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Biomedical subjects

S Krishnaswami

Publications and source records attributed to S Krishnaswami.

At least 19 recordsLinked to original sources
PubMed2005

Interpretation of absorption rate data for inhaled fluticasone propionate obtained in compartmental pharmacokinetic modeling.

OBJECTIVE: Reports characterizing the pharmacokinetics of inhaled fluticasone propionate (FP) using compartmental approaches have suggested that the absorption of FP into the systemic circulation is rapid with a half-life of approximately 10 min. We believe that this is a classical case of misassignment of the pharmacokinetic parameter estimates, a problem often encountered while modeling pharmacokinetic data. The objective of this study was to illustrate and analyze this problem using actual blood level data of FP obtained in 14 healthy subjects. MATERIALS AND METHODS: Serum concentration-time data of FP were obtained from a double-blind, randomized study involving single and multiple twice-daily inhalations of 500 microg via a dry powder device, Diskus. The profiles were fitted using one- and two-compartment pharmacokinetic models with first order absorption. Various permutations of the resulting exponential rate constants were analyzed to determine the combination that was most consistent with the underlying physical process. RESULTS: The two-compartment body model with first order absorption gave excellent fits for the observed FP concentrations after both single and multiple dosing. Even though peak levels were reached relatively early (30 - 90 min) after inhalation, the combination that most appropriately described the underlying process was alpha > Ka > beta, i.e. slow absorption, rapid distribution and slower elimination kinetics. The absorption, distribution and elimination half-lives resulted to be 3.8 h, 9.9 min and 13.6 h, respectively, consistent with the high lipophilicity and sustained dissolution characteristics observed in vitro. CONCLUSIONS: Analysis of FP pharmacokinetics after inhalation represents a classical case of potential misassignment of the exponential rate constants, which if ignored, could lead to erroneous interpretations regarding the underlying process. The study also elucidates the pitfall of using t(max) to calculate absorption rate.

Absorption↗
PubMed2003

238U series isotopes and 232Th in carbonates and black shales from the Lesser Himalaya: implications to dissolved uranium abundances in Ganga-Indus source waters.

238U and (232)Th concentrations and the extent of (238)U-(234)U-(230)Th radioactive equilibrium have been measured in a suite of Precambrian carbonates and black shales from the Lesser Himalaya. These measurements were made to determine their abundances in these deposits, their contributions to dissolved uranium budget of the headwaters of the Ganga and the Indus in the Himalaya and to assess the impact of weathering on (238)U-(234)U-(230)Th radioactive equilibrium in them. (238)U concentrations in Precambrian carbonates range from 0.06 to 2.07 microg g(-1). The 'mean' U/Ca in these carbonates is 2.9 ng U mg(-1) Ca. This ratio, coupled with the assumption that all Ca in the Ganga-Indus headwaters is of carbonate origin and that U and Ca behave conservatively in rivers after their release from carbonates, provides an upper limit on the U contribution from these carbonates, to be a few percent of dissolved uranium in rivers. There are, however, a few streams with low uranium concentrations, for which the carbonate contribution could be much higher. These results suggest that Precambrian carbonates make only minor contributions to the uranium budget of the Ganga-Indus headwaters in the Himalaya on a basin wide scale, however, they could be important for particular streams. Similar estimates of silicate contribution to uranium budget of these rivers using U/Na in silicates and Na* (Na corrected for cyclic and halite contributions) in river waters show that silicates can contribute significantly (approximately 40% on average) to their U balance. If, however, much of the uranium in these silicates is associated with weathering resistant minerals, then the estimated silicate uranium component would be upper limits. Uranium concentration in black shales averages about 37 microg g(-1). Based on this concentration, supply of U from at least approximately 50 mg of black shales per liter of river water is needed to balance the average river water U concentration, 1.7 microg L(-1) in the Ganga-Indus headwaters. Data on the abundance and distribution of black shales in their drainage basin are needed to test if this requirement can be met. (234)U/(238)U activity ratios in both carbonates and black shales are at or near equilibrium, thus preferential mobilization of (234)U from these deposits, if any, is within analytical uncertainties. (230)Th is equivalent to or in excess of (238)U in most of the carbonates. (230)Th/(238)U>1 indicates that during weathering, uranium is lost preferentially over Th. (232)Th concentrations in carbonates are generally quite low, <0.5 microg g(-1), though with a wide range, 0.01-4.8 microg g(-1). The variation in its concentrations seem to be regulated by aluminosilicate content of the carbonates as evident from the strong positive correlation between (232)Th and Al.

Carbonates↗
PubMed2001

Single-dose and steady-state pharmacokinetic and pharmacodynamic evaluation of therapeutically clinically equivalent doses of inhaled fluticasone propionate and budesonide, given as Diskus or Turbohaler dry-powder inhalers to healthy subjects.

Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosing in the same subjects are scarce. The objective of this study was to compare thePK/PDproperties of clinically equivalent, single, and multiple doses of dry-powder formulations of inhaled fluticasone propionate (FP 200 and 500 microg via Diskus) and budesonide (BUD, 400 and 1,000 microg via Turbohaler). Fourteen healthy subjects completed a double-blind, double-dummy, randomized, placebo-controlled, five-way crossover study consisting of a single dose administered at 8 a.m. on day 1 followed by 4 days of twice-daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/ mass spectrometry assays. The 24-hour cumulative cortisol suppression (CCS) in serum was monitored as the pharmacodynamic surrogate marker. Peak serum concentrations following single and multiple dosing were observed 10 to 30 minutes after inhalation for BUD and 30 to 90 minutes afterinhalation of FP with no influence of dose ordosingregimen. After a single dose of 1000 microg BUD and 500 microg FP the median estimates of terminal half-life and mean residence time were 3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively. Using previously reported intravenous data, the mean absorption times (MAT) were calculated to be around 2 hours and 7 hours for BUD and FP respectively. On average, the area under the curve (A UC) at steady state (day 5) was up to 30% higher for BUD compared to that over a 12-hour period following the first dose on day 1, whereas A UC estimates were 50% to 80% higherforFP at steady state, indicating accumulation. However, the steady-state Cmax values were seven to eight times and AUC values three to four times higher for BUD than for FP. Comparison of active treatment data with placebo showed that CCS after a single dose was not pronounced for any of the doses/drugs studied. On day 5, both doses of BUD caused statistically significant suppression (CCS of 19% for the 400 microg dose and 36% for the 1,000 microg dose). For FP only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 microg dose and 27% for the 500 microg dose). Compared to BUD, FP has slower pulmonary absorption and slower elimination kinetics. However, following inhalation of therapeutically equipotent, multiple twice-daily doses in healthy subjects, the systemic effects of FP delivered via Diskus on AUC24 serum cortisol were relatively low and similar to those of BUD delivered via Turbohaler.

Administration, Inhalation↗
PubMed2000

Clinical and pharmacological aspects of accidental triamcinolone acetonide overdosage: a case study.

Local administration of corticosteroids for rheumatic diseases have had a long history of effective and well-tolerated use. We report here the pharmacodynamics and pharmacokinetics of an accidental triamcinolone acetonide (TCA) overdose. The presented patient was treated with 200 mg TCA and developed Cushing's syndrome 6 weeks later (cortisol and ACTH concentrations were below limits of detection, TCA concentrations were > 3 micrograms/l). Because of her severe symptoms, mifepristone was administered for a period of 19 days. Cortisol concentrations became detectable 2 days after initiation of mifepristone treatment and persisted, being detectable for a period of at least a week after cessation of the drug. Twenty days after cessation, cortisol concentrations were undetectable again. Cushing's syndrome persisted more than 6 months while TCA concentrations remained detectable for at least 80 days. Based on plasma TCA concentrations in our patient, we calculated a terminal half-life of TCA of 33 days as opposed to 5 days observed after intra-articular administration of a therapeutic dose of 40 mg TCA. We conclude that after an accidental overdose in this patient, body TCA disappearance was strongly prolonged due to a very slow (absorption) half-life of the drug in comparison to a therapeutic dose. This finding is explained by a 'flap-flop phenomenon' where drug absorption is the rate-limiting step of overall drug disposition. Caution is, therefore, needed to prevent undesired accumulation of TCA that may lead to protracted Cushing's syndrome.

Anti-Inflammatory Agents↗
PubMed2000

A sensitive LC-MS/MS method for the quantification of fluticasone propionate in human plasma.

A sensitive and selective LC-(APCI) MS/MS method capable of quantifying fluticasone propionate (FP) at levels down to 10 pg ml(-1) in human plasma is reported. The method was validated over a linear range from 10 to 1000 pg ml(-1) using a previously published solid-phase extraction procedure with a 13C3-labeled internal standard. The inter and intra batch precision (coefficient of variation) and accuracy (% bias) of the quality controls samples (20, 25, 50, 100, 200, 500 and 1000 pg ml(-1)) were less than 15 and 11%, respectively. The method is robust, rapid (analysis time of 2 min), selective and hence is ideally suited for pharmacokinetic investigations involving inhalation of therapeutic doses of FP.

Administration, Inhalation↗
PubMed2000

An interactive algorithm for the assessment of cumulative cortisol suppression during inhaled corticosteroid therapy.

The objective of the study was to develop an algorithm based on a pharmacokinetic-pharmacodynamic (PK/PD) modeling approach to quantify and predict cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. Two Excel spreadsheets, one for single dose and another for steady-state multiple doses of inhaled steroids, were developed for predicting CCS. Four of the commonly used inhaled steroids were chosen for the purposes of simulation: fluticasone propionate (FP), budesonide (BUD), flunisolide (FLU), and triamcinolone acetonide (TAA). Drug-specific PK and PD parameters were obtained from previous single- and multiple-dose studies. In cases in which multiple-dose data were not available, the single-dose data were extrapolated. The algorithm was designed to calculate CCS based on 5 input parameters: name of drug, dose, dosing interval, time(s) of dosing, and type of inhaler device. In addition, a generalized algorithm was set up to calculate CCS based on clearance, volume of distribution, absorption rate, protein binding, pulmonary deposition, oral bioavailability, and unbound EC50 of the corticosteroid of interest. The spreadsheet allowed predictions of CCS for single doses as well as steady-state conditions. A simple method has been developed that facilitates comparisons between various drugs and dosing regimens and has the potential to significantly reduce the number of comparative clinical trials to be performed for evaluating the short-term systemic activity of inhaled corticosteroids.

Administration, Inhalation↗
PubMed2000

Optimized therapeutic ratio of inhaled corticosteroids using retrometabolism.

During recent years, the treatment of pulmonary diseases could be significantly improved due to the introduction of modern retrometabolism-based corticosteroids with improved therapeutic ratio. It is the goal of all inhaled corticosteroids to produce long lasting therapeutic effects at the pulmonary target site and to minimize systemic side effects by rapid clearance of the absorbed drug and low oral bioavailability. The development of PK/PD models allows predictions of drug effects based on the administered dose. For example, the cumulative suppression of endogenous cortisol release (CCS) as one of the major systemic side effects of inhaled corticosteroid therapy can be described with an integrated Emax based PK/PD model. In order to assess the predictive power of this model, a study was conducted to compare the PK/PD-based predictions with CCS data obtained from actual clinical trials for flunisolide, fluticasone propionate, budesonide and triamcinolone acetonide. CCS was predicted for different single doses from different inhaler devices for each drug and a good correlation was observed. Thus, the presented PK/PD model proved to be a valid tool for predicting CCS of inhaled corticosteroids. By fully understanding the underlying mechanisms it will be possible to further improve their therapeutic index.

Administration, Inhalation↗
PubMed1999

Enhanced transgene expression in rat brain cell cultures with a disulfide-containing cationic lipid.

The transfection efficiency of a disulfide-containing cationic lipid, 1',2' dioleoyl-sn-glycero-3'-succinyl-2-hydroxyethyl disulfide ornithine conjugate (DOGSDSO) and its non-disulfide analog (DOGSHDO) were compared in neuronal, astroglial and microglial cultures from newborn rat cerebral cortex. We hypothesized that the relatively high intracellular concentrations of reductive substances in the cytoplasm may help to cleave the reversible disulfide bond in DOGSDSO, thus increasing free DNA and decreasing toxicity due to rapid degradation of the lipid. We have demonstrated through mass spectrometric analysis that a reductive compound, e.g. dithiothreitol (DTT) could degrade the disulfide lipid. DOGSDSO was more efficient at transfecting each type of brain cell than were the non-disulfide DOGSHDO and DOTAP (1,2-dioleoyl-3-trimethyl-ammonium-propane) liposomes. These results demonstrate that disulfide-containing cationic liposomes facilitate gene transfection in cultured rat brain cells.

Animals↗
PubMed1999

Pharmacokinetic-pharmacodynamic profile of systemic nitric oxide-synthase inhibition with L-NMMA in humans.

AIMS: It has been demonstrated that inhibition of endothelium derived nitric oxide with NG-monomethyl-L-arginine (L-NMMA) results in a different cardiac and peripheral vascular response. The purpose of this study was to investigate the pharmacokinetic-pharmacodynamic profile of L-NMMA and pharmacokinetic interactions with L-arginine in healthy subjects. METHODS: Plasma pharmacokinetics were analysed from two different studies: In study 1, 3 mg kg-1 L-NMMA was administered i.v. over 5 min and systemic haemodynamics, cardiac output (CO), fundus pulsation amplitude (FPA), and NO-exhalation (exhNO) were measured at baseline and 15, 65, 95, 155, and 305 min after start of drug administration (n=7). In study 2, 17 mg kg-1 min-1 of the physiologic substrate for nitric oxide synthase, L-arginine, was coinfused i.v. over 30 min with a primed constant infusion of 50 microg kg-1 min-1 L-NMMA (n=8). RESULTS: Bolus infusion of L-NMMA resulted in a maximum plasma concentration of 12. 9+/-3.4 microg ml-1 (mean+/-s.d.) with elimination half-life of 63. 5+/-14.5 min and clearance of 12.2+/-3.5 ml min-1 kg-1 and caused a small hypertensive response, decreased CO by 13%, FPA by 26%, exhNO by 46% and increased systemic vascular resistance by 16% (P<0.05 each) 15 min after start of drug administration. Although only limited data points were available in the L-NMMA plasma concentration range between 0 and 4 microg ml-1, drug effects over time were in good agreement with an Emax model (r2>0.98 each), which also suggested that concentrations producing half-maximum effects were higher for FPA than for CO and exhNO. The coinfusion with L-arginine caused a nearly two-fold increase in plasma L-NMMA levels, indicating a pharmacokinetic interaction. CONCLUSIONS: In the absence of a systemic hypertensive response, L-NMMA significantly decreased CO, exhNO, and FPA. The concentration calculated to produce a half maximal effect was equivalent for exhNO and CO, but markedly higher for FPA. Furthermore, measurement of FPA is susceptible to changes in L-NMMA levels at small plasma concentrations.

Adult↗
PubMed1999

Effects of intranasal challenge with group A beta haemolytic streptococcus M type 49 in Swiss albino mice.

Mice are susceptible to natural infections with streptococci and therefore can serve as suitable animal models to study experimental streptococcal infections. In an earlier study, we had shown the development of pharyngeal colonization, antibody response and histopathological changes in the heart following intranasal (IN) challenge with a rheumatogenic serotype of group A beta haemolytic streptococcus, the M type 18. To determine if nonpharyngitis associated serotypes can also elicit similar responses, 30 Swiss albino mice were challenged intranasally with 2 x 10(7) colony forming units of a skin associated serotype of group A beta haemolytic streptococcus, the M type 49. Pharyngeal colonization varied from 64% (n = 30) in the first week to 69% (n = 16) during the fourth week after IN challenge. Eleven (36.7%) of the 30 animals studied showed antibody response to DNase B (ADNB) with peak titers varying from 150 to 1200 units. Wide variations were seen in ADNB titers in individual mice. Histopathological evidence for cardiac lesions were seen in three animals. The changes were mild and varied from mild to chronic endocardial inflammation to calcification. The study shows that Swiss albino mice are also susceptible to IN challenge with skin associated strains of GABHS and therefore can serve as useful models to study the effects of experimental infection with diverse serotypes of GABHS.

Administration, Intranasal↗
PubMed1998

Rheumatic fever chemoprophylaxis in adults.

In 2340 adult patients above the age of 26 years with rheumatic valvular disease (RHD) seen since 1987, injection benzathine penicillin (once in 3 weeks) was discontinued and the patients were followed for evidence of rheumatic fever for a period of one to nine years (mean of 3 years). Recurrence of rheumatic fever was seen in 5 patients (0.21%). This study confirms that recurrence of rheumatic fever in patients with RHD above 26 years of age is very low and hence we recommend long term chemoprophylaxis to the patients above the age of 26 on an individual basis.

Adolescent↗
PubMed1998

Pharyngeal colonisation, ADNB response and development of cardiac lesions in mice following intranasal inoculation with group A beta haemolytic streptococcus M type 18.

Swiss albino mice from a randomly bred colony were inoculated intranasally with 1.6, 2 or 2.4 x 10(7) colony forming units of a mid-logarithmic phase culture of group A beta haemolytic streptococcus M type 18 for 3 days, 6 days or once a week respectively for three weeks. Pharyngeal colonisation could be observed in 67 (59.8%) of 112 mice on 4th day after inoculation and 14 (38%) of the 37 mice on 21st day. Out of 27 mice tested for determination of antibodies to deoxyribonuclease B at regular intervals for 98 days, 15 (55.5%) showed responses, with maximum titers varying from 50 units to 4800 units in individual mice. Histopathological evidence for cardiac lesions were seen in five (3.03%) of the 165 animals studied. These included one case of severe endocarditis, two cases of endocarditis with valvular lesions and one case with non-specific lymphocyte infiltration in the heart. One other animal showed subendocardial oval nodular aggregates. Although the cellular nature of these lesions were not determined, this study shows that Swiss albino mice can serve as suitable animal models to study experimental streptococcal infections. However these are preliminary observations and are to be confirmed and revalidated by further controlled experiments.

Animals↗
PubMed1997

Transseptal approach to aortography and carotid artery stenting in pulseless disease.

We report on a patient with pulseless disease (Takayasu's arteritis) in whom access to the central circulation by extremity arterial cannulation was not possible due to absent pulses in all four limbs. The transseptal approach was used for aortography, bilateral selective carotid angiography, and successful elective stent deployment in the right common carotid artery.

Adult↗
PubMed1997

Mechanisms of cardiac perforation leading to tamponade in balloon mitral valvuloplasty.

Mechanisms of cardiac perforation in 10 cases of cardiac tamponade encountered in a single-center series of 903 balloon mitral valvuloplasty procedures were elucidated by precise localization of the site of perforation at subsequent surgery. These mechanisms were perforation of the aortic root and adjacent right atrium by sliding up of the transseptal set (2), apical tears by straight-tip balloon catheters driven distally during mitral valve dilatation (3), apical perforations by guidewires introduced through catheters wedged in the apex (2), tear of the posterior right atrial wall by dilatation of the track produced by very low septal punctures (2), and right ventricular perforation by a pacing catheter (1). Multivariate analysis showed cardiac perforation to be significantly related to the total experience at the center (inversely) and to patient age (directly). Left ventricular perforation occurred exclusively in patients > 40 yr of age. Understanding these mechanisms has enabled formulation of effective strategies to prevent cardiac perforation.

Adolescent↗
PubMed1997

Combined brachial and femoral approach to balloon angioplasty in coarctation of aorta.

Transfemoral balloon angioplasty of native aortic coarctation was initially not feasible in two patients, because of inability to cannulate the femoral artery percutaneously in one, and to cross the coarctation in the other. The percutaneous brachial approach helped overcome both these problems, after which utilization of intravascular snares allowed successful transfemoral completion of angioplasty.

Adult↗
PubMed1997

Transjugular approach to transseptal balloon mitral valvuloplasty.

The feasibility of a transjugular approach to septal puncture and Inoue-balloon mitral valvuloplasty (BMV) was studied in 20 patients with severe mitral stenosis and varying degrees of anatomic atrial distortion. Left atrial entry by transjugular septal puncture was achieved without difficulty and BMV completed in all patients. In all of 16 patients who had high septal punctures, crossing the mitral valve with the Inoue-balloon was consistently simple and quick. In one patient, septal dilation after very high septal puncture led to a tear extending to the atrial free wall, resulting in cardiac tamponade requiring surgery. Another patient developed severe mitral regurgitation after BMV and required mitral valve replacement. Excellent results were obtained in 16 patients. The transjugular approach simplifies BMV procedure significantly in patients with distorted atrial anatomy and allows rapid patient mobilization. Its safety and efficacy need to be established in larger studies.

Adolescent↗
PubMed1997

Do behavior changes herald physical illness in adults with mental retardation?

A longitudinal study of 62 individuals with profound mental retardation was conducted to determine if direct care staff can identify behavior change prior to identifying symptoms of acute illness. Results indicate that staff were able to notice changes in sluggishness prior to the onset of illness. Self-care behavior was of borderline significance and there was no significant change in eight behavior dimensions (vocalizations, peer conflict, stereotypy, aggression, self injurious behavior, restlessness, distractibility, and depression). This finding should alert physicians and caregivers to the importance of prompt response to symptoms. Reliance on behavioral observation of direct care staff is not always sensitive enough to pick up changes in health status in less restrictive residential environments.

Activities of Daily Living↗