• Biomolecules & Therapeutics
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• v.19 no.3
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• pp.364-370
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• 2011

The purpose of this study was to investigate the effects of curcumin on the pharmacokinetics of loratadine in rats. The effect of curcumin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Pharmacokinetic parameters of loratadine were also determined after oral and intravenous administration in the presence or absence of curcumin. Curcumin inhibited CYP3A4 activity with an IC50 value of 2.71 ${\mu}M$ and the relative cellular uptake of rhodamine-123 was comparable. Compared to the oral control group, curcumin significantly increased the area under the plasma concentration-time curve and the peak plasma concentration by 39.4-66.7% and 34.2-61.5%. Curcumin also significantly increased the absolute bioavailability of loratadine by 40.0-66.1% compared to the oral control group. Consequently, the relative bioavailability of loratadine was increased by 1.39- to 1.67-fold. In contrast, curcumin had no effect on any pharmacokinetic parameters of loratadine given intravenously, implying that the enhanced oral bioavailability may be mainly due to increased intestinal absorption caused via P-gp and CYP3A4 inhibition by curcumin rather than to reduced renal and hepatic elimination of loratadine. Curcumin enhanced the oral bioavailability of loratadine in this study. The enhanced bioavailability of loratadine might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced fi rst-pass metabolism of loratadine via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by curcumin.

• Biomolecules & Therapeutics
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• v.13 no.1
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• pp.26-31
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• 2005

The present study examined effects of a water-soluble fraction from mulberry leaves (ML water fraction) on the circulatory and autonomic nervous systems, which were compared with those of acetylcholine (ACh) used as a reference drug in order to elucidate its mechanism of action. Intravenous administration of ACh or a ML water fraction produced temporary depressor and tachycardiac responses in a dose-dependent manner in unrestrained, conscious Sprague-Dawley rats. The systemic hemodynamic effects of ACh and a ML water fraction were almost completely blocked by pretreatment with atropine, a muscarinic antagonist. The depressor responses to ACh and a ML water fraction were slightly enhanced and prolonged by pretreatment with neostigmine, an anticholinesterase, whereas the tachycardiac responses were remarkably blocked by pretreatment with pentolinium, a ganglionic blocking agent. In vitro experiments using the ileum isolated from rats showed that ACh and a ML water fraction increased ileal contractility in a dose-dependent manner. The increases in ileal contractility were also completely abolished in the presence of atropine. Finally, the specific binding of [$^3H$]quinuclidinyl benzilate, a muscarinic antagonist, to rat cortical synaptic membranes was inhibited by a ML water fraction in a concentration-dependent manner with an IC$_{50}$ value of 9.5 mg/ml. The results suggest that the effects of a ML water fraction are mediated through direct stimulation of muscarinic cholinergic receptors by unknown cholinomimetic substance(s) contained in that fraction.

• The Korean Journal of Physiology
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• v.9 no.2
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• pp.17-22
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• 1975

Adult nonpregnant female rabbits were subjected to the study of the effects of carbon monoxide inhalation on the uterine motility. Animals were anesthetized with intravenous injection of nembutal, 35 mg/kg, and the uteri were exposed. Polyethylene tubing which had a small hole near the blind tip was inserted in the loop and normal saline was infused at a constant rate of 1.5 ml/min. On the other end of the loop, an outlet of fluid was made. When a peristaltic wave proceeded to the hole, a rise of the pressure was ensued and it was transmitted to the pressure transducer, making an upward deflection of the recording pen on the physiograph. Carbon monoxide, 1,000 ppm in the concentration, was inhaled through a tracheal cannula for 30 minutes, following fresh air for 30 minutes. In some cases, pure oxygen was also supplemented for another 30 minutes. Uterine motility was expressed in terms of the impulse that was the time integral of the pressure and of the frequency of the peristaltic waves. The results obtained were as follows. 1. When 1,000 ppm carbon monoxide was inhaled for 30 minutes, the impulse dropped to $72{\pm}16.5%$ and the frequency to $75{\pm}22.7%$ of the values obtained before the gas administration. 2. By fresh air for 30 minutes, the impulse and the frequency restored to $77{\pm}25.7%$ and $92{\pm}21.1%$, respectively. 3. By the supplement of pure oxygen for 30 minutes, no remarkable improvement were revealed, showing $89{\pm}35.2%$ in the impulse and $91{\pm}10.8%$ in the frequency, respectively. 4. There was an appreciable discrepancy in the recovery courses of the impulse and the frequency, suggesting different mechanisms attributable to the alteration by carbon monoxide inhalation.

• The Korean Journal of Pharmacology
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• v.12 no.2 s.20
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• pp.43-49
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• 1976

The facts that $PGE_2$ produced diuresis in the rabbit when given into a lateral ventricle of the brain and that $PGF_{2{\alpha}}$ is abundantly found in the brain prompted us to investigate the effects of $PGF_{2{\alpha}}$ introduced directly into the ventricle on the renal function. $PGF_{2{\alpha}}$ given intraventriculary in doses of $10{\mu}g\;and\;100{\mu}g$ elicited prompt diuresis, 10-fold increase of sodium excretion and two-fold increment of potassium excretion. Free water reabsorption also increased along with the increased osmolar clearance. Neither renal plasma flow nor glomerular filtration rate did change significantly. This, along with the fact that the percentage of reabsorbed sodium filtered decreased from 99.5 to 93.9, indicates the tubular site of the diuretic and natriuretic action. Atropine pretreatment did not influence the renal effects of intraventricular $PGF_{2{\alpha}}$. Intravenously administered $PGF_{2{\alpha}}$ in doses of 30 to $100{\mu}g$ did not produce any significant change in renal function. Intraventricular $PGF_{2{\alpha}}$ had no effect on the systemic blood pressure, whereas intravenous administration brought about a transient hypotension. These observations suggest that $PGF_{2{\alpha}}$ induces diuresis and natriuresis via central mechanism, that the site of the action resides in renal tubules, and that the reabsorption of sodium is inhibited in the proximal tubule, possibly through mediation of certain humoral agent. Overall, it is suggested that $PGF_{2{\alpha}}$ might play a roll in regulating renal function through the center.

• Clinical and Experimental Pediatrics
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• v.61 no.2
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• pp.64-67
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• 2018

We report the case of a 12-year-old girl who had mild encephalopathy with a reversible splenial lesion (MERS) associated with acutepyelonephritis caused by Escherichia coli. The patient was admitted with a high fever, and she was diagnosed with acute pyelonephritis based on pyuria and the results of urine culture, which detected cefotaxime-sensitive E. coli. Although intravenous cefotaxime and tobramycin were administered, her fever persisted and her C-reactive protein level increased to 307 mg/L. On day 3 of admission, she demonstrated abnormal neuropsychiatric symptoms, such as delirium, ataxia, and word salad. Magnetic resonance imaging (MRI) of the brain performed on day 4 showed marked hyperintensities in the bilateral corpus callosum and deep white matter on diffusion-weighted images, with corresponding diffusion restriction on apparent diffusion coefficient mapping. No abnormalities or pathogens were detected in the cerebrospinal fluid; however, lipopolysaccharides (LPS, endotoxin) were detected in plasma (41.6 pg/mL), associated with acute neurological deterioration. Her clinical condition gradually improved, and no neurological abnormalities were observed on day 6. Follow-up brain MRI performed 2 weeks later showed near-disappearance of the previously noted hyperintense lesions. In this patient, we first proved endotoxemia in a setting of MERS. The release of LPS following antibiotic administration might be related to the development of MERS in this patient. The possibility of MERS should be considered in patients who present with acute pyelonephritis and demonstrate delirious behavior.

• The Korean Journal of Pain
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• v.14 no.2
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• pp.225-230
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• 2001

Background: Opioids such as morphine are widely used in the treatment for pain, but chronic treatment with morphine can be complicated by the development of tolerance. The mechnisms of tolerance were still not completely understood, but recently it has been reported that NOS inhibitors can prevent development of morphine tolerance in animals. The present study accessed the possible role of supraspinal NO on antinociceptive effect of morphine in morphine tolerance using a highly specific inhibitor of the neuronal isoform of NOS, 1-(2-trifluoromethylphenyl) imidazole (TRIM). Methods: Thirty two male SD rats (300 g) were prepared with intracerebroventricular (icv) and IV cannulae. We administrated IV morphine, 3 mg/kg, daily for 4 days, resulting in tolerance. On the fifth day, a challenge dose of morphine, 3 mg/kg, was administered following pretreatment with icv TRIM, $10{\mu}g$. We also evaluated the antinociceptive effect of icv TRIM alone and the effect on a single dose of morphine (3 mg/kg) in morphine nave rats. Antinociception from morphine was determined by response to intraplantar injection of 5% formalin $100{\mu}l$ was qualified as the number of flinches in the first 0-10 min (first phase), 10-40 min Phase IIa, and 40-60 min (Phase IIb). Results: Pretreatment with icv TRIM significantly enhanced the antinociceptive effects of systemically administered morphine in morphine tolerant rats. The antinociceptive effect of morphine in opioid nave rats was also significantly increased by pretreatment with icv TRIM. Conclusions: Our results further support the hypothesis that supraspinal NO modulates morphine-sensitive nociceptive process in morphine tolerance due to chronic intravenous administration.

• The Korean Journal of Pain
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• v.14 no.2
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• pp.186-192
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• 2001

Background: Epidural test doses containing epinephrine are an incomplete marker for the detection of inadvertent intravascular injection. Therefore, many investigators have attempted to find a more reliable marker as an alternative to epinephrine in adult patients anesthetized with enflurane. The present study was designed to test whether two different simulated intravenous test doses of isoproterenol could be used as a reliable marker for the detection of inadvertent intravascular injection in adult patients anesthetized with $O_2-N_2O$-enflurane. Methods: Forty healthy adult patients were anesthetized with 1% end-tidal enflurane and nitrous oxide after endotracheal intubation and were randomized to one of two groups according to the dose of isoproterenol. Group 1 and 2 (n = 20 each) received 3 ml of 1.5% lidocaine with 3 and 5 g isoproterenol intravenously, respectively, to simulate an intravascularly administered test dose. Heart rate (HR) and systolic blood pressure (SBP) were measured at 20-second intervals for 4 min after injection. Results: Mean maximal HR increases were $24{\pm}17$, $35{\pm}11$ bpm (P < 0.05), mean maximal SBP increases were $14{\pm}8$, $13{\pm}9$ mmHg and mean maximal SBP decreases $20{\pm}11$, $22{\pm}9$ mmHg following the IV injection of 3, $5{\mu}g$ isoproterenol, respectively. The incidence of hypotension was similar in both groups. Isoproterenol 3 and $5{\mu}g$ produced 75%, 100% sensitivity in the HR criteria ($\geq$ 20 bpm increase) and 60%, 70% sensitivity in the SBP criteria ($\geq$ 15 mmHg), respectively. Conclusions: These results indicate that based on the HR response, the epidural test dose containing $5{\mu}g$ isoproterenol to simulate an intravascular administration is a more reliable marker than $3{\mu}g$ isoproterenol in adult healthy patients during enflurane anesthesia.

• Journal of Pharmaceutical Investigation
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• v.34 no.5
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• pp.385-391
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• 2004

The purpose of the present study was to formulate the aqueous solution of $20-O-{\beta}-D-glucopyranosyl-20(S)-protopanaxadiol\;(IH-901)$, an intestinal bacterial metabolic derivative from Ginseng protopanaxadiol saponin. For this purpose, the effects of various solubilization agents such as cosolvents [ethanol, propylene glycol (PG), polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), glycerin], surfactants $(Tween\;80,\;Cremophor^{\circledR}\;RH40,\;Cremophor^{\circledR}\;EL,\;Poloxamer\;407,\;Poloxamer\;188)$ and a complexation agent $[hydroxypropyl-{\beta}-cyclodextrin\;(HPBCD)]$, on the solubility of IH-90l in aqueous solution were evaluated. The solubility of IH-901 in water was under $1\;{\mu}g/ml\;at\;20^{\circ}C$. Cosolvents such as ethanol, PG, PEG 300, PEG 400 and glycerin did not enhance the solubility of IH-901 at the 0 - 40% concentration range. The solubility of IH-901 was significantly elevated by the addition of cosolvents over the 80% concentration range. On the other hand, tween 80, $Cremophor^{\circledR}\;EL,\;Cremophor^{\circledR}\;RH40$ and HPBCD showed enhanced effects on the solubility of IH-901. The enhanced effects of Poloxamer 407 or Poloxamer 188 on the IH-901 solubility were less pronounced compared with $Cremophor^{\circledR}\;EL\;or\;Cremophor^{\circledR}\;RH40$. As a results, $Cremophor^{\circledR}$ aqueous solution was selected as an optimum solvent system. The aqueous solutions containing 10% $Cremophor^{\circledR}\;EL$ and 7% $Cremophor^{\circledR}\;RH40$ were formulated as dosing solutions containing 5.0 mg/ml of IH-901 for its intravenous and oral administration, respectively. The formular showed physical stability after stored for 7 days at $4^{\circ}C$.

• Journal of Nutrition and Health
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• v.33 no.6
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• pp.619-624
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• 2000

The purpose of this study was to investigate the effects of vitamin E on microsomal mixed function oxidase system of kidney in streptozotocin(STZ) induced diabetic rats. Sprague-Dawley male rats weighing 140$\pm$10g were randomly assigned to one control and three STZ-diabetic groups which were subdivided into vitamin E free diet(DM-0E group) 40mg vitamin E per kg diet(DM-40E group) and 400mg vitamin E per kg diet(DM-400E group). Vitamin E level of normal group was 40 mg per kg diet. Diabetes was experimentally induced by intravenous administration of 55 mg/kg B.W of STZ in citrate buffer(pH4.3) after 4 weeks feeding of experimental diets. Animals were sacrificed at the 6th day of diabetic state. The contents of cytochrome P450 in kidney were increased by 82, 54, 41% in DM-0E, DM-40E and DM-400E groups respectively when compared with normal group. The contents of cytochrome b5 in kidney were increased by 28% in DM-0E when compared with normal group but those of DM-40E and DM-400E groups were similar to that of normal group. The activities of NADPH-cytochrome P450 reductase in kidney that were increased by 35% in DM-0E group. Levels of TBARS(thiobarbituric acid reactive substance) in kidney were increased by 207, 129% and 72% in DM-0E and DM-400E groups respectively when compared with normal group but those of DM-40E and DM-400E groups were 26,44% lower than that of DM-0E groups. It is know that the activities of MFO system and lipid peroxidation were inhibited in kidney of STZ-induced diabetic rat by administeration of high doses of vitamin E.(Korean J Nutrition 33(6) : 619~624, 2000)

• Journal of Korean Neurosurgical Society
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• v.42 no.5
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• pp.377-381
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• 2007

Objective : High-molecular-weight hydroxyethyl starch (HES) compromises blood coagulation more than does low-molecular-weight HES. We compared the effects of low- and high-molecular-weight HES for the treatment of vasospasm and investigated the dose relationship with each other. Methods : Retrospectively, in a series of consecutive 102 patients with subarachnoid hemorrhage (SAH), 35 patients developed clinical symptoms of vasospasm of these fourteen patients were treated with low-molecular weight HES for volume expansion while the other 21 received high-molecular-weight HES as continuous intravenous infusion. Prothrombin time (PT), partial thromboplastin time (PIT), fibrinogen level, and platelet count were all measured prior to initiation, during treatment and after termination of therapy for symptomatic vasospasm. The total dose of HES ranged from 5 L to 14 L and median infusion duration was 10 days. Results : A more pronounced PTT prolongation was observed in high-molecular-weight HES group compared with low-molecular-weight HES group. No other coagulation parameters were altered. Dosage (=duration) shows a positive correlation with PTT. Clinically, significant bleeding episodes were noted in four patients who received high-molecular-weight HES. Conclusion : Coagulopathy was developed in direct proportion to molecular weight of starch and dosages. We propose the extreme caution in the administration of HES solution for the vasospasm treatment.