM tranyl-cypromine or pargyline. Mouse liver microsomes, which do not contain MAO, did not convert NADAH to 6AcHA and, in control experiments, did not degrade 6AcHA. The HMBA metabolite, DAH, was a substrate for DAO, producing 3,4,5,6-tetrahydro-2H-azepine. Participation of DAO in the metabolism of HMBA implies potential interaction of HMBA and metabolites with polyamine metabolism and may represent a mechanism for HMBA's effects on cellular growth and differentiation. Metabolism of NADAH, also a differentiator, by MAO implies that concurrent use of HMBA and an MAO inhibitor may be clinically useful.

Acetamides↗
PubMed1988

Estimation of nongravid uterine volume based on a nomogram of gravid uterine volume: its value in gynecologic uterine abnormalities.

To facilitate accurate and standard methods of reporting pathologic uterine corpus enlargement, we constructed a nomogram using the gravid uterine corpus volumes from five to 20 weeks' gestation in 186 patients. The volume was calculated by measuring the maximum length and anteroposterior and transverse diameters of the uterine corpus, and using the formula for the volume of a prolate ellipsoid: V = 0.52 X (L X AP X T). Clinicians can use the nomogram for better understanding in assessing uterine volume.

Female↗