Bioequivalence of acenocoumarol in chilean volunteers: an open, randomized, double-blind, single-dose, 2-period, and 2-sequence crossover study for 2 oral formulations.

The aim of this study was to compare the bioavailability of an oral formulation of the coumarin derivative-vitamine K antagonist acenocoumarol (Acebron™ 4 mg, Test) with the reference formulation (Neo-Sintrom™ 4 mg). We performed a single-dose, double-blind, fasting, 2-period, 2-sequence, crossover study design. Plasma concentrations of acenocoumarol were determined using a validated UPLC-MS/MS method. 24 healthy Chilean volunteers (11 male, 13 female) were enrolled and all of them completed the study. Adverse events were monitored throughout the study. The values of the pharmacokinetic parameters were (mean ± SD): AUC0-24 =1 364.38±499.26 ngxh/mL for the test and 1 328.39±429.20 ngxh/mL for the reference; AUC0-∞ =1 786.00±732.85 ngxh/mL for the test and 1 706.71±599.66 ngxh/mL for the reference; Cmax =180.69±35.11 ng/mL with a Tmax of 1.83±0.95 h for the test and 186.97±38.21 ng/mL with a Tmax of 2.19±0.83 h for the reference. Regarding half life measurements, the mean ± SD of t1/2 were 11.84±4.54 h for the test and 11.08±3.28 h for the reference. The 90% confidence intervals for the test/reference ratio using logarithmic transformed data were 97.89-100.87%, 98.62-101.99% and 98.64-102.38% for Cmax, AUC0-t(24) and AUC0-∞. There were no significant differences in pharmacokinetic parameters between groups.The results obtained in this study lead us to conclude, based on FDA criteria, that the test acenocoumarol formulation (Acebron™, 4 mg tablets) is bioequivalent to the reference product (Neo-Sintrom™, 4 mg tablets).

Relative bioavailability study with two oral formulations of topiramate using a validated UPLC-MS/MS method.

Changes in bioavailability of anticonvulsant drugs such as topiramate may cause loss of or worsened seizure control. Thus, the purpose of this study was to evaluate, in a double-blind crossover design, the bioavailability between two oral formulations of topiramate in healthy volunteers after a single dose. The protocol, approved by the Institutional Committee of Ethics, consisted of administration of 1 tablet of 100 mg of topiramate of each formulation (Toprel and Topamax), to 20 healthy volunteers after a 12 h overnight fast, using an open, two-period, randomized, crossover and double-blind design. Thus, the plasma concentrations (Cp) of topiramate were measured at predetermined intervals of time, from 0 to 24 h, using a validated UPLC-MS/MS method. Based on plasma concentration-time profiles we obtained the following pharmacokinetic parameters: AUC(0-inf) 63,418.31 +/- 22,141.69 and 67,094.70 +/- 22,487.2 ngh/ml; AUC0-24: 30,421.02 +/- 9,964.0 and 30,489.35 +/- 9,407.17, ng x h/ml; tmax: 2.77 +/- 1.76 and 1.95 +/- 1.89 h; C(max): 2,143.33 +/- 724.26 and 2,262.51 +/- 751.12 ng/ml, for A (Toprel) and B (Topamax), respectively. All these differences were not statically significant with 90% confidence interval. The test of bioequivalence showed that Cmax, AUC(0-24) and AUC(0-inf) parameters are found within the range of 0.8 - 1.25 recommended by the FDA with a probability of bioequivalence of 100%. In accordance with these results, we can conclude that Toprel 100 mg, A (Test), is a bioequivalent generic and interchangeable with Topamax 100 mg, B (Reference).

[New assessment variables in the Clock Drawing Test (CDT) allow an early and easy diagnosis of degrees of cognitive impairment]. / Nuevas variables de evaluación del test del reloj permiten un precoz y fácil diagnóstico del grado de deterioro cognitivo.

OBJECTIVE: We developed new subroutines and scoring procedures of the CDT to detect markers of early cognitive impairment. SUBJECTS AND METHODS: We compared the performance of 41 mild Alzheimer's patients (AD) (MMSE 22.7+/-3.2); and 18 mild cognitive impairment patients (MCI) (MMSE 28.3+/-1.4), with 33 age and education matched normal controls (NC) regarding their ability in drawing a clock on command, copying a printed clock, setting hands and reading the time. We search for differences in the placement of the hands using a colloquial hour code ("a quarter to ten") and a formal numeric code ("10:45"). We focused our attention on placement and clock hands size. The drawing of hands pointing at 2:50 hs and 8:40 hs were of particular interest. RESULTS: Planning strategies, placement of clock hands using a formal numeric code, clock hands size and hands drawing pointing at 2:50 hs. and 8:40 hs. were the variables that best discriminated AD, MCI and NC ( p<0.01). A stepwise regression analysis using as dependent variables (AD - NC ) and (MCI - NC) showed in both cases that the best predictor model was that formed by: planning strategies, clock hands pointing to 8:40, clock hands size, reading hours and set up clock hands following a formal numeric code (p<.001). CONCLUSIONS: Our proposed modifications in this test convert it in an appropriate tool for cognitive impairment screening because they do not only detect visuoconstructional abilities but also frontal planning, contents and processing of the hour memory code and transcodification of semantic memory processes.

Nuevas variables de evaluación del test del reloj permiten un precoz y fácil diagnóstico del grado de deterioro cognitivo / [New assessment variables in the Clock Drawing Test (CDT) allow an early and easy diagnosis of degrees of cognitive impairment]

OBJECTIVE: We developed new subroutines and scoring procedures of the CDT to detect markers of early cognitive impairment. SUBJECTS AND METHODS: We compared the performance of 41 mild Alzheimer’s patients (AD) (MMSE 22.7+/-3.2); and 18 mild cognitive impairment patients (MCI) (MMSE 28.3+/-1.4), with 33 age and education matched normal controls (NC) regarding their ability in drawing a clock on command, copying a printed clock, setting hands and reading the time. We search for differences in the placement of the hands using a colloquial hour code ([quot ]a quarter to ten[quot ]) and a formal numeric code ([quot ]10:45[quot ]). We focused our attention on placement and clock hands size. The drawing of hands pointing at 2:50 hs and 8:40 hs were of particular interest. RESULTS: Planning strategies, placement of clock hands using a formal numeric code, clock hands size and hands drawing pointing at 2:50 hs. and 8:40 hs. were the variables that best discriminated AD, MCI and NC ( p<0.01). A stepwise regression analysis using as dependent variables (AD - NC ) and (MCI - NC) showed in both cases that the best predictor model was that formed by: planning strategies, clock hands pointing to 8:40, clock hands size, reading hours and set up clock hands following a formal numeric code (p<.001). CONCLUSIONS: Our proposed modifications in this test convert it in an appropriate tool for cognitive impairment screening because they do not only detect visuoconstructional abilities but also frontal planning, contents and processing of the hour memory code and transcodification of semantic memory processes.

Nuevas variables de evaluación del test del reloj permiten un precoz y fácil diagnóstico del grado de deterioro cognitivo. / [New assessment variables in the Clock Drawing Test (CDT) allow an early and easy diagnosis of degrees of cognitive impairment]

OBJECTIVE: We developed new subroutines and scoring procedures of the CDT to detect markers of early cognitive impairment. SUBJECTS AND METHODS: We compared the performance of 41 mild Alzheimers patients (AD) (MMSE 22.7+/-3.2); and 18 mild cognitive impairment patients (MCI) (MMSE 28.3+/-1.4), with 33 age and education matched normal controls (NC) regarding their ability in drawing a clock on command, copying a printed clock, setting hands and reading the time. We search for differences in the placement of the hands using a colloquial hour code ([quot ]a quarter to ten[quot ]) and a formal numeric code ([quot ]10:45[quot ]). We focused our attention on placement and clock hands size. The drawing of hands pointing at 2:50 hs and 8:40 hs were of particular interest. RESULTS: Planning strategies, placement of clock hands using a formal numeric code, clock hands size and hands drawing pointing at 2:50 hs. and 8:40 hs. were the variables that best discriminated AD, MCI and NC ( p<0.01). A stepwise regression analysis using as dependent variables (AD - NC ) and (MCI - NC) showed in both cases that the best predictor model was that formed by: planning strategies, clock hands pointing to 8:40, clock hands size, reading hours and set up clock hands following a formal numeric code (p<.001). CONCLUSIONS: Our proposed modifications in this test convert it in an appropriate tool for cognitive impairment screening because they do not only detect visuoconstructional abilities but also frontal planning, contents and processing of the hour memory code and transcodification of semantic memory processes.

Estudio de biodisponibilidad comparativa de dos formulaciones de risperidona existentes en el mercado chileno / Comparative bioavailability study of two formulations of risperidone available in the Chilean market

BACKGROUND: Bioavailability of a particular drug can vary according to the formulation used. Therefore, studies of comparative bioavailability of different formulations of a same drug are worthwhile. AIM: To compare the bioavailability of two risperidone formulations available in the Chilean market. MATERIAL AND METHODS: The bioavailability of a local risperidone formulation (Spiron) was compared with the original formulation of the drug (Risperdal) in 12 healthy volunteers, aged 19 +/- 1 years. A single dose of 3 mg was given orally, using a randomized double blind protocol in two periods. Fifteen blood samples were obtained at regular intervals, until 24 h after drug administration. Risperidone plasma levels were measured by high pressure liquid chromatography. pharmacokinetic parameters were calculated using a computer program that is independent of compartmental analysis. RESULTS: The area under the curve of plasma concentration versus time, from 0 to infinite (ABC0-infinity) and from 0 to 24 h (ABC0-24), early exposure (ABC from 0 to maximal time) and maximal plasma concentrations were significantly lower for Spiron. Half life time and time to achieve the maximal concentration were similar for the two formulations. CONCLUSIONS: According to bioequivalence tests suggested by the Food and Drug Administration (FDA) of the United States (90 per cent confidence interval for the difference of long transformed mean pharmacokinetic parameters), the formulations Risperdal and Spiron, cannot be considered interchangeable.

[Comparison of the efficacy of intraarticular and intraarterial injections of two betamethasone preparations in patients with osteoarthritis or epicondilytis]. / Comparación de la eficacia clínica de una inyección intraarticular o intralesional de dos preparados de betametasona en pacientes con artrosis o epicondilitis.

BACKGROUND: Local infiltration with corticoids is a simple therapy for rheumatic disorders devoid of systemic adverse reactions. AIM: To compare the efficacy of two betametasone preparations from two different pharmaceutical laboratories in the treatment of patients with osteoarthritis or epicondylitis. PATIENTS AND METHODS: Fourty patients with knee osteoarthritis and 12 patients with epicondylitis were studied. Using a double blind protocol, one of the two betametasone preparations was used for local infiltration of the lesions. The change in a global score of clinical variables including pain and disability was assessed after 30 days of the infiltration. RESULTS: In patients with osteoarthritis, the global score decreased significantly with both preparations, but no differences were observed between preparations (7.3 +/- 1.8 to 3.9 +/- 2.3 with preparation A and 7.8 +/- 1.9 to 3.6 +/- 2.3 with preparation B). In patients with epicondylitis, pain was also significantly reduced but no differences between preparations was observed (7 +/- 2.1 to 1.4 +/- 2.5 for preparation A and 4.6 +/- 2.8 to 1.2 +/- 1.6 for preparation B). CONCLUSIONS: Local infiltration with both betametasone preparations was equally effective in the treatment of patients with knee osteoarthritis or epicondilytis.

[Plasma concentrations and amiodarone/desethylamiodarone relations in patients subjected to chronic treatment]. / Concentraciones plasmáticas y relación amiodarona/desetilamiodarona en pacientes sometidos a tratamiento crónico.

We measured plasma concentrations of amiodarone and desethylamiodarone by HPLC in 44 outpatients aged 24 to 67 years old (21 male), receiving the drug during at least three months. The drug was indicated for supraventricular arrhythmias in 37 patients and ventricular arrhythmias in seven. Plasma concentrations of amiodarone, desethylamiodarone and their ratio were 1.71 +/- 0.82, 0.85 +/- 0.42 micrograms/ml and 2.02 respectively, for a mean daily dose of 223 +/- 88 mg. In 41 patients, arrhytmias were successfully treated. These patients received a mean daily dose of 220 +/- 86 mg and concentrations of amiodarone, desethylamiodarone and their ratio were 1.75 +/- 0.86, 0.88 +/- 0.45 micrograms/ml and 1.99 respectively. In three patients with treatment failure, receiving a daily dose of 257 +/- 115 mg, these figures were 1.2 +/- 0.3, 0.5 +/- 0.1 micrograms/ml and 2.4 respectively. We conclude that our patients had lower plasma concentrations of desethylamiodarone and higher amiodarone/desethylamiodarone ratios than those reported in other countries.

[Amiodarone absorption and elimination after oral and intravenous administration in healthy individuals]. / Absorción y eliminación de amiodarona después de su administración oral e intravenosa en individuos sanos.

We studied amiodarone absorption and disposal in eight male healthy subjects aged 21 +/- 1 years old and weighting 69.8 +/- 7.1 kg. An intravenous dose of 5 mg/kg and an oral dose of 600 mg of amiodarone were administered. Amiodarone concentrations were measured by HPLC and calculations were performed using a compartment model independent pharmacokinetic analysis program. After oral administration a Cmax of 1.17 +/- 0.3 mg/ml was achieved at 3.25 +/- 0.46 h (tmax). Absolute bioavailability ranged from 50.4 to 87.8% (68.6 +/- 12.6%). Compared to previous reports, the variability of this parameter is similar and the mean value is one of the highest informed. After intravenous administration, Amiodarone had a half life of 7.53 +/- 0.96 h, a total body clearance of 4.25 +/- 0.73 ml/kg/min and a distribution volume of 2.99 +/- 0.71 l/kg. Except the later figure, which is in the inferior range, all other parameters are within previously reported values. It is concluded that amiodarone absorption and disposal values found in Chilean subjects are similar to those reported abroad.

[Phenytoin pharmacokinetics in young and older adults]. / Farmacocinética de fenitoina en adultos jóvenes y senescentes.

To study the effect of old age on phenytoin pharmacokinetics, twelve young and nine old adults aged 21.7 +/- 1.8 and 71.8 +/- 4.9 years respectively, were studied. No significant differences of phenytoin indicating the drug distribution and elimination does not change with aging. After oral administration, significant differences were observed between young and old adults for absorption, measured through oral residence half time (36.89 +/- 5.07 h in young and 29.25 +/- 8.64 h in old adults p < 0.05), absorption half time (6.91 +/- 3.6 vs 3.29 +/- 2.35 h) and maximal concentration (1.45 +/- 0.37 vs 2.0 +/- 0.79 micrograms/ml). However, absolute bioavailability of the drug was not different in both age groups (72.9 and 67.6% in young and old adults respectively). It is concluded that no modifications of phenytoin dosage are necessary in elderly people.

[Determination of plasma concentration of amiodarone and desethylamiodarone with high pressure liquid chromatography. Preliminary experience]. / Determinaciones plasmáticas de amiodarona y desetilamiodarona por cromatografía líquida de alta presión. Experiencia preliminar.

A simple specific and sensitive high pressure liquid chromatography method (HPLC) to measure amiodarone and desethylamiodarone is described. The plasma sample is deproteinized with acetonitrile and a 50 ul aliquote run in the HPLC system with reverse phase column (C-18). Methanol-ammonium hydroxide is used to separate and spectrophotometric measurements are read at 254 nm.95% of the drug present in plasma is extracted with this method, with a sensitivity of 0.03 ug/ml and a day to day variation under 3%. Preliminary measurements were analyzed in 14 subjects receiving amiodarone for treatment of supraventricular arrhythmia. With a mean dose of 267 +/- 116 (SD) mg/day, plasma levels of 1.3 +/- 0.6 ug.ml for amiodarone and 0.9 +/- 0.5 mg/ml for desethylamiodarone were obtained.

[The bioavailability of 4 sustained-release theophylline preparations from the Chilean market]. / Biodisponibilidad de cuatro preparados de teofilina de liberación sostenida del mercado nacional.

We evaluated pharmacokinetic parameters and bioavailability of 4 sustained release theophylline preparations. A crossover design was used in 12 healthy males aged 22 to 27 years old. Each individual received 250 mg iv followed by 250 mg orally of each preparation, and then 400 mg rapid acting aminophylline. A 7 day period was allowed between drug courses. HPLC was used to determine plasma levels of theophylline at regular intervals up to 48 hr following drug administration. Significant (p < 0.05) differences in pharmacokinetic parameters were found among preparations, 2 of them having larger integrals of plasma levels and one of them different times to peak plasma level and peak plasma concentration, compared to both remaining preparations.

[Carbamazepine: the bioavailability of 4 oral pharmaceutical products]. / Carbamazepina: biodisponibilidad de cuatro productos farmaceuticos orales.

The bioavailability of carbamazepine from 4 commercially available products was evaluated in 12 healthy volunteers. A crossover design was used and each patients received 400 mg of each product. Plasma levels of the drug were determined periodically for 72 h using a gas-liquid chromatographic method. An open model of one compartment for first-order absorption was assumed to derive pharmacokinetic parameters. Dissolution kinetics was also evaluated in each product. Significant differences in bioavailability were shown for one product. Results correlated with the in vitro dissolution findings.

Variables epidemiológicas de pacientes con linfomas no hodgkinianos en el Instituto Nacional de Oncología y Radiobiología, 1970 - 1982 / Epidemiologic variables of patients presenting non-hodgkin's lymphomas at the National Institute of Oncology and Radiology during 1970 -1982 period

Se estudian las variables epidemiológicas de pacientes inscriptos en el INOR entre los años 1970 a 1982 con diagnóstico de linfoma no hodgkin. Se analiza sexo, edad, histopatología, etapa clínica y presencia de síntomas y se correlacionan las variables entre si. Predominó el sexo masculino en todas las edades, excepto entre 50 y 69 años. La ausencia de síntomas generales se evidenció en el grupo. El linfoma linfocítico bién diferenciado predominó el tipo mixto y el linfoma histiocítico, con 76 y 69

respectivamente (significativo en el 95

). La etapa I se vió más frecuente en pacientes mayores de 50 años; la etapa III entre 30 a 69 años; y la etapa IV en menor proporción en mayores de 70 años (p<0,01). Las variables nodulares fueron más frecuentes en etapas I y II y las difusas en las etapas IV (p<0,01)

Aspectos epidemiológicos de pacientes que presentan linfomas no hodgkinianos en el Instituto Nacional de Oncología y Radiobiología entre los años 1970 y 1982 / Epidemiologic aspects of patients presenting non-hodgkin's lymphomas at the National Institute of Oncology and Radiobiology during 1970 - 1982 period

En 171 pacientes del Instituto Nacional de Oncología y Radiobiología que presentaban linfomas no hodgkinianos entre los años 1970-1982 se analizaron diferentes variables: síntomas de consulta y tiempo de éstos: presencia de síntomas A y B: localizaciones no ganglionares iniciales y variedad histológica. La presencia de adenopatías periféricas se presentó en el 60,2

; hubo 12 pacientes con lesiones cutáneas y de éstos 5 fueron micosis fungoides, 9 pacientes presentaron tumores oculares (5,3

) y 8 con tumores de región orofaringea (4,7

). Sólo el 15,8

(27 pacientes) refirieron síntomas "B". El 72,5

de los pacientes refirió síntomas de menos de 6 meses. El 6,4

(11 pacientes) presentó toma esplénica, 6,4

toma hepática y 5,3

toma pulmonar. La variedad nodular fue más frecuente en las localizaciones de la órbita, mientras que la difusa fue más frecuente en piel, higado y pulmón

Aspectos epidemiológicos de pacientes que presentan linfomas no hodgkinianos en el Instituto Nacional de Oncología y Radiobiología entre los años 1970 y 1982 / Epidemiologic aspects of patients presenting non-hodgkin's lymphomas at the National Institute of Oncology and Radiobiology during 1970 - 1982 period

En 171 pacientes del Instituto Nacional de Oncología y Radiobiología que presentaban linfomas no hodgkinianos entre los años 1970-1982 se analizaron diferentes variables: síntomas de consulta y tiempo de éstos: presencia de síntomas A y B: localizaciones no ganglionares iniciales y variedad histológica. La presencia de adenopatías periféricas se presentó en el 60,2 %; hubo 12 pacientes con lesiones cutáneas y de éstos 5 fueron micosis fungoides, 9 pacientes presentaron tumores oculares (5,3 %) y 8 con tumores de región orofaringea (4,7 %). Sólo el 15,8 % (27 pacientes) refirieron síntomas "B". El 72,5 % de los pacientes refirió síntomas de menos de 6 meses. El 6,4 % (11 pacientes) presentó toma esplénica, 6,4 % toma hepática y 5,3 % toma pulmonar. La variedad nodular fue más frecuente en las localizaciones de la órbita, mientras que la difusa fue más frecuente en piel, higado y pulmón

Variables epidemiológicas de pacientes con linfomas no hodgkinianos en el Instituto Nacional de Oncología y Radiobiología, 1970 - 1982 / Epidemiologic variables of patients presenting non-hodgkin's lymphomas at the National Institute of Oncology and Radiology during 1970 -1982 period

Se estudian las variables epidemiológicas de pacientes inscriptos en el INOR entre los años 1970 a 1982 con diagnóstico de linfoma no hodgkin. Se analiza sexo, edad, histopatología, etapa clínica y presencia de síntomas y se correlacionan las variables entre si. Predominó el sexo masculino en todas las edades, excepto entre 50 y 69 años. La ausencia de síntomas generales se evidenció en el grupo. El linfoma linfocítico bién diferenciado predominó el tipo mixto y el linfoma histiocítico, con 76 y 69 % respectivamente (significativo en el 95 %). La etapa I se vió más frecuente en pacientes mayores de 50 años; la etapa III entre 30 a 69 años; y la etapa IV en menor proporción en mayores de 70 años (p<0,01). Las variables nodulares fueron más frecuentes en etapas I y II y las difusas en las etapas IV (p<0,01)

[Determination of plasma levels of phenytoin. Evaluation of 2 techniques]. / Determinación de níveles plasmáticos de fenitoina. Evaluación de dos técnicas analíticas.

We compared 2 techniques for determination of plasma levels of phenytoin, liquid-gas chromatography (LGC) and homogeneous enzymatic immunoassay (EI) in samples from 72 patients receiving monotherapy with this drug. Determinations were also made in samples of normal plasma with known concentrations of phenytoin. Good correlation of both techniques was observed in patient samples containing less than 15 micrograms/ml of the drug but not with higher concentrations. LGC was accurate in determination of known concentrations of phenytoin, whereas immunoassay showed an exponential deviation with overestimation of phenytoin levels. Thus LGC is a better technique for determination of phenytoin levels; however EI may be used in most clinical situations when the concentration of phenytoin lies under 20 micrograms/dl.