A Behavioral Study of Promethazine Interaction with Analgesic Effect of Diclofenac: Pain Combination Therapy

Amidi, Niloofar,Izadidastenaei, Zohreh,Araghchian, Malihe,Ahmadimoghaddam, Davoud KOREAN PHARMACOPUNCTURE INSTITUTE 2020 Journal of pharmacopuncture Vol.23 No.1

Objectives: Pain is considered as a cause of sickness and the most prevalent symptom which makes people visit a physician. Nowadays, combination therapy is becoming useful to relieve chronic and postsurgical pain. The aim of this study was to study the promethazine (as an antihistamine) interactions with antinociceptive effect of diclofenac (as a non-steroidal anti-inflammatory drugs). Methods: In initial part of the study, we investigate the analgesic effect of diclofenac. Using writhing test, we demonstrate that diclofenac significantly reduces writhe response induced by acetic acid in a dose-dependent manner. In this study, we evaluate the combination effect of promethazine on diclofenac analgesic effect. Results: We observed that diclofenac inhibited pain in the dose dependent manner which means that by increasing dose of diclofenac a significant decrease in pain was observed. This experimental setup allowed calculation of the dose that caused 50% antinociception (ED50) for diclofenac. The ED50 for diclofenac in this study was determined to be 9.1 mg/kg according our previous study. Additionally, promethazine was showed a dose-dependent inhibition of writhes. The combination of different doses of promethazine (2, 4, 6 mg / kg) with diclofenac ED50 (9.1 mg / kg) was injected to mice. Promethazine 4 and 6 mg / kg in combination with diclofenac had significantly led to increase analgesic effect of diclofenac. Conclusion: In conclusion, these results add important information to the existing knowledge on combination of diclofenac and antihistamine in pain therapies to be used in clinical practice and maybe helpful in designing the future guidelines.

A Behavioral Study of Promethazine Interaction with Analgesic Effect of Diclofenac: Pain Combination Therapy

Niloofar Amidi,Zohreh Izadidastenaei,Malihe Araghchian,Davoud Ahmadimoghaddam 대한약침학회 2020 Journal of pharmacopuncture Vol.23 No.1

Objectives: Pain is considered as a cause of sickness and the most prevalent symptom which makes people visit a physician. Nowadays, combination therapy is becoming useful to relieve chronic and postsurgical pain. The aim of this study was to study the promethazine (as an antihistamine) interactions with antinociceptive effect of diclofenac (as a non-steroidal anti-inflammatory drugs). Methods: In initial part of the study, we investigate the analgesic effect of diclofenac. Using writhing test, we demonstrate that diclofenac significantly reduces writhe response induced by acetic acid in a dose-dependent manner. In this study, we evaluate the combination effect of promethazine on diclofenac analgesic effect. Results: We observed that diclofenac inhibited pain in the dose dependent manner which means that by increasing dose of diclofenac a significant decrease in pain was observed. This experimental setup allowed calculation of the dose that caused 50% antinocicep-tion (ED50) for diclofenac. The ED50 for diclofenac in this study was determined to be 9.1 mg/kg according our previous study. Additionally, promethazine was showed a dose-dependent inhibition of writhes. The combination of different doses of promethazine (2, 4, 6 mg / kg) with diclofenac ED50 (9.1 mg / kg) was injected to mice. Promethazine 4 and 6 mg / kg in combination with diclofenac had significantly led to increase analgesic effect of diclofenac. Conclusion: In conclusion, these results add important information to the existing knowledge on combination of diclofenac and antihistamine in pain therapies to be used in clinical practice and maybe helpful in designing the future guidelines.

디클로페낙의 심혈관계 부작용 발생 위험 분석: 후향적 코호트

엄진희,엄혜연,박소정,이경진,김봉기,최은미,김수진,정수연,구본기 한국병원약사회 2017 병원약사회지 Vol.34 No.3

Diclofenac is one of the most prescribed NSAIDs. However there have been concerns regarding its cardiovascular risk. Our study aimed to examine whether diclofenac was associated with increased risk of cardiovascular diseases (CVDs) in general population. Using the National Health Insurance database, we designed a retrospective cohort study including 8,386,076 patients aged 18 years and over, who were new users of diclofenac, ibuprofen, and naproxen, between 2011 and 2012. All study patients were monitored until their diagnosis of CVDs, their deaths, or the end of the study. We evaluated the incidence of CVDs, and the relationship between CVDs and diclofenac, using the Cox proportional model after adjusting for age, sex, history of medications and diseases. All the rates were expressed per 1,000 person-year. Compared with naproxen, the hazard ratios (HRs) of diclofenac were 1.16 (95% CI=1.14-1.17). The incidence rates of CVDs were 15.3/1,000 in users of diclofenac. Among these users, the incidence of event in the aspirin group was 51.1/1,000, hypertension 42.8/1,000, diabetes mellitus 41.8/1,000, female 16.2/1,000, and aged 65 years and older 60.8/1,000. Our results indicate an increased risk of cardiovascular events in diclofenac users. We further confirmed the association between diclofenac and CVDs reported in previous studies. Although diclofenac shows lesser gastrointestinal complications than ibuprofen or naproxen, patients with hypertension, diabetes mellitus, or the elderly, need to be careful for cardiovascular events while taking diclofenac.

한국인 골관절염 환자에 대한 Celecoxib와 서방형 Diclofenac의 유효성 및 안전성 비교: 다기관 임상연구

안홍준 ( Hong Joon Ahn ),이찬희 ( Chan Hee Lee ),정성모 ( Sung Mo Chung ),이상헌 ( Sang Heon Lee ),이충기 ( Choong Ki Lee ),배성권 ( Sung Kwon Bae ),송정수 ( Jung Soo Song ),박원 ( Won Park ),배상철 ( Sang Cheol Bae ),유대현 ( Da 대한류마티스학회 2002 대한류마티스학회지 Vol.9 No.4

Objective: Long-term use of the analgesic acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis is limited due to the lack of effectiveness and presence of side effects. Celecoxib is a selective inhibitor of cyclo-oxygenase (COX)-2 and expected to help NSAIDs in expressing the effective anti-inflammatory effect by not inhibiting COX-1. Thus, 200 mg of celecoxib and 100 mg of slow releasing diclofenac were compared for their effectiveness and safety in Korean patients with knee osteoarthritis. Methods: We administered 200 mg of celecoxib or 100 mg of slow releasing diclofenac in 223 randomly selected patients with knee osteoarthritis for 4 weeks. The effectiveness of these drugs on osteoarthritis was assessed by evaluating pain in each patient, making overall evaluation on osteoarthritis by the patient and his/her attending physician, and measuring the severity indices on osteoarthritis before treatment, and 2 weeks and 4 weeks after treatment. Moreover, safety and drug resistance were evaluated by assessing the rate of adverse effects, rate of withdrawal, laboratory tests, and vital signs. Results: The clinical symptoms of osteoarthritis were improved significantly by 4 weeks after treatment with celecoxib and diclofenac. According to the results of overall evaluation made by attending physicians 2 weeks after treatment, the rate of improvement was 49.5% in celecoxib group and 35.7% in diclofenac group, showing a statistically significant difference (p=0.023). Other than this difference, no other significant difference was present between the two groups with other variables used for the evaluation of effectiveness. The rate of adverse effects was significantly lower in celecoxib group compared with diclofenac group. According to laboratory findings, no abnormal figure was found in both groups but total bilirubin, SGOT, and SGPT were consistently higher in patients in diclofenac group. Thirteen patients dropped out of the study due to side effects (10 patients) and treatment failure (3 patients). Conclusion: Our findings from the clinical comparison of celecoxib and diclofenac in Korean patients with knee osteoarthritis were similar to those results found in previous studies. Although celecoxib showed similar effectiveness as diclofenac on knee osteoarthritis in the treatment of symptoms, it showed a lower rate of adverse effects; thus, we concluded that celecoxib is safer compared with diclofenac.

한국인에서 초음파유화흡입술을 이용한 백내장수술시 diclofenac sodium의 축동 방지효과

조희태,안영 동국대학교 경주대학 1997 東國論集 Vol.16 No.1

한국인과 같이 짙은 색을 띤 홍채에 초음파유화흡입술을 이용한 백내장수술시 Diclofenac sodium의 축동방지효과를 알아보고자, 40명의 백내장환자를 각 20명씩 2군(diclofenac치료군, 대조군)으로 나누어 double blind test로 본 연구를 시행하였다. 모든 대상 환자들은 백내장수술시 일상적으로 투약되는 약을 술전에 점안했고 치료군은 0.1% diclofenac sodium을 수술 2시간전부터 30분 간격으로 국소 점안하였다. 초음파유화흡입술로 백내장을 제고하고, 추방인공수정체를 삽입한 후 측정한 수술전 후의 동공 변화는 치료군은 -1.31±0.154㎜, 대조군에서 -2.51±0.232㎜로 diclofenac sodium투여군이 술후 축동이 작게 일어나는 것으로 나타났으며, 두 군 사이에 통계학적 유의성이 있었다(p=0.001). Forty patients undergoing elective phacoemulsification with intraocular lens insertion were divided in to a control group(n=20), treated group(n=20) in a double blind, prospective, randomized clinical study to evaluated the nonsteroidal, anti inflammatory drug, diclofenac sodium chloride as an aid for maintaining pupil dilatation during surgery in darkly pigmented iris like Korean. Both groups received the routine preoperative dilating drops and the treated group also received 0.1% topical diclofenac sodium chloride. After lens remove with phacoemulsifier and posterior chamber intraocular lens insertion, the change in pupil diameter from the preoperative measurement average -1.31±0.154㎜ in treated group and -2.51±0.232㎜ in the control group. The difference between groups was significant(p=0.001), favoring diclofenac sodium for maintaining pupil dilatation

산화공정에서의 Diclofenac, Ibuprofen 및 Naproxen의 제거특성 평가

손희종(Hee Jong Son),유수전(Soo Jeon Yoo),황영도(Young Do Hwang),노재순(Jae Soon Roh),유평종(Pyung Jong Yoo) 大韓環境工學會 2009 대한환경공학회지 Vol.31 No.10

본 연구에서는 염소, 오존 및 오존/과산화수소 산화공정에서의 의약물질 3종의 제거특성을 살펴본 결과 diclofenac과 naproxen은 쉽게 산화공정에서 제거가 가능한 것으로 나타난 반면 ibuprofen의 경우는 산화공정에서 제거가 어려운 것으로 나타났다. 오존 단독공정 보다는 오존/과산화수소 산화공정에서의 의약물질의 제거효율이 높았으며, H₂O₂/O₃ 비가 1 이상에서는 제거율의 상승이 둔화되었다. 염소, 오존 및 오존/과산화수소 투입농도별 의약물질 3종에 대한 산화분해 속도 상수와 반감기를 살펴본 결과 염소, 오존 단독 투입에 비하여 오존/과산화수소 공정에서의 산화분해 속도상수가 높게 나타났고, 반감기는 단축되었다. In order to evaluate a removal characteristic of diclofenac, ibuprofen and naproxen by oxidizing agents, Cl₂, O₃ and O₃/H₂O₂ are used as oxidants in this study. In case of that Cl₂ is used for oxidizing pharmaceuticals, ibuprofen is not removed entirely at Cl₂ dose range of 0.5~5.0 mg/L for 60 minutes, however, removal tendency of diclofenac and naproxen are so obviously at Cl₂ dose higher than 0.5 mg/L. In addition, as Cl₂ dose and contact time are increased, the removal rate of diclofenac and naproxen is enhanced. When O₃ is used as oxidizing agent, ibuprofen is not eliminated at O₃ dose range of 0.2~5.0 mg/L. On the contrary, 72~100% of diclofenac and 49~100% of naproxen are removed at O₃ dose of 0.2~5.0 mg/L. From experiments using O₃/H₂O₂ as an oxidant, we can find that O₃/H₂O₂ is much more effective than O₃ only for removal of diclofenac and naproxen. Moreover, the efficiency is raised according to increase of H₂O₂ dose, however, experiments using O₃/H₂O₂ show that oxidation of pharmaceuticals is less effective as H₂O₂ to O₃ ratio increased to above approximately 1.0. On reaction rate constant and half-life of diclofenac, ibuprofen and naproxen depending on Cl₂, O₃ and O₃/H₂O₂ dose, an oxidation of pharmaceuticals by Cl₂ and O₃ particularly has a comparatively high reaction rate constant and short half-life comparing O₃/H₂O₂. From above results, we can fine that diclofenac and naproxen can be easily eliminated in oxidation processes.

덱사메타존과 디클로페낙이 각막실질세포에 미치는 영향

이지은,이승욱,김종환,이종수,Ji-Eun Lee,M,D,Seung-Uk Lee,M,D,Jong Hwan Kim,M,D,Jong Soo Lee,M,D 대한안과학회 2005 대한안과학회지 Vol.46 No.1

Purpose: To evaluate the inhibitory effect of dexamethasone and diclofenac on the proliferation of cultured human keratocytes, and to investigate the apoptotic response and the cellular morphologic changes associated with dexamethasone and diclofenac in vitro. Methods: Human corneal keratocytes were exposed to 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, and 3.2 mM concentration of dexamethasone and diclofenac for 4, 24, and 48 hours. MTT based calorimetric assay, flow cytometric analysis, fluorescent micrograph, inverted phase-contrast micrograph, and electron microscopy were used to evaluate the results. Results: The inhibitory effect of human keratocyte proliferation increased at higher concentrations and longer exposure times of dexamethasone and diclofenac (p<0.05). In flow cytometry, the maximal apoptotic response developed at 0.4 mM concentration of dexamethasone and 1.6 mM concentration of diclofenac after 4 hours. Apoptotic cells were demonstrated in fluorescent micrograph. Dexamethasone-treated cases showed a more damaged appearance, more swollen rather than spindle shaped, with greater detachment from the bottom of the dish and the chromatin of the nuclear remnant condensed along the nuclear periphery with cytoplasmic vesication and cytoplasmic blebs formation, and partial disruption of the nuclear membrane compared with diclofenac. Conclusions: The apoptotic response of dexamethasone and diclofenac is associated with the inhibitory effect of human corneal keratocyte proliferation. For inhibition of cellular proliferation of human corneal keratocytes, dexamethasone may be more effective at lower concentration and shorter exposure time than diclofenac.

제왕절개술 후 통증관리 방법 선택이 제통 효과와 수술 후 경과에 미치는 영향

이영(Young Lee),김사진(Sa Jin Kim),권인(In Kwun),정대영(Dae Young Chung),김창이(Chang Yi Kim),김수평(Soo Pyung Kim),송지민(Ji Min Song),류진희(Jin Hee Yoo),이지영(Ji Young Lee),한상아,김진철(Jin Chul Kim),김창재(Chang Je Kim) 대한산부인과학회 1999 Obstetrics & Gynecology Science Vol.42 No.11

목적 : 본 연구는 통증 관리 방법 선택에 따른 제통 효과의 차이와 수술후 회복기에 미치는 영향을 연구하고자 하였다. 연구 방법 : 총 90명의 제왕절개술을 시술 받은 산모들을 무작위로 군 당 30 명씩 배정하여 이중 맹검 법으로 연구하였다. 수술후 통증은 고식적인 아편양제재의 근 주법(IM군)과 통증자가조절장치를 이용하여(D군, DV군) 조절하였고 수술후 산모가 깨어나 통증을 호소할 때부터 수술후 48시간까지 시행하였다. DV군에선 diclofenac 을 통증관리 보조제로 이용하여 75 mg을 첫 근주후 매 12 시간마다 근 주 하였다. 사용된 아편양 제재의 총량, 통증 점수, 부작용 및 술후 첫 보행시기를 비교하여 각 통증 관리 방법의 유용성 과 안전성을 비교하였다. 결과 : 총 아편양제재의 사용량이 DV군에서 다른 두 군에 비해 40-50% 감소되었다. 통증 점수는 DV군에서 6, 12 및 24시간에 다른 두군에 비해 의의 있게 낮았다(p <0.05).오심, 구토 및 어지럼증의 발생은 IM 군에서 통증자가조절장치를 이용한 두 군 보다 의의 있게 높았다(p<0.05). diclofenac을 통증 관리 보조제로 사용한 군 과 사용하지 않은 군간에 혈색소치, 헤마토크리트, 혈소판수 및 출혈시간 등 검사 결과에 차이가 없었다. 수술후 첫 보행은 DV군에서 다른 두 군에 비해 의의있게 일찍 개시되었다(p <0.05). 결론 : 제왕절개술후 통증 관리에 아편양제재를 통증자가조절장치로 투여하며 diclofenac을 보조 제로 이용한 방법이 가장 효과적이고 안전한 방법이었다. 그러나 diclofenac의 출혈 경향 유무에 대한 더 자세한 연구가 필요하리라 여겨진다 Objective: We investigated influence of choice of pain control method on analgesic effect and postoperative course after cesarean section. Methods: Ninety parturients were randomly allocated to three groups and each group had 30 women. The postoperative pain was controlled with classical intramuscular injection in IM group and PCA (patient-controlled analgesia)device in meperidine (D) and meperidine+diclofenac (DV) group for up to 48 hours after Cesarean section when the parturients awoke and complained pain. The parturients received intramuscular diclofenac 75 mg every 12 hours in DV group. We evaluated usefulness and safety of each pain control method on postoperative opioid requirement, numerical rating score of pain, side effect and first ambulation time for 48 hours after operation. Results: Total opioid requirement was decreased almost 40-50% in DV group. Pain score lowered significantly at 6, 12 and 24 hours in DV group(p <0.05). Nausea,Vomiting and Dizziness were increased in IM group than PCA group(p <0.05). There was no difference in laboratory data including hemoglobin, hematocrit, platelet count and bleeding time in diclofenac used group. Ambulation was started earlier significalty in DV group after Cesarean section(p <0.05). Conclusion: We concluded that diclofenac combined PCA is the most effective and safe method in pain control after cesarean section. But it is necessary to try further evaluation of hemostatic effect of diclofenac.

요로결석 환자에서 diclofenac과 caroverine의 통증조절 효과의 비교연구

이광정,김성은,전영진 대한응급의학회 2001 대한응급의학회지 Vol.12 No.4

Background: Ureteral colic due to acute obstruction of urine flow is a frequent and painful condition presenting in the emergency department. Proper control of ureteral colic is important in the management of such a patient, Many drugs, including narcotics, had been used to control ureteral colic, and of them, nonsteroidal anti-inflammatory drugs are most commonly used. This study was carried out to compare the analgesic effect of diclofenac with that of caroverine which is used empirically in ureteral colic. Methods: We carried out a randomized, prospective clinical trial in the emergency department of a university hospital. Sixty patients in whom ureteral colic had been diagnosed on the basis of physical signs and symptoms were included in this study. Each patients received an IM dose of diclofenac 75 mg, a IV bolus dose of caroverine 20 mg, or a continuous infusion of caroverine 60 mg. An additional dose of medication was added 20 min after the initial medication if needed. Results: The main outcome was measured by using both the visual analogue scale(VAS), four-point categorial pain scale at times of 20,40, and 60 min after initial medication. The requirement for supplemental medication was also measured. At 40 min, diclofenac was more effective than the other two treatments according to its pain- relieving capacity(p<0.05) and the categorial pain scale. By 60 min, caroverine continuous infusion was less effective than the other two treatments according to visual analogue scale(VAS) and the categorial pain scale(p<0.05). There were no significant differences between the diclofenac group and the caroverine bolus injection group at this time, The diclofenac group needed significantly less rescue medication for pain control(p<0.05). Conclusion: IM diclofenac, a non-steroidal antiinflammatory drug, was superior to the spasmolytics, single bolus or continuous intravenous infused, in treatment of urethral colic.

리포솜을 이용한 디클로페낙의 방출 조절

박경구 ( Kyung Goo Park ),서성훈 ( Seong Hoon Seo ) 경희대학교 동서약학연구소 2001 경희약대 논문집 Vol.29 No.-