Zidolam In The Treatment Of Hiv Biology Essay

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Zidolam is an antiretroviral combination therapy for the treatment of HIV infection. 30 albino rats with body weight (bwt) of 150 - 230 gm were used for the 2-phase study. Solution of the drug in sterile water was administered via oral cannula to the 2 groups of 10 rats (5 males and 5 females) each at daily dose of 1.29mg/100gm bwt respectively for 21 days during phase I. Phase II was a recovery study involving 10 rats (5 males and 5 females) exposed to dose regimen as in phase I, and sacrificed after 21-day withdrawal of treatment. The control group of 10 animals (5 males and 5 females) was given sterile water ad-libitum. Liver enzymes were determined using kits obtained from Randox Laboratories, Ltd, UK.

Zidolam caused significant increase (P< 0.05) in the liver enzymes: serum pyruvate aminotransferase, serum alkaline phosphatase and serum alanine aminotransferase of the animals.

Discontinuation of the drug use however caused gradual recovery of the values of liver enzymes. The results suggested that Zidolam could induce reversible changes in values of liver enzymes of rats, and by extension man. The present study has shown that there was a significant increase in all the measured liver enzymes indicating some degree of damage to the tissues in the liver.

Key words: Zidolam, liver enzymes, wistar rats, antiretroviral therapy.

INTRODUCTION

Human Immunodeficiency Virus is an RNA retrovirus, infectious agent that causes acquired immunodeficiency syndrome (AIDS), a disease that leaves a person vulnerable to life-threatening infections. Scientists have identified two types of this virus. HIV-1 is the primary cause of AIDS worldwide. HIV-2 is found mostly in West Africa. (1). Already, 18.8 million people around the world have died of AIDS, 3.8 million of them children. Nearly twice that many-34.3 million-are now living with HIV, the virus. (1). The core component of treatment and care of PLHIV is provision of antiretroviral treatment (ART).

Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. Optimal ART increases the length and quality of life of HIV-infected patients, and reduces the onward transmission of the virus. When several such drugs, typically three or four, are taken in combination, the approach is known as highly active antiretroviral therapy, or HAART. (2)

Not much work has been done on antiretroviral (ARV) therapy in Nigeria until recently. This can be attributed to the poor coordination efforts in the fight against human immunodeficiency virus (HIV) (3). In 1984, it became clear that HIV was the known cause of acquired immunodeficiency syndrome (AIDS). Not quite long after this knowledge, drugs that could devastate the virus were placed on clinical trials (3)

Recent advances in the treatment of HIV-1 infection involving co- administration of reverse transcriptase and protease inhibitors to achieve near-complete suppression of HIV-RNA concentrations have led to considerable improvements in life expectancy of infected individuals (4). Highly active antiretroviral therapy, i.e., the use of aggressive combination antiretroviral regimens consisting of reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs), has become the standard of care (5 and 6).

Zidolam is an antiretroviral drug belonging to the antiretroviral group called nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is used in antiretroviral combination therapy for the treatment of HIV infection. It reduces the amount of HIV in the body, and keeps it at a low level. It also increases CD4 cell counts. CD4 cells are a type of white blood cells that plays an important role in maintaining a healthy immune system to help fight infection.

The different components of HAART are each associated with different risks of liver toxicity. Most drugs are metabolized by cytochrome P450 enzymes in the liver, and this may be affected by liver disease. The mechanisms for drug-induced liver injury include dose-dependent toxicity, hypersensitivity reactions, idiosyncratic reactions, mitochondrial toxicity, and immune reconstitution (7).

With the advent of highly active antiretroviral therapy, the reduction in overall mortality and morbidity in HIV patients has been accompanied by the emergence of liver disease as a leading cause of death. Elevated liver enzymes may be due to HAART or to other risk factors, including hepatitis co-infection and alcohol use. (7)

It therefore becomes imperative to add more to the body of knowledge on the possible effects of such combinations on body organs, hence this research was designed to investigate the effects of Zidolam on liver enzymes-AST, ALT and ALK in uninfected adult wistar rats of both sexes.

MATERIALS AND METHOD

Animals

Thirty adult wistar strain rats of both sexes (15 females and 15 males) weighing between 150gm and 220gm were obtained from our departmental animal house and were housed five animals per cage at room temperature where they were acclimatized for a period of seven days. The animals were fed with standard rat pellets (Ladokun Feeds Nig. Ltd.) and water ad libitum.

Experimental procedure

The study was divided into two phases involving the use of drug and sampling in the first phase, as well as drug administration, recovery period followed by sample collection in the second phase. Zidolam was obtained from General Hospital, Ijebu Igbo, Nigeria. The drug was administered orally at therapeutic (T) dose of 1.29mg per 100gm body weight (bwt) respectively to the rats daily for 21 days.

Phase 1 entails the use of 10 rats (5 males and 5 females). Each rat in the group was treated with 1.29mg/100gm bwt of Zidolam daily for 21 days.

Phase 2 was a recovery study involving ten rats (5 males and 5 females).The animals were given 1.29mg/100gm bwt of Zidolam each for twenty one days and allowed to recover from the treatment for another twenty one days.

There was a group of 10 rats (5 males and 5 females) given sterile water throughout the study, and these serve as the control (C) in both phases.

Analytical procedure

The rats were weighed prior to treatment and at the end of each phase to obtain differential weight gains (if any). The animals were anaesthetized with di-ethyl ether after which they were sacrificed by exsanguination.

Enzyme Analysis

Serum pyruvate aminotransferase, serum alanine aminotransferase and serum alkaline phosphatase values were determined using kits from Randox Laboratories, Ltd, UK.

Statistics

All calculations were done using the SPSS-V15 statistical software package (Norusis, 1998) (8) for analysis of the data. The data were presented as Means ± Standard deviation (SD), and statistical analysis carried out using the Student's t-test and ANOVA. Differences were considered to be of statistical significance at an error probability of less than 0.05 (P<0.05)

RESULTS

On Alkaline phosphatase: The results are shown in Table 1.

Table 1:   

Groups

ALK(U/L)

Control Group male

0.03+0.01

Control Group female

0.02+0.01

Test Group male

0.06+0.01*

Test Group female

0.05+0.01*

Recovery Group male

0.04+0.01*

Recovery Group female

0.05+0.02*

*P < 0.05 (p is significant at p < 0.05).

Administration of Zidolam at 1.29mg/100gm of body weight/day for 21days significantly increased (p<0.05) the values of alkaline phosphatase in both male and female rats and these values gradually return to normal values.

On Alanine aminotransferase: The results are shown in Table 2.

Table 2 :

Groups

ALT(U/L)

Control Group male

0.06 +0.01

Control Group female

0.09 +0.02

Test Group male

0.11 +0.02*

Test Group female

0.13 +0.03*

Recovery Group male

0.08 +0.02*

Recovery Group female

0.09 +0.02*

*P < 0.05 (p is significant at p < 0.05).

Administration of Zidolam at 1.29mg/100gm of body weight/day for 21days significantly increased (P< 0.05) the alanine aminotransferase values in both male and female rats. The values gradually return to normal after allowing the rats to recover from effects of the drug.

On Pyruvate aminotransferase: Administration of Zidolam at 1.29 mg/100gm of body weight/day for 21days significantly increased (p<0.05) the values of pyruvate aminotransferase in both male and female rats. The values return to normal after allowing the rats to recover from effects of the drug as observed in table 3.

Table 3:

Groups

AST(U/L)

Control Group male

0.04 +0.02

Control Group female

0.03 +0.02

Test Group male

0.09 +0.06*

Test Group female

0.09 +0.04*

Recovery Group male

0.06 +0.02*

Recovery Group female

0.05 +0.02*

*P < 0.05 (p is significant

Discussion

This investigation demonstrated that administration of Zidolam to rats significantly (P<0.05) increased the liver enzymes of the animals. (Tables 1, 2 and 3).

Elevated liver enzymes (ALT or AST) are a sign of liver inflammation, and may be a warning of progressive liver disease including cirrhosis. (7)

The study also demonstrated that the noticeable effect is reversible as observed in the recovery group. The reversal is noticed to be time dependent and this may not be unconnected with plasma clearance of the drug and subsequent excretion.

Liver enzymes are usually raised in acute hepatotoxicity (9 and 10). Increase in liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST) are common findings in liver toxicity (10, 11 and 12) while increased activity of these enzymes may be found in damaged tissues. (13).

With the advent of highly active antiretroviral therapy (HAART), the reduction in overall mortality and morbidity in HIV patients has been accompanied by the emergence of liver disease as a leading cause of death. Elevated liver enzymes may be due to HAART or to other risk factors, including hepatitis co-infection (7). The different components of HAART are each associated with different risks of liver toxicity. Most drugs are metabolized by cytochrome P450 enzymes in the liver, and this may be affected by liver disease. (7)

The mechanisms for drug-induced liver injury include dose-dependent toxicity, hypersensitivity reactions, idiosyncratic reactions, mitochondrial toxicity, and immune reconstitution. (7)

The present study has shown that there was a significant increase in all the measured liver enzymes indicating some degree of damage to the tissues in the liver.

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