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Biomedical subjects

A K Agrawal

Publications and source records attributed to A K Agrawal.

At least 19 recordsLinked to original sources
PubMed1996

Neonatal phenobarbital-induced persistent alterations in plasma testosterone profiles and testicular function.

Daily sc injections of phenobarbital at anticonvulsant therapeutic doses for the rat (40 mg/kg) for the first 7 days of life resulted in below normal levels of serum testosterone from around birth to before puberty, normal levels during puberty and above normal levels of the androgen after puberty and in adulthood. Cluster analysis of the plasma testosterone secretory profiles obtained at 15-min intervals from phenobarbital-treated rats at 65 and 165 days of age revealed a significant increase in both the peak amplitudes and their durations resulting in a 100% increase in the amount of hormone secreted during the peak periods. In general, most of the rats (control and experimental) secreted testosterone as two large peaks, each 3 to 4 hr in duration, during the 10-hr lights-on collection period. In addition to permanently disrupting the ultradian profiles of plasma testosterone, neonatal exposure to the barbiturate altered testicular responsiveness to steroidogenic regulatory agents. That is, neonatal exposure to phenobarbital enhanced the responsiveness to exogenous hCG as measured by an above-normal increase in testosterone concentration. Moreover, phenobarbital-induced reductions in serum testosterone levels were delayed in adult rats neonatally exposed to the barbiturate. Whereas a single challenge dose of phenobarbital (1 or 10 mg/kg) reduced serum testosterone concentrations in control animals by almost 80% within 3 hr, a decline in serum androgen levels in the neonatally phenobarbital exposed males was not observed until 12 hr after the challenge dose. These results indicate that postpartum exposure to therapeutic levels of phenobarbital can permanently disrupt testosterone secretory profiles and alter pathways regulating testicular steroidogenesis.

Aging↗
PubMed1996

Membrane characterization of amastigote-like forms of Leishmania donovani.

During in vitro transformation, Leishmania donovani promastigotes converted into amastigote-like forms and underwent several changes in membrane parameters. They exhibited significantly increased microviscosity comparable to true amastigotes. Activities of several functionally important membrane bound enzymes were also altered, thereby indicating a change in their orientation. Peanut agglutinin was found to be specific for agglutination of stationary phase promastigotes whereas wheat-germ agglutinin was specific for the amastigote-like forms as well as for pure amastigotes, implying the presence of specific glycoconjugates on the parasite surface.

Animals↗
PubMed1996

Polyethylene glycol modification: relevance of improved methodology to tumour targeting.

Of all the polymers applied to molecule altering structural chemistry, polyethylene glycol (PEG) modification has numerous benefits and relatively few drawbacks. PEG is now increasingly being applied to the problems of tumour targeting, both in the context of the passive targeting of PEG-liposomes and in active targeting strategies using PEGylated anti-tumour antibodies. PEG can also serve as a useful linker molecule between targeting moieties and other agents, including cytotoxic or imaging agents and targeted liposomes. Despite these demonstrated benefits and the level of attention which PEGylation has received, relatively little consideration has been given to two key areas: first, the extent to which the coupling method has an impact on both the functionality of the PEG-adduct and the acquisition of beneficial properties; second, that the impact of PEGylation on biodistribution is complex, thus any attempt to optimise a PEG-peptide or PEG-liposome for a particular task must involve an examination of all the individual facets of the effects of PEGylation. Studies investigating the underlying principles of tumour targeting suggest that current views concerning the optimisation of PEGylated vehicles for tumour localisation need to be re-examined.

Antibody Formation↗
PubMed1996

Phenobarbital induction of hepatic CYP2B1 and CYP2B2: pretranscriptional and post-transcriptional effects of gender, adult age, and phenobarbital dose.

Chemical induction of hepatic monooxygenases should not be viewed as an extracorporal process but rather as one that is liable to be influenced by numerous endogenous factors. In this regard, we examined the interactions of gender, adult age, and barbiturate dose on the course of phenobarbital induction of hepatic CYP2B1 and CYP2B2. We observed that femaleness and youth were associated with the greatest inhibition, so that both the rate and initiation of CYP2B1 and CYP2B2 induction were suppressed most in the young adult (65 days of age) females, followed by the mature adult (150 days of age) females and then by the young adult males, with the mature adult males exhibiting the least suppression of phenobarbital induction. The differential expression rates of hepatic CYP2B1 mRNA in the young and mature male and female rats, similarly reflected at the protein level, suggest that gender- and age-dependent suppression of CYP2B1 occurs at a pretranscriptional or transcriptional level. In contrast, transcript levels of CYP2B2 were unaffected by gender or age. However, accumulation of cytochrome P450 (P450) 2B2 protein was affected by the animal's age and gender, suggesting regulation of a post-transcriptional event. Highly selective (androstenedione 16beta-hydroxylase) as well as nonspecific (total P450 and hexobarbital hydroxylase) P450 2B1- and 2B2-dependent catalytic activities were in agreement with protein levels. Determination of gender- and age-dependent circulating growth hormone profiles indicates that the continuous secretion of the hormone characteristic of the female is more suppressive of CYP2B induction than the episodic pattern growth hormone secretion found in males. The considerably elevated growth hormone pulse amplitudes observed in the young rats of both genders seem to be an additional inhibitory signal antagonizing phenobarbital induction of CYP2B1 and CYP2B2. Phenobarbital administration did not interfere with the normal gender- and age-dependent growth hormone secretory profiles. Last, although as little as 1 mg/kg phenobarbital increased CYP2B1 mRNA concentrations by 100%, there was no translation into detectable levels of protein. In contrast, the same low dose of barbiturate inducing an equal percent increase in CYP2B2 mRNA did result in an expression of protein. Unlike use of the 10 mg/kg dose, CYP2B1 and CYP2B2 induction by phenobarbital at 1 mg/kg was unaffected by age or gender.

Age Factors↗
PubMed1995

Neurobehavioral, neurochemical and electrophysiological studies in 6-hydroxydopamine lesioned and neural transplanted rats.

Unilateral injection of 6-hydroxydopamine (6-OHDA) into the caudate nucleus of rat caused degeneration of dopaminergic terminals, evidenced by significant (P < 0.05) elevation of spontaneous and drug-induced motor behaviour, enhanced DA receptor binding and significant increase in the neuronal firing rate of caudate neurons, suggesting supersensitivity of dopaminergic receptors. Eight weeks following the transplantation of embryonic cell suspensions from caudate at the lesioned site, a significant restoration of the enhanced 3H spiperone binding and neuronal activity of caudate neurons was observed in comparison with lesioned rats. These results clearly demonstrate that transplanted embryonic neuronal tissue at the lesioned site is capable of restoring the neuronal deficits caused by 6-OHDA as evidenced by significant amelioration in neurochemical, behavioral and electrophysiological alterations.

Action Potentials↗
PubMed1995

Gender differences in drug metabolism regulated by growth hormone.

Gender differences in drug metabolism in rats have been known for more than 60 years when it was first reported that the much shorter duration of drug action in the male was due to the effects of testicular androgens. More recent studies have demonstrated that this sexual dimorphism in rat drug metabolism results from the differential expression of a possible dozen, or so sex-dependent hepatic forms of cytochrome P450. Moreover, it is the sexually dimorphic plasma profiles of growth hormone, and not androgens, that directly regulate the expression of these individual forms of hepatic cytochrome P450. Male rats secrete growth hormone in an "on-off" episodic rhythm in which interpulse periods contain no detectable levels of the hormone. Growth hormone secretion in the female rat is also pulsatile, but can be characterized as "continuous" since hormone levels are always present in the circulation. It would appear that the duration of the interpulse period is at least one "signal" in the growth hormone profile regulating hepatic expression of the sex-dependent forms of cytochrome P450, and thus establishing the gender differences in drug metabolism. The exaggerated gender differences in rat drug metabolism (i.e. 300-500%) have made it the standard, and understandably an ideal model in which to investigate the mechanisms regulating these dimorphisms. However, it is also possible that these studies have limited value when extrapolated to other species, such as humans, in which the magnitude of the sexual differences are much smaller, and the dimorphism may be reversed (F > M). In this regard, the mouse model, in which the sexual differences (F > M) in drug metabolizing enzyme activities vary by only 40-100%, are also regulated by sex-dependent plasma growth hormone profiles, and may be more representative of the vast majority of outbred species in which only subtle gender differences occur in drug metabolism.

Animals↗
PubMed1995

Neonatal phenobarbital-induced defects in age- and sex-specific growth hormone profiles regulating monooxygenases.

Growth hormone was secreted in sexually dimorphic patterns in both 65- and 150-day-old rats (i.e., "on-off" pulsatile for males and "continuous" pulsatile for females), but as a result of a 200-400% increase in pulse levels the mean concentration of hormone in the circulation was about two times as great in the younger animals. Neonatal exposure to phenobarbital at anticonvulsant therapeutic doses for the rat reduced the pulse amplitudes of circulating growth hormone in both the 65- and 150-day-old males but only in the 65-day-old females. As expected, neonatal administration of the barbiturate produced an almost immediate increase in the activities of the hepatic monooxygenases, as measured by hexobarbital metabolism, which declined to noninduction levels after treatment ceased. Contrary to the well-known transient effects of phenobarbital, at around the time of sexual maturity when gender-dependent differences in hepatic monooxygenases appear (males > females), we observed a second "round" of enzyme induction that persisted in both sexes for the remainder of the study (180 days). Because growth hormone is the primary regulator of sex-dependent hepatic monooxygenases, we have proposed that the abnormal plasma growth hormone profiles produced by neonatal phenobarbital are responsible for the permanent induction of hepatic monooxygenases.

Aging↗
PubMed1994

Altered platelet functions in non-insulin-dependent diabetes mellitus (NIDDM).

We have studied platelet aggregation and membrane fluidity, along with various biochemical parameters, in 19 non-insulin-dependent diabetes mellitus (NIDDM) patients prior to control of blood sugar, 11 patients after control of blood sugar, and 26 normal subjects. Platelet cholesterol: phospholipid ratio and basal levels of)[Ca+] were comparable between normal and uncontrolled NIDDM. Basal levels of malonaldehyde (MDA) and the levels of [Ca++]i, as well as MDA after the addition of arachidonic acid, were 2.5-fold, 5-fold, and 2.5-fold higher, respectively, in the uncontrolled NIDDM group than normals. Platelet aggregation in response to ADP (0.25 microM), epinephrine (1.25 microM), and arachidonic acid (0.25 mM) was significantly higher in uncontrolled NIDDM than in normals (75%, 40% and 52%, respectively). Platelet fluorescence polarization was also higher in NIDDM patients indicating decreased membrane fluidity in such patients as compared to normals. After control of blood sugar in 11 NIDDM patients, agonist-stimulated platelet aggregation and other biochemical parameters were comparable to normals.

Adult↗
PubMed1994

Modulation of acrylamide-induced neurochemical and behavioral deficits by cerebellar transplants in rats.

Acrylamide (30 mg/kg body wt.) administered intraperitoneally daily to young adult male rats, five times a week for 3 consecutive weeks, affected the cerebellar functions, as exhibited by a significant reduction in rotarod performance, spontaneous locomotor activity, glutathione-S-transferase activity, and 3H-flunitrazepam binding in cerebellum. Transplantation of dissociated fetal cerebellar cells (E14) to cerebellum resulted in a significant recovery in behavioral and neurochemical parameters evaluated 9 weeks after transplantation. Light- and electron-microscopic studies confirmed the viability and specificity of cerebellar grafts.

Acrylamides↗
PubMed1993

Evaluation of Manning's criteria in the diagnosis of irritable bowel syndrome.

Six symptoms of Manning et al are widely used in clinical practice to diagnose irritable bowel syndrome (IBS). We studied 123 patients to evaluate the diagnostic value of Manning's criteria, using a preformed bowel symptom questionnaire which included these six symptoms. This study included 65 patients with IBS, 35 patients with non-ulcer dyspepsia, 23 patients with organic diseases of colon and 45 healthy controls. Sensitivity of presence of three or more symptoms of Manning's criteria discriminating irritable bowel syndrome from all other groups was 66.1%. Manning's criteria discriminated irritable bowel syndrome from organic diseases of colon with specificity and positive predictive value of 66.9% and 82.6%. When irritable bowel syndrome was compared with non-ulcer dyspepsia and healthy controls, specificities of Manning's criteria were 91.4% and 93.3% and positive predictive values 93.4% and 93.4% respectively.

Adolescent↗
PubMed1993

Obstructive jaundice--a diagnostic appraisal.

One hundred and eight suspected cases of obstructive jaundice (OJ) were analysed using ultrasonography, percutaneous transhepatic cholangiography (PTC) or Endoscopic retrograde cholangiopancreatography (ERCP) or both. Clinical evaluation had accuracy of 93% in identifying OJ and establishing aetiology in 62%, however, it lacked specificity. Ultrasonography was useful in differentiating obstructive jaundice from medical jaundice in 91% of cases. However, the cause and site of biliary obstruction could be identified in 55% and 46% respectively. PTC was helpful in detecting the site of obstruction in 80.4% and nature in 63% of cases. Its failures were mostly associated with the presence of metastasis in the liver. ERCP successfully attained cholangiography in 58% and pancreatogram in 70% of cases. Overall diagnostic yield of ERCP was 67% in view of additional endoscopic findings in 18 cases. The complications were occasional and could be managed effectively with medical treatment. This study suggests utility of clinical evaluation in OJ inspite of its poor specificity and comparative value of PTC and ERCP in establishing the site as well as nature of lesion.

Cholangiopancreatography, Endoscopic Retrograde↗
PubMed1992

Phencyclidine binds to blood platelets with high affinity and specifically inhibits their activation by adrenaline.

The ion channel probe phencyclidine [1-(1-phenylcyclohexyl)piperidine; PCP] selectively inhibited aggregation, secretion and ultrastructural changes in platelets induced by adrenaline, but did not affect activation induced by other common platelet agonists such as alpha-thrombin, ADP, collagen or ionophore A23187. [3H]PCP bound to platelets with high affinity (Kd 134 +/- 33 nM; 3600 +/- 1020 sites/platelet), as did the thienyl analogue [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine). PCP binding to platelets was increased 3-4-fold in N-methylglucamine buffer in the absence of Na+ ions. Binding was unaffected by haloperidol and was only weakly inhibited (EC50 10-20 microM), without significant stereoselectivity by the two sets of stereoselective ligands, dexoxadrol/levoxadrol and (+)MK801/(-)MK801. Binding of PCP was not competed for by adrenaline or yohimbine. Only the high-affinity binding of [3H]PCP to platelets was blocked by prior treatment of the platelets with the covalent affinity probe Metaphit, and these platelets no longer aggregated in response to adrenaline although they responded normally to alpha-thrombin, ADP and collagen. These results suggest that platelets contain high-affinity receptors for PCP that can modulate adrenaline-induced platelet activation.

Binding, Competitive↗
PubMed1992

Ultrasonographic patterns of hepatobiliary mass lesions.

The study deals with an analysis of ultrasonographic (USG) patterns in 100 consecutive patients with hepatobiliary mass lesions. Amoebic liver abscess, carcinoma (CA) gall bladder and secondaries in liver comprised nearly 70% of cases. USG appearances in liver abscess, hepatoma, secondaries in liver and CA gall bladder were variable, but were characteristic in hydatid disease and congenital polycystic disease. Two patients with cholangiocarcinoma revealed dilated biliary channels with an intraluminal mass in common bile duct.

Adenoma, Bile Duct↗
PubMed1992

Endoscopic sphincterotomy: preliminary experience at a university hospital.

Endoscopic sphincterotomy (ES) was attempted in 38 patients with biliary calculi. There were 21 patients (55.3%) with common bile duct (CBD) stones following cholecystectomy, 14 patients (36.8%) with intact gall bladder and 3 patients with retained CBD stones along with T tube in the early post-operative period. Endoscopic sphincterotomy was possible in all but one patient and duct clearance was attained in 34 (89.4%) patients. Spontaneous clearance of calculi occurred in 31 (81.6%) patients while 3 patients required instrumental extraction. Four patients failed to clear stones and required surgical intervention. Complications occurred in 4 (10.5%) patients--haemorrhage in two, pancreatitis and cholangitis in one each. One patient died of bleeding on the 4th day following ES while hemostasis was achieved in other after two units of blood. Other complications were managed conservatively without any mortality. Endoscopic sphincterotomy appears to be a simple, effective and safe therapeutic modality for the management of biliary calculi.

Adolescent↗
PubMed1991

Ammonia-induced alterations in glutamate and muscimol binding to cerebellar synaptic membranes.

Binding of glutamate and muscimol (an agonist for GABAA receptors) to their respective receptors has been studied in the cerebellum of normal and hyperammonemic rats. There was a decrease in both high- and low-affinity binding of glutamate in the cerebellum during hyperammonemia. Kinetic studies revealed that the decrease is due to a reduction in the number of binding sites, but not due to changes in the binding affinities. Further studies also revealed that the decrease was only in the N-methyl-D-aspartate (NMDA)-specific binding sites without any alterations in the binding to non-NMDA sites represented by kianic acid (KA)- and quisqualic acid (QQ)-sensitive receptor sites. These effects were also mimicked when the membrane preparations from the cerebellum of normal animals were incubated with ammonium acetate. Enhancement of muscimol binding was observed in animals injected with ammonium acetate. It is concluded that hyperammonemic states, even in the presence of a functional liver, are capable of altering amino acid neurotransmission and this might play an important role in cerebral dysfunction under these conditions.

Ammonia↗
PubMed1991

Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450.

Plasma growth hormone (GH) profiles are sexually differentiated in many species and regulate the sex-dependence of peripubescent growth rates and liver function, including steroid hydroxylase cytochrome P450 expression, by mechanisms that are poorly understood. By use of an external pump to deliver to hypophysectomized rats pulses of rat GH of varying frequency and amplitude, a critical element for liver discrimination between male and female GH patterns was identified. Liver expression of the male-specific steroid 2 alpha (or 16 alpha)-hydroxylase P450, designated CYP2C11, was stimulated by GH at both physiological and nonphysiological pulse amplitudes, durations, and frequencies, provided that an interpulse interval of no detectable GH was maintained for at least 2.5 hr. This finding suggests that hepatocytes undergo an obligatory recovery period after stimulation by a GH pulse. This period may be required to reset a GH-activated intracellular signaling pathway or may relate to the short-term absence of GH receptors at the hepatocyte surface after a cycle of GH binding and receptor internalization. These requirements were distinguished from those necessary for the stimulation by GH of normal male growth rates in hypophysectomized rats, indicating that different GH responses and, perhaps, different GH-responsive tissues recognize distinct signaling elements in the sexually dimorphic patterns of circulating GH.

Activity Cycles↗