| dc.description.abstract | Background Nucleoside analogues: stavudine and lamivudine represent the
cornerstone of antiretroviral regimens. These drugs are associated with a range
of toxicities such as peripheral neuropathy, myopathy, pancreatitis and lactic
acidosis with hepatic steatosis. Fat lipodystrophy is also seen on long term
antiretroviral therapy with nucleoside analogues. Given the low cost of their
production compared to other antiretroviral drugs, this study was carried out
to establish the role of riboflavin in protecting against mitochondrial toxicity
and lipodystrophy due to their use.
Methodology Swiss albino mice models were used for this study. Three dose
levels of test drugs were used: half human; human equivalent and double
human dose for stavudine, lamivudine and riboflavin. Four drug combinations
were experimented consisting of stavudine only; stavudine and lamivudine;
stavudine, lamivudine and riboflavin; and stavudine and riboflavin. The
mitochondrial DNA damage was established using real time (rt) polymerase
chain reaction (rt-PCR). Experimental toxicity was monitored by assessing body
weight, general body appearance, glucose, lipid profile, haematology
(prothrombin time-PT and activated partial thromboplastin time-APTT) and
histology. Liver and adipose tissue were extracted and blood collected. Data
were analysed using SPSS version 17.0.
Results The reference ranges for the parameters: live weight, liver, blood
glucose, lipid and haematological profile for healthy untreated mice were
established. These wre subsequently applied in the interpretation of
experimental data.There was statistical significant rise in blood glucose levels
in groups treated with stavudine and lamivudine at all dose levels (p= 0.001-
0.011). Although there was an increase in blood glucose levels in groups
treated with combination of stavudine and lamivudine plus riboflavin, the
increase was not statistically significant except for the groups treated with
double human equivalent dose (p= 0.001-0.007). However, groups treated with
double human equivalent dose of stavudine and riboflavin showed decrease in
blood glucose (p= 0.003). There was no dyslipidaemia noted in the groups
treated with human and double human equivalent dose. However, the total
cholesterol and triglycerides levels were below the reference range for groups
treated with combination containing riboflavin for half human equivalent
group. The statistical significance for the total cholesterol and triglycerides in
the group treated with combination of half human equivalent dose stavudine
and riboflavin were statistically significant at 0.034 and 0.02 respectively.
Adipose tissue was depleted in the groups treated with stavudine human
equivalent and double human equivalent doses. There was significant increase
in PT for groups treated with human equivalent dose of stavudine and
stavudine plus lamivudine (p= 0.024-0.03). However, addition of riboflavin to
double human equivalent dose of stavudine was associated with a significant
decrease in PT (p= 0.000). Similarly, the APTT significantly increased for group
treated with human equivalent dose of stavudine and combination of stavudine
and lamivudine (p= 0.008-0.016) but significantly decreased on addition of
riboflavin to double dose of stavudine (p= 0.000). This is a beneficial effect.
Generally, there was liver derangement leading to hepatitis, steatosis and
granuloma however, these were found to be less severe in groups treated with
riboflavin. Mitochondrial DNA was measured by decrease in ct values
compared with untreated group. For the group treated with half human
equivalent dose of stavudine, the ct values for the liver (p=0.02) and adipose
tissue (0.02) were increasing. The same trend for increasing ct values (liver
p=0.03; and adipose tissue p=0.012) was reported in the group treated with
half human equivalent dose combination of stavudine and lamivudine. The ct
values decreased on addition of riboflavin. The ct values for the liver in group
treated with human equivalent dose combination of stavudine and lamivudine
was reported to increase compared to untreated group (p=0.003). The ct values
for the liver reduced in the groups treated with human equivalent dose
combinations of: stavudine, lamivudine and riboflavin (p=0.021); and stavudine
and riboflavin (p=0.002). The group treated with double human equivalent dose
combination of stavudine and lamivudine, liver and adipose tissue ct values
were increased with statistical correlation of 0.001 and 0.007 respectively.
Conclusion The reference ranges for biochemical and haematological
parameters were established. Toxicity due to the drugs stavudine and
lamivudine was confirmed for human and double human equivalent doses.
Riboflavin was found to have protective effect to mtDNA when in combination
with stavudine; and stavudine and lamivudine in animal model. Half human
equivalent dose was found to cause minimal toxicity | en_US |
| dc.description.department | a
Department of Psychiatry, University of Nairobi, ; bDepartment of Mental Health, School of Medicine,
Moi University, Eldoret, Kenya | |
