Santiago, 31 de Octubre | En las farmacias que operan en Chile pocas veces se actúa con la dedicación y vigilancia que requieren los medicamentos porque el sistema no está fundado en el servicio sino en el lucro. Esta afirmación no es una apreciación ligera. Es una evidencia reiterada y fácil de constatar.
Las farmacias de cadena constituyen el fenómeno de mayor incidencia y gravitación producido en el mercado farmacéutico chileno, comparable tan solo en cuanto a impacto con el que produjo el Formulario Nacional de Medicamentos en la década de los 70 y parte de los 80. Aquel sistema que promovió la producción y dispensación de medicamentos esenciales con denominación genérica, de calidad y baratos, sirvió para satisfacer en gran medida las necesidades de la población y produjo una evidente regulación de precios.
Este sistema que se inició en 1969, impulsado por el gobierno de Frei Montalva, sirvió de modelo para la política de medicamentos esenciales que la OMS puso en marcha ocho años más tarde. Fue tal el efecto social que produjo el sistema que 25 años después de su desaparición la gente aún sigue pidiendo productos del formulario nacional. Las farmacias de cadena se insertan, en cambio, en un contexto puramente comercial y de hecho han producido efectos muy negativos en la salud pública. Estos resultados no se aprecian directamente porque en nuestro país no hay cultura del medicamento ni sistemas de farmacovigilancia que los pongan en evidencia.
Estas farmacias operan según un modelo que las concibe como "puntos de venta" y se desarrollan con el menor control y regulación posibles dentro de la economía de libre mercado. En este esquema el medicamento es considerado como un bien de consumo. Se opone a este modelo la farmacia "centro de salud" que existe en muchos países europeos. En ellas, el medicamento es tratado como un "bien social" y junto a su entrega al paciente se le agrega información, orientación y consejos para el correcto uso de los fármacos.
Las farmacias de cadena dominan casi sin contrapeso el mercado de medicamentos en Chile. Según los últimos datos (IMS) absorben el 92,5% de la venta al público. La opción de la gente por ellas ha estado siempre provocada por sus precios y por la prestación de servicios adicionales como el uso de tarjetas de crédito. Al comienzo del sistema los precios fueron efectivamente menores. Hoy no es así, pero estas farmacias insisten en que tienen los mejores precios del mercado. El público ha seguido favoreciéndolas motivado por estrategias publicitarias engañosas en que se presentan ofertas y promociones atractivas que a la hora de su concreción se diluyen. La colusión detectada hace un par de años entre las tres grandes cadenas que alzaron los precios de 222 medicamentos fue como la "guinda de la torta" de una política mentirosa y abusiva.
La instalación y desarrollo de las farmacias de cadena se hizo posible gracias a medidas que impuso el gobierno de Pinochet, que constituyen en su conjunto lo que se conoce como la "desregulación farmacéutica". Antes hubo algunas cadenas de farmacias que no prosperaron porque aún no se había implantado la economía de libre mercado. La "desregulación farmacéutica" comenzó el 15 de Marzo de 1974 con la derogación de la "Ley del circuito" (ley 1.142) que establecía la prohibición de instalar una nueva farmacia a menos de 400 metros de otra ya existente. Era una sabia medida destinada a asegurar un buen rendimiento de la farmacia protegida y garantizar con ello una mejor atención a la población del entorno.
Enseguida, el mismo año, se dejó sin efecto la exigencia de la propiedad farmacéutica. Se abrió así el dominio de una farmacia a cualquier comerciante que deseara operar en el rubro. Las mejores farmacias del mundo están en los países nórdicos y en algunos latinos: Suecia, Noruega, Finlandia, Bélgica, España, Italia y Francia, entre ellos, donde estos establecimientos son de dominio exclusivamente profesional. En ellos no hay cadenas farmacéuticas. Hungría acaba de sumarse a esta situación.
El 9 de Mayo de 1980 se decretó el precio libre de los medicamentos y casi simultáneamente la incorporación de las farmacias al horario de libre atención. Se configuró de esta manera un cuadro absolutamente liberalizado que trajo como consecuencia una proliferación en progresión geométrica de estas farmacias, concentradas en barrios comerciales y sectores residenciales de mayores recursos económicos, muchas veces una al lado de otra.
Las farmacias nuevas tenían otro rostro nada diferente de otros establecimientos comerciales y en muchos casos con una presentación parafernálica muy agresiva. La idea era atraer al público con precios menores favorecidas por las rebajas que recibían por escala de parte de los fabricantes y al mismo tiempo ampliando la venta a productos ajenos a la farmacia tradicional.
La gente se sintió efectivamente atraída por el sistema a tal punto que en encuestas destinadas a medir el grado de aceptación de establecimientos en que se presta atención a público, las farmacias de cadena obtuvieron uno de los primeros lugares. Este hecho, por cierto, revela la falta de cultura del medicamento que padece nuestra gente, manifestada en este caso en una calificación en que no estuvieron presentes los parámetros que más importan.
Un programa de televisión ("Contacto") denunció algunas de las malas prácticas con que operan habitualmente estas farmacias: cambio de medicamentos prescritos, registro impreso (fotocopias) de recetas para objetivos de promoción médica, ventas favorecidas para ciertos laboratorios y negación de venta de productos de denominación genérica, los más baratos y de baja rentabilidad. Pero, lo peor es la información sesgada o errada que entrega el personal auxiliar mientras el profesional farmacéutico está confinado a funciones administrativas. Todas estas situaciones son la consecuencia del modelo en curso cuyas características centrales son la mercantilización exacerbada, la ausencia de compromiso sanitario y la primacía absoluta del lucro sobre el servicio.
Varias son las características que se observan en el funcionamiento de estas farmacias. Una de ellas es el predominio de la "velocidad de rotación" como clave para su éxito comercial. La idea es vender rápido para hacer pronto la utilidad. Por cierto que ello se hace en desmedro de una mejor atención.
Se observa además lo que se llama "integración vertical". Esta es un acuerdo entre un laboratorio y una cadena en cumplimiento del cual se privilegia la venta de ciertos productos y se niega la de aquellos que no están incluidos. Este método ha derivado a expresiones aún peores.De hecho, contraviniendo la ley, ya hay farmacias y laboratorios del mismo dueño.
Las remuneraciones del personal auxiliar es otro problema con graves consecuencias. Las remuneraciones pactadas son muy menores, lo cual obliga al dependiente a aumentarlas con la "canela"1 que pagan ciertos laboratorios como incentivo para favorecer la venta de sus productos. Está claro que este personal se esmera por aumentar de esta manera sus ingresos, sin importar si daña a la dispensación correcta.
El farmacéutico es el profesional idóneo formado para prestar la mejor atención sanitaria. Pues bien, las empresas lo sacan de los "puntos hot" porque la atención que está llamado a cumplir exige tiempo, entrega de orientación y actuar como filtro y ello no favorece sino que frena las ventas. Entonces, es mejor derivarlo a funciones administrativas, inhibirlo, alejarlo del público.
Los medicamentos son productos especiales, muy distintos de otros. Esto queda claro si se consideran los objetivos a que están destinados. Esto es, recuperar la salud perdida, atenuar síntomas o prevenir enfermedades.
Por ello su manejo debe ser muy cuidadoso, informado y seguro. No hay fármacos inocuos. Muchos tienen efectos tóxicos e incluso deletéreos, si se administran en dosis excesivas (Paracelso dijo: El veneno lo hace la dosis). Buena parte de ellos producen efectos adversos previsibles que deben ser advertidos, así como hay muchas contraindicaciones e interacciones que deben ser informadas.
El doctor Enrique Paris, especialista toxicólogo y presidente del Colegio Médico, informó recientemente que la mayor parte de las intoxicaciones que se registran en Chile son causadas por medicamentos. Pues bien, en las farmacias que operan en Chile pocas veces se actúa con la dedicación y vigilancia que requieren los medicamentos porque el sistema no está fundado en el servicio sino en el lucro. Esta afirmación no es una apreciación ligera. Es una evidencia reiterada y fácil de constatar.
Así, el sistema se constituye en un riesgo sanitario que, desgraciadamente, no se capta en su real dimensión por parte de la gente y, lo que es peor, de las autoridades públicas y sanitarias. La falta de cultura del medicamento es grave y al amparo de esta falencia el sistema se ha perpetuado. Las autoridades, por su parte, creen que no hay problemas con los medicamentos. Modificarían su apreciación si los pacientes pudiesen hacer marchas de protesta.
En estas condiciones al gobierno no se le ha ocurrido nada mejor que proponer la venta de los medicamentos sintomáticos en cualquier parte. Es decir, auspicia un modelo peor que el que tenemos a la vista. Ojalá no prospere el proyecto en trámite parlamentario cuya inconciencia es reemplazar lo malo por un sistema peor.
A todo esto, las farmacias independientes, situadas especialmente en barrios populares y comunas periféricas, se defienden como pueden. Los precios de los medicamentos se han equiparado bastante y por ello, y por cercanía, logran mantener una especie de público cautivo.La mayor demanda en estas farmacias se concentra en productos de denominación genérica, que suelen ser negados en las farmacias de cadena.
De estas farmacias hay en Chile algo más de 600, respecto a las 1200 de cadena. Tienen apenas el 7,5% de la venta al público. Se sustentan por la facilidad con que el público accede sin receta a muchos medicamentos y en ciertos casos a fraccionamientos de contenido.
Estas farmacias independientes son un engendro del sistema vigente. No son un buen modelo alternativo y mal se podrían considerar como herederas de las farmacias comunitarias profesionales anteriores a la "desregulación farmacéutica".
Para decirlo muy derechamente, los modelos de farmacia que tenemos en Chile están entre los peores del mundo y nadie protesta. ¿Será que no nos damos cuenta o que no nos interesa?
LOs Travestis ExisteN!!!!! =O
remover sucias aguas de tontos
lunes, 14 de noviembre de 2011
martes, 11 de octubre de 2011
domingo, 2 de octubre de 2011
sdfghj
ORIGINAL ARTICLE
Different effects of light food on pharmacokinetics and
pharmacodynamics of three benzodiazepines, quazepam,
nitrazepam and diazepam
A. Yamazaki* MS, Y. Kumagai MD, T. Fujita MD, T. Hasunuma MD, S.Yokota ,
M. Maeda , Y. Otani MD and M. Majima* MD
*Department of Molecular Pharmacology, Kitasato University Graduate School of Medicinal graduate
course, Kanagawa, Clinical Trial Center, Kitasato University East Hospital, Kanagawa and Center for
Clinical Pharmacology, Kitasato Institute, Kanagawa, Japan
SUMMARY
Objective: Quazepam, nitrazepam and diazepam
are administered under fed or fasted conditions
for insomnia or anxiety disorder. Light bedtime
food may have clinically relevant effects on the
plasma levels of those drugs and hence on psychomotor
performance. This study assessed the
effect of light food on the pharmacokinetics and
pharmacodynamics of these drugs.
Method: Twenty-one eligible subjects were
randomized to one of three groups of seven subjects:
quazepam 20 mg, diazepam 5 mg or nitrazepam
5 mg. Each healthy subject took a single
oral dose of the assigned drug after overnight
fasting and after light food, on a separate occasion.
Blood samples were collected until 72 h
after dosing. The plasma samples were assayed
using high-pressure liquid chromatography with
spectrophotometric detection. Reaction time,
critical flicker fusion test and visual analogue
scales were conducted.
Results: The peak plasma concentration (Cmax)
and area under the concentration–time curve
(AUC) of quazepam with light food were 1Æ2-fold
[90% confidence interval (CI): 1Æ1–1Æ5; P < 0Æ05]
and 1Æ5-fold (90% CI: 1Æ3–1Æ9; P < 0Æ05) higher
than that without light food, respectively. For
nitrazepam and diazepam, the time to peak was
delayed about 1 h in fed condition (P > 0Æ05).
However it had no effect on their Cmax and AUC.
Reaction time of quazepam with light food was
prolonged at 4 and 6 h after dosing and its area
under the effect–time curve from 0 to 10 h was
increased (P < 0Æ05).
Conclusion: Light food increased the bioavailability
of quazepam and affected psychomotor
performance. Light food delayed Tmax of nitrazepam
and diazepam but had no effect on Cmax and
AUC.
Keywords: benzodiazepine, food–drug interactions,
pharmacodynamics, pharmacokinetics
INTRODUCTION
Quazepam, nitrazepam and diazepam are benzodiazepine
drugs used in insomnia or anxiety disorder.
Food may have significant effects on the
bioavailability of various drugs (1, 2). Quazepam,
nitrazepam and diazepam are highly lipophillic (3,
4) and their absorption is often enhanced by food
(1). Increased bioavailability of drugs have been
reported not only with fatty meals but also with
protein or carbohydrate meals (5). Therefore, a very
low fat meal or a light food such as a bed-time
snack may interact with these benzodiazepines.
The effect of food on the pharmacokinetics of
quazepam have been reported by Yasui-Furukori
et al. (4, 6) and Kim et al. (7). However, the effect of
light food such as a bed time snack on the drug’s
pharmacokinetics and pharmacodynamics is not
known. There is also little information on the effects
of food on oral diazepam and published studies
have used a variety of foods (8). Furthermore, oral
Received 2 June 2006, Accepted 26 November 2006
Correspondence: Akira Yamazaki, Department of Molecular
Pharmacology, Kitasato University Graduate School of Medicinal
graduate course, 1-15-1 Kitasato, Sagamihara, Kanagawa
2288555, Japan. Tel.: +81 42 778 8111; fax: +81 42 778 8111;
e-mail: yamazaa@jcom.home.ne.jp
Journal of Clinical Pharmacy and Therapeutics (2007) 32, 31–39
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd 31
nitrazepam has not been assessed for the possibility
of drug–food interaction. Therefore, we evaluated
the effect of light food on the pharmacokinetics and
pharmacodynamics of quazepam, nitrazepam and
diazepam in healthy subjects.
MATERIALS AND METHODS
Materials
Doral tablets (20 mg quazepam), Benzalin tablets
(5 mg nitrazepam) and Cercine tablets (5 mg diazepam)
were purchased from Mitsubishi Pharma
Corporation (Osaka, Japan), Shionogi & Co., Ltd
(Osaka, Japan) and Takeda Pharmaceutical Company
Ltd (Osaka, Japan), respectively. The light
food was used a Japanese traditional healthy bedtime
snack, ‘otyaduke’ which is cooked as follows:
boiled rice 100 g sprinkled with ‘otyadukenori’ 6 g
(Nagatanien Co., Ltd, Tokyo, Japan) was poured
150 mL of hot water. Otyadukenori consisted of
sodium, cubic rice crackers and dried seaweed
flakes. It contained approximately 166 kcal (0Æ44 g
lipid, 37Æ8 g carbohydrates, 2Æ7 g protein and
sodium 1Æ9 mg).
Study design and clinical protocol
This study was approved by the institutional
review board at Kitasato East hospital and all
subjects provided written informed consent prior
to any study procedures. Twenty-one healthy male
volunteers between the ages of 20 and 33 years
(22Æ5 ± 2Æ9) and body mass index within 18Æ9–
26Æ6 kg/m2 (21Æ6 ± 2Æ3) were enrolled for the study.
Study subjects were determined to be healthy by a
complete medical history, physical examination,
alcohol and drug abuse history, vital signs, 12-lead
electrocardiogram, and laboratory tests, serologic
test for syphilis and virology tests (HIV, hepatitis B
and hepatitis C). Subjects were excluded if they
had any of the following: subjects with evidence of
donation of blood more than 200 mL within
1 month or more than 400 mL within 3 months
before this study; subjects who were enrolled in
any other clinical study within 4 months prior to
this study; subjects predisposed to drug hypersensitivity
reactions; subjects who were considered
unsuitable for participation in this study by the
investigator.
This was a randomized, parallel dosing, twoway
crossover, single-dose study in 21 healthy men
with a 2-week washout between the drug administrations.
Twenty-one eligible subjects were randomized
to one of three cohort groups (seven
subjects each): (i) a single 20 mg tablet of quazepam,
(ii) a single 5 mg tablet of diazepam, and (iii)
a single 5 mg tablet of nitrazepam.
Eligible subjects were admitted to the study site
on the day before dose administration on each of
the two treatment periods. The subjects slept at
least 8 h before the start of each study session. The
subjects received a study drug with 200 mL of
water 30 min after the light food and under fasting
condition. The subjects and persons in charge of
psychomotor function tests were not aware of
which study drug was administered to the subjects.
The pharmacist who administered the study drug
to the subjects was unblinded to it. Blood was
collected at pre-dose and at 0Æ5, 1, 2, 3, 4, 5, 6, 8, 12,
24, 48 and 72 h after dosing. All subjects fasted for
at least 10 h before and until 4 h after dosing. All
subjects received a standardized lunch and supper
4 and 10 h after dosing, respectively. The volunteers
were not allowed to use any medication
within 24 h preceding the treatment as well as
during the entire study. Alcohol, caffeine, cola,
beverage including grapefruit and smoking was
prohibited for 12 h prior to and following drug
administration. The volunteers had to avoid
excessive physical exercise throughout the study.
Analytical procedures
The plasma samples were assayed using high-pressure
liquid chromatography with spectrophotometric
detection (HPLC/UV) and column switching.
Quazepam and its metabolite 2-oxoquazepam,
N-desmethyl-2-oxoquazepam and cisapride as an
internal standard were supplied by Mitsubishi
Pharma Corporation. Diazepam and its metabolite
N-desmethyl-diazepam and nitrazepam were purchased
from Sigma–Aldrich Japan K.K. (Tokyo,
Japan).
The plasma samples were assayed for quazepam,
2-oxoquazepam, N-desmethyl-2-oxoquazepam.
After sample alkalization with 0Æ5 mL of
NaOH (0Æ05 mol/L), the test compound and internal
standard, cisapride, were extracted from
plasma using toluene-n-heptane (15 : 85, v/v). The
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
32 A. Yamazaki et al.
organic phase was evaporated to dryness and the
residue was dissolved with 800 lL of mobile phase.
The clean-up and preconcentration of sample
(500 lL) was performed on C8 TSK-BSA (5 lm,
10 · 4Æ6 mm ID) pretreatment column from Tosoh
Corporation, Tokyo, Japan. The mobile phase consisted
of acetnitrile and phosphate buffer
(0Æ02 mol/L, pH 4Æ6) (13 : 87, v/v) and was delivered
at a flow rate of 1Æ2 mL/min. Subsequent
separations were carried out on C18 STR ODS-II
analytical column (5 lL, 150 · 4Æ6 mm ID, Shimadzu
Techno-Research Inc., Tokyo, Japan) analytical
column. The mobile phase consisted of
acetnitrile and phosphate buffer (0Æ02 mol/L, pH
4Æ6) (13 : 87, v/v) for quazepam and 2-oxoquazepam,
and acetnitrile, perchloric acid (6 mol/L) and
phosphate buffer (0Æ02 mol/L, pH 4Æ6)
(41Æ5 : 0Æ05 : 58Æ45, v/v/v) for N-desmethyl-2-oxoquazepam
and was delivered at a flow rate of
0Æ6 mL/min. The peak was detected using a UV
detector set at 286 nm for diazepam and 254 nm for
metabolite. Relative errors at 30 ng/mL of quazepam,
2-oxoquazepam, N-desmethyl-2-oxoquazepam
were 2Æ5%, 3Æ9% and 2Æ6%, respectively. The
limit of quantification was 0Æ7 ng/mL for each
compound.
The plasma samples for nitrazepam, diazepam
and N-desmethyl-diazepam were assayed by same
method except the following. The samples were
alkalized with 0Æ5 mL of NaOH (0Æ5 mol/L) for
nitrazepam assay, and with 0Æ5 mL NaOH
(0Æ01 mol/L) for diazepam and N-desmethyl-diazepam.
Relative errors at 15 ng/mL of nitrazepam,
diazepam and N-desmethyl-diazepam were 3Æ2%,
2Æ9% and 2Æ9%, respectively. The limit of quantification
was 0Æ8 ng/mL for each compound.
Pharmacodynamic measures
Psychomotor function tests were conducted before
and 2, 4, 6, 10 and 24 h after drug administration.
The subject’s agility and ability to react from
cognition to movement was assessed using reaction
time (RT). Subjects were required to press an
electrical switch, when a yellow light flashed. The
special equipment consisted of a light stimulus
generator (T.T.K.331), a digital timer (T.T.K.315), a
push-button switch set and a selective reaction
control (T.T.K.333) (Takei Scientific Instruments
Co., Niigata, Japan). This produced random
sequences of three-colour stimuli (yellow, red and
blue light). The RTs and the computed average RT
of 10 stimuli were calculated at each point. Critical
Flicker Fusion Test (CFFT) assessed the subject’s
wakefulness and degree of fatigue. The score was
determined by measuring the frequency for distinguishing
the flicker from 12 runs of ascending
and 12 runs of descending frequencies. Lightemitting
diodes (Leeds Flicker Fusion Tester Type
II, T.T.K.501.b; Takei Scientific Instruments Co.)
produced the stimuli. The seated subjects peered
through a cylindrical tube to see the flickers with
both eyes in a quiet room. Subjects were required
to depress an electrical switch, when flicker fusion
(continuous lighting) was observed for ascending
CFFT or continuous lighting flickering for descending
CFFT. The number of flicks per second
(Hz) was recorded. Visual analogue scales (VAS)
were used to subjectively rate sedation using 0–
100 mm VAS, as described by Norris (9), and
Bond and Lader (10). In this study the six indicators
were selected to assess three domains of
sedation with two indicators each: mental sedation
(alert–drowsy and clear headed–muzzy),
tranquilization (calm–excited and relaxed–tense),
and physical sedation (well coordinated–clumsy
and energetic–lethargic).
Pharmacokinetic and pharmacodynamic analysis
Individual plasma concentration–time profiles was
analysed by using a non-compartmental method,
using WINNONLIN (Pharsight Corporation, Mountain
View, CA, USA). The following parameters were
obtained: Cmax and Tmax were determined from
observed data. Area under the plasma concentration–
time curve from time zero to the last quantifiable
concentration (AUClast) was determined by the
linear trapezoidal rule. The terminal rate constant
(kel) was determined by linear regression of the
terminal linear portion of the ln concentration–time
curve. The terminal half-life (t1/2) was calculated as
ln/kel. The mean transit time (MTT) was calculated
as the area under the first moment curve (AUMC)/
AUC. AUMC was determined by the linear trapezoidal
rule, and the following pharmacodynamic
parameters were obtained: the area under the
effect–time curve (AUC) was determined by the
trapezoidal rule from 0 to 10 h and from 0 to 24 h
for RT and CFFT. For RT and VAS, a raw score was
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 33
used. The CFFT variables were assessed by changed
scores from baseline.
Statistical analysis
Differences in pharmacokinetic parameters (excluding
Tmax) and pharmacodynamic parameters (RT
and CFFT) were evaluated using a paired t-test.
Differences in Tmax were evaluated using Wilcoxon’s
matched-pairs signed ranks. VAS was not
evaluated statistically due to the large inter-individual
variance. Each pharmacodynamic parameter
at each time point was used for statistical
analysis for comparing fed and fasting states. Differences
were considered significant when
P < 0Æ05. The 90% confidence intervals (CIs) of the
fed/fasting ratios for Cmax and AUClast (log transformed)
were determined.
RESULTS
Pharmacokinetics
Mean plasma concentration–time profiles of quazepam
following single-dose oral administration
are illustrated in Fig. 1. Relevant pharmacokinetic
parameters corresponding to the plasma concentration
profiles are listed in Table 1. It is seen that
the plasma concentration–time profiles of quazepam
between fasting and fed conditions are different.
The 90% CIs of ratios for Cmax and AUClast
were 1Æ1–1Æ5 and 1Æ3–1Æ9, respectively, for the fed
relative to the fasted state indicating that the rate
and the extent of quazepam absorption were
increased when administered with food. Similar
results were found using the paired t-test (P < 0Æ05).
Other pharmacokinetic parameters, Tmax, t1/2 and
MTTlast, did not change significantly. Contrary to
the parent compound, its metabolites, 2-oxoquazepam
and N-desmethy-2-oxoquazepam were not
significantly different between fasted and fed conditions,
except t1/2 of 2-oxoquazepam (Table 1).
For nitrazepam and diazepam, mean plasma
concentration–time profiles following single-dose
oral administration are illustrated in Figs 2 and 3.
There were no significant differences between
the fed and fasting states with regard to Cmax and
AUClast (P > 0Æ05). The 90% CIs of ratios for Cmax
Table 1. Pharmacokinetic parameters (mean ± SD) for quazepam and its metabolites under fasted and fed conditions
(n = 7)
Quazepam 2-Oxoquazepam N-desmethyl-2-oxoquazepam
Fasted Fed Fasted Fed Fasted Fed
Cmax (ng/mL) 44Æ7 ± 38Æ0 52Æ8 ± 36Æ9* 21Æ2 ± 5Æ3 21Æ9 ± 5Æ8 35Æ7 ± 9Æ7 32Æ6 ± 9Æ4
Ratio; 90% CI 1Æ2; 1Æ1–1Æ5 1Æ0; 0Æ9–1Æ2 0Æ9; 0Æ9–1Æ4
Tmax (h) 2 (2–3) 2 (2–4) 3 (2–4) 3 (2–4) 24 (8–24) 12 (12–48)
AUClast (ngÆh/mL) 291 ± 181 445 ± 227* 168 ± 48 174 ± 57 2237 ± 639 2019 ± 604
Ratio; 90% CI 1Æ5; 1Æ3–1Æ9 1Æ0; 0Æ8–1Æ3 0Æ9; 0Æ9–1Æ3
t1/2 (h) 14Æ3 ± 4Æ8 16Æ8 ± 4Æ4 17Æ6 ± 4Æ3 14Æ2 ± 4Æ4* NA NA
MTTlast (h) 10Æ0 ± 2Æ3 12Æ1 ± 1Æ6 11Æ2 ± 2Æ8 10Æ7 ± 3Æ0 10Æ0 ± 2Æ3 12Æ1 ± 1Æ6
For Cmax and AUClast, 90% confidence intervals (CIs) are determined for the ratios between fed and fasting states. Tmax is reported as
median and range. NA = not applicable.
*Difference from fasted condition at P < 0Æ05: significance was tested by paired t-test, except Tmax was tested by Wilcoxon’s matchedpairs
signed ranks.
0
10
20
30
40
50
60
70
0 5 10 15 20 25
Hours
Plasma quazepam (ng/mL)
Fasted
Fed
Fig. 1. Plasma concentration of quazepam after oral
administration of 20 mg quazepam under fasted and fed
conditions. Data are shown as mean and SEM (n = 7).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
34 A. Yamazaki et al.
and AUClast of nitrazepam were 1Æ0–1Æ1 and 0Æ9–1Æ1,
and those of diazepam were 0Æ9–1Æ1 and 1Æ0–1Æ2
(Table 2). Comparison of Tmax, however, indicated
that there was a statistically significant increase in
Tmax in the fed vs. fasted state (P > 0Æ05). Both Tmax of
nitrazepam and diazepam were delayed about 1 h in
fed condition (Table 2). Elimination half-life and
MTTlast did not change upon food ingestion either
for nitrazepam or diazepam. N-desmethyl-diazepam
was not significantly difference between fasted
and fed conditions. The plasma concentration of
N-desmethyl-diazepam continuously increased up
to the last sampling point.
Pharmacodynamics
Quazepam, nitrazepam and diazepam had CNSdepressant
effect assessed by several psychomotor
function tests up to 24 h after drug administration.
For quazepam, food produced significant changes
on RT (Fig. 4). RT was prolonged at 4 and 6 h after
dosing in fed condition (P < 0Æ05). The AUC0–10 of
RT was significant different between the fasted and
fed conditions (P < 0Æ05) (Table 3). Subjects seemed
drowsier at 2 h in the fed condition (alert–drowsy
and clear headed–muzzy) of VAS (Fig. 5). There
were no differences in the other pharmacodynamic
measures of quazepam between the two conditions.
For nitrazepam and diazepam, RT and CFFT
showed no significant differences between the
fasted and fed conditions (Figs 4 and 6). On mental
sedation VAS and CFFT, subjects who were
Table 2. Pharmacokinetic parameters (mean ± SD) for nitrazepam, and diazepam and its metabolites under fasted and
fed conditions (n = 7)
Nitrazepam Diazepam N-desmethyl-diazepam
Fasted Fed Fasted Fed Fasted Fed
Cmax (ng/mL) 51Æ8 ± 4Æ6 52Æ0 ± 4Æ9 109Æ9 ± 28Æ4 107Æ0 ± 25Æ4 33Æ0 ± 7Æ8 29Æ9 ± 10Æ 2
Ratio; 90% CI 1Æ0; 1Æ0–1Æ1 1Æ0; 0Æ9–1Æ1 0Æ9; 1Æ0–1Æ4
Tmax (h) 1 (1–2) 2 (0Æ5–2)* 1 (0Æ5–2) 2 (1–3)* 72 (48–72) 72 (72–72)
AUClast (ngÆh/mL) 1401 ± 370 1383 ± 284 2411 ± 842 2272 ± 819 1911 ± 488 1732 ± 580
Ratio; 90% CI 1Æ0; 0Æ9–1Æ1 0Æ9; 1Æ0–1Æ2 0Æ9; 0Æ9–1Æ4
t1/2 (h) 37Æ2 ± 5Æ3 35Æ1 ± 5Æ4 38Æ3 ± 12Æ5 38Æ2 ± 12Æ7 NA NA
MTTlast (h) 26Æ1 ± 1Æ0 25Æ8 ± 1Æ0 25Æ6 ± 1Æ7 25Æ0 ± 2Æ2 41Æ1 ± 1Æ9 40Æ7 ± 1Æ4
For Cmax and AUClast, 90% confidence intervals (CIs) are determined for the ratios between fed and fasting states. Tmax is reported as
median and range. NA, not applicable.
*Difference from fasted condition at P < 0Æ05: significance was tested by paired t-test, except Tmax was tested by Wilcoxon’s matchedpairs
signed ranks.
Plasma diazepam (ng/mL)
0 5 10 15 20 25
Hours
0
20
40
60
80
120
100 Fasted
Fed
Fig. 3. Plasma concentration of diazepam after oral
administration of 5 mg diazepam under fasted and fed
conditions. Data are shown as mean and SEM (n = 7).
Plasma nitrazepam (ng/mL)
0 5 10 15 20 25
Hours
0
10
20
30
40
50
60
Fasted
Fed
Fig. 2. Plasma concentration of nitrazepam after oral
administration of 5 mg nitrazepam under fasted and fed
conditions. Data are shown as mean and SEM (n = 7).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 35
administered nitrazepam seemed drowsier at 2 h
in both fasted and fed condition. Subjects who were
administered diazepam did not show this effect.
The tranquillization score VAS was not significantly
altered for any of the three drugs. Among
these drugs, the mental sedation VAS increased at
2 h in subjects who were administered quazepam
in fed condition and nitrazepam in both fed and
fasted conditions when compared with subjects
who were administered diazepam. Quazepam with
light food increased RT while nitrazepam
decreased the CFFT in both condition.
DISCUSSION
This study is a randomized, parallel dosing, twoway
crossover study to evaluate the effect of light
100
150
200
250
300
350
Reaction time (ms) Reaction time (ms) Reaction time (ms)
Fasted
Fed
100
150
200
250
300
350 Fasted
Fed
100
150
200
250
300
350 Fasted
Fed
Quazepam
Nitrazepam
Diazepam
*
*
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
Fig. 4. Reaction time of quazepam, nitrazepam and
diazepam under fasted and fed conditions. Data are
shown as mean and SD (n = 7). *Difference from fasted
condition at P < 0Æ05.
Table 3. Pharmacodynamic parameters (mean and range) for quazepam, nitrazepam and diazepam under fasted and fed conditions (n = 7)
Quazepam Nitrazepam Diazepam
Fasted Fed Fasted Fed Fasted Fed
RT
AUC0–10 (msÆh) 2275 (1912–2516) 2514* (2365–2686) 2510 (1869–3551) 2426 (2089–2890) 2343 (1979–2763) 2419 (1958–3157)
AUC0–24 (msÆh) 5496 (4766–6287) 5685 (5319–6285) 5714 (4300–7762) 5747 (4934–7202) 5482 (4927–6268) 5725 (4983–7355)
CFFT
AUC0–10 (HzÆh) 3Æ5 ()2Æ6 to 19Æ5) 3Æ4 ()8Æ8 to 18Æ2) )9Æ7 ()26Æ8 to 5Æ3) )6Æ8 ()18Æ2 to 4Æ1) )4Æ4 ()17Æ1 to 5Æ8) )3Æ1 ()24Æ7 to 10Æ0)
AUC0–24 (HzÆh) 13Æ8 ()4Æ3 to 46Æ3) 10Æ1 ()16Æ6 to 34Æ0) )13Æ1 ()54Æ2 to 14Æ6) )4Æ3 ()26Æ6 to 23Æ7) )10Æ8 ()49Æ2 to 30Æ9) )5Æ1 ()41Æ0 to 30Æ2)
RT, reaction time; CFFT, critical flicker fusion test.
*Difference from fasted condition at P < 0Æ05: significance was tested by paired t-test.
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
36 A. Yamazaki et al.
food on the pharmacokinetics and pharmacodynamics
of quazepam, nitrazepam and diazepam.
As quazepam is characterized by low solubility
and high fat-solubility, with increased absorption
with fatty meals, the absorption of quazepam was
influenced by food intake. Yasui-Furukori et al.
(4, 6) reported that Cmax and AUC of quazepam
increased 2Æ3-fold with a standard breakfast (fat
30Æ2 g; 660 kcal) or low-fat meal (fat 5Æ9 g; 440 kcal).
Kim et al. (7) also reported Cmax of quazepam 1Æ6-
fold higher with food. Dietary fat increases bile
secretion and gastrointestinal fluid volume, providing
a better dissolution medium for poorly dissolving
drugs (1, 2). This effect may explain the
increased Cmax and AUC. However, increased
bioavailability of drugs in the presence of food may
be due not only to fat content but also to protein
and carbohydrate contents (5). The present study
shows that a very low fat meal such a light food
may alter quazepam pharmacokinetics. The 90%
CI of the mean ratio for Cmax and AUClast in fed vs.
fasted subjects overlapped but extended beyond
the 0Æ8–1Æ25 region for bioequivalence (the 90% CIs
of Cmax and AUClast were 1Æ1–1Æ5 and 1Æ3–1Æ9,
respectively) (11). Other pharmacokinetic parameters,
Tmax, t1/2 and MTTlast were not different. This
study used a Japanese traditional healthy bedtime
snack, ‘otyaduke’, as a light food. It is reasonable to
assume that the light food which contained mainly
carbohydrates might increase release of bile salts
and lipolysis products. The presence of food may
also prolong gastric emptying period and increase
splanchnic blood flow.
For oral administration of diazepam, this study
results are similar to those previously observed.
Robert and Leff (12) reported the time to peak
20
30
40
50
60
70
80
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
VAS: mental (mm)
VAS: physical (mm) VAS: physical (mm) VAS: physical (mm)
VAS: mental (mm) VAS: mental (mm)
20
30
40
50
60
70
80
20
30
40
50
60
70
80
M1-Fasted M1-Fed
M2-Fasted M2-Fed
20
30
40
50
60
70
80
P1-Fasted P1-Fed
P2-Fasted P2-Fed
20
30
40
50
60
70
80
20
30
40
50
60
70
80
.
Nitrazepam Nitrazepam
Diazepam Diazepam
Quazepam Quazepam
Fig. 5. Mean visual analogue scores
(VAS) of quazepam, nitrazepam
and diazepam under fasted and fed
conditions. Data are shown as
mental sedation (M1: alert-drowsy
and M2: clear headed-muzzy;
0–100 mm) and physical sedation
(P1: well coordinated-clumsy and
P2: energetic-lethargic; 0–100 mm).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 37
(Tmax) was longer with triglyceride oil 18 g and
6 oz of fat-free milk than with water. Greenblatt
et al. (8) also reported that administration of diazepam
with food resulted in longer Tmax (1Æ2 h).
However the food in this study was not identical.
The Tmax of both nitrazepam and diazepam
increased with food. This effect might be the result
of prolonged gastric emptying time and small
intestinal transit time due to the presence of food.
The major plasma metabolites of quazepam are
2-oxoquazepam, N-desalkyl-2-oxoquazepam, and
3-hydroxy-2-oxoquazepam (13). Quazepam is
metabolized by CYP2C19 (14) as is diazepam to its
major, pharmacologically active plasma metabolite,
N-desmethyl-diazepam (15–18). Nitrazepam is
mainly metabolized to its 7-amino-derivative and
7-acetamino-derivative by acetylation (19), both of
which are pharmacologically inactive (20). These
pathways are known to be polymorphic to 2-oxoquazepam
and N-desalkyl-2-oxoquazepam and
are pharmacologically active (21, 22). Hilbert et al.
(22) reported that brain concentrations of quazepam
and its metabolites paralleled plasma concentrations
following single oral doses in mice. As the pharmacokinetics
of these metabolites were no different
between the fasted and fed conditions, increased
plasma quazepam was probably responsible for the
observed differences in the psychomotor function
tests. Norris (9) reported that nitrazepam (7Æ5 and
10 mg) altered mental sedation on the VAS by
approximately 20–25 mm, and physical sedation by
15–20 mm from the baseline, 80 min after single
administration. Luurila et al. (23) reported that nitrazepam
5 mg altered the drowsiness scale by
approximately 20 mm at 2 h. Nitrazepam and diazepam
both had CNS-depressant effect as assessed
by CFFT in both of the fasted and fed conditions. No
significant difference was seen between the fasted
and fed conditions. Therefore it is reasonable to
assume that the drug can be given with light food as
used in this study. Food with a high fat, protein or
fiber content may yield different results. Greenblatt
et al. (24) reported that with diazepam administered
intravenously, clinical activity, measured using
computerized analysis of the electroencephalogram,
was maximal at the end of the infusion. Because of its
high lipid solubility and extensive peripheral distribution,
diazepam appears to have a short duration
of clinical action after intravenous administration.
For oral administration, the rate-limiting step for the
onset of clinical action generally is attributable to the
rate of absorption. Nitrazepam is also high lipid
soluble. The Tmax of both nitrazepam and diazepam
increased in the fed condition. In conclusion, light
food increased the bioavailability of quazepam and
altered psychomotor performance. Light food also
delayed the Tmax of nitrazepam and diazepam but
had no effect on Cmax and AUClast.
ACKNOWLEDGEMENTS
The authors thank the staff at Kitasato East Hospital,
Clinical trial center for their excellent work
during the clinical conduct of the study, Mr
Yoshimasa Inoue for technical support of HPLC
measurement.
–5
–4
–3
–2
–1
0
1
2
–5
–4
–3
–2
–1
0
1
2
–5
–4
–3
–2
–1
0
1
2
Changed in CFFT (Hz) Changed in CFFT (Hz) Changed in CFFT (Hz)
Fasted
Fed
Fasted
Fed
Fasted
Fed
Quazepam
Nitrazepam
Diazepam
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
Fig. 6. Change in scores from baseline in critical flicker
fusion test (CFFT) of quazepam, nitrazepam and diazepam
under fasted and fed conditions. Data are shown as
mean and SD (n = 7).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
38 A. Yamazaki et al.
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2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 39
Different effects of light food on pharmacokinetics and
pharmacodynamics of three benzodiazepines, quazepam,
nitrazepam and diazepam
A. Yamazaki* MS, Y. Kumagai MD, T. Fujita MD, T. Hasunuma MD, S.Yokota ,
M. Maeda , Y. Otani MD and M. Majima* MD
*Department of Molecular Pharmacology, Kitasato University Graduate School of Medicinal graduate
course, Kanagawa, Clinical Trial Center, Kitasato University East Hospital, Kanagawa and Center for
Clinical Pharmacology, Kitasato Institute, Kanagawa, Japan
SUMMARY
Objective: Quazepam, nitrazepam and diazepam
are administered under fed or fasted conditions
for insomnia or anxiety disorder. Light bedtime
food may have clinically relevant effects on the
plasma levels of those drugs and hence on psychomotor
performance. This study assessed the
effect of light food on the pharmacokinetics and
pharmacodynamics of these drugs.
Method: Twenty-one eligible subjects were
randomized to one of three groups of seven subjects:
quazepam 20 mg, diazepam 5 mg or nitrazepam
5 mg. Each healthy subject took a single
oral dose of the assigned drug after overnight
fasting and after light food, on a separate occasion.
Blood samples were collected until 72 h
after dosing. The plasma samples were assayed
using high-pressure liquid chromatography with
spectrophotometric detection. Reaction time,
critical flicker fusion test and visual analogue
scales were conducted.
Results: The peak plasma concentration (Cmax)
and area under the concentration–time curve
(AUC) of quazepam with light food were 1Æ2-fold
[90% confidence interval (CI): 1Æ1–1Æ5; P < 0Æ05]
and 1Æ5-fold (90% CI: 1Æ3–1Æ9; P < 0Æ05) higher
than that without light food, respectively. For
nitrazepam and diazepam, the time to peak was
delayed about 1 h in fed condition (P > 0Æ05).
However it had no effect on their Cmax and AUC.
Reaction time of quazepam with light food was
prolonged at 4 and 6 h after dosing and its area
under the effect–time curve from 0 to 10 h was
increased (P < 0Æ05).
Conclusion: Light food increased the bioavailability
of quazepam and affected psychomotor
performance. Light food delayed Tmax of nitrazepam
and diazepam but had no effect on Cmax and
AUC.
Keywords: benzodiazepine, food–drug interactions,
pharmacodynamics, pharmacokinetics
INTRODUCTION
Quazepam, nitrazepam and diazepam are benzodiazepine
drugs used in insomnia or anxiety disorder.
Food may have significant effects on the
bioavailability of various drugs (1, 2). Quazepam,
nitrazepam and diazepam are highly lipophillic (3,
4) and their absorption is often enhanced by food
(1). Increased bioavailability of drugs have been
reported not only with fatty meals but also with
protein or carbohydrate meals (5). Therefore, a very
low fat meal or a light food such as a bed-time
snack may interact with these benzodiazepines.
The effect of food on the pharmacokinetics of
quazepam have been reported by Yasui-Furukori
et al. (4, 6) and Kim et al. (7). However, the effect of
light food such as a bed time snack on the drug’s
pharmacokinetics and pharmacodynamics is not
known. There is also little information on the effects
of food on oral diazepam and published studies
have used a variety of foods (8). Furthermore, oral
Received 2 June 2006, Accepted 26 November 2006
Correspondence: Akira Yamazaki, Department of Molecular
Pharmacology, Kitasato University Graduate School of Medicinal
graduate course, 1-15-1 Kitasato, Sagamihara, Kanagawa
2288555, Japan. Tel.: +81 42 778 8111; fax: +81 42 778 8111;
e-mail: yamazaa@jcom.home.ne.jp
Journal of Clinical Pharmacy and Therapeutics (2007) 32, 31–39
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd 31
nitrazepam has not been assessed for the possibility
of drug–food interaction. Therefore, we evaluated
the effect of light food on the pharmacokinetics and
pharmacodynamics of quazepam, nitrazepam and
diazepam in healthy subjects.
MATERIALS AND METHODS
Materials
Doral tablets (20 mg quazepam), Benzalin tablets
(5 mg nitrazepam) and Cercine tablets (5 mg diazepam)
were purchased from Mitsubishi Pharma
Corporation (Osaka, Japan), Shionogi & Co., Ltd
(Osaka, Japan) and Takeda Pharmaceutical Company
Ltd (Osaka, Japan), respectively. The light
food was used a Japanese traditional healthy bedtime
snack, ‘otyaduke’ which is cooked as follows:
boiled rice 100 g sprinkled with ‘otyadukenori’ 6 g
(Nagatanien Co., Ltd, Tokyo, Japan) was poured
150 mL of hot water. Otyadukenori consisted of
sodium, cubic rice crackers and dried seaweed
flakes. It contained approximately 166 kcal (0Æ44 g
lipid, 37Æ8 g carbohydrates, 2Æ7 g protein and
sodium 1Æ9 mg).
Study design and clinical protocol
This study was approved by the institutional
review board at Kitasato East hospital and all
subjects provided written informed consent prior
to any study procedures. Twenty-one healthy male
volunteers between the ages of 20 and 33 years
(22Æ5 ± 2Æ9) and body mass index within 18Æ9–
26Æ6 kg/m2 (21Æ6 ± 2Æ3) were enrolled for the study.
Study subjects were determined to be healthy by a
complete medical history, physical examination,
alcohol and drug abuse history, vital signs, 12-lead
electrocardiogram, and laboratory tests, serologic
test for syphilis and virology tests (HIV, hepatitis B
and hepatitis C). Subjects were excluded if they
had any of the following: subjects with evidence of
donation of blood more than 200 mL within
1 month or more than 400 mL within 3 months
before this study; subjects who were enrolled in
any other clinical study within 4 months prior to
this study; subjects predisposed to drug hypersensitivity
reactions; subjects who were considered
unsuitable for participation in this study by the
investigator.
This was a randomized, parallel dosing, twoway
crossover, single-dose study in 21 healthy men
with a 2-week washout between the drug administrations.
Twenty-one eligible subjects were randomized
to one of three cohort groups (seven
subjects each): (i) a single 20 mg tablet of quazepam,
(ii) a single 5 mg tablet of diazepam, and (iii)
a single 5 mg tablet of nitrazepam.
Eligible subjects were admitted to the study site
on the day before dose administration on each of
the two treatment periods. The subjects slept at
least 8 h before the start of each study session. The
subjects received a study drug with 200 mL of
water 30 min after the light food and under fasting
condition. The subjects and persons in charge of
psychomotor function tests were not aware of
which study drug was administered to the subjects.
The pharmacist who administered the study drug
to the subjects was unblinded to it. Blood was
collected at pre-dose and at 0Æ5, 1, 2, 3, 4, 5, 6, 8, 12,
24, 48 and 72 h after dosing. All subjects fasted for
at least 10 h before and until 4 h after dosing. All
subjects received a standardized lunch and supper
4 and 10 h after dosing, respectively. The volunteers
were not allowed to use any medication
within 24 h preceding the treatment as well as
during the entire study. Alcohol, caffeine, cola,
beverage including grapefruit and smoking was
prohibited for 12 h prior to and following drug
administration. The volunteers had to avoid
excessive physical exercise throughout the study.
Analytical procedures
The plasma samples were assayed using high-pressure
liquid chromatography with spectrophotometric
detection (HPLC/UV) and column switching.
Quazepam and its metabolite 2-oxoquazepam,
N-desmethyl-2-oxoquazepam and cisapride as an
internal standard were supplied by Mitsubishi
Pharma Corporation. Diazepam and its metabolite
N-desmethyl-diazepam and nitrazepam were purchased
from Sigma–Aldrich Japan K.K. (Tokyo,
Japan).
The plasma samples were assayed for quazepam,
2-oxoquazepam, N-desmethyl-2-oxoquazepam.
After sample alkalization with 0Æ5 mL of
NaOH (0Æ05 mol/L), the test compound and internal
standard, cisapride, were extracted from
plasma using toluene-n-heptane (15 : 85, v/v). The
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
32 A. Yamazaki et al.
organic phase was evaporated to dryness and the
residue was dissolved with 800 lL of mobile phase.
The clean-up and preconcentration of sample
(500 lL) was performed on C8 TSK-BSA (5 lm,
10 · 4Æ6 mm ID) pretreatment column from Tosoh
Corporation, Tokyo, Japan. The mobile phase consisted
of acetnitrile and phosphate buffer
(0Æ02 mol/L, pH 4Æ6) (13 : 87, v/v) and was delivered
at a flow rate of 1Æ2 mL/min. Subsequent
separations were carried out on C18 STR ODS-II
analytical column (5 lL, 150 · 4Æ6 mm ID, Shimadzu
Techno-Research Inc., Tokyo, Japan) analytical
column. The mobile phase consisted of
acetnitrile and phosphate buffer (0Æ02 mol/L, pH
4Æ6) (13 : 87, v/v) for quazepam and 2-oxoquazepam,
and acetnitrile, perchloric acid (6 mol/L) and
phosphate buffer (0Æ02 mol/L, pH 4Æ6)
(41Æ5 : 0Æ05 : 58Æ45, v/v/v) for N-desmethyl-2-oxoquazepam
and was delivered at a flow rate of
0Æ6 mL/min. The peak was detected using a UV
detector set at 286 nm for diazepam and 254 nm for
metabolite. Relative errors at 30 ng/mL of quazepam,
2-oxoquazepam, N-desmethyl-2-oxoquazepam
were 2Æ5%, 3Æ9% and 2Æ6%, respectively. The
limit of quantification was 0Æ7 ng/mL for each
compound.
The plasma samples for nitrazepam, diazepam
and N-desmethyl-diazepam were assayed by same
method except the following. The samples were
alkalized with 0Æ5 mL of NaOH (0Æ5 mol/L) for
nitrazepam assay, and with 0Æ5 mL NaOH
(0Æ01 mol/L) for diazepam and N-desmethyl-diazepam.
Relative errors at 15 ng/mL of nitrazepam,
diazepam and N-desmethyl-diazepam were 3Æ2%,
2Æ9% and 2Æ9%, respectively. The limit of quantification
was 0Æ8 ng/mL for each compound.
Pharmacodynamic measures
Psychomotor function tests were conducted before
and 2, 4, 6, 10 and 24 h after drug administration.
The subject’s agility and ability to react from
cognition to movement was assessed using reaction
time (RT). Subjects were required to press an
electrical switch, when a yellow light flashed. The
special equipment consisted of a light stimulus
generator (T.T.K.331), a digital timer (T.T.K.315), a
push-button switch set and a selective reaction
control (T.T.K.333) (Takei Scientific Instruments
Co., Niigata, Japan). This produced random
sequences of three-colour stimuli (yellow, red and
blue light). The RTs and the computed average RT
of 10 stimuli were calculated at each point. Critical
Flicker Fusion Test (CFFT) assessed the subject’s
wakefulness and degree of fatigue. The score was
determined by measuring the frequency for distinguishing
the flicker from 12 runs of ascending
and 12 runs of descending frequencies. Lightemitting
diodes (Leeds Flicker Fusion Tester Type
II, T.T.K.501.b; Takei Scientific Instruments Co.)
produced the stimuli. The seated subjects peered
through a cylindrical tube to see the flickers with
both eyes in a quiet room. Subjects were required
to depress an electrical switch, when flicker fusion
(continuous lighting) was observed for ascending
CFFT or continuous lighting flickering for descending
CFFT. The number of flicks per second
(Hz) was recorded. Visual analogue scales (VAS)
were used to subjectively rate sedation using 0–
100 mm VAS, as described by Norris (9), and
Bond and Lader (10). In this study the six indicators
were selected to assess three domains of
sedation with two indicators each: mental sedation
(alert–drowsy and clear headed–muzzy),
tranquilization (calm–excited and relaxed–tense),
and physical sedation (well coordinated–clumsy
and energetic–lethargic).
Pharmacokinetic and pharmacodynamic analysis
Individual plasma concentration–time profiles was
analysed by using a non-compartmental method,
using WINNONLIN (Pharsight Corporation, Mountain
View, CA, USA). The following parameters were
obtained: Cmax and Tmax were determined from
observed data. Area under the plasma concentration–
time curve from time zero to the last quantifiable
concentration (AUClast) was determined by the
linear trapezoidal rule. The terminal rate constant
(kel) was determined by linear regression of the
terminal linear portion of the ln concentration–time
curve. The terminal half-life (t1/2) was calculated as
ln/kel. The mean transit time (MTT) was calculated
as the area under the first moment curve (AUMC)/
AUC. AUMC was determined by the linear trapezoidal
rule, and the following pharmacodynamic
parameters were obtained: the area under the
effect–time curve (AUC) was determined by the
trapezoidal rule from 0 to 10 h and from 0 to 24 h
for RT and CFFT. For RT and VAS, a raw score was
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 33
used. The CFFT variables were assessed by changed
scores from baseline.
Statistical analysis
Differences in pharmacokinetic parameters (excluding
Tmax) and pharmacodynamic parameters (RT
and CFFT) were evaluated using a paired t-test.
Differences in Tmax were evaluated using Wilcoxon’s
matched-pairs signed ranks. VAS was not
evaluated statistically due to the large inter-individual
variance. Each pharmacodynamic parameter
at each time point was used for statistical
analysis for comparing fed and fasting states. Differences
were considered significant when
P < 0Æ05. The 90% confidence intervals (CIs) of the
fed/fasting ratios for Cmax and AUClast (log transformed)
were determined.
RESULTS
Pharmacokinetics
Mean plasma concentration–time profiles of quazepam
following single-dose oral administration
are illustrated in Fig. 1. Relevant pharmacokinetic
parameters corresponding to the plasma concentration
profiles are listed in Table 1. It is seen that
the plasma concentration–time profiles of quazepam
between fasting and fed conditions are different.
The 90% CIs of ratios for Cmax and AUClast
were 1Æ1–1Æ5 and 1Æ3–1Æ9, respectively, for the fed
relative to the fasted state indicating that the rate
and the extent of quazepam absorption were
increased when administered with food. Similar
results were found using the paired t-test (P < 0Æ05).
Other pharmacokinetic parameters, Tmax, t1/2 and
MTTlast, did not change significantly. Contrary to
the parent compound, its metabolites, 2-oxoquazepam
and N-desmethy-2-oxoquazepam were not
significantly different between fasted and fed conditions,
except t1/2 of 2-oxoquazepam (Table 1).
For nitrazepam and diazepam, mean plasma
concentration–time profiles following single-dose
oral administration are illustrated in Figs 2 and 3.
There were no significant differences between
the fed and fasting states with regard to Cmax and
AUClast (P > 0Æ05). The 90% CIs of ratios for Cmax
Table 1. Pharmacokinetic parameters (mean ± SD) for quazepam and its metabolites under fasted and fed conditions
(n = 7)
Quazepam 2-Oxoquazepam N-desmethyl-2-oxoquazepam
Fasted Fed Fasted Fed Fasted Fed
Cmax (ng/mL) 44Æ7 ± 38Æ0 52Æ8 ± 36Æ9* 21Æ2 ± 5Æ3 21Æ9 ± 5Æ8 35Æ7 ± 9Æ7 32Æ6 ± 9Æ4
Ratio; 90% CI 1Æ2; 1Æ1–1Æ5 1Æ0; 0Æ9–1Æ2 0Æ9; 0Æ9–1Æ4
Tmax (h) 2 (2–3) 2 (2–4) 3 (2–4) 3 (2–4) 24 (8–24) 12 (12–48)
AUClast (ngÆh/mL) 291 ± 181 445 ± 227* 168 ± 48 174 ± 57 2237 ± 639 2019 ± 604
Ratio; 90% CI 1Æ5; 1Æ3–1Æ9 1Æ0; 0Æ8–1Æ3 0Æ9; 0Æ9–1Æ3
t1/2 (h) 14Æ3 ± 4Æ8 16Æ8 ± 4Æ4 17Æ6 ± 4Æ3 14Æ2 ± 4Æ4* NA NA
MTTlast (h) 10Æ0 ± 2Æ3 12Æ1 ± 1Æ6 11Æ2 ± 2Æ8 10Æ7 ± 3Æ0 10Æ0 ± 2Æ3 12Æ1 ± 1Æ6
For Cmax and AUClast, 90% confidence intervals (CIs) are determined for the ratios between fed and fasting states. Tmax is reported as
median and range. NA = not applicable.
*Difference from fasted condition at P < 0Æ05: significance was tested by paired t-test, except Tmax was tested by Wilcoxon’s matchedpairs
signed ranks.
0
10
20
30
40
50
60
70
0 5 10 15 20 25
Hours
Plasma quazepam (ng/mL)
Fasted
Fed
Fig. 1. Plasma concentration of quazepam after oral
administration of 20 mg quazepam under fasted and fed
conditions. Data are shown as mean and SEM (n = 7).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
34 A. Yamazaki et al.
and AUClast of nitrazepam were 1Æ0–1Æ1 and 0Æ9–1Æ1,
and those of diazepam were 0Æ9–1Æ1 and 1Æ0–1Æ2
(Table 2). Comparison of Tmax, however, indicated
that there was a statistically significant increase in
Tmax in the fed vs. fasted state (P > 0Æ05). Both Tmax of
nitrazepam and diazepam were delayed about 1 h in
fed condition (Table 2). Elimination half-life and
MTTlast did not change upon food ingestion either
for nitrazepam or diazepam. N-desmethyl-diazepam
was not significantly difference between fasted
and fed conditions. The plasma concentration of
N-desmethyl-diazepam continuously increased up
to the last sampling point.
Pharmacodynamics
Quazepam, nitrazepam and diazepam had CNSdepressant
effect assessed by several psychomotor
function tests up to 24 h after drug administration.
For quazepam, food produced significant changes
on RT (Fig. 4). RT was prolonged at 4 and 6 h after
dosing in fed condition (P < 0Æ05). The AUC0–10 of
RT was significant different between the fasted and
fed conditions (P < 0Æ05) (Table 3). Subjects seemed
drowsier at 2 h in the fed condition (alert–drowsy
and clear headed–muzzy) of VAS (Fig. 5). There
were no differences in the other pharmacodynamic
measures of quazepam between the two conditions.
For nitrazepam and diazepam, RT and CFFT
showed no significant differences between the
fasted and fed conditions (Figs 4 and 6). On mental
sedation VAS and CFFT, subjects who were
Table 2. Pharmacokinetic parameters (mean ± SD) for nitrazepam, and diazepam and its metabolites under fasted and
fed conditions (n = 7)
Nitrazepam Diazepam N-desmethyl-diazepam
Fasted Fed Fasted Fed Fasted Fed
Cmax (ng/mL) 51Æ8 ± 4Æ6 52Æ0 ± 4Æ9 109Æ9 ± 28Æ4 107Æ0 ± 25Æ4 33Æ0 ± 7Æ8 29Æ9 ± 10Æ 2
Ratio; 90% CI 1Æ0; 1Æ0–1Æ1 1Æ0; 0Æ9–1Æ1 0Æ9; 1Æ0–1Æ4
Tmax (h) 1 (1–2) 2 (0Æ5–2)* 1 (0Æ5–2) 2 (1–3)* 72 (48–72) 72 (72–72)
AUClast (ngÆh/mL) 1401 ± 370 1383 ± 284 2411 ± 842 2272 ± 819 1911 ± 488 1732 ± 580
Ratio; 90% CI 1Æ0; 0Æ9–1Æ1 0Æ9; 1Æ0–1Æ2 0Æ9; 0Æ9–1Æ4
t1/2 (h) 37Æ2 ± 5Æ3 35Æ1 ± 5Æ4 38Æ3 ± 12Æ5 38Æ2 ± 12Æ7 NA NA
MTTlast (h) 26Æ1 ± 1Æ0 25Æ8 ± 1Æ0 25Æ6 ± 1Æ7 25Æ0 ± 2Æ2 41Æ1 ± 1Æ9 40Æ7 ± 1Æ4
For Cmax and AUClast, 90% confidence intervals (CIs) are determined for the ratios between fed and fasting states. Tmax is reported as
median and range. NA, not applicable.
*Difference from fasted condition at P < 0Æ05: significance was tested by paired t-test, except Tmax was tested by Wilcoxon’s matchedpairs
signed ranks.
Plasma diazepam (ng/mL)
0 5 10 15 20 25
Hours
0
20
40
60
80
120
100 Fasted
Fed
Fig. 3. Plasma concentration of diazepam after oral
administration of 5 mg diazepam under fasted and fed
conditions. Data are shown as mean and SEM (n = 7).
Plasma nitrazepam (ng/mL)
0 5 10 15 20 25
Hours
0
10
20
30
40
50
60
Fasted
Fed
Fig. 2. Plasma concentration of nitrazepam after oral
administration of 5 mg nitrazepam under fasted and fed
conditions. Data are shown as mean and SEM (n = 7).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 35
administered nitrazepam seemed drowsier at 2 h
in both fasted and fed condition. Subjects who were
administered diazepam did not show this effect.
The tranquillization score VAS was not significantly
altered for any of the three drugs. Among
these drugs, the mental sedation VAS increased at
2 h in subjects who were administered quazepam
in fed condition and nitrazepam in both fed and
fasted conditions when compared with subjects
who were administered diazepam. Quazepam with
light food increased RT while nitrazepam
decreased the CFFT in both condition.
DISCUSSION
This study is a randomized, parallel dosing, twoway
crossover study to evaluate the effect of light
100
150
200
250
300
350
Reaction time (ms) Reaction time (ms) Reaction time (ms)
Fasted
Fed
100
150
200
250
300
350 Fasted
Fed
100
150
200
250
300
350 Fasted
Fed
Quazepam
Nitrazepam
Diazepam
*
*
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
Fig. 4. Reaction time of quazepam, nitrazepam and
diazepam under fasted and fed conditions. Data are
shown as mean and SD (n = 7). *Difference from fasted
condition at P < 0Æ05.
Table 3. Pharmacodynamic parameters (mean and range) for quazepam, nitrazepam and diazepam under fasted and fed conditions (n = 7)
Quazepam Nitrazepam Diazepam
Fasted Fed Fasted Fed Fasted Fed
RT
AUC0–10 (msÆh) 2275 (1912–2516) 2514* (2365–2686) 2510 (1869–3551) 2426 (2089–2890) 2343 (1979–2763) 2419 (1958–3157)
AUC0–24 (msÆh) 5496 (4766–6287) 5685 (5319–6285) 5714 (4300–7762) 5747 (4934–7202) 5482 (4927–6268) 5725 (4983–7355)
CFFT
AUC0–10 (HzÆh) 3Æ5 ()2Æ6 to 19Æ5) 3Æ4 ()8Æ8 to 18Æ2) )9Æ7 ()26Æ8 to 5Æ3) )6Æ8 ()18Æ2 to 4Æ1) )4Æ4 ()17Æ1 to 5Æ8) )3Æ1 ()24Æ7 to 10Æ0)
AUC0–24 (HzÆh) 13Æ8 ()4Æ3 to 46Æ3) 10Æ1 ()16Æ6 to 34Æ0) )13Æ1 ()54Æ2 to 14Æ6) )4Æ3 ()26Æ6 to 23Æ7) )10Æ8 ()49Æ2 to 30Æ9) )5Æ1 ()41Æ0 to 30Æ2)
RT, reaction time; CFFT, critical flicker fusion test.
*Difference from fasted condition at P < 0Æ05: significance was tested by paired t-test.
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
36 A. Yamazaki et al.
food on the pharmacokinetics and pharmacodynamics
of quazepam, nitrazepam and diazepam.
As quazepam is characterized by low solubility
and high fat-solubility, with increased absorption
with fatty meals, the absorption of quazepam was
influenced by food intake. Yasui-Furukori et al.
(4, 6) reported that Cmax and AUC of quazepam
increased 2Æ3-fold with a standard breakfast (fat
30Æ2 g; 660 kcal) or low-fat meal (fat 5Æ9 g; 440 kcal).
Kim et al. (7) also reported Cmax of quazepam 1Æ6-
fold higher with food. Dietary fat increases bile
secretion and gastrointestinal fluid volume, providing
a better dissolution medium for poorly dissolving
drugs (1, 2). This effect may explain the
increased Cmax and AUC. However, increased
bioavailability of drugs in the presence of food may
be due not only to fat content but also to protein
and carbohydrate contents (5). The present study
shows that a very low fat meal such a light food
may alter quazepam pharmacokinetics. The 90%
CI of the mean ratio for Cmax and AUClast in fed vs.
fasted subjects overlapped but extended beyond
the 0Æ8–1Æ25 region for bioequivalence (the 90% CIs
of Cmax and AUClast were 1Æ1–1Æ5 and 1Æ3–1Æ9,
respectively) (11). Other pharmacokinetic parameters,
Tmax, t1/2 and MTTlast were not different. This
study used a Japanese traditional healthy bedtime
snack, ‘otyaduke’, as a light food. It is reasonable to
assume that the light food which contained mainly
carbohydrates might increase release of bile salts
and lipolysis products. The presence of food may
also prolong gastric emptying period and increase
splanchnic blood flow.
For oral administration of diazepam, this study
results are similar to those previously observed.
Robert and Leff (12) reported the time to peak
20
30
40
50
60
70
80
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
0 2 4 6 8 10
Hours
VAS: mental (mm)
VAS: physical (mm) VAS: physical (mm) VAS: physical (mm)
VAS: mental (mm) VAS: mental (mm)
20
30
40
50
60
70
80
20
30
40
50
60
70
80
M1-Fasted M1-Fed
M2-Fasted M2-Fed
20
30
40
50
60
70
80
P1-Fasted P1-Fed
P2-Fasted P2-Fed
20
30
40
50
60
70
80
20
30
40
50
60
70
80
.
Nitrazepam Nitrazepam
Diazepam Diazepam
Quazepam Quazepam
Fig. 5. Mean visual analogue scores
(VAS) of quazepam, nitrazepam
and diazepam under fasted and fed
conditions. Data are shown as
mental sedation (M1: alert-drowsy
and M2: clear headed-muzzy;
0–100 mm) and physical sedation
(P1: well coordinated-clumsy and
P2: energetic-lethargic; 0–100 mm).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 37
(Tmax) was longer with triglyceride oil 18 g and
6 oz of fat-free milk than with water. Greenblatt
et al. (8) also reported that administration of diazepam
with food resulted in longer Tmax (1Æ2 h).
However the food in this study was not identical.
The Tmax of both nitrazepam and diazepam
increased with food. This effect might be the result
of prolonged gastric emptying time and small
intestinal transit time due to the presence of food.
The major plasma metabolites of quazepam are
2-oxoquazepam, N-desalkyl-2-oxoquazepam, and
3-hydroxy-2-oxoquazepam (13). Quazepam is
metabolized by CYP2C19 (14) as is diazepam to its
major, pharmacologically active plasma metabolite,
N-desmethyl-diazepam (15–18). Nitrazepam is
mainly metabolized to its 7-amino-derivative and
7-acetamino-derivative by acetylation (19), both of
which are pharmacologically inactive (20). These
pathways are known to be polymorphic to 2-oxoquazepam
and N-desalkyl-2-oxoquazepam and
are pharmacologically active (21, 22). Hilbert et al.
(22) reported that brain concentrations of quazepam
and its metabolites paralleled plasma concentrations
following single oral doses in mice. As the pharmacokinetics
of these metabolites were no different
between the fasted and fed conditions, increased
plasma quazepam was probably responsible for the
observed differences in the psychomotor function
tests. Norris (9) reported that nitrazepam (7Æ5 and
10 mg) altered mental sedation on the VAS by
approximately 20–25 mm, and physical sedation by
15–20 mm from the baseline, 80 min after single
administration. Luurila et al. (23) reported that nitrazepam
5 mg altered the drowsiness scale by
approximately 20 mm at 2 h. Nitrazepam and diazepam
both had CNS-depressant effect as assessed
by CFFT in both of the fasted and fed conditions. No
significant difference was seen between the fasted
and fed conditions. Therefore it is reasonable to
assume that the drug can be given with light food as
used in this study. Food with a high fat, protein or
fiber content may yield different results. Greenblatt
et al. (24) reported that with diazepam administered
intravenously, clinical activity, measured using
computerized analysis of the electroencephalogram,
was maximal at the end of the infusion. Because of its
high lipid solubility and extensive peripheral distribution,
diazepam appears to have a short duration
of clinical action after intravenous administration.
For oral administration, the rate-limiting step for the
onset of clinical action generally is attributable to the
rate of absorption. Nitrazepam is also high lipid
soluble. The Tmax of both nitrazepam and diazepam
increased in the fed condition. In conclusion, light
food increased the bioavailability of quazepam and
altered psychomotor performance. Light food also
delayed the Tmax of nitrazepam and diazepam but
had no effect on Cmax and AUClast.
ACKNOWLEDGEMENTS
The authors thank the staff at Kitasato East Hospital,
Clinical trial center for their excellent work
during the clinical conduct of the study, Mr
Yoshimasa Inoue for technical support of HPLC
measurement.
–5
–4
–3
–2
–1
0
1
2
–5
–4
–3
–2
–1
0
1
2
–5
–4
–3
–2
–1
0
1
2
Changed in CFFT (Hz) Changed in CFFT (Hz) Changed in CFFT (Hz)
Fasted
Fed
Fasted
Fed
Fasted
Fed
Quazepam
Nitrazepam
Diazepam
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
0 5 10 15 20 25
Hours
Fig. 6. Change in scores from baseline in critical flicker
fusion test (CFFT) of quazepam, nitrazepam and diazepam
under fasted and fed conditions. Data are shown as
mean and SD (n = 7).
2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
38 A. Yamazaki et al.
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2007 The authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 31–39
Food and benzodiazepines interactions 39
miércoles, 18 de mayo de 2011
miércoles, 11 de mayo de 2011
Death proof
Tremenda película, definitivamente fue una muy buena unión tarantino-rodriguez salio muy bien realizado el tema grindhouse. Todo esto es pa que no se me olvide
domingo, 8 de mayo de 2011
ESTUDIAR
Por la conchemimare, mi vecino tiene una moto culia mas ruidosa que la chucha y quiero estudiar!!
LA IDEA ES APRENDER
Tras una reunión con la directiva del Colegio de Químico Farmacéuticos, el titular del Minsal señaló que esta agencia comenzará a funcionar en el ámbito del Instituto de Salud Pública, pero "va a estar amparado por una ley completamente independiente, nueva, está destinada a establecer garantías de calidad y generar acceso a medicamentos de calidad al menor costo posible"; De que modo es producente para la sociedad de la salud el enviar proyectos que si de cierta forma son útiles, pero definitivamente no atienden a un problema real y facto que se vive hoy en día en la comunidad farmacéutica, lo que trato de de decir es que hoy en día debemos luchar por crean una entidad que nos anexe definitivamente de las grandes cadenas y oligopolios comerciales que de nada ayudan a la labor de sanar y tratar solo son entidades que ademas de lucrar con los problemas de la salud, tienen como por objetivo un bien máximo para un numero reducido de personas, los cueles están al mando completo de una industria.
Hablo de que los controles de calidad internacionales son eficaces y que en chile los métodos analiticos son de igual forma positivos, entonces para que crear una entidad encargada del control de medicamentos si estos serán dirigidos por los mismos "mandamases" de siempre solo para aparentar un control no monodirigido y solo se utiliza de pantalla. Deberás creo que las ideas, opciones, "agencias" y plataformas de discusión deben estar 100% enfocadas en cambiar la imagen cliente-paciente, que estar redundando en huevadas que parecen ser innovadoras pero la verdad es que solo son una fachada para decir estamos "trabajando" y así dejan de lado las cosas que realmente son importantes. dicen que con esta agencia se reducirán los precios a publico de los medicamentos. Yo les diré como se pueden bajar los precios de medicamentos, solo el puto gobierno tiene que apoyar a las compañías emprendedoras y crear mayor competencia y competencia eficaz con esto aumenta la cantidad demanda y disminuyen los precios por competencia, solo tienen que disminuir la barrera de entrada en el mercado de los medicamentos y listo. preocúpense de dar atención de calidad en las farmacias y eso se logra no vendiendo el fármaco mas caro sino tratando bien a una persona que entra como cliente pero debe salir como paciente, lo cual evidentemente no sucede, es por esto que protesto por que las grandes compañías y el colegio de químicos farmacéuticos no den mas jugo y que de por si se entienda que lo importante es realzar el nombre de los QUÍMICOS FARMACÉUTICOS como una carrera del área de la salud y no del área comercial como se hace ver ante la atenta mirada del hoy cliente y futuro paciente.
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