• 대한수의학회지
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• 제39권6호
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• pp.1161-1167
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• 1999

To investigate the effect of diazepam on fetal development in pregnant rats, this experiment was performed in eighty Sprague-Dawley female rats which were 8 weeks old and grouped into two according to different diazepam treatment period during 5-9 days of gestation and 10-14 days of gestation. Both experimental groups were included by saline treated groups (control) and diazepam-treated groups (6mg, 12mg and 24mg), respectively. Diazepam was injected to pregnant rats subcutaneously, which were sacrified on 20 days of gestation and mean litter size, fetal body weight, fetal crown-rump length (CRL) and pathological findings were examined. 1. Concerning mean litter size, diazepam-treated groups showed lower mean litter size than control in both 5-9 days and 10-14 days of gestation groups(p < 0.05) without difference according to dosage of diazepam and day of gestation. 2. Concerning fetal body weight, diazepam-treated groups during 5-9 days of gestation showed lower fetal body weight than control and the other treated group during 10-14 days(p < 0.01) without difference according to dosage of diazepam. Diazepam-treated group during 10-14 days of gestation showed no difference among experimented groups. 3. Concerning fetal crown-rump length (CRL), diazepam-treated groups during 5-9 days of gestation showed shorter CRL than control and the other treated group during 10-14 days of gestation(p < 0.01) without difference according to dosage of diazepam. 4. Reduction of mean litter size, fetal body weight and CRL was shown from when treated by the dosage of 6mg/kg of diazepam. 5. Maternal mortality according to dosage of the 20mg/kg of diazepam were 30% and 20% in the treated group during 5-9 days and 10-14 days of gestation, respectively. These results indicated that diazepam treatment in pregnant rats caused considerable reduction of mean litter size, fetal body weight and fetal crown-rump length when treated during 5-9 days of gestation.

• Journal of Yeungnam Medical Science
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• 제6권2호
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• pp.13-22
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• 1989

Benzodiazepine 계통의 약물들은 진정, 최면제로 진정, 최면, 불안의 감소와 함께 횡문근 이완과 항 경련 작용을 가진다는 것은 이미 잘 알려진 바이나 이러한 약리 작용의 기전에 대해서는 아직 확실하게 밝혀진 바가 없다. 최근 이러한 약리 작용과 연관성을 지니는 것으로 알려진 뇌내의 benzodiazepine의 수용체(receptor)를 통한 자극 전달 기전에 calcium 이온의 역할이 큰 비중을 차지할 수 있음이 대두되었다. 또 뇌 이외의 다수의 말초 조직에서도 benzodiazepine의 수용체가 있으며, 이들도 calcium 이온과 상호 작용 할 것이라고 보고된 바가 있으나 이들의 약리 작용과 그 작용 기전에 대해서는 아직 확실히 밝혀진 바가 없다. 이에 저자는 benzodiazepine 계통 약물 중 대표적이라 할 수 있는 diazepam을 사용하여 diazepam이 장관 평활근의 수축성에 미치는 영향을 calcium 이온과 연관시켜 검색하기 위하여 흰쥐 회장 평활근에서 적출한 종주근 절편을 적출 근편 실험조내에서 diazepam 처치 전후의 carbachol, histamine 및 calcium 유발 수축성의 변화를 등척성 장력 측정기를 사용하여 관찰하여 다음과 같은 결과를 얻었다. 1. Diazepam은 흰쥐 회장 절편의 기본 장력을 농도 의존적으로 감소시켰다. 2. Diazepam은 흰쥐 회장 절편의 carbachol-유발 수축 작용을 고농도에서는 억제시켰으며 저농도에서는 오히려 증강시키는 이중 효과를 나타내었다. 3. Diazepam 존재하에서 흰쥐 회장 절편의 histamine-유발 수축 작용은 억제되었으며, diazepam의 농도가 증가함에 따라 그 억제도는 증가하였다. 4. 칼슘 배제 용액에서 칼슘 재 투여로 인한 회장 절편의 장력의 회복율은 diazepam 전처치에 의해 억제되었으며, diazepam의 농도가 증가함에 따라 그 억제도는 증가하였다. 이상의 실험 결과로 미루어 diazepam은 흰쥐 회장 종주근의 수축성을 억제시키며 이 작용은 diazepam이 평활근 세포내로의 calcium의 유입을 억제함으로써 나타나는 것으로 사료된다.

• 한국임상수의학회지
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• 제9권1호
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• pp.301-309
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• 1992

The present study was carried out to compare xylazine(2.2mg/kg, IV), xylazine/acepromazine(1.1mg/kg. IV : 0.2mg/kg, IV) and xylazine/diazepam(1.1mg/kg, IV :1.0mg/kg, IV) anesthesia, to determine useful method out of three kinds of anesthesia and tr evaluate this selected method at hypovolemic state. In xylazine, kylazine/acepromazine and kylazine/diazepam anesthesia, the heart rate was increases after administration of atropine until 10minutes after administration of anesthetics and then decreased gradually in all types of anesthesia. The respiratory rate was decreased after administration of anesthetics in all types of anesthesia. The body temperature was rarely changed in xyiazine/acepromazine and xylazine/diazepam anesthesia, but decreased continuously in xylazine anesthesia. In xylazine and kylazine/acepromazine anesthesia the pedal and corneal reflex were not disappeared completely, but reactions to pin pricking were disappeared. In xylazine/diazepam anesthesia their reflex and reactions were disappeared together. The time from head-up to standing was shortest(32.00min) in kylazine/diazepam anesthesia in comparision with xylazine and kylazine/acepromazine anesthesia. In xylazine/diazepam anesthesia, the heart rates in hypovolemic dogs were decreased soon after administration of anesthetics but recovered immediately. The changes in systolic and diastolic blood pressure in hypovolemic dogs revealed similar trends to their changes in normal dogs after administration of anesthetics. It is considered that rylazine/diazepam anesthesia is one of the useful anesthetic methods in healthy dogs and also in hypovolemic dogs.

• Biomolecules & Therapeutics
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• 제7권3호
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• pp.242-248
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• 1999

Diazepam, a benzodiazepine (BDZ) agonist, produces sedation and flumazenil, a BDZ antagonist, blocks these actions. The aim of this study was to examine the effects of BDZs on cortical electroencephalogram (EEG) in rats. The recording electrodes were implanted over the frontal and parietal cortices bilaterally, and the reference and ground electrodes over cerebellum under ketamine anesthesia. To assess the effects of diazepam and flumazenil, rats were injected with diazepam (1 mgHg, i.p.) and/or flumazenil ( 1 mg/kg, i.p.), and the EEG was recorded before and after drugs. Normal awake had theta peak in the spectrum and low amplitude waves, while normal sleep showed large amplitude of slow waves. The powers of delta, theta and alpha bands were increased during sleep compared with during awake. Diazepam reduced the mobility of the rat and induced sleep with intermittent fast spindles and large amplitude of slow activity, and it produced broad peak over betaL band and increased the power of gamma band, which were different from EEG patterns in normal sleep. Saline injection awakened rats and abolished fast spindles for a short period about 2-5 min from EEG pattern during diazepam-induced sleep. Flumazenil blocked both diazepam-induced sleep and decreased the slow activities of delta, theta, alpha and betaL, but not of gamma activity for about 10 min or more. This study may indicate that decrease in power of betaL and betaH bands can be used as the measure of central action of benzodiazepines, and that the EEG parameters of benzodiazepines have to be measured without control over the behavioral state by experimenter.

• 대한기관식도과학회지
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• 제4권1호
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• pp.64-72
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• 1998

This study aimed at observing the effect of diazepam on the contractility of trachealis muscle isolated from canine trachea, possible involvement of central or peripheral type benzodiazepine receptor, and the calcium related mechanism of action of diazepam. Trachealis muscle strips of 15 mm long were suspended in an isolated organ bath containing 1 ml of physiologic salt solution maintained at $37^{\circ}C$, and aerated with 95% $O_2$ /5% $CO_2$. Isometric myography was performed. Diazepam reduced the basal tone concentration dependently, and this inhibitory action was not affected by neither flumazenil, a central benzodiazepine receptor antagonist, nor PK11195, a peripheral benzodiazepine receptor antagonist. Pretreatment with diazepam showed the inhibitory effect on the concentration-response curves to agonists such as bethanechol, 5-hydroxytryptamine and histamine. Diazepam also caused concentration-related inhibition of contraction with potassium chloride 30 mM. The effect of diazepam on the basal tone and potassium chloride-induced contraction with calcium channel blockers were compared. Similar results were obtained in canine trachealis with verapamil, nifedipine and diltiazem. These results suggest that diazepam relax an airway muscle not via specific receptors but by a similar action as calcium channel blockers in canine trachealis muscle.

• 생명과학회지
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• 제19권8호
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• pp.1009-1015
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• 2009

Flavonoid류와 진정제의 시험관 내 암세포증식억제효과를 관찰하기 위하여, 암세포의 말초형 benzodiazepine 수용체(이하 PBR로 약함) 활성도와 포도당 활용도에 대한 효과를 유방암 세포를 대상으로 검색하였다. 동시에 이미 항암활성이 잘 알려진 flavonoid류와의 상호작용도 관찰하였다. Fisetin (3,7,3',4'-tetrahydroxyflavone)과 diazepam의 암세포 증식 억제 효과는 악성도가 높은 MDA-MB-231 유방암 세포에서 MCF-7 유방암세포보다 저명하게 관찰되었다. MDA-MB-231 유방암세포에서, Apigenin (4',5,7-Trihydroxyflavone)과 fisetin 같은 flavonoid류처럼, $10^{-6}$ M 농도의 dazepam을 3일간 처치하였을 때 암세포 증식 억제효과를 나타내었으며, 이는 PBR 배위자들의 암세포 증식 증진효과와는 차이를 나타낸 것이다. Flavonoid 류처럼, MDA-MB-231 유방암세포에서, $10^{-6}$ M dazepam의 3일간 처치는 암세포의 PBR mRNA 발현에 큰 영향을 미치지 않았다. $10^{-6}$ M diazepam의 6 일간 처치는 암세포의 증식억제 효과가 증가되어 나타났으며, 암세포의 PBR mRNA 발현도 억제되었다. MDA-MB-231 유방암 세포에서, apigenin, fisetin과 diazepam은 포도당 유용도를 억제하였으며, 인슐린에 의한 포도당 유용도 증강효과도 억압하였다. Apigenin은 diazepam의 암세포 증식 억제 효과를 부가적으로 증강시켰다. 요약하면, 본 연구결과는 flavonoid류와 진정제의 시험관내 암세포 증식 억제효과와 부가적인 상호작용을 보여주고 있다. 결론적으로, 본 연구는 향후 좀더 진척된 시험을 위한 실험적인 기반 정보이다.

• Journal of Yeungnam Medical Science
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• 제9권2호
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• pp.359-381
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• 1992

Benzodiazepine계 약물들은 진정 최면제의 대표적인 약물로서, 중추신경계에서의 그 작용은 gamma amino butyric acid(GABA) 수용체와 짝지워져 있는 benzodiazepine 수용체를 통해서 나타나며 또한 뇌에 있는 synaptosome에서 전위 의존성 calcium channel을 통한 calcium의 섭취를 억제함으로써 진정작용 및 최면 작용이 나타난다. 이와 아울러 말초 장기에서도 benzodiazepine 수용체와 GABA 수용체가 발견 되었는데 이들의 기능과 상호관계는 잘 알려져 있지 않다. 이에 본 실험에서는 benzodiazepine계통의 대표적인 약물이며 중추신경과 말초 장기에 동시에 작용하는 diazepam이 흰쥐 적출자궁의 자발 수축 및 oxytocin 유발 수축에 미치는 영향을 검색하고, 이러한 diazepam의 효과와 GABA 수용체 및 calcium과의 상호관계를 검색함으로써 그 작용기전을 추구해 보기 위하여 다음과 같은 실험을 하였다. 난소를 제거한 후 estrogen(17 beta-estradiol : $500{\mu}g/kg/day$)을 4일 동안 전 처치한 흰쥐의 자궁을 적출하여 등척성 장력을 측정함으로써 그 수축력의 변화를 관찰하였다. Diazepam과 GABA 수용체 효현제 및 그 봉쇄제들이 자궁절편의 자발 수축과 oxytocin 유발 수축에 미치는 영향을 검색하였고, 또 이들 약물의 작용에 관련된 calcium 동원기전에 대하여 관찰하여 다음과 같은 결과를 얻었다. Diazepam은 흰쥐 적출자궁의 자발수축 및 oxytocin 유발수축을 농도 의존적으로 억제하였다. GABA, GABA A 수용체 효현제인 muscimol, GAGA A 수용체의 상경적 봉쇄제인 bicuculline, GABA A 수용체의 비상경적 봉쇄제인 picrotoxin, GABA B 수용체 효현제인 boclofen, 그리고 GABA B 수용체 봉쇄제인 delta-aminovaleric acid는 흰쥐 적출 자궁의 자발 수축 및 oxytocin 유발수축에 아무런 영향을 미치지 않았다. 자발 수축 및 oxytocin 유발수축에 대한 diazepam의 억제 작용은 GABA 수용체 효현제 및 봉쇄제의 영향을 받지 않았다. 그러나 bicuculline은 diazepam의 억제 작용에 상가적으로 작용하였는데, bicuculline의 이러한 작용은 muscimol에 의해서 길항되지 않았다. 정상 PSS 내에서 diazepam에 의해 억제되었던 자발수욱 및 oxytocin유발수촉은 calcium의 첨가 및 calcium inophore인 A23187의 첨가로 일부 회복되었다. Calcium 배제 용액내에서는 diazepam이 calcium 첨가로 인한 수축력 회복을 방해하였으며 calcium inophore인 A23187에 의한 수축력 증가는 막지 못하였다. 또 세포외액에 calcium이 결핍된 상태에서는 oxytocin 자체에 의한 수축을 방해하지 못하였으나 이어 첨가된 calcium에 의한 oxytocin 유발 수축의 증가는 일부 억제하였다. 이상의 실험결과로 미루어 볼 때 diazepam은 자궁의 자발수측 및 oxytocin 유발 수축을 억제할 수 있으며, 이러한 작용은 GABA 수용체 의존성이 아닌 세포외액의 calcium의 유입을 억제함으로써 나타나는 것으로 사료된다.

• 대한약리학회지
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• 제19권1호
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• pp.115-122
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• 1983

The influences of diazepam and naloxone on the increase of plasma corticosterone level induced by morphine, pentazocine, ACTH, or picrotoxin were investigated in male mice. The results obtained were summarized as follows: 1) The increase induced by morphine or pentazocine of plasma corticosterone level was not affected by naloxone pretreatment but markedly suppressed by diazepam pretreatment. 2) The increase induced by ACTH of plasma corticosterone level was not affected by diazepam or naloxone pretreatment. 3) The picrotoxin markedly increased plasma corticosterone level, and the inceease was not affected by diazepam or naloxone pretreatment. This above results suggest that the increase induced by opioids of plasma corticosterone level seems to be rather related with other than opiate- or GABArerecptor.

• The Korean Journal of Physiology and Pharmacology
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• 제2권5호
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• pp.555-563
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• 1998

The renal function is under regulatory influence of central nervous system (CNS), in which various neurotransmitter and neuromodulator systems take part. However, a possible role of central GABA-benzodiazepine system on the central regulation of renal function has not been explored. This study was undertaken to delineate the renal effects of diazepam. Diazepam, a benzodiazepine agonist, administered into a lateral ventricle (icv) of the rabbit brain in doses ranging from 10 to 100 ${\mu}g/kg,$ elicited dose-related diuresis and natriuresis along with improved renal hemodynamics. However, when given intravenously, 100 ${\mu}g/kg$ diazepam did not produce any significant changes in all parameters of renal function and systemic blood pressure. Diazepam, 100 ${\mu}g/kg$ icv, transiently decreased the renal nerve activity (RNA), which recovered after 3 min. The plasma level of atrial natriuretic peptide (ANP) increased 7-fold, the peak coinciding with the natriuresis and diuresis. Muscimol, a GABAergic agonist, 1.0 ${\mu}g/kg$ given icv, elicited marked antidiuresis and antinatriuresis, accompanied by decreases in systemic blood pressure and renal hemodynamics. When icv 0.3 ${\mu}g/kg$ muscimol was given 3 min prior to 30 ${\mu}g/kg$ of diazepam icv, urinary flow and Na excretion rates did not change significantly, while systemic hypotension was produced. These results indicate that icv diazepam may bring about natriuresis and diuresis by influencing the central regulation of renal function, and that the renal effects are related to the increased plasma ANP levels, not to the decreased renal nerve activity, and suggest that the effects may not be mediated by the activation of central GABAergic system.

• Archives of Pharmacal Research
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• 제6권1호
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• pp.7-16
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• 1983

A methadone-diazepam interaction study in rats was performed in which conjugated metabolites of methadone were analyzed using deuterated biosynthetic internal standards. Diazepam (5mg/kg) was given to rats through a cannulate djugular vein and a subcutaneous dose of methadone (10mg/kg) was given. Bile was collecte through the cannulate dbile duct over a period of 24 hours. The deuterium label of the internal standards was found to be stable under conditions of the prolonged incubation. There was no significant difference in the excretion of the metabolites between the control and the diazepam treated rats. Feasibility of using biosynthetic internal standards with selected ion monitoring was established for the drug metabolism and kinetic studies.