• 생물정신의학
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• 제8권1호
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• pp.156-161
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• 2001

두부 외상을 받은 환자는 여러 가지 다양한 병태생리학적인 과정을 통해 뇌손상을 받으며 이로 인해 다양한 신경정신과적인 장애를 나타낸다. 두부외상을 받은 두 명의 환자에서 이에 대한 약물학적인 접근으로 amantadine을 사용하였고 증세의 호전을 경험하였다. 이에 대한 이론적인 근거로는 amantadine은 전연접(presynaptic)과 후연접(postsynaptic)에서 도파민 신경전달(dopamine neurotransmission)을 증진시켜 인지기능과 전두엽 기능장애에서 발생되는 특징적인 정신 행동학적인 증상을 호전시키고, NMDA 수용체 길항제(NMDA receptor antagonist)로 작용하여 흥분성 독성물질(excitotoxic substrate)에 의한 이차적인 신경손상을 차단하는 신경보호제(neuroprotective agent)로 작용한다. 이와 같이 amantadine은 급성과 만성 외상성 뇌손상 환자 모두에서 나타나는 인지, 기분과 행동장애의 치료에 효과적이고 안전하며 비싸지 않은 가격으로 사용될 수 있을 것으로 사료된다. 또한 이 영역에서 더욱 많은 대조군 연구가 필요하고, 나아가서 외상성 뇌손상 환자의 인지기능 호전을 위한 약물학적인 개입에 관한 연구가 필요할 것으로 사료된다.

• 생물정신의학
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• 제7권1호
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• pp.55-63
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• 2000

Avariety of symptoms can occur following traumatic brain injury(TBI) or other types of acquired brain injury. These symptoms can include problems with short-term memory, attention, planning, problem solving, impulsivity, disinhibition, poor motivation, and other behavioral and cognitive deficit. These symptoms may respond to certain drugs, such as dopaminergic agents. Amantadine may protect patients from secondary neuronal damage after brain injury as a effect of NMDA receptor antagonists and may improve functioning of brain-injured patients as a dopaminergic agonist. Clinically, based on current evidence, amantadine may provide a potentially effective, safe, and inexpensive option for treating the cognitive, mood, and behavioral disorders of individuals with brain injury. The rationales for using amantadine are discussed, and pertinent literatures are reviewed.

• Archives of Pharmacal Research
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• 제29권5호
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• pp.405-411
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• 2006

Biphenyl dimethyl dicarboxylate (DDB) is a hepatoprotectant, which is used as an adjuvant agent in a treatment for chronic hepatitis. Amantadine is an antiviral agent, which is utilized primarily in the treatment of influenza, but also, occasionally in the treatment of hepatitis C. In a previous study, we reported that DDB, coupled with amantadine, would exert an anti-HBV effect, via the induction of interferon-inducible gene expression in the HepG2 2.2.15 cell line. The primary objective of the present study was to determine whether or not DDB and/or amantadine exhibit anti-HBV properties, and what mechanisms of action might be involved in such properties. In our study, we were able to determine that DDB stimulates Jak/Stat signaling, and induces the expression of interferon alpha $(IFN-\alpha)$ stimulated genes, most notably 6-16 and ISG12. In addition, the antiviral effectors induced by $IFN-\alpha$, PKR, OAS, and MxA, were regulated in the presence of DDB at its optimal concentration $(250{\mu}g/mL)$, to a degree commensurate with the degree of induction associated with the $IFN-\alpha$ treated group. Finally, we determined that the replication of pregenomic RNA and HBeAg was inhibited by DDB treatment, and this inhibition was maximized when coupled with the administration of amantadine $(25{\mu}g/mL)$. In conclusion, the results of this study demonstrated clearly that DDB, as well as the combination of DDB/amantadine, directly inhibited $IFN-\alpha$ signaling-mediated replication of HBV in infected hepatocytes, and thus may represent a novel treatment for chronic hepatitis B, which would be characterized principally by its improved safety over other treatment strategies.

• Archives of Pharmacal Research
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• 제28권4호
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• pp.451-457
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• 2005

Experimental studies have demonstrated that the triple combination of amantadine (A)/ ursodeoxycholic acid (UDCA, U)/ biphenyl dimethyl dicarboxylate (DDB, D) might have a preferential antiviral effect compared with that observed in interferon-induced antiviral signal pathways, such as those of $STAT1\alpha$ and the 6-16 genes. To confirm the results, this study examined whether th signal transduction for the antiviral activity in HepG2 2.2.15 was induced dependently or independently of interferon. To accomplish this, the correlation between the $STAT1\alpha$ and 6-16 genes, and nitric oxide, for the mediation of the antiviral activity was assessed. The increase in nitric oxide in the UDCA groups suggests that the inhibition of viral gene replication was enhanced by the amantadine combinations (AU and AUD), and might be more effective if incubated for longer periods. It was found that $STAT1\alpha$ was activated by the amantadine combination, although to a lesser extent than that of $interferon-\alpha$, and the primary endpoints examined for the inhibition of gene expression (HBsAg and HBcAg) were remarkably well regulated. This suggests that the amantadine triple, or at least the double, combination had better clinical benefits than those of $IFN-\alpha$ and the nucleoside analogue single treatment. This demonstrates that the amantadine combination might be a substitute for the existing HBV therapy if the results of in vivo and in vitro studies concur.

• 대한의생명과학회지
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• 제6권1호
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• pp.19-28
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• 2000

농도와 기간에 따른 바이러스 감염 및 항바이러스제인 amantadine병행 첨가 시 Maddin Darby canine kidney (MDCK) 세포 내의 free radical 해독계 효소인 glutathione S-transferase (GST)와 lactate dehydrogenase (LDH)의 활성 변동을 상호비교 관찰하였다. 바이러스에 감염된 MDCK세포는 감염 3일 후 1 TCID$_{50}$ 군은 80%이상, 10 TCID$_{50}$ 군은 거의 대부분의 단층세포가 탈락되는 병변 효과가 나타났다. Amantadine cytotoxic dose %가 증가함에 따라 MDCK 세포 내의 GST 및 LDH 활성은 농도에 따라 유의하게 감소되었고, 감염배지 내 LDH 활성은 대조군 보다 유의한 증가를 보였다. 인플루엔자 바이러스 type A 접종농도와 기간에 따른 MDCK세포 내의 GST및 LDH활성은 1 및 10 TCID$_{50}$ 감염군에서 감염 3일 후부터 유의하게 감소되었고, 감염배지 내의 LDH활성은 10배 이상 증가되었다. 인플루엔자 바이러스 type A 100 TCID$_{50}$ 감염과 amantadine병행 첨가 시 GST 및 LDH 활성은 바이러스만 감염한 군 보다 MDCK세포 내에서 대조군에 비하여 감소율이 낮았고, 감염배지 중 LDH 활성 역시 증가율이 낮았다. 또한 바이러스 감염 후 amantadine 90 $\mu\textrm{g}$/ml 첨가 시에 세포 내와 감염배지 중에서 가장 낮은 감소와 증가를 나타냈다.

• 약학회지
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• 제51권3호
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• pp.194-198
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• 2007

The mouse hepatitis virus (MHV-2) induces broad collapses, focal necrosis and cytolysis of hepatocytes, and leads to death after three to five days of intraperitoneal injection in mice. The present study investigated whether the combinatorial treatment of dimethyl dicarboxylate/amantadine (2:1) showed hepatoprotective and/or antiviral properties in MHV-2 infected ICR mice. In the study, we found that dimethyl dicarboxylate/amantadine group (VDDBA) increased the survival rate (30.8%) when compared to positive control, VL (7.7%) and that VDDBA lengthened the survival time (4.2 d)after MHV-2 infection. In addition, ALT and AST were well regulated when treated with VDDBA (p<0.01). Finally, we concluded that those results were probably from the inhibition of viral replication and at least antiproliferative effect on MHV-2.

• Archives of Pharmacal Research
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• 제14권4호
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• pp.285-289
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• 1991

A convenient spectrophotometric method was examined for the determination of amantadine sulfate (AMTS) which has no UV-VIS chromopohores. AMTS was ion-paired quantitatively with methyl orange (MO) at $70^{\circ}C$ for 30 min. The ion-paired complex was extracted with dichloromethane and the absorbance was measured at 421.5 nm. A linear relationship was observed in the range of $2.5{\times}10^{-7}\;M$ to $3.75{\times}10^{-6}\;M$ and the correlation coefficient was 0.999 (n=3). This assay method was applied to the quantification of AMTS in commercial tablet form with good recovery and high precision.

• 약학회지
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• 제49권2호
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• pp.151-155
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• 2005

For decades, the demand for new antiviral strategies, especially in hepatitis, has increased markedly due to its devastating pathogenic outcome, In the present study, we examin ed the antiviral effect of the combination of amantadine and biphenyl dimethyl dicarboxylate (DDB) in HepG2 2.2.15, which is transfected with HBV DNA. The study demonstrated that the combination not the single treatment may have an anti-HBV effect through a synergism of antiviral, anti-inflammatory and cytoprotective activities in STAT1 ${\alpha}$, 6-16 gene, and pro-inflammatory components such as nitric oxide and IL-1${\beta}$ expression. In addition, hepatitis B surface and core gene expression were examined as a final end point for the anti-HBV activities, which was also significantly suppressed comparing to normal control (p<0.01).

• Biomolecules & Therapeutics
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• 제31권4호
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• pp.402-410
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• 2023

Long-term administration of levodopa (L-DOPA) to patients with Parkinson's disease (PD) commonly results in involuntary dyskinetic movements, as is known for L-DOPA-induced dyskinesia (LID). 5-Hydroxytryptophan (5-HTP) has recently been shown to alleviate LID; however, no biochemical alterations to aberrant excitatory conditions have been revealed yet. In the present study, we aimed to confirm its anti-dyskinetic effect and to discover the unknown molecular mechanisms of action of 5-HTP in LID. We made an LID-induced mouse model through chronic L-DOPA treatment to 6-hydroxydopamine-induced hemi-parkinsonian mice and then administered 5-HTP 60 mg/kg for 15 days orally to LID-induced mice. In addition, we performed behavioral tests and analyzed the histological alterations in the lesioned part of the striatum (ST). Our results showed that 5-HTP significantly suppressed all types of dyskinetic movements (axial, limb, orolingual and locomotive) and its effects were similar to those of amantadine, the only approved drug by Food and Drug Administration. Moreover, 5-HTP did not affect the efficacy of L-DOPA on PD motor manifestations. From a molecular perspective, 5-HTP treatment significantly decreased phosphorylated CREB and ΔFosB expression, commonly known as downstream factors, increased in LID conditions. Furthermore, we found that the effects of 5-HTP were not mediated by dopamine1 receptor (D1)/DARPP32/ERK signaling, but regulated by AKT/mTOR/S6K signaling, which showed different mechanisms with amantadine in the denervated ST. Taken together, 5-HTP alleviates LID by regulating the hyperactivated striatal AKT/mTOR/S6K and CREB/ΔFosB signaling.

• Archives of Pharmacal Research
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• 제19권2호
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• pp.95-99
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• 1996

Four N-adamantyl n-alkanamides were prepared by amide condensation reaction between amantadine and n-alkanoic acid. Their enhancing activity on the penetration of ibuprofen through rabbit skin from petrolatum ointment was evaluated in in-vivo experiment. The experiments showed that the compounds have a strong transdermal penetration-enhancing activity, and their activities were comparable with that of Azone. The measurements of the fluorescence polarization of DP[-i-labelled DPPC liposomes showed that these compounds considerablly decreased the phase transition temperature of the liposomes. The mechanism of the transdermal penetration-enhancing activity of the compounds was ascribed to the reduction of the resistance to drug flux of the stratum corneum lipid layers due to the loose packing of the layers when the bulk head group of the enhancers inserts into the layers.