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BACKGROUND: Warfarin potassium (Wf) commercial tablets originally formulated for adults are ground before administration to pediatric patients and elderly patients with dysphagia. OBJECTIVE: The present study investigated the effect of tablet grinding on the photostability of four types of commercial Wf tablets and predicted the photostability of the tablet powders by chemometric analysis. METHODS: The photodegradation of Wf content was evaluated by reversed-phase column high-performance liquid chromatography with ultraviolet (HPLC-UV). RESULTS: The bulk Wf powder was relatively photostable, whereas ground Wf tablets underwent substantial photodegradation. The photostability of the ground powders of a brand-name Wf commercial tablet and three generic Wf commercial tablets was quantitatively assessed and compared. In certain cases, the Wf in all the three ground generic tablets was less photostable than in the ground brand-name tablets. After 28 days of light irradiation, the Wf content decreased to 69.79% in the brand-name tablets, while it was 31.90% in some generic tablets. To clarify the factors influencing the relative photostability in various Wf formulations, we analyzed the intermolecular interactions between the active ingredient and the excipients by partial least-squares regression analysis based on photostability screening for each additive. CONCLUSION: The results suggested that the additives light anhydrous silicic acid and povidone adversely affect the stability of Wf tablets. In addition, the light stability of ground tablets was affected considerably by their formulation.

60歳代男性．慢性心房細動のためワルファリンカリウムを内服していた．過去に副腎皮質腺腫を指摘されたが非機能性であり経過観察されていた．右側腹部痛のため近医受診したところ，腹部造影CTで右副腎周囲に造影剤の血管外漏出像を伴う血腫を認め，精査加療目的に当院へ転院搬送された．来院時全身状態は安定しており貧血は認めなかった．プロトロンビン時間（国際標準比）（PT-INR）は1.85であった．当院での造影CTでは血腫の増大はなく，安静とワルファリン拮抗で加療した．入院後貧血は進行せず，第6病日の腹部CTでは血腫の増大を認めなかった．また，各種副腎ホルモンの異常を認めなかった．ワルファリンはPT-INRが通常の治療域で出血したこともあり，直接経口抗凝固薬に変更して第11病日に退院とした．副腎腫瘍のうち非機能性副腎皮質腺腫からの出血は比較的稀である．また，循環動態が安定していれば保存的加療が可能である．

Lenvatinib is approved as a standard systemic therapy for unresectable hepatocellular carcinoma (HCC) patients; however, experience with lenvatinib in clinical practice is insufficient. We present the case of a patient with advanced HCC whose prothrombin time - international normalized ratio (PT-INR) was elevated after cotreatment with lenvatinib and warfarin potassium. The patient was a 26-year-old man with congenital abnormalities who had to take warfarin potassium because he had a mechanical heart valve. He was diagnosed with unresectable HCC at 24 years old and was treated by transcatheter arterial chemoembolization and transcatheter arterial infusion. After some interventional radiology treatments, lenvatinib was started. After 4 days of treatment with lenvatinib and warfarin potassium, his PT-INR increased to 4.13, and the treatment had to be stopped. No changes were observed in other Child-Pugh score factors. The elevation in the PT-INR after cotreatment with lenvatinib and warfarin potassium was thought to be caused by pharmacological effects of concurrent use or pharmacological sensitivity to warfarin potassium in this patient with liver dysfunction. The PT-INR must be monitored when lenvatinib is given to advanced HCC patients taking warfarin potassium.

抗トロンビン薬であるダビガトランが、非弁膜症性心房細動に起因する心原性塞栓症予防に有効であることが証明され、臨床利用されて5年が経過した。適応疾患である非弁膜症性心房細動だけでなく、適応外である機械弁置換術後にダビガトランが使用され、直後に脳塞栓症を発症した症例の治療を経験した。61歳男性 2011年11月大動脈弁閉鎖不全症に対し機械弁による弁置換術を施行された。2012年4月に患者希望でワルファリンからダビガトランに変更され、1ヵ月後に右内頸動脈閉塞による左片麻痺(NIHSS=15/42)を発症した。血栓回収療法を行ったが改善が得られなかった。(著者抄録)

Background Toxic epidermal necrolysis (TEN) is a rare life-threatening condition almost exclusively attributed to drugs. The main etiologic factors for TEN are sulphonamides, anticonvulsants, and antibiotics; however, there are no published reports of warfarin causing TEN. Case presentation We present the case of a 3-year-old patient who developed TEN while receiving treatment for Henoch–Schönlein purpura nephritis (HSPN). With multiple-drug therapy comprising prednisolone, mizoribine, dipyridamole, and warfarin, it is difficult to detect which drug is the causative agent. While in most cases, diagnosis of the causative drug is based on clinical history without a lymphocyte transformation test (LTT), we performed the test three times and identified the causative drug as warfarin at the late phase. We continued HSPN treatment without warfarin, and results showed good renal function without life-threatening complications. Conclusion To our knowledge, this is the first report about TEN caused by warfarin. Repeated LTTs could be useful for identifying TEN-causative drugs even in the late phase.

お茶飲料のうち、浸出液タイプ(A)、浸出液にお茶の粉末入りタイプ(B)、包装記載のおいしい入れ方に従い調製したお茶粉末混合タイプ(C)、それぞれのお茶飲料中のビタミンK1含有量を高速液体クロマトグラフィーで定量した。澤田らおよびKurnikらの報告に基づき、1日25μgのビタミンK1摂取により、ワルファリンカリウム服用患者の抗凝血作用に影響が現れると仮定し、食品・医薬品相互作用が発現する恐れのあるお茶飲料の1日摂取量を計算したところ、(A)141±40.0L(B)11.3±5.58L(C)2.91±0.370Lとなった(n=3、mean±SD)。とくに、包装記載のおいしい入れ方に従い調製したお茶粉末混合タイプを飲用する場合、ビタミンK1とワルファリンカリウムとの食品・医薬品相互作用の発現が懸念された。お茶を摂取しているワルファリンカリウム服用患者では、どのような種類のお茶を摂取しているかについて聴き取りを行い、服薬指導を行う必要性が明らかとなった。The vitamin K1 content in several tea beverages, tea leaf infusion (type A), tea leaf infusion with powdery tea leaves (type B), and powdery tea leaves added to water following package instructions for making good tea (type C), were determined using highperformance liquid chromatography (HPLC). Assuming that the anticoagulant effect was influenced by ingesting 25 μg of vitamin K1 a day in patients taking warfarin potassium based on the report by Sawada et al. and Kurnik et al., we evaluated potential daily intake for each tea beverage contributing to the food-drug interaction; type A is 141 ± 40.0 L, type B is 11.3 ± 5.58 L, and type C is 2.91 ±0.370 L (n = 3, mean ± SD). There is concern that an interaction between vitamin K1 and warfarin potassium could occur especially when taking type C tea beverage. Pharmacists need to confirm the kind of tea beverage patients are intaking when giving patient compliance instructions to patients taking warfarin potassium and tea beverages.

東医療センター内科・血液浄化部 佐中孜教授退任記念特別号

We report herein a case of a 28-year-old woman with persistent livedo racemosa and recurrent ulcerations on the lower extremities. The clinical presentation, together with histopathological findings of vascular occlusion without overt vasculitis in the dermis, led to the diagnosis of livedoid vasculopathy. The patient experienced recurrence of ulcerations and developed peripheral neuropathy affecting the distal extremities during the course of treatment with sarpogrelate hydrochloride. The skin lesions and neurological symptoms improved dramatically after adding low-dose warfarin potassium to the treatment regimen. This case suggests that administration of low-dose warfarin is an effective therapy of choice for patients with livedoid vasculopathy.

Warfarin potassium (Wf) interacts with a wide range of drugs and occasionally causes severe bleeding.We report the case of a 60-year-old female patient on Wf therapy who received 5 courses of cancer chemotherapy with doxorubicin,paclitaxel,and cisplatin.The Wf dose had to be reduced immediately after the chemotherapy due to an increase in international normalized ratio (INR).We then steadily increased the Wf dose till it had reached the previous level,which took almost 11 days from the time of receiving the anti-cancer agents.Although we could not determine which agent was interacting with Wf to cause the rise in INR in this case,we feel that attention must be paid to Wf drug-interactions for chemotherapy agents that have not previously been reported to interact with Wf in order to avoid the risk of bleeding.Therefore,there is a need for pharmacists to check medicines prescribed to patientsundergoingcancerchemotherapybyothermedicaldepart-ments and other medical clinics,especially for outpatients.

To evaluate combination therapy with warfarin potassium (WF) and bucolome (BUC),we assigned patients on warfarin potassium (WF) at Kochi University Medical School Hospital to a group also receiving BUC (BUC-combination group) and a group not receiving BUC (non-combination group),and compared the WF doses and TT values.In each patient,we investigated the doses of WF before and after the start or discontinuation of combination therapy with BUC.There was no significant difference in TT values between the two groups.However,the WF dose in the BUC-combination group was significantly lower than that in the non-combination group.BUC was therefore useful for maintaining anticoagulation activity and decreasing the dose of WF.Furthermore,there was a correlation between the doses of WF before and after the start or discontinuation of combination therapy with BUC in each patient.Based on the regression line obtained using WF doses,in the presence and absence of BUC,the subsequent dose of WF could be predicted at the start or discontinuation of combination therapy with BUC,suggesting that it would be useful in anticoagulation control.

A very important instruction given to patients prescribed warfarin potassium(Wf)is to seek urgent medical help if bleeding occurs.However,it is a good idea for patients to seek help and ensure that they are being adequately treated with vitamin K(VK)injection before bleeding actually occurs.We retrospectively investigated the causes of enhanced international normalized ratio(INR)in outpatients prescribed Wf and using VK injection from 2000-2004.Owing to a higher INR,nine outpatients(mean age : 72.3)were injected with VK in this period.Two of them were injected with VK at the first consultation after hospitalization during which Wf therapy had been started,and the remaining 7 had appetite loss due to various causes,exacerbation of their underlying disease,overwork or drinking.Therefore,patients prescribed Wf should be instructed to seek immediate medical help when they have appetite loss of various causes before actual bleeding occurs and pay attention to bleeding,especially soon after the dose of Wf is determined.

The taste responses to the optical isomers of potassium warfarin, dipotassium glutamyl glutamate, and a mixture of both the substances in laboratory mice were studied using licking activity as an indicator of taste effectiveness. The offensive effectiveness of the optical isomers of potassium warfarin was the same. Every optical isomer of dipotassium glutamyl glutamate was avoided, the taste avoidance of dipotassium D-glutamyl D-glutamate being the strongest. The taste avoidance of potassium warfarin was greatly increased by the addition of every isomers of dipotassium glutamyl glutamate, and its cause was related to synergistic effects.

To study the long-term results of the St. Jude medical prosthesis in the mitral position, 520 patients were evaluated who had undergone mitral valve replacement with St. Jude medical (SJM) prosthesis. Eighteen patients or 3.5% died in the early postoperative period (within 30 days after operation). The total follow-up was 2872 patient-years and late deaths occurred in 23 cases. Postoperative cerebral embolism occurred in six, bleeding complication in five, and thrombosed valve in two patients. Postoperative anti-coagulant therapy was initiated with both dipyridamole (300 mg/day) and warfarin potassium. After discharge from our hospital the patients underwent routine examination of their thrombo-tests or prothrombin times at least every 2-3 months, and the major thromboembolic or bleeding complication rate was 0.45%/100 patient-years. In a period of 12 years, severe hemolysis following implantation was seen in seven patients. The cause of this hemolysis was perivalvular leakage in two patients but there were no leakages in the other five patients, although preoperative moderate to severe liver dysfunction was noted. Ninety-three percent of the patients were followed up, and their postoperative New York Heart Association functional classes were I or II in 88.6% of the cases. Their clinical results after mitral valve replacement with SJM prosthesis in the anti-anatomical position showed excellent durability and a low incidence of valve-related complications.

It is well-known that pulmonary embolism sometimes accompanies a bronchoconstrictive symptom, but the precise mechanism is not clearly understood. We report a unique case of antithrombin (AT) abnormality with no heparin-binding activity accompanied by pulmonary thromboembolism and asthmatic symptoms. Keeping AT activity >60% by infusion of AT concentrates, we successfully treated the asthmatic symptom, which did not respond to ordinary treatment for bronchial asthma and the anticoagulant therapy by warfarin potassium for pulmonary thromboembolism. Key Words: Antithrombin concentrates—Bronchial asthmatic symptom—Pulmonary thromboembolism—Antithrombin abnormality with no heparin binding activity

Purpose: We reviewed the records of 10 patients who had impending central retinal vein occlusion in order to judge whether anticoagulant treatment with warfarin potassium Warfarin® was indicated. Patients: Six men and four women, ranging in age from 25 to 83 (average 55) years were studied. Results: Of 6 eyes, retinal hemorrhage disappeared completely within 6 months. Four patients whose visual acuity was 0.1 or less at one month needed photocoagulation. Four other patients whose late venous circulation time at fluorescein angiography improved within 30 seconds had good visual prognosis. Three eyes of four patients aged 65 or older were not successful in regaining their visual acuity. Conclusion: Warfarin® was not effective for patients who had clearly lost their visual acuity and the elderly in this series. Late venous circulation time at fluorescein angiography was a useful index for this treatment.

warfarin potassiumによる肝障害は極めて稀であり,内外で数例の報告をみるにすぎない.著者らはwarfarin potassiumによる薬剤性肝炎を経験したので報告する.症例は55歳の男性でaorto-coronary bypass術後の抗凝固療法としてwarfarin potassiumが投与され,約50日後黄疸とトランスアミナーゼおよび胆道系酵素の著明な上昇を示した.HBウイルスマーカー,IgM HA抗体は陰性で薬剤性肝障害が示唆されたため同薬剤の投与を中止したところ速やかに肝機能検査は正常となった.肝生検所見では急性肝炎回復期と診断された.warfarin potassiumによるリンパ球培養試験は陰性を示し臨床上抗凝固療法を必要としたため再度warfarin potassiumを投与したところ3日後全身倦怠感とともに肝機能検査に異常を来した.再度同剤によるリンパ球培養試験を行ったところstimulation indexは320%と陽性でwarfarin potassiumによる薬剤性肝障害と診断された.

This collaborative study was undertaken to determine if the anticoagulants acenocoumarol, phenprocoumon, and potassium warfarin could be analyzed by the automated analysis system described in the collaborative study for the analysis of sodium warfarin and dicumarol. Collaborators were supplied with a composited tablet sample of each anticoagulant. Results agreed well with the National Formulary methods for phenprocoumon and potassium warfarin, and an unpublished method for acenocoumarol. For acenocoumarol, coefficients of variation on individual sets of data ranged from 0.30 to 1.94% For phenprocoumon, coefficients of variation ranged from 0.52 to 1.20%. For potassium warfarin, coefficients of variation ranged from 0.54 to 1.79%. The results of this study show that acenocoumarol, phenprocoumon, and potassium warfarin can be analyzed by the official AOAC method for the analysis of sodium warfarin and dicumarol tablets.