Amantadine, development

Case reports Three patients who took amantadine developed diffuse corneal edema [272 ]. In two cases the symptoms started within a few weeks and in the third case after 6 years. In the first two cases withdrawal of amantadine resulted in resolution of the corneal edema. However, the other patient received a full-thickness corneal transplant while still taking amantadine, and edema developed in the grafted cornea withdrawal of amantadine then resulted in resolution of the comeal edema in both eyes, but the ungrafted comeal eventually also became edematous, requiring transplantation. Histopathology showed significant loss of endothelial cells. As in the last of these cases, another report documented comeal edema in a corneal transplant until amantadine withdrawn [273" ]. 

A 2-year-old boy who took 0.8-1.5 g of amantadine developed generalized seizures followed by status epilepticus, with alternating generalized tonic-clonic and partial seizures, over 7 hours he also had a sinus tachycardia and reactive bilateral mydriasis [292 ]. All the symptoms resolved within 20 hours. 

Two entry-blockers, amantadine and rimantidine, have been introduced into medicinal practice. A second approach is to target the processes that synthesize virus components after a virus invades a cell. One way of doing this is to develop nucleotide or nucleoside analogs that look like the building blocks of RNA or DNA, but jam the enzymes that synthesize the RNA or DNA once the analog is incorporated. 

Prophylaxis - Start in anticipation of contact or as soon as possible after exposure. Use daily for at least 10 days following a known exposure. The infectious period extends from shortly before onset of symptoms to up to 1 week after. Because amantadine does not appear to suppress antibody response, it can be used in conjunction with inactivated influenza A virus vaccine until protective antibody responses develop administerfor 2 to 4 weeks after vaccine has been given. When the vaccine is unavailable or contraindicated, give amantadine for the duration of known influenza A in the community because of repeated and unknown exposure. 

CHF or peripheral edema Closely follow patients with a history of CHF or peripheral edema as there are patients who developed CHF while receiving amantadine. Glaucoma Because amantadine has anticholinergic effects and may cause mydriasis, do not give to patients with untreated angle closure glaucoma. 

Seizures An increased incidence of seizures has been reported in patients with a history of epilepsy who received the related drug amantadine. In clinical trials, the occurrence of seizure-like activity was observed in a small number of patients with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine. If seizures develop, discontinue the drug. 

Antibodies against the virus but also amantadine and derivatives, interfere with host cell penetration. There are nucleoside analogues such as aciclovir and ganciclovir, which interfere with DNA synthesis, especially of herpes viruses. Others like zidovudine and didanosine, inhibit reverse transcriptase of retroviruses. Recently a number of non-nucleoside reverse transcriptase inhibitors was developed for the treatment of HIV infections. Foscarnet, a pyrophosphate analogue, inhibits both reverse transcriptase and DNA synthesis. Protease inhibitors, also developed for the treatment of HIV infections, are active during the fifth step of virus replication. They prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new vi-rons. 

Viral resistance develops rapidly in approximately 30% of individuals treated with amantadine or rimantadine. Resistant viruses are associated with the failure of drug prophylaxis in close contacts of infected individuals who have been treated with these antiviral agents. Mutation in the transmembrane domain of the M2 protein is the most frequent cause of resistance to amantadine and rimantadine. 

The Centers for Disease Control s (CDC) Immunization Practices Advisory Committee recommends annual vaccination as the method of choice in the prevention of influenza infection. However, when vaccination is contraindicated or early vaccination is not possible, amantadine and rimantadine are effective prophylactic agents that have been shown to protect approximately 70 to 90% of patients from influenza A infection. Since these drugs do not prevent the host immune response to influenza A, they may be used to prevent infection during the 2- to 4-week period required to develop immunity following vaccination. An additional use of amantadine, unrelated to its antiviral activity, is in the therapy of Parkinson s disease (see Chapter 31). 

The third major difficulty in developing cold cures arises from the fact that the HRVs are RNA viruses. When presented with any selective pressure, including chemotherapeutic or antibody challenge, RNA viruses mutate rapidly [9]. This ability to mutate is most clearly illustrated in influenza viruses (RNA viruses), where new strains continuously arise to circumvent immunity in a population. Influenza A viruses have been shown to mutate around the anti-influenza drug Amantadine, after a single passage through a susceptible human host. The mutated viruses shed from a host treated with Amantadine are now resistant to Amantadine. These mutated viruses appear to be as virulent as the parent strain of virus [10]. 

In a randomized trial in 74 patients with chronic hepatitis C treated with interferon alfa-2b and ribavirin, plus placebo or amantadine, two developed glutamic acid decarboxylase (GAD) autoantibodies, but none developed IA-2 or insulin autoantibodies (543). One had an increased titer of GAD autoantibodies during a first sequence of interferon alfa monotherapy, then a further rise during subsequent combination therapy, and finally developed diabetes mellitus after 5 months of treatment. The authors suggested that repetitive treatment with interferon alfa could increase the risk of type 1 diabetes in patients previously positive for islet antibodies. 

A 34-year-old woman, who developed amenorrhea while taking risperidone, regained her normal menstrual pattern along with a marked fall in serum prolactin concentration 8 weeks after being switched to olanzapine, whereas amantadine had failed to normalize the menses and had apparently reactivated the psychotic symptoms (856). 

While taking amantadine, an elderly man developed the Othello syndrome, a severe delusion of marital infidelity, as described in Shakespeare s plays Othello and A Winter s Tale, it abated with drug withdrawal (SEDA-17,170). 

A 48-year-old woman with a 17-year history of Parkinson s disease developed a sensorimotor peripheral neuropathy after taking amantadine 300 mg/day for 8 years (12). She had livedo reticularis after only 1 year of treatment and this had become increasingly extensive. Attempts to withdraw the drug resulted in worsening Parkinsonian symptoms. However, after the neuropathy had been diagnosed, amantadine was withdrawn, with improvement of the neurological symptoms within 6 weeks and complete resolution after 6 months. However, the livedo reticularis was still present 18 months after withdrawal. 

Three Japanese women aged 78-87 years who had taken amantadine 100-200 mg/day for 1 month to 5 years, in two cases together with co-careldopa, developed multifocal myoclonus and two were confused (13). Amantadine concentrations were high in the two patients in whom they were measured, at over 3000 ng/ml a concentration over 1000 ng/ml is regarded as toxic. Amantadine was withdrawn and the myoclonus disappeared within 1-2 weeks and did not recur. Cortical myoclonus has also been described with levo-dopa and bromocriptine, but the mechanism is not known. 

Rimantadine hydrochloride, an alpha-methyl derivative of amantadine (alpha-methyl-l-adamantane methylamine hydrochloride), is more active than amantadine against influenza A viruses in vitro and in laboratory animals. It is an alternative to amantadine for the prevention and treatment of influenza A virus infections in adults and for the prevention of influenza in children. Adverse effects have been considered to be less common with rimantadine (SEDA-8, 143), and it is generally tolerated better than amantadine, because it causes fewer nervous system adverse effects (1). Unfortunately, rimantadine is more costly, which has led many institutions to develop influenza treatment guidelines. Both drugs work by blocking the M2 ion channel, which is needed to affect a pH change that helps to initiate viral uncoating. 

Note Fifty to 90% of patients receiving amantadine for Parkinsonism develop a more or less livedo reticularis ... 

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