MEDICINE AND FARMATION NEWS, 2010, № 6 (312)
ГАЗЕТА «НОВОСТИ МЕДИЦИНЫ И ФАРМАЦИИ» 6(312) 2010
ABSORBING PROPERTIES OF ENTEROSORBENT ENTEROSGEL IN REGARDS TO
THE ESSENTIAL ANTIRETROVIRAL DRUGS
(ПОГЛОЩАЮЩИЕ СВОЙСТВА ЭНТЕРОСОРБЕНТА ЭНТЕРОСГЕЛЬ
ОТНОСИТЕЛЬНО ОСНОВНЫХ АНТИРЕТРОВИРУСНЫХ ПРЕПАРАТОВ)
Authors: Bardahivskaya K.I., Nikolaev V.G., Gurin N.M. Institute of Experimental Pathology, Oncology
and Radiobiology named after Kavetsky R.E. National Academy of Sciences of Ukraine, Kiyv
A wide range of drugs active against HIV has given birth to a new approach in the treatment of HIV
infection - highly active anti-retroviral therapy (HAART), which refers to administration of at least three
antiretroviral (ARV) drugs in patients. HAART application has allowed to reduce significantly the
incidence of the most severe secondary infections, which in turn has led to mortality reduction from
AIDS (7-8 times). [1]
However, all ARV drugs are characterized by their high toxicity [7]. In particular, the majority of ARV
drugs cause toxic liver injury accompanied by increased transaminase levels in the blood plasma and
development of acute hepatitis, especially in patients with chronic hepatitis B and C. This can make
necessary suspension or even termination of the treatment of HIV-infected patients [11, 17, 18, 21].
Some preparations of HIV nucleoside reverse transcriptase inhibitors and HIV protease inhibitors have
nephrotoxic effects and can cause both acute and chronic kidney diseases [12, 20].
Use of HAART significantly prolongs life expectancy of HIV-infected and AIDS patients, however, there is
a strong liability of patients to cardiovascular diseases. Since the virus itself may be an independent
factor in the development of atherosclerosis and coronary vessels disorders, regarding HAART, it is also
advisable to take into account pharmacodynamics specific of antiretroviral drugs for prevention of
myocardial infarction and other cardiac and metabolic complications in patients with multisystem
disease [5, 8]. HAART also plays an important role in the development of oxidative stress [15, 16, 22]
and complications associated with mitochondrial dysfunction - polyneuropathy, myopathy, dyslipidemia
and lipodystrophy [14].
One of the most frequent and dangerous symptoms in HIV-infected patients and patients with AIDS is
diarrhea, which, according to various sources, is observed in 50-90% patients. The cause of diarrhea can
be viruses, bacteria, fungi and protozoa infections and HIV itself as well as antiretroviral drugs, in
particular HIV protease inhibitors [3, 4, 19]. Parasitic infections are determined in 30-35% patients, and
low CD4-cell counts is to the large extent associated with opportunistic infections [6, 13]. In patients
receiving HAART, chronic diarrhea for 6 weeks significantly increases early mortality in comparison with
patients without diarrhea [6].
To reduce toxic effects of ARVs and complex treatment of diarrheal syndromeб a variety of means is
used. Thus, the use of probiotics, soluble fibers, and L-glutamine significantly reduces diarrhea in
patients receiving HIV-protease inhibitor [10]. Reduced glutathione is the most potent intracellular
antioxidant that plays an important role in detoxification of many electrophilic components and
peroxide in the treatment of viral infections, including HIV [9]. L-carnitine demonstrates antioxidant,
neuro-and cardioprotective, immunomodulatory effects in treatment of HAART complications in HIV
patients [14]. Use of organosilicone enterosorbent Enterosgel is an effective treatment for diarrhea
syndrome in HIV patients at both early and late stages of the disease and is accompanied by rapid
positive dynamics of the main clinical symptoms. [2]
Despite significant advances in the treatment of HIV and AIDS patients, the problem of body
detoxification is quite relevant, since HAART implies lifelong administration ARV drugs.
Study objective: in vitro definition of absorption properties of enterosorbent Enterosgel against major
ARVs in the media that meet the acidity of gastric (pH = 1.6) and pancreatic (pH = 6.8) juices.
MATERIALS AND METHODS
The study objective was organosilicone enterosorbent Enterosgel, paste for oral use manufactured by
JSC "Ecoprotection company "Kreoma Farm"(Kiyv, Ukraine), in comparison with the carbon sorption
material AUVM. Sorption parameters of such marker compounds as vitamin B12 (substance marker of
average molecular weight, 1355 Da) and creatinine (low molecular weight marker, 133 Da) were taken
into account. Sorption activity of Enterosgel towards vitamin B12 was 3.85 mg/g, for AUVM - 25.4 mg/g,
regarding creatinine - 0.86 mg/g and 19.14 mg/g, respectively.
To study absorption properties of Enterosgel towards ARVs, the following drugs were used: HIV
nucleoside reverse transcriptase inhibitors - stag 30 (stavudine 30 mg capsules, "Hetero Drags Limited",
India), geptavir-150 (150 mg lamivudine coated tablets, "Hetero Drags Limited", India); non-nucleoside
HIV reverse transcriptase inhibitors - eferven (efavirenz 200 mg capsules, "Ranbaxy Laboratories
Limited", India), nevimun (nevirapine 200 mg tablets, "Cipla Ltd", Mumbai, India) and HIV protease
inhibitor kaletra (lopinavir 133.3 mg / ritonavir 33.3 mg soft gelatin capsules, "Abbott Laboratories Ltd",
UK)
Adsorption quantity of pharmaceutical substances was determined by difference in sorbate
concentration before and after contact with the sorbent in a static mode. The contact time was 2 hours.
The sorption was carried out in environments that meet the acidity of gastric (pH 1.6), and pancreatic
(pH = 6.8) juices. Concentration of substances in medicinal products was carried out using HPLC.
Statistical analysis was performed using Microsoft Excel: arithmetic mean (M) and the mean square
error (m) were calculated.
RESULTS AND DISCUSSION
The study has established absorption properties of enterosorbent Enterosgel (paste for oral
administration) for the main ARVs - stavudine, lamivudine, efavirenz, nevirapine and kaletra (lopinavir /
ritonavir). Stavudine absorption data are shown in Table. 1.
Table 1 shows that stavudine sorption by Enterosgel in the medium corresponding to gastric acidity (pH
= 1.6) is absent, and 1 g AUVM absorbs more than 25 mg of the drug. In the neutral medium, only
insignificant amount of stavudine is sorbed by Enterosgel - almost 150 times less than AUVM.
Table. 2 shows lamivudine absorption. AUVM actively absorbs the drug in both environments, and the
rate of lamivudine sorption by Enterosgel is 70-150 times lower. It is noteworthy that both medications
of NRTI group - stavudine and lamivudine - absorbed somewhat more actively in the medium that
corresponds to pancreatic acidity.
Table. 3-4 presents data on the absorption of non-NRTI drugs - efavirenz and nevirapine.
As can be seen from Table. 3, both sorbents absorbed efavirenz weakly enough in acidic and neutral
media. However, AUVM sorption value was 13-15 times higher than that of Enterosgel. In the acidic
medium both sorbents absorbed efavirenz 1.5 times less actively.
Values of nevirapine sorption (Table. 4) for enterosorbent Enterosgel were 4 times lower than in acidic
medium compared to neutral, for AUVM - high in both environments. In the neutral medium, Enterosgel
absorbed nevirapine 20 times less than AUVM, in the acidic medium - more than 80 times weaker than
AUVM.
Thus, similarly to NRTI group, non-NRTI drugs - efavirenz and nevirapine – were less absorbed in the
medium corresponding to gastric acidity.
Table. 5-6 shows sorption values of HIV protease inhibitor group - kaletra – lopinavir-ritonavir. Lopinavir
HIV-1 and HIV-2 inhibitor providing antiviral effect of the drug, while ritonavir inhibits lopinavir
metabolism in the liver, mediated by CYP3A enzyme, leading to increased lopinavir concentrations in the
plasma.
According to Table 5, lopinavir sorption by enterosorbent Enterosgel in the acidic medium was more
than 50 times, and in the neutral medium - 15 times lower than that of AUVM. In the neutral medium,
sorption activity of both sorbents was also lower than in the acid: for Enterosgel - 1.5 times, for AUVM 4.5 times.
Ritonavir sorption by the sorbents was also lower in the neutral medium: for Enterosgel - more than 2
times, for AUVM - more than 2.5 times (Table. 6). Sorption activity of Enterosgel towards ritonavir in the
acidic medium was 20 times, and in the neutral medium - 17 times lower than AUVM.
CONCLUSIONS
Preparations of NRTI group - stavudine and lamivudine - have little or no affinity for Enterosgel and can
be administered regardless of the time of its administration.
Non-NRTI drug efavirenz is rather poorly absorbed by organosilicone and carbon sorbents, although
sorption rates for Enterosgel are 13-15 times lower than for AUVM. Nevirapine is also much weaker (2080 times) absorbed by enterosorbent Enterosgel in the medium that meets gastric and pancreatic
acidity.
Unlike drugs of NRTi and non-NRTI groups, HIV protease inhibitors kaletra - lopinavir and ritonavir – are
less absorbed in the neutral medium. Sorption indicators for Enterosgel towards lopinavir and ritonavir
are significantly lower (15-50 times) in comparison with AUVM.
Thus, no absorbing activity of organosilicone enterosorbent Enterosgel has been detected on the main
anti-retroviral drugs, so in case of need Enterosgel can be given to patients with HIV / AIDS regardless of
administration of ARV drugs.
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