• Korean Journal of Clinical Pharmacy
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• v.19 no.1
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• pp.32-36
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• 2009

The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of nicardipine in rats. Pharmacokinetic parameters of nicardipine were determined after an oral administration of nicardipine (12 mg/kg) to rats coadministered with simvastatin (0.3 and 1.0 mg/kg). Compared with the control (given nicardipine alone), coadministration of simvastatin (1.0 mg/kg) significantly (p<0.05) increased the area under the plasma concentration (AUC) and peak plasma concentration ($C_{max}$) of nicardipine. The relative bioavailability (RB%) of nicardipine increased from 1.19- to 1.48-fold. However there were no significant changes in $t_{max}$, and $t_{1/2}$ of nicardipine. The enhanced oral bioavailability of nicardipine might be due to an inbition of cytochrom P450 3A mediated-metabolism of nicardipine in the intestine and in the liver by simvastatin. Based on these results, the concurrent use of simvastatin significantly enhanced the oral exposure of nicardipine in rats. The dosage regimen of nicardipine should be taken into consideration for potential drug interaction when combined with simvastatin in clinics.

• The Korean Journal of Pain
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• v.35 no.1
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• pp.59-65
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• 2022

Background: There is still unmet need in treating neuropathic pain and increasing awareness regarding the use of drug combinations to increase the effectiveness of treatment and reduce adverse effects in patients with neuropathic pain. Methods: This study was performed to determine the individual and combined effects of pregabalin, tianeptine, and clopidogrel in a rat model of neuropathic pain. The model was created by ligation of the L5-L6 spinal nerve in male Sprague-Dawley rats; mechanical allodynia was confirmed using von Frey filaments. Drugs were administered to the intrathecal space and mechanical allodynia was assessed; drug interactions were estimated by isobolographic or fixed-dose analyses. Results: Intrathecal pregabalin and tianeptine increased the mechanical withdrawal threshold in a dose-dependent manner, but intrathecal clopidogrel had little effect on the mechanical withdrawal threshold. An additive effect was noted between pregabalin and tianeptine, but not between pregabalin and clopidogrel. Conclusions: These findings suggest that intrathecal coadministration of pregabalin and tianeptine effectively attenuated mechanical allodynia in the rat model of neuropathic pain. Thus, pregabalin plus tianeptine may be a valid option to enhance the efficacy of neuropathic pain treatment.

• Tuberculosis and Respiratory Diseases
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• v.38 no.4
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• pp.372-378
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• 1991

Some kinds of newer fluoroquinolone antibiotics are known to interact with theophylline, which is widely used as a potent bronchodilator in asthma or chronic obstructive lung disease. To evaluate the effect of enoxacin and ciprofloxacin on the metabolism of theophylline, aminophylline was administered intravenously in bolus (6 mg/kg) over 30 minutes to 6 healthy volunteers (age: $23.3{\pm}4.2$ year, body weight: $63.2{\pm}9.0\;kg$, height: $169.0{\pm}6.5\;cm$, female 3, male 3) before and after per oral 5-day medication of enoxacin and ciprofloxacin, respectively and we measured the level of theophylline in serum. The results were as follows: 1) Enoxacin and ciprofloxacin did not influence the volume of distribution significantly. 2) Enoxacin decreased the clearance of theophylline significantly (from $42.9{\pm}14.6\;ml/min$ to $30.1{\pm}6.3\;ml/min$: p<0.05), but ciprofloxacin did not cause significant decrease (to $32.8{\pm}6.2\;ml/min$: p>0.005). 3) Enoxacin increased the elimination half life of theophylline significantly (from $496{\pm}83\;min$ to $693{\pm}32\;min$: p<0.001), but ciprofloxacin did not cause significant increase (to $687{\pm}222\;min$: p>0.05). These results suggested that enoxacin influenced clearance and elimination half life significantly and thorough monitoring of the level of theophylline in patients with coadminstration of enoxacin and theophylline was necessary. In case of ciprofloxacin, the influence on the metabolism of theophylline was not statistically significant, but one exceptionally large decrease of the clearance and increase of the elimination halflife of theophylline suggested the necessity of monitoring of theophylline level during coadministration of ciprofloxacin and theophylline.

• Korean Journal of Biological Psychiatry
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• v.6 no.2
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• pp.253-258
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• 1999

The fluoxetine is one of the most frequently prescribed drugs for the treatment of depression and obsessive-compulsive disorder(OCD). This has been known as one of the most safest medication. But since the advent of this drug, there have been several reports of side effects-the mania and suicidal ideation-encountered during coadministration of fluoxetine with or without other psychotropic drugs. We experienced a case of 20 years old male OCD patient who developed into abrupt manic state and also was preoccupied with intense suicidal ideation following fluoxetine use. He was a only child in his family and his father had a history of alcoholism about 15years ago. Our patient's obsessive-compulsive symptoms have been occured since puberty. His OCD symptoms and anxiety were aggravated since joining the army. Beside these facts, we could not find any other psychiatric history such as depressive disoder and bipolar disorder. We used the fluoxetine starting dosage of 20mg and increased to 40mg at second week. About 3 weeks after the treatment, he developed sudden manic symptom and more aggravated suicidal ideation without any OCD symptoms. He felt vitalized and energetic without having enough sleep and food. These symptoms were ceased over two weeks by stopping medication. Up to this point, the reason why fluoxetine induces mania and suicidal preoccupation is unclear. But somehow the fluoxetine has effects on serotonin receptor and serotonin-dopamine regulations, thus we could make an assumption that fluoxetine can induce mania, extrapyramidal symptoms(EPS) and suicidal ideation in some part of the serotonin unbalanced patients. We think this would be the first report to remark on fluoxetine's suicidal and manic side effects in Korea. So here we present the case with the summary of reviewed articles.

• Journal of Pharmaceutical Investigation
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• v.33 no.4
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• pp.299-304
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• 2003

The purpose of this study was to investigate the effect of coadministration (2.5, 10, 20 mg/kg) and 3 or 7 days-pretreatment (10 mg/kg) of diltiazem on the pharmacokinetic parameters of paclitaxel (50 mg/kg) given orally in rats. The plasma concentrations of paclitaxel coadministered or pretreated with diltiazem were significantly (p<0.05 at 20 mg/kg coadmin., p<0.05 at pretreat.) increased compared to that of control, from 0.5 hr to 24 hr. Area under the plasma concentration-time curve (AUC) of paclitaxel coadministered or pretreated with diltiazem was significantly (p<0.05 at 20 mg/kg coadmin., p<0.01 at pretreat.) higher than that of control. Peak concentrations $(C_{max})$ of paclitaxel with diltiazem were significantly (p<0.05 at 20 mg/kg coadmn. and pretreat.) increased compared to that of control. Elimination rate constants $(K_{el})$ of paclitaxel with diltiazem were significantly (p<0.05 at 20 mg/kg and 7 days-pretreat.) reduced compared to those of control. Half-life $(t_{1/2})$ and mean residence time (MRT) of paclitaxel with diltiazem was significantly (p<0.05 at 20 mg/kg ad 7 days-pretreat.) prolonged compared to those of control. Absolute bioavailability (AB%) of paclitaxel with diltiazem was significantly (p<0.05 at 20 mg/kg and 3 days-pretreat, p<0.01 at 7 days -pretreat.) increased compared to that of control. Based on these results, it might be considered that diltiazem may inhibit cytochrome $P_{450}$ and P-glycoprotein, which are respectively engaged in paclitaxel absorption and metabolism in liver and gastrointestinal mucosa.

• The Journal of Korean Medicine
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• v.25 no.2
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• pp.165-172
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• 2004

Objectives: Warfarin is a representative anticoagulant, and it has been the preferred drug for treating thromboembolic diseases and preventing ischemic stroke. It should be administered in a delicate manner, because combined therapy with other drugs could affect the INR (International Normalized Ratio), thus bleeding tendency might occur. Interaction with herbal medicines still remains controversial. We aimed to examine the effect of herbal medicine on INR in patients being treated with warfarin. We aimed to examine the effect of herbal medicine on INR in the patients being treated with warfarin. Methods: We enrolled subjects being treated with a combined therapy of warfarin and herbal medicine from 1 October, 2002 to 20 November, 2003 at the Department of Cardiovascular & Neurologic Diseases (Stroke Center), Hospital of Oriental Medicine, Kyung Hee Medical Center. INR was monitored per 1 to 2 weeks and the significance of change was examined by Wilcoxon signed rank test or repeated measure analysis Results: Eighty-three subjects were included in the final analysis. As a whole, their INR was not significantly changed. There were only 9 cases in which INR changed more than 1.0; 7 showed increasing tendency, and 2 showed decreasing tendency of INR. Among the 9 cases, only 5 were suspected to have a relation to herbal medicine. Conclusions: We suggest that there was no strong evidence that herbal medicine has an influence on INR, but there is a need to perform further evaluation on larger samples to reach a concrete conclusion.

• The Korean Journal of Pain
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• v.18 no.2
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• pp.99-106
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• 2005

Background: Cyclic guanosine monophosphate (cGMP) and opioid receptors are involved in the modulation of nociception. Although the opioid receptors agonists are active in pain, the effect of an phospodiesterase inhibitor (zaprinast) for increasing the level of cGMP has not been thoroughly investigated at the spinal level. This study examined the effects of intrathecal zaprinast and morphine in a nociceptive test and we also examined the nature of the pharmacological interaction after the coadministration of zaprinast with morphine. The role of the nitric oxide (NO)-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. Methods: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, $50{\mu}l$ of 5% formalin solution was applied to the hindpaw. Isobolographic analysis was used for the evaluation of the drug interaction between zaprinast and morphine. Furthermore, NO synthase inhibitor ($_L-NMMA$), guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide) were intrathecally administered to verify the involvement of the NO-cGMP- potassium channel pathway on the antinociception effect of zaprinast. Results: Both zaprinast and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after the intrathecal administration of the zaprinast-morphine mixture in both phases. Intrathecal $_L-NMMA$, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase. Conclusions: These results suggest that zaprinast, morphine and the mixture of the two drugs are effective against acute pain and they facilitated pain state at the spinal level. Thus, the spinal combination of zaprinast with morphine may be useful for the management of pain. However, the NO-sensitive cGMP-potassium channel pathway did not contribute to the antinocieptive mechanism of zaprinast in the spinal cord.

• Environmental Analysis Health and Toxicology
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• v.4 no.3_4
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• pp.7-14
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• 1989

Amygdalin has been used for a long time as an anticancer agent. But because of its toxicity, it is difficult to administer continuously for treatment of cancer. This paper was attempted to reduce the side effect and toxicity of amygdalin. That is, effects of cysteine and streptomycin on the toxicity of amygdalin were investigated in rats orally administered amygdalin. 1. The group administered only amygdalin 400 mg/kg was effected on the lung and body weight, hematocrit, hemoglobin, clotting time, SGOT and albumin value. That is, lung and body weight, hematocrit hemoglobin and albumin value were significantly decreased. SGOT and clotting time were significantly increased compared with those of normal group. 2. Weight of lung was significantly increased in the C group (administred amygdalin 400 mg/kg and cysteine 300 mg/kg), D group (amygdalin 400 mg/kg and streptomycin 10 mg/kg), E group (amygdalin 400 mg/kg, streptomycin 10 mg/kg and cysteine 200 mg/kg)and F group (amygdalin 400 mg/kg, streptomycin 10 mg/kg and cysteine 300 mg/kg). 3. Values of hematocrit and hemoglobin were significantly increased, and clotting time was significantly decreased, in the I group and F group compared with those of A group. 4. SGOT was significantly decreased in the C group, E group and F group compared with that of A group. 5. The blood cyanide concentration was significantly decreased in the E group and F group compared with that fo A group. 6. In short, coadministration of cysteine and streptomycin are considered to reduce the toxicity of amygdalin in rats orally administered.

• The Korean Journal of Pain
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• v.11 no.1
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• pp.47-53
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• 1998

Background: Epidural coadministration of opioids and local anesthetics has provided excellent analgesia during postoperative period. However, it is usually associated with the occurance of many side effects which were induced by epidural morphine. Low dose of intravenous naloxone has been known to reduce morphine-induced side effects without reversing analgesia, but the effect of epidural naloxone has not been defined in human study. Therefore we evaluated side effects and analgesia when naloxone was administered via epidural route. Methods: Eighty patients having epiduro-general anesthesia for hysterectomy were randomly assigned to one of four study groups. As a mean of postoperative pain control, all received 2 mg of epidural morphine bolusly at 1 hr before the end of surgery and continuous epidural infusion was started by Two-day Infusor containing morphine 4 mg in 0.125% bupivacaine 100 ml with either none of naloxone(Group 1, n=20), 2 ug/kg/day of naloxone(Group 2, n=20), 3 ug/kg/day of naloxone(Group 3, n=20) or 4 ug/kg/day of naloxone(Group 4, n=20). Study endpoints included visual analog scales(VAS) for pain, severity of nausea, itching, somnolence and respiratory depression. They were assessed at 2, 4, 8, 16, 32, and 48 hr postoperatively. Results: VAS for pain showed significant difference in Group 4 compared with Group 1 at all of the evaluation time. Itching score decreased significantly in Group 3 and 4 after 8 hr postoperatively and nausea score decreased significantly in Group 3 after 4 hr postoperatively. Alertness score decreased significantly in Group 3 and 4 especially in early postoperative period. Conclusion: This study suggests that epidural naloxone reduce morphine-induced side effects in dose-dependent fashion without reversal of the analgesic effect of epidural morphine.

• The Korean Journal of Pain
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• v.14 no.2
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• pp.150-155
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• 2001

Background: Tramadol is known to be a weak opioid. However, it has also been shown that tramadol is an effective norepinephrine and serotonin uptake blocker, which may be effective in the treatment of neuropathic pain. The present study was undertaken in order to assess the antinociceptive action of tramadol and to investigate possible antinociceptive mechanisms by using antagonists in an animal neuropathic pain models in rats. Methods: Rats were prepared with tight ligation at the left 5 and 6th lumbar spinal nerves (Kim and Chung's neuropathic pain model). The antinociceptive effects of tramadol (10, 20, and 50 mg/kg i.p.) in rats with neuropathic pain were assessed. Additionally, following coadministration of antagonists such as naloxone (1 mg/kg i.p.), yohimbine (1 mg/kg i.p.) and ritanserin (1 mg/kg i.p.) with 50 mg/kg of tramadol, the responses to mechanical and thermal stimuli were measured over a two-hour period. Results: Tramadol displayed potent antinociceptive effects in a dose-dependent manner on rats with neuropathic pain (P < 0.05). The effects of tramadol were inhibited by coadministered naloxone and yohimbine in rats with mechanical and thermal allodynia, respectively (P < 0.05). However, there were no significant changes in the pain behaviors in the case of ritanserin. Conclusions: Tramadol showed significant antinociceptive effects in rats with regards to neuropathic pain against both mechanical and thermal allodynia. The antinociceptive effect on the mechanical stimuli is medicated via an opioid receptor. However, it appears that the antinociceptive effects on thermal allodynia are mediated via a noradrenalin receptor vice a serotonergic receptor.