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Biomedical subjects

M Aravagiri

Publications and source records attributed to M Aravagiri.

At least 37 records · Page 2Linked to original sources
PubMed1993

Field dependent transverse relaxation rate increase may be a specific measure of tissue iron stores.

The degree to which MRI magnet field strength affects measured transverse relaxation rates (R2) defines a measure termed the field dependent R2 increase (FDRI). We report here the results of in vivo and in vitro experiments that were conducted to evaluate whether FDRI is a potentially useful measure of tissue iron stores. T2 relaxation times were obtained using two clinical MRI instruments operating at 0.5 and 1.5 Tesla, and relaxation rates (R2) were calculated as the reciprocal of T2. The in vivo experiment measured R2 in human brain frontal white matter, caudate nucleus, putamen, and globus pallidus. The FDRI was very highly correlated with published brain iron levels for the four regions examined. The in vitro experiment measured R2 in agarose gel-based phantoms containing physiologic forms and amounts proteins involved in iron storage and transport (ferritin, apoferritin, transferrin, and apotransferrin). Significant field dependence was observed only for the ferritin phantoms. The differences in the R2 values obtained at the two field strengths were striking, and were proportional to the ferritin levels of the phantoms. These studies suggest that FDRI may be a specific measure of tissue ferritin. The quantitative significance of the results to imaging and possible applications to the clinical investigation of pathologic states are discussed.

Adult↗
PubMed1993

Clinical perspectives of some neuroleptics through development and application of their assays.

Attempts to investigate relationships between plasma levels of neuroleptics and therapeutic outcome in schizophrenic patients have been hampered due to such factors as the chemical nature of these drugs, their metabolism, and the very heterogeneous nature of the disease states. Two clinical studies are described that investigate the relationship between plasma levels of fluphenazine (FLU) and its metabolites and therapeutic outcome in schizophrenic patients. In the first of these studies the levels of FLU and fluphenazine sulfoxide (FLUSO) in schizophrenics receiving either 5 or 25 mg of fluphenazine decanoate (FLUD) intramuscularly every 2 weeks were monitored. Patients given 25 mg of FLUD required 3 months to reach plasma level steady state. The results suggest that such patients, when being switched from the oral to the depot formulation of FLU, should continue to receive oral supplementation during the 1st 3 months after conversion. The relationship between log-transformed plasma levels at 26 and 38 weeks with subsequent psychotic exacerbation was investigated with the use of logistic regression and survival analysis. Both demonstrated significant relationships between FLU plasma levels and a risk of psychotic exacerbation at 26 and 38 weeks. The possibility of any correlations between neurological side effects and plasma concentrations were also investigated, with statistically significant correlations between FLU levels and akinesia found at 2 and 26 weeks. In the second of these studies the levels of FLU, FLUSO, 7-hydroxyfluphenazine (7-OHFLU), and fluphenazine N4'(-)-oxide (FLUNO) in schizophrenics receiving 5, 10, or 20 mg of oral fluphenazine dihydrochloride daily for 4 weeks were monitored. The relationships between log-transformed plasma levels, disabling side effects, and global improvement were examined by logistic regression for the 4-week period. The study showed a significant correlation between increases in both plasma levels and disabling side effects such that at a plasma level of 2.7 ng/ml, approximately 90% of acutely ill patients experienced disabling side effects. Conversely, the study also showed that at a plasma level of 0.67 ng/ml, 48% of patients experienced improvement without the development of disabling side effects. When relationships between metabolite levels, disabling side effects, and global improvement were examined by logistic regression, a stronger correlation between disabling side effects and FLUNO levels than between side effects and FLU levels was found.(ABSTRACT TRUNCATED AT 400 WORDS)

Antipsychotic Agents↗
PubMed1993

Systematic dosage reduction in treatment-resistant schizophrenic patients.

Thirteen treatment-resistant, chronically institutionalized schizophrenic patients on high-dose neuroleptic (the equivalent of at least 50 mg of haloperidol (HPL) daily) were transferred to a special research ward for a trial of systematic dosage reduction. In these 13 patients, it was possible to reduce the dose of HPL from 63.1 mg/day (SD +/- 12.5, range = 50-80 mg/day) to 23.1 mg/day (SD +/- 16.3, range = 0-65 mg/day) over a mean period of 32 weeks (SD +/- 9.6, range = 15-46 weeks). Their total Brief Psychiatric Rating Scale (BPRS) scores were improved (p = .04), they definitely experienced fewer extrapyramidal side effects (p = .01), and 6 of the patients showed global improvement. On several behavioral rating scales there was, if anything, an improvement in negativistic behavior. The substantial dosage reduction was paralleled by a comparable drop in plasma levels. HPL plasma levels at baseline were 38.8 ng/mL (SD +/- 17.8, range = 21.5-69.5 ng/mL) and at the lowest effective dose were 12.4 ng/mL (SD +/- 10.3, range = 0-43.4 ng/mL).

Adult↗
PubMed1993

Metabolism of phenothiazine and butyrophenone antipsychotic drugs. A review of some recent research findings and clinical implications.

Whereas some metabolites of antipsychotic drugs are psychoactive and contribute to clinical improvement, recent studies have provided evidence that certain metabolites contribute to side-effects which can be disabling enough to negate clinical improvement as regards the psychosis. The route of administration of the drug can determine the amount of metabolite produced in the body and affect how the patient feels in response to the treatment.

Animals↗
PubMed1991

Neuroleptic plasma levels.

There is enormous variation in plasma levels of most neuroleptics in patients on the same dose. Much of the past research on the relation between plasma levels of antipsychotic drugs and clinical change, however, has been difficult to interpret. It does appear that decreased bioavailability, at least in public institutions, is rarely the cause of treatment failure. Aberrantly low plasma levels are more likely due to surreptitious noncompliance or drug interactions with enzyme inducers such as carbamazepine. Therapeutic plasma level ranges, in which good antipsychotic effect occurs without undue side effects, have been tentatively identified for perphenazine, haloperidol, fluphenazine, and chlorpromazine. The extent to which aberrantly high plasma levels are associated with inferior antipsychotic response is unclear. Antipsychotic plasma levels may be most useful when the distinction between side effects and worsening psychosis is unclear. The utility of high neuroleptic plasma levels in the treatment-resistant patient is unclear.

Antipsychotic Agents↗
PubMed1991

Plasma levels of fluphenazine in patients receiving fluphenazine decanoate. Relationship to clinical response.

The levels of fluphenazine and fluphenazine sulphoxide in schizophrenic patients who were randomly assigned to receive either 5 mg or 25 mg of fluphenazine decanoate every two weeks were monitored. Patients treated with 25 mg of fluphenazine decanoate required three months to reach a steady-state plasma level, indicating that those patients who are being converted from oral to depot fluphenazine should continue to receive oral supplementation during the first three months of treatment with fluphenazine decanoate. Plasma levels of fluphenazine sulphoxide were lower than levels of fluphenazine. At six and nine months following randomisation, there was a statistically significant relationship between lower fluphenazine plasma levels and an increased risk of psychotic exacerbations. A relatively weak relationship was found between fluphenazine plasma levels and akinesia, but non-significant relationships between fluphenazine levels and other neurological side-effects including akathisia, retardation, and tardive dyskinesia. Monitoring the plasma levels may be helpful to clinicians who are attempting to treat stabilised patients with the lowest effective dose of fluphenazine decanoate.

Adult↗
PubMed1991

Plasma fluphenazine levels and clinical response in newly admitted schizophrenic patients.

Seventy-two newly readmitted, drug-free men with the diagnosis of schizophrenia by DSM-III were assigned randomly to receive fluphenazine hydrochloride at 5 mg, 10 mg, or 20 mg daily for 4 weeks. Fluphenazine (FLU), fluphenazine sulfoxide, 7-hydroxyfluphenazine, and fluphenazine N-oxide were measured by highly specific and sensitive radioimmunoassays. Data were analyzed by logistic regression using the Clinical Global Impressions Disabling Side Effects and Global Improvement as the outcome measures. Disabling side effects were defined as "side effects that significantly interfered with patient's functioning" or "side effects that outweigh therapeutic effects" (National Institute of Mental Health 1985, p. 839). Higher plasma FLU levels (up to 4.23 ng/mL) were significantly (p = .015) associated with a higher rate of global improvement. However, close to 90 percent of these acute patients had disabling side effects at a plasma FLU level of 2.7 ng/mL. At least in the patient's view, these disabling side effects negated or compromised the improvement in psychosis. Fluphenazine N-oxide may be a toxic metabolite in that it was more powerfully associated with side effects than was the parent FLU.

Adult↗
PubMed1990

Therapeutic monitoring of steady-state plasma levels of the N4'-oxide metabolite of fluphenazine in chronically treated schizophrenic patients determined by a specific and sensitive radioimmunoassay.

Highly specific and sensitive antisera for fluphenazine-N4'-oxide (FLUNO) were obtained from New Zealand white rabbits immunized with a bovine serum albumin conjugate of 7-(3-carboxypropionyl)propchlorperazine-N4'-oxide. One of the antisera was used to develop a radioimmunoassay (RIA) procedure that enabled for the first time the determination of steady-state plasma levels of FLUNO, an active metabolite, in patients treated with oral or intramuscular (i.m.) fluphenazine (FLU). This method has sufficient sensitivity to quantitate accurately 20 pg of FLUNO in 200 microliters of plasma extract with a coefficient of variation of less than 8%. The antiserum had negligible cross-reactivity (less than 2%) with FLU and its major metabolites such as FLU sulfoxide, 7-hydroxy-FLU, and N-deshydroxyethyl-FLU. To confirm that the developed RIA procedure specifically quantitated FLUNO, FLUNO was selectively reduced to FLU by sodium dithionite in plasma samples from patients. A good correlation (r2 = 0.9646) was observed between the total FLU level and the sum of FLU and FLU equivalent to FLUNO determined separately in the same plasma. The steady-state plasma concentrations of FLUNO in patients receiving a daily oral dose of 5 to 20 mg of FLU dihydrochloride ranged from 13 to 378% of that of FLU, whereas this value ranged from 10 to 214% in plasma samples from patients treated with a biweekly intramuscular (i.m.) dose of 5 mg of FLU decanoate.

Administration, Oral↗
PubMed1990

Fluphenazine plasma levels and clinical response.

We monitored fluphenazine plasma levels in 39 schizophrenic patients who participated in a 2-year double-blind comparison of 5 mg and 25 mg of fluphenazine decanoate (FD) administered every 14 days. We investigated the relationship between log-transformed plasma levels at 3, 6, and 9 months and subsequent psychotic exacerbations with logistic regression and survival analysis. Using logistic regression, the relationship was nonsignificant at 3 months (chi-square = .21, df = 1, p = .65), but significant at 6 months (chi-square = 4.38, df = 1, p = .04) and 9 months (chi-square = 8.98, df = 1, p = .003). Using survival analysis with fluphenazine levels as a covariate (Cox models), we also found significant relationships between the fluphenazine plasma level and the risk of exacerbations at 6 months (chi-square = 3.77, df = 1, p = .052) and 9 months (chi-square = 12.21, df = 1, p = .0005), but not at three months (chi-square = 0.87, df = 1, p = .65). These findings suggest that the measurement of fluphenazine plasma levels may be helpful in decision-making about the dosage of FD.

Adult↗
PubMed1989

Chronic neuroleptic treatment in rats produces persisting changes in GABAA and dopamine D-2, but not dopamine D-1 receptors.

The effects of continuous treatment with haloperidol (HAL) or fluphenazine (FLU) for 10 months on dopamine and GABA receptors in the rat brain was examined using in vitro autoradiography. Rats treated with HAL, but not FLU, showed an increase in D-2 receptor binding in the caudate-putamen as revealed by [3H]spiperone. Labeling of D-1 receptors by [3H]SCH23390 revealed no changes in either drug-treated group. Both drug-treated groups, however, exhibited a significant increase in [3H]muscimol binding in substantia nigra, pars reticulata (SNR). These dopaminergic-GABAergic receptor alterations may be related to previously reported changes in oral movement activity seen in these neuroleptic-treated animals.

Animals↗
PubMed1989

Plasma levels of parent drug and metabolites in patients receiving oral and depot fluphenazine.

We evaluated the metabolism of fluphenazine (FLU) in patients treated with either the oral form of FLU or with fluphenazine decanoate (FD). Samples for both patient populations were analyzed using four different radioimmunoassays developed in our laboratories for fluphenazine, fluphenazine sulfoxide (FS), 7-hydroxy fluphenazine (7OHFLU), and fluphenazine N-oxide (FLUNO). In patients receiving oral FLU the levels of FS and 7OHFLU were significantly higher than levels of FLU. In patients receiving FD, the levels of metabolites were significantly lower than FLU levels. This supports the view that drug metabolism is likely to be a more important factor for patients treated with an oral as opposed to a depot phenothiazine neuroleptic.

Delayed-Action Preparations↗
PubMed1988

Radioimmunoassay for fluphenazine sulfoxide in human plasma.

Antisera to fluphenazine sulfoxide were raised in New Zealand white rabbits to an immunogen synthesized by covalent linkage of bovine serum albumin to 10-[[3-[4-(4-carboxybutyl)-1-piperazinyl] propyl]]-2-trifluoromethyl-10H-phenothiazine 5-sulfoxide. With use of an antiserum, a radioimmunoassay for fluphenazine sulfoxide was developed that is able to quantitate 0.156 ng ml-1 using only a 200 microliter plasma sample with a coefficient of variation less than 5%. The antiserum had negligible cross-reactivities to fluphenazine (less than 1%) and its important metabolites, such as fluphenazine N4'-oxide (1%), 7-hydroxyfluphenazine (less than 1%), and N4'-deshydroxy-ethylfluphenazine (1%). The cross-reactivities with structurally similar phenothiazine 5-sulfoxides, such as those of trifluoperazine, prochlorperazine, perphenazine, and N4'-deshydroxyethylfluphenazine, were considerable, such that the antiserum can be used to develop a quantitative radioimmunoassay for any of these compounds. The reported radioimmunoassay was found to be suitable and adequate to quantitate fluphenazine sulfoxide in the plasma of patients treated with oral or intramuscular fluphenazine.

Fluphenazine↗
PubMed1986

Development and application of a specific radioimmunoassay for trifluoperazine N4'-oxide to a kinetic study in humans.

A hapten derivative of prochlorperazine N4'-oxide, 7-(3-carboxy-propionyl)-prochlorperazine N4'-oxide, was synthesized and coupled to bovine serum albumin. Immunization of New Zealand White rabbits with this conjugate generated antibodies which were utilized to develop a radioimmunoassay (RIA) for the quantitation of trifluoperazine N4'-oxide (TFPNO). This assay enabled for the first time the quantitation of TFPNO in plasma, and 20 pg can be measured in a 200-microliter plasma sample with a coefficient of variation less than 5%. Statistically, indistinguishable results were obtained by the assay procedure with or without the selective extraction of TFPNO, and also in the presence or absence of an excess of trifluoperazine (TFP) and other major metabolites, such as trifluoperazine sulfoxide and 7-hydroxytrifluoperazine. This RIA and a previously reported RIA for TFP were used to directly determine plasma concentrations of TFP and TFPNO after administration of a single 5-mg p.o. dose of TFP to six healthy male volunteers. The mean +/- S.D. for the peak concentration, time to peak concentration, area under the curve from 0 to 72 hr and the elimination T1/2 for the terminal portion of the plasma concentration vs. time curve for TFPNO were found to be 3.7 +/- 0.7 ng/ml, 3.2 +/- 0.4 hr, 51.1 +/- 9.8 ng X hr/ml and 26.9 +/- 14.0 hr, respectively, whereas the corresponding values for TFP were found to be 2.7 +/- 0.7, 3.1 +/- 0.8, 42.2 +/- 6.9 and 21.9 +/- 6.5, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Radioimmunoassay for the 7-hydroxy metabolite of trifluoperazine and its application to a kinetic study in human volunteers.

A hapten derivative of the 7-hydroxy metabolite of trifluoperazine, 7-hydroxy-10-[[3-[4-(2-carboxyethyl)-1-piperazinyl]propyl]]-2 -tri-fluromethyl-10H-phenothiazine, was synthesized and coupled to bovine serum albumin. Immunization of New Zealand white rabbits with this drug-protein conjugate resulted in the production of antisera, one of which was subsequently utilized in the development of an RIA procedure. The described RIA for the first time enables the quantitation of the 7-hydroxy metabolite of trifluoperazine in human plasma after oral administration of single and therapeutic doses of trifluoperazine, in which 20 pg of the nonconjugated 7-hydroxy metabolite in 200 microL of plasma can be measured with a CV of less than 3% in B/Bo readings. Similar results were obtained by this assay procedure with or without the selective extraction of the 7-hydroxy metabolite and in the presence or absence of a large excess of trifluoperazine and other suspected major metabolites, such as the sulfoxide and N4'-oxide metabolites. This RIA procedure, together with a previously developed RIA for trifluoperazine, was used to directly determine plasma concentrations of trifluoperazine and its 7-hydroxy metabolite after administration of a single 5-mg oral dose of trifluoperazine to six healthy male volunteers. The mean +/- SD for the peak concentration (Cmax), the time to Cmax, the area under the curve from 0 to 24 h and, the apparent terminal elimination half-life for the 7-hydroxy metabolite were found to be 0.86 +/- 0.2 ng/mL, 6.2 +/- 1.6 h, 11.1 +/- 4.9 ng . h/mL, and 10.6 +/- 5.7 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗