The observations obtained from the present histopathological study illustrated that oral administration of Tamiflu and Adamine to male mice have induced mild, moderate, and severe lesions in liver tissue. The pathological responses of the liver tissues to Tamiflu and Adamine were time-dependent.
Remarkable abundance of the infiltrative inflammatory cells were seen in addition to marked congestion and dilatation of the central and portal veins, which were associated with erosion in their endothelial linings and the accumulation of stagnant blood cells in their lumens.
The present study illustrated marked consequences in the hepatic vasculatures including congestion, dilatation of the hepatic central veins and surrounding sinusoids, besides erosion of their endothelial lining cells and the activation of the phagocytic Kupffer cells in the liver of mice treated with Tamiflu and Adamine. These results agree with results of Arcidi Jr et al.  and Dai et al.  who found that congestion of the liver is reflected by sinusoidal dilation, congestion, and hepatocyte atrophy. Elevated hepatic venous pressures may precipitate extravasation of red blood cells into the space of Disse. In addition to the extent of necrosis, inflammation, and dilation has been correlated with right atrial and hepatic pressures  although ischemia may lead to findings of necrosis as well. Chronic congestion leads to perivenular fibrosis and, eventually, cirrhosis. This finding is in accordance with those observed by [8, 9] who reported such alteration in the hepatocytes of the treated mice post monosodium glutamate application and post depakine and epanutin on other treated mice.
The results of present work are in agreement with those obtained by Ju et al. , who mentioned that Kupffer cells can be a protective from drug-induced liver injury and Kaji et al. , who reported two patients with hepatoma associated with liver cirrhosis after treatment with the neuraminidase inhibitors zanamivir and oseltamivir administered as a prophylactic agent.
Also present results agree with the study which obtained by Gao et al. , who suggested that oseltamivir may inhibit both viral entry and release but may also enhance apoptosis of infected cells and interfere with natural killer cell (NK) function during influenza infection.
At the ultrastructural level, the alterations are time-dependent and involved the mitochondria, endoplasmic reticulum, lysosomes, nucleus, and Kupffer cells. The present results have displayed picture for the mitochondria differ from the control ones, being affected by the Tamiflu and Adamine administration. The mitochondria became swollen and lost their cristae, progressively damaged, and their debris were thrown into their heavily electron dense matrices.
Mitochondria are essential double-membrane subcellular organelles. Their function is to support aerobic respiration and production of ATP by oxidative phosphorylation . In addition to oxidative phosphorylation, the mitochondria control cytosolic calcium concentration  and the major source of endogenous reactive oxygen species . Also, mitochondria act as gate keepers of cell life and cell death regulate both apoptotic and necrotic cell death, and so its disturbances involving these pathways may trigger cell death .
The results of the present study are in agreement with the results obtained by Giovanni et al.  in their study on isolated mouse liver mitochondria demonstrated that amantadine induces hyperpolarization of the membrane potential. Moreover, amantadine treatment increased the calcium threshold required to trigger mitochondrial permeability transition opening.
In the present study, the rough endoplasmic reticulum has undergone marked fragmentation into small stacks. Also, the smooth endoplasmic reticulum has undergone dilatation.
The results of the present study agree with the results observed by Forchap et al. , who reported that in longer term experiments, both drugs (amantadine and prazosin) paradoxically increase the cytotoxicity of all three currently licensed tyrosine kinase inhibitors, imatinib, nilotinib, and dasatinib. This effect is due to release of intracellular calcium from the endoplasmic reticulum, with changes in mitochondrial calcium and alterations in mitochondrial membrane permeability, resulting in caspase-mediated apoptosis. These results indicate that calcium release from the ER, here induced by amantadine or prazosin, may prime BCR-ABL-positive cells to tyrosine kinase inhibitors-induced apoptosis.
The observations in the present study have found an increase in number of lysosomes, these observation previously described by Phillips et al.  to be involved in the metabolism or storage of a number of drugs and any lysosomal changes occur could be due to focal cytoplasmic degradation, a process in which lysosomes are associated with digestion of damaged portions of the hepatic cytoplasm.
The present study showed an increase of lysosomes in hepatocytes. These observations are in accordance with those reported by Sakr  who illustrated distinct change in lysosomes of the hepatocytes of mouse treated with tamoxifen.
Many hepatocytes showed nuclear changes include erosion and rupture of the nuclear envelope and more electron dense chromatin attached to inner membrane of the nuclear envelope. Also, pyknotic nuclei were observed in the present work.
Hypertrophied Kupffer cells were common ultrastructural finding in adverse drug and toxic reactions of the liver as clearly designated in the present work and symptomized by the presence of many lysosomal granules in their cytoplasm and extension of filopodia. The phagocytic activity of Kupffer cells could be a result of hypertrophy of the rough endoplasmic reticulum and an increase in the number and size of lysosomes in Kupffer cells. Kupffer cells are usually associated with extensive hepatocellular injury ‘necrosis’ . This finding is in accordance with those observed by Sakr  who reported such alteration of Kupffer cells in the hepatocytes of the treated mice post tamoxifen application.
On the other hand, these results contradict with the findings obtained by Nassim et al. , who reported that Amantadine monotherapy has no impacts upon liver histology.