See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/225466155

In vitro studies of the interaction between cetirizine and H2 receptor

antagonists using spectrophotometry and reversed-phase high-performance
liquid chromatography

Article in Medicinal Chemistry Research · April 2010

DOI: 10.1007/s00044-009-9204-x

CITATIONS READS

10 491

3 authors, including:

Najma Sultana Mohammed Saeed Arayne

University of Karachi University of Karachi
461 PUBLICATIONS 4,558 CITATIONS 452 PUBLICATIONS 4,390 CITATIONS

SEE PROFILE SEE PROFILE

All content following this page was uploaded by Najma Sultana on 26 May 2014.

The user has requested enhancement of the downloaded file.

Med Chem Res
MEDICINAL
DOI 10.1007/s00044-009-9204-x
CHEMISTRY
RESEARCH
ORIGINAL RESEARCH

In vitro studies of the interaction between cetirizine

and H2 receptor antagonists using spectrophotometry
and reversed-phase high-performance liquid
chromatography

Najma Sultana Æ M. Saeed Arayne Æ Hina Shamshad

Received: 1 February 2009 / Accepted: 20 March 2009

Ó Birkhäuser Boston 2009

Abstract Cetirizine, a second-generation H1 receptor antagonist, is used for the

treatment of allergic disorders. For some of these diseases, combined H1 and H2
therapy generally is more effective than treatment exclusively with H1 or H2,
although this synergistic effect has not been found in all studies. Moreover,
extensive in vivo studies have investigated the effects that the coadministration of
the H2 receptor antagonists have on the pharmacokinetics and pharmacodynamics of
the H1 receptor antagonists. The current study therefore adopted an in vitro
approach to investigate the interaction of cetirizine with commonly administered H2
receptor antagonists (i.e., cimetidine, ranitidine, and famotidine) in simulating body
fluids at different pH levels and at 37°C using reversed-phase high-performance
liquid chromatography (RP-HPLC) and ultraviolet (UV) spectrophotometry. An RP-
HPLC method also was developed and validated for the simultaneous determination
of these drugs. The mobile phase consisted of methanol:water (80:20) pumped at a
flow rate of 1 mL/min. The chromatogram was monitored at 230 nm. The results
from the UV spectrophotometry and RP-HPLC clearly indicated that the availability
of cetirizine was unaffected by simultaneous administration of H1 and H2 receptor
antagonists. Hence the two drugs can be safely administered with one another.

Keywords Cetirizine
H1 receptor antagonist
H2 receptor antagonist

HPLC
UV spectrophotometry

N. Sultana (&)
H. Shamshad

Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy,
University of Karachi, Karachi 75270, Pakistan
e-mail: dr.najma9@gmail.com

M. Saeed Arayne
Department of Chemistry, University of Karachi, Karachi 75270, Pakistan
 Med Chem Res

Introduction

Cetirizine dihydrochloride (RS)-2-[2-[4-[(4-chlorophenyl) phenyl methyl)] pipera-

zin-1-yl] ethoxy] acetic acid dihydrochloride (Fig. 1) (European Pharmacoepia,
2000) has ionization and lipophilicity behavior and can directly dissolve into the
cell membrane and stabilize it. It is supposed that it inhibits the DNA binding
activity of NF-kappa B (Hayashi and Hashimoto, 1999), which plays a pivotal role
in the expression of inflammatory cytokines, chemokines, adhesion molecules, and
inflammatory mediators (Virag and Szabo, 2002).
For most of the allergic diseases (wheal and flare urticaria and dermatographism),
findings have shown that concomitant administration of an H1 receptor antagonist
with an H2 receptor antagonist is more effective than the administration of an H1
antagonist or an H2 antagonist alone (Johnson et al., 1984; Marks and Greaves,
1977; Nathan et al., 1981; Smith et al., 1979). Furthermore, it also has been
observed that combined pretreatment with H1 and H2 antagonists caused a greater
inhibition of histamine-induced nasal blockage than did H1 antagonism alone
(Baker et al., 1996; Havas et al., 1986; Secher et al., 1982; Taylor et al., 2005). It
appears that another non-H1/H2 pathway is responsible for the residual nasal
blockage, suggesting some degree of interaction between the H1 and H2 mediated
pathways (Howarth et al., 2000).
Few studies have demonstrated an effective reduction of objectively measured
nasal blockage with the combination of H1 and H2 antagonists (Holmberg et al.,
1989; Wang et al., 1996). Several interactions of H2 receptor antagonists have
already been reported (Arayne et al., 2008a, b).
Several ultraviolet (UV) spectrophotometric and high-performance liquid
chromatography (HPLC) methods have been reported for determining cetirizine
(Arayne et al., 2005; Gowekar et al., 2007; Sultana et al., 2008) and H2 receptor
antagonists (Akhtar et al., 2008; Ashirua et al., 2007) in bulk, dosage formulations,
and human serum. However, no method for simultaneous determination of the drugs
in both active and dosage formulations has been studied to date.
It therefore became apparent that a method for estimating these drugs in bulk
material, dosage formulations, and human serum simultaneously needed to be
developed and validated using reversed-phase HPLC (RP-HPLC). This validated
method also was used to study the possible in vitro interaction of cetirizine with H2
receptor antagonists (cimetidine, ranitidine, and famotidine) in different simulated

Cl O CO 2 H
N

.2 H Cl

Cetirizine dihydrochloride

Fig. 1 Cetirizine dihydrochloride

Med Chem Res

body environments. In addition, a UV-visible spectrophotometer was used to lend

further support to the results of an in vitro study examining cetirizine interaction
with H2 receptor antagonists.
Several problems were resolved in the simultaneous determination of the
compounds investigated. The first was the selection of separation conditions to
ensure efficient extraction of the two drugs as well as the internal standard from
human serum with minimum interference from serum endogenous compounds. The
second problem was the choice of proper chromatographic conditions to obtain
separation of the three components from the endogenous compounds.

Experimental procedure

Materials

The antihistamine cetirizine dihydrochloride (Zyrtec 10 mg) and the H2 receptor

antagonists cimetidine (Ulcerax 400 mg), famotidine (Hiler 20 mg), ranitidine
(Nulcer 150 mg), and internal standard propylparaben of pharmaceutical purity
were obtained from various pharmaceutical companies. The methanol used was of
HPLC grade. All the reagents used were of analytical grade including hydrochloric
acid (E. Merck), potassium chloride, sodium hydroxide, potassium dihydrogen
orthophosphate, and orthophosphoric acid (E. Merck). Deionized water was freshly
prepared in the laboratory.

Equipment

The electrical balance (Mettler Toledo #AB54, Columbus, USA), pH meter (Mettler
Toledo MP 220, Columbus, USA), UV-Visible 1601 Shimadzu double-beam
spectrophotometer, 1-cm rectangular quartz cells, deionizer (Stedec CSW-300,
Lahore, Pakistan), and distillation unit (GFL Type 2001/2, Germany) were used.
The Shimadzu HPLC system (Kyoto, Japan) equipped with an LC-10 AT VP pump,
DGU-14 AM online degasser, Rheodyne manual injector fitted with a 20-lL loop,
column, and SPD-10 A VP UV–VIS detector were used. The chromatographic
system was integrated via a Shimadzu model CBM-102 Communication Bus
Module to PIV computer. Shimadzu CLASS-GC software (Version 5.03) was used
for data acquisition and mathematical calculations.

Methods

UV-visible spectrophotometry

Solution preparations

Primary solutions comprising a 1-mmol concentration of cetirizine and H2 blockers

(cimetidine, famotidine, ranitidine) were prepared individually in buffers with a pH
 Med Chem Res

ranging from 1 to 9, and from these primary solutions; stock solutions of 0.1 mmol
were prepared. Working standard solutions with a concentration of 0.01 to 0.1 mmol
were prepared by diluting the appropriate amount of stock solution in the same buffer.

Quantitation of drugs via simultaneous equation and derivative spectroscopic

technique

To estimate these drugs, a method using the UV-visible spectrophotometer was

designed to measure the quantities of two drugs present in the same solution
simultaneously without separating them. For this purpose a mathematical relation-
ship was used that gave the concentration of two drugs simultaneously when
measured at their absorption maxima:
A1
a2  A2
a1
Cb ¼ ð1Þ
a 2
b1  a 1
b2
Similarly,
A 1
b2  A 2
b1
Ca ¼ ð2Þ
a 1
b2  a 2
b1
where b is the path length of the cell (1 cm in our experiments) and c is the
concentration of the solution.
These equations were used to calculate the concentration of cetirizine,
cimetidine, and famotidine in the presence of each other. This relation holds well
when both components in the solution are absorbing at distinctly different
wavelengths fairly far from each other.
Because zero-crossing derivative spectra is the most common procedure for
simultaneous determination of overlapping spectra in binary mixtures (Abdel et al.,
2005), the first derivative spectrophotometric method was applied for simultaneous
estimation of overlapping spectras of cetirizine and ranitidine in the presence of
each other.

HPLC

Optimization of the mobile phase

To develop an RP-HPLC method, initially, methanol:water (90:10) was tried for

simultaneous estimation of cetirizine with H2 receptor antagonists (cimetidine,
ranitidine, and famotidine). Individual drug solutions were injected into the column
at a concentration of 100 lg/mL, and both the elution pattern and the resolution
parameters were studied as a function of pH.
The findings showed that at this mobile phase, all the H2 receptors together with
cetirizine eluted out at the same retention time (i.e., 2.5 min), and no profound
effect was observed with the adjustment of pH. Therefore, other ratios also were
tested for the required purpose. For this, methanol:water (80:20) was tried, and
findings showed that at this ratio, the H2 receptor separates out with cetirizine at a
different retention time. However, a further decrease of methanol in the mobile
Med Chem Res

phase had no effect on the H2 receptor antagonist but only increased the retention
time of cetirizine. The pH effect showed that optimized conditions are reached when
the pH value is 3.5, producing well-resolved and sharp peaks for all drugs assayed.

Wavelength selection

In addition, the UV spectra of individual drugs were recorded in the wavelength

range of 200 to 400 nm and compared. The choice to use the isobestic point set at
227 nm was considered satisfactory, permitting the detection of all drugs with
adequate sensitivity.

Chromatographic conditions

Methanol:water (80:20) was the simplest mobile phase for rapid and simultaneous
estimation of cetirizine with H2 receptor antagonists. Propyl paraben was chosen to
be the internal standard, eluting out at 5.5 min. The retention times were found to be
2.5 min for the H2 receptor antagonists and 3.5 min for cetirizine, with a flow rate
of 1 mL/min.

Sample preparations

Separate stock solutions of cetirizine and cimetidine were prepared by dissolving

10 mg of each drug in 100 mL of 80% aqueous methanol so that the final
concentration was 100 lg/mL. Working solutions also were prepared separately by
diluting from the standard solutions to obtain a concentration between 3.33 and
33.33 lg/mL. However, the concentration of the internal standard remained
constant (i.e., 16.66 lg/mL) in all the working standard solutions. The same
procedure was repeated for famotidine and ranitidine, respectively.

Assay in formulations

To determine the content of both drugs in the formulations (cimetidine, famotidine,

and ranitidine), 20 tablets of each drug, powdered and equivalent to 10 mg of
cetirizine and 10 mg of H2 antagonists, were weighed, and the solution was made up
to 100 mL with 80% aqueous methanol. The resulting solution was filtered, and the
filtrate was analyzed for the drug content. Aliquots of each solution were
accordingly diluted with the same solvent used in standard solution to obtain
solutions with the final concentration. All sample and standard solutions were
filtered through 0.45 l filter paper before injection into the system. A placebo
tablet also was subjected to the above mentioned process. The possibility of
excipient interference in the analysis was studied.

Assay in serum

Plasma samples obtained from healthy volunteers were collected and stored frozen.
To 1 mL of plasma, 10 mL of acetonitrile was added. The mixture was vortexed for
 Med Chem Res

1 min, then centrifuged for 10 min at 10,000 rpm. The supernatant was filtered by a
membrane filter with a pore size of 0.45 lm. An aliquot serum sample was fortified
with each drug to achieve the final concentration.
These solutions were stored at –20°C. For the analysis of each sample, five
concentration levels ranging from 33.3 to 3.33 lg/mL were prepared, and 10 lL of
solution was injected and chromatographed. From this, linearity and percentage of
relative standard deviation (%RSD) values were evaluated.

In vitro interaction studies

Buffer preparations

To prepare buffer with pH levels of 1 and 4, a 0.1-mol/L solution of potassium

chloride was prepared, with hydrochloric acid (0.2 mol/L) added until the
appropriate pH was attained. For preparation of pH 7.4 potassium dihydrogen
orthophosphate (0.6 g), disodium hydrogen orthophosphate (6.4 g) and sodium
chloride (5.85 g) were dissolved in sufficient deionized water to produce 1,000 mL,
with the pH adjusted if necessary. In the same manner, 4.98 g of ammonium
chloride was dissolved in 1,000 mL of water, with the pH adjusted to 9 using liquid
ammonia.

Procedure

The interaction studies were performed by preparing 200-lg/mL stock solutions of

each drug in buffers of an empty stomach pH of 1, a full stomach pH of 4, an
intestinal pH of 9, and a blood pH of 7.4. Next, 20 mL of stock cetirizine solution
was transferred in a conical flask, and to this was added 20 mL of stock cimetidine
solution. The conical flask was placed in a water bath at 37°C for 3 h. The samples
were withdrawn every half hour and analyzed using the UV visible spectropho-
tometer and HPLC after suitable dilutions had been made. Absorbances and peak
areas were recorded, and from this record, the degree of interactions was evaluated.
The same procedure was repeated for other H2 receptor antagonists as well. The
results thus obtained by using both the techniques were compared, and conclusions
were drawn based on these results. The UV method was used to increase the
sensitivity of the method.

Results

UV-visible spectrophotometer

Calibration and calculations

For linearity studies, 10 different concentrations of each drug were prepared in

different buffers and scanned. The absorption maxima of cetirizine and cimetidine
were observed at 231 nm and 216 nm. For famotidine, the absorption maximum
Med Chem Res

was found to be 265 nm at pH 1 and 4, whereas 284 nm was observed at pH 7.4 and
9, respectively.
These drugs were estimated using simultaneous equation. Molar absorptivities
were used for calculating the quantities of these drugs in a solution of unknown
concentration. The absorption maximum of ranitidine was found to be at 225 nm,
which overlapped the maximum of cetirizine (231 nm). Therefore, after application
of the second-derivative (Fig. 2) spectrophotometric method, the different absoption
maxima for cetirizine and ranitidine were recorded at different pH levels.
The calibration curves also were found to be linear within the concentration
range of 0.01 to 0.1 mmol/L for cetirizine and ranitidine. The procedure was found
to be simple, rapid, and reliable. In all the cases, the coefficient of variance was
found to be not more than 2%.

Method validation (HPLC)

Specificity

Representative chromatograms were generated to show that other components

possibly present in the sample matrix are resolved from the parent analyte. No
significant changes in area under the curve (AUC) or retention time of the drugs in
the presence or absence of propylparaben (internal standard) clearly indicated the
specificity of the method (Fig. 3).

Linearity, limit of detection (LOD), and limit of quantitation (LOQ)

For linearity studies, six different mixture concentrations (33.33, 16.66, 13.33, 10,
6.66, 3.33 lg/mL) of each drug, in presence of the internal standard were assayed.
The linearity of the method was observed within the expected concentration range,

Fig. 2 First-order derivative spectra of cetirizine and ranitidine

 Med Chem Res

Fig. 3 Representative chromatogram of analytes

Table 1 Regression statistics LOD and LOQ

Drugs Regression equation R2 LOD LOQ
(y) lg/ lg/
mL mL

Cetirizine 33,867x ? 10,919 0.999 0.103 0.031

Famotidine 26,708x ? 85,006 0.998 0.003 0.001
Cimetidine 60,173x – 30,907 0.999 0.44 0.132
Ranitidine 31,632x ? 14,814 0.999 0.04 0.014

LOD limit of detection, LOQ limit of quantitation

demonstrating its suitability for analysis. The standard curve, slope, intercept, and
correlation coefficient were determined. For calculation of the standard curve, plots
of the peak areas against the concentration were used. The regression statistics LOD
and LOQ are shown in Table 1.

Accuracy and precision

The intraday precision and accuracy of the method were evaluated at three different
independent concentrations, namely, 30, 25, and 20 lg/mL by adding known
quantities of the analyte to the drug product. The result for accuracy showed that the
method was accurate for all the above mentioned purposes.
The method passed the test for repeatability, as determined by %RSD for the area
of the peaks of six replicate injections at a 100% test concentration. The results for
intermediate precision are shown in Table 2.

Robustness

For the robustness study of the proposed method, deliberate modifications in pH

values of the mobile phase were made. It can be seen that for every condition used,
the chromatographic parameters are in accordance with the established value. A
Med Chem Res

Table 2 Intermediate precision (%RSD) of the method

Conc. lg/mL Cetirizine Famotidine Cimetidine Ranitidine

Interday Intraday Interday Intraday Interday Intraday Interday Intraday

33.33 0.5 0.13 0.17 0.42 0.07 0.18 0.2 0.07

16.66 0.1 0.13 0.25 0.56 0.03 0.8 0.1 0.94
13.33 0.5 0.34 0.83 0.53 0.26 0.64 0.11 0.16
10 0.06 0.52 1.31 0.57 0.88 0.23 0.17 0.48
6.66 0.3 0.6 1.13 0.31 0.31 0.39 0.12 0.96
3.33 0.28 0.69 0.63 0.37 0.01 0.28 0.3 1.31

%RSD percentage of relative standard deviation

Table 3 % Recoveries of different brands

Conc. Zyrtec Ulcerax Hiler Nulcer
lg/mL
%Reco. Found %Reco Found %Reco Found %Reco Found

33.3 103.98 32.03 109.8 30.32 104.97 31.72 96.74 34.45

16.6 102.82 16.15 96.32 17.23 102.18 16.25 97.24 17.13
13.3 106.4 12.5 99.72 13.33 100.85 13.19 99.03 13.46
10 100.58 9.94 94.09 10.62 102.8 9.73 105.39 9.49
6.6 100.22 6.59 97.03 6.8 98.47 6.7 103.59 6.43
3.33 94.56 3.51 104.16 3.16 100.25 3.32 97 3.43

±0.1-unit pH change of about 3.50 (pH of the mobile phase) had no considerable
impact on chromatographic performance.

Applicability of the method

The developed method was applied to determine different drug contents in marketed
formulations. The assay results shown in Table 3, demonstrate the suitability of the
method. The similarly of the %recoveries and the r2 of the drugs in the presence of
serum exhibited in Table 4 show the applicability of the method for therapeutic
purposes.

Interaction results

The interaction results obtained from the UV-visible spectrophotometer after

application of the simultaneous equation and second-derivative technique clearly
indicated that no interaction occurred between cetirizine and H2 blockers. Similar
results were observed after data were obtained from HPLC. The availability values
of cetirizine and H2 blockers in presence of one another were found to be 100%,
with no changes in availability values for the absence or presence of each other in
all of the buffers studied, as shown in Table 5.
 Med Chem Res

Table 4 Analysis in serum

Conc. lg/mL % Recovered R2

25 20 10 15 5

Cetirizine 99.28 103.65 95.81 99.38 104.1 0.999

Cimetidine 96.93 101.19 102.5 104.45 101.45 0.999
Famotidine 95.52 100.54 101.58 102.15 100.74 0.998
Ranitidine 97.45 101.75 100.45 101.87 103.84 0.999

Table 5 Interaction studies

% Recoveries

Cetirizine Cimetidine Famotidine Ranitidine

UV HPLC UV HPLC UV HPLC UV HPLC

100.27 100.12 100.74 100.24 100.54 100.01 100.55 100.47

99.52 100.45 97.52 101.12 98.67 100.87 99.88 100.07
99.14 99.57 99.14 100.47 99.74 99.52 99.74 99.89
97.25 99.87 97.78 98.74 99.24 99.12 98.45 99.31
98.3 98.24 98.47 99.17 100.65 98.75 97.33 98.74
99.74 99.87 99.55 100.34 97.00 98.88 98.32 99.89

UV ultraviolet, HPLC high-performance liquid chromatography

Moreover, our method was found to be widely applicable and reproducible. For
the above mentioned reasons, together with analysis time, ease of operation, and
widespread availability of commercial instruments with derivative capability, the
described procedures offer a distinct advantage over other techniques. Furthermore,
the findings confirm the suitability of these procedures for routine analysis of
cetirizine and H2 receptor antagonist mixtures and for the purpose of controlling the
pharmaceutical dosage of these drugs.

Discussion

Concerning the choice of drugs, cetirizine and H2 receptor antagonists were selected
for their importance in the therapeutic field. Because one of the studies showed
synergism between hydroxyzine or cetirizine and cimetidine in suppressing the
histamine-induced cutaneous response, it was concluded that this synergistic effect
was due to the pharmacokinetic interaction between the two drugs (Braggio et al.,
1996). No evidence of additional benefit from coadministration of famotidine with
acrivastine, cetirizine, and loratadine in the treatment of chronic idiopathic urticaria
was observed (Chen et al., 1994).
In another study, coadministration of hydroxyzine with cimetidine resulted in
significantly increased serum hydroxyzine concentrations and increased wheal and
Med Chem Res

flare suppression, thus confirming the rationale for a trial of these medications
administered concomitantly to some patients with chronic urticaria unresponsive to
treatment with an H1 antagonist alone. It was concluded that there is no therapeutic
rationale for coadministering cetirizine with cimetidine for the treatment of urticaria
and that these medications may be coadministered safely without fear of medication
interaction (Nilgun et al., 1999). However, this synergistic effect was not found in
all the studies (Estelle et al., 1995; Cook and Shuster, 1983).
Based on the first part of the study, a simultaneous RP-HPLC was developed and
validated for the determination of cetirizine in the presence of H2 receptor
antagonists. Propylparaben was selected as an internal standard because it is
commercially available and used mostly as a preservative in tablets. The
chromatographic method was validated by assessing linearity, accuracy, selectivity,
limit of quantitation, and precision. Analytical development and validation studies
demonstrated that this method for assay of cetirzine and H2 receptor antagonists was
linear, selective, and quantitative. The method was free of interference from
excipients. It was used to evaluate the possible in vitro interactions between
cetirizine and H2 receptor antagonists.
In the second part of the study, the UV-visible spectroscopic technique was used
to study the interactions. For this reference, standards of all the drugs in different
buffer mediums were run, and epsilon values were calculated. These values were
used later to calculate the possible interactions between the drugs, and results were
compared with those of HPLC. From the results, it was clearly evident that no
interactions occurred in any of the buffers, and no change in percentage of
availability values were observed.
Although this research did not attempt to investigate the in vivo studies, the
current method could be applied successfully to the study of samples involving in
vivo subjects. From the current study, it also is suggested that the synergistic effects
produced by the combination of these drugs should be studied at the receptor or
enzyme level.

Conclusion

After all the results obtained by HPLC studies had been analyzed, it was concluded
that the current method is fast and easy to perform, has low LOD and LOQ values,
shows a high percentage of recoveries, and is linear up to a wide range of
concentrations. Moreover, on the basis of interaction results obtained from both
techniques, it was concluded that no interaction occurred between cetirizine and H2
receptor antagonists.

References

Abdel AY, El-Sayed NA, Salem Al (2005) Recent developments of derivative spectrophotometry and
their analytical applications. Anal Sci 21:595. doi:10.2116/analsci.21.595
 Med Chem Res

Akhtar N, Aziz G, Ahmad M, Madni AU, Ashraf M, Mahmood A (2008) HPLC method for determination
of famotidine in human plasma and its application in bioequivalence studies. J Chem Soc Pak
30:567–570
Arayne MS, Sultana N, Siddiqui FA (2005) Determination and quantification of cetirizine HCl in dosage
formulations by RP-HPLC. Pak J Pharm Sci 18:7–11
Arayne MS, Sultana N, Afzal M, Mirza AZ (2008a) Interaction studies of cephradine with H2-receptor
antagonist. J Chem Soc Pak 30:734–739
Arayne MS, Sultana N, Bahadur SS (2008b) H2-receptor antagonist interaction with cefixime. J Chem
Soc Pak 30:726–733
Ashirua DA, Patel R, Basti AW (2007) Simple and universal HPLC-UV method to determine cimetidine,
ranitidine, famotidine, and nizatidine in urine: application to the analysis of ranitidine and its
metabolites in human volunteers. GlaxoSmithKline, Harlow, pp 29–39
Baker WR, Lau L, Howarth PH (1996) Histamine and the nasal vasculature: the influence of H1 and H2
histamine receptor antagonism. Clin Otolaryngol 21:348–352. doi:10.1111/j.1365-2273.1996.
tb01085.x
Braggio S, Barnaby R, Grossi P, Cugola M (1996) A strategy for validation of bioanalytical methods. J
Pharm Biomed Anal 14:375–388. doi:10.1016/0731-7085(95)01644-9
Chen X, Simons FE, Simons KJ (1994) Effect of the H2-receptor antagonist cimetidine on the
pharmacokinetics and pharmacodynamics of the H1-receptor antagonists hydroxyzine and cetirizine
in rabbits. Pharm Res 11:295–300. doi:10.1023/A:1018971828065
Cook LJ, Shuster S (1983) Lack of effect of cimetidine in chronicidiopathic urticaria. Acta Derm
Venereol 63:265–267
Estelle F, Simons R, Gordon SL, Keith SJ (1995) Effect of the H2-antagonist cimetidine on the
pharmacokinetics and pharmacodynamics of the HI-antagonists hydroxyzine and cetirizine in
patients with chronic urticaria. J Allergy Clin Immunol 95:685–693
European Pharmacoepia (2000) Her Majesty Stationary Office, pp 342–343
Gowekar NM, Pande VV, Kasture AV, Tekade AR, Chandorkar JG (2007) Spectrophotometric
estimation of ambroxol and cetirizine hydrochloride from tablet dosage form. Pak J Pharm Sci
20:250–251
Havas TE, Cole P, Parker L, Oprysk D, Ayiomamitis A (1986) The effects of combined H1 and H2
histamine antagonists on alterations in nasal airflow resistance induced by topical histamine
provocation. J Allergy Clin Immunol 78:856–860. doi:10.1016/0091-6749(86)90230-7
Hayashi S, Hashimoto S (1999) Antiinflammatory actions of new antihistamine. Clin Exp Allergy
29:1593–1596. doi:10.1046/j.1365-2222.1999.00703.x
Holmberg K, Pipkorn U, Bake B, Blychert LO (1989) Effects of topical treatment with H1 and H2
antagonists on clinical symptoms and nasal vascular reactions in patients with allergic rhinitis.
Allergy 44:281–287. doi:10.1111/j.1398-9995.1989.tb01070.x
Howarth PH, Salagean M, Dokic D (2000) Allergic rhinitis: not purely a histamine-related disease.
Allergy 55:7–16. doi:10.1034/j.1398-9995.2000.00802.x
Johnson CE, Weiner JS, Wagner DS, McLean JA (1984) Effects of H1 and H2 receptor blockade on the
inhibition of immediate cutaneous reactions. Clin Pharm 3:60–64
Marks R, Greaves MW (1977) Vascular reactions to histamine and compound 48/80 in human skin:
suppression by a histamine H2-receptor blocking agent. Br J Clin Pharmacol 4:367–369
Nathan RA, Segall N, Schocket AL (1981) A comparison of the actions of H1 and H2 antihistamines on
histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients. J
Allergy Clin Immunol 67:171–177. doi:10.1016/0091-6749(81)90057-9
Nilgun B, Rebiay A, Dilek B, Peniz D (1999) Comparison of acrivastine, loratadine, and cetirizine
monotherapies, and coadministration with famotidine in the treatment of chronic idiopathic
urticaria. Turkiye Klinikleri Dermatol 9:206–209
Secher C, Kirkegaard J, Borum P, Maansson A, Osterhammel P, Mygind N (1982) Significance of H1 and
H2 receptors in the human nose: rationale for topical use of combined antihistamine preparations. J
Allergy Clin Immunol 70:211–218. doi:10.1016/0091-6749(82)90044-6
Smith JA, Mansfield LE, Nelson HS (1979) The effect of cimetidine on the immediate cutaneous response
to allergens. Ann Allergy 42:353–354
Sultana N, Arayne MS, Shamshad H (2008) Optimization of quantitative analysis of cetirizine in bulk
drug, dosage formulations, and human serum using spectrophotometry. J Chem Soc Pak 30:563–566
Taylor CT, Sodha R, Warner B, Foreman JC (2005) Histamine receptors that influence blockage of the
normal human nasal airway. Br J Pharmacol 144:867–874
Med Chem Res

Virag L, Szabo C (2002) The therapeutic potential of poly (ADP-ribose) polymerase inhibitors.
Pharmacol Rev 54:375–429. doi:10.1124/pr.54.3.375
Wang D, Clement P, Smitz J (1996) Effect of H1 and H2 antagonists on nasal symptoms and mediator
release in atopic patients after nasal allergen challenge during the pollen season. Acta Otolaryngol
116:91–96. doi:10.3109/00016489609137720

View publication stats