TWI650423B - Risk assessment for lamotrigine-induced cutaneous adverse drug reactions and detecting agent thereof and use thereof - Google Patents

Risk assessment for lamotrigine-induced cutaneous adverse drug reactions and detecting agent thereof and use thereof Download PDF

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TWI650423B
TWI650423B TW106137259A TW106137259A TWI650423B TW I650423 B TWI650423 B TW I650423B TW 106137259 A TW106137259 A TW 106137259A TW 106137259 A TW106137259 A TW 106137259A TW I650423 B TWI650423 B TW I650423B
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TW201917217A (en
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鐘文宏
洪舜郁
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長庚醫療財團法人林口長庚紀念醫院
國立陽明大學
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Abstract

一種評估抗癲癇藥物拉莫三嗪(Lamotrigine)引發皮膚藥物不良反應(Cutaneous Adverse Drug Reactions,CADRs)風險的方法,其中皮膚藥物不良反應包括但不限於:斑丘疹(maculopapular eruption,MPE)、固定型藥疹(fixed drug eruption,FDE)、史帝文生-強生症候群(Stevens Johnson Syndrome,SJS)、毒性表皮壞死症(toxic epidermal necrolysis,TEN)、藥物疹合併嗜伊紅血症及全身症狀(drug rash with eosinophilia and systemic symptoms,DRESS)。亦提供一種用於評估患者發展出皮膚藥物不良反應風險之檢測試劑,包括測定特定HLA對偶基因之試劑。 A method for assessing the risk of skin drug adverse drug reactions (Calaneous Adverse Drug Reactions, CADRs) by the anti-epileptic drug Lamotrigine, including but not limited to: maculopapular eruption (MPE), fixed type Fixed drug eruption (FDE), Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia, and systemic symptoms (drug rash with Eosinophilia and systemic symptoms, DRESS). A detection reagent for assessing the risk of developing a dermatological adverse drug reaction in a patient, including an agent for determining a specific HLA dual gene, is also provided.

Description

評估抗癲癇藥物拉莫三嗪引發皮膚藥物不良反應風險的方 法、其檢測試劑及其用途 Assessing the risk of skin drug adverse reactions induced by the anti-epileptic drug lamotrigine Method, its detection reagent and its use

本發明係提供一種評估引發皮膚藥物不良反應(Cutaneous Adverse Drug Reactions)風險的方法,尤指抗癲癇藥物拉莫三嗪(Lamotrigine)引發皮膚藥物不良反應風險的方法。 The present invention provides a method for assessing the risk of causing drug adverse drug reactions (Cutaneous Adverse Drug Reactions), and more particularly to a method for the risk of skin drug adverse reactions caused by the anti-epileptic drug Lamotrigine.

皮膚藥物不良反應(Cutaneous Adverse Drug Reactions,CADRs)一直以來為臨床重大問題,其表現非常多樣化,從輕微之丘疹(maculopapular eruption,MPE)、固定型藥疹(fixed drug eruption,FDE)至嚴重皮膚藥物不良反應(severe cutaneous adverse drug reactions,SCARs),包含:藥物疹合併嗜伊紅血症及全身症狀(drug rash with eosinophilia and systemic symptoms,DRESS)、史帝文生-強生症候群(Stevens Johnson Syndrome,SJS)及毒性表皮壞死症(toxic epidermal necrolysis,TEN)等。丘疹(MPE)為最常見的藥物疹,通常開始時以散發之小紅斑及丘疹為主,然後融合成瀰散性紅疹。固定型藥疹(FDE)是指病人在每次服用同 類藥物後,都會在相同部位出現藥物疹的情況。最常發生的部位為臉部、唇部、外生殖器及肢端。症狀通常為產生圓形或卵圓形紅紫色斑塊,伴隨著搔癢及刺痛症狀,斑塊可以是單一個或多處,較嚴重者會變成大水皰。急性期過後,會留下棕黑色的色素沉著。史帝文生-強生症候群(SJS)及毒性表皮壞死症(TEN)在發病前期常常出現一些類似感冒的症狀,包括發燒、喉嚨痛、唇部腫脹等症狀,接著急遽發展出全身性紅斑、水泡、眼睛、口腔、生殖器黏膜發炎及潰爛,嚴重時有如全身燙傷的病人。兩者最大分別只是在表皮分離的範圍若低於體表面積10%時稱為SJS,超過30%則為TEN。藥物疹合併嗜伊紅血症及全身症狀(DRESS)臨床上主要特徵包括發燒、皮膚疹、血中嗜伊紅性白血球增加、淋巴結腫大和內部器官的侵犯。最常見且最嚴重侵犯的器官是肝臟,可能會併發猛爆性肝炎,而成為病人最常見的死因,其他的還有腎炎、心肌炎、肺炎、甲狀腺發炎等。 Cutaneous Adverse Drug Reactions (CADRs) have long been a major clinical problem, and their performance is very diverse, ranging from maculopapular eruption (MPE), fixed drug eruption (FDE) to severe skin drugs. Severe cutaneous adverse drug reactions (SCARs), including: drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson Syndrome (SJS) And toxic epidermal necrosis (TEN). Papillary rash (MPE) is the most common drug rash, usually beginning with small erythema and papules, and then fused into a diffuse rash. Fixed drug eruption (FDE) refers to the patient taking each time After drug-like drugs, drug rashes will appear in the same area. The most common sites are the face, lips, external genitalia and extremities. Symptoms usually produce round or oval red-purple plaques, accompanied by itching and stinging symptoms, plaques can be single or multiple, and more severe can become large blisters. After the acute phase, brownish black pigmentation will remain. Stevenson-Strong Syndrome (SJS) and Toxic Epidermal Necrosis (TEN) often have symptoms similar to the common cold in the early stage of the disease, including fever, sore throat, swelling of the lips, etc., followed by irritable development of systemic erythema, blisters, Inflammation and ulceration of the eyes, mouth, and genital mucosa, as in the case of severe burns. The biggest difference between the two is that SJS is called when the range of epidermal separation is 10% lower than the body surface area, and TEN is more than 30%. The main clinical features of drug rash combined with eosinophilic and systemic symptoms (DRESS) include fever, skin rash, increased eosinophilic leukocytes in the blood, swollen lymph nodes, and internal organ involvement. The most common and most serious organ of invasion is the liver, which may be accompanied by violent hepatitis, which is the most common cause of death in patients. Others include nephritis, myocarditis, pneumonia, and thyroid inflammation.

藥物不良反應常和免疫反應有關,若曾對某種藥物過敏的病人,之後又使用同一種藥物,則第二次的藥物不良反應將發生的更迅速且更嚴重。然而免疫機制非常複雜,如:HLA-A約有300多種基因型;HLA-B約有600多種基因型。因此找出造成藥物不良反應之免疫機制困難重重。 Adverse drug reactions are often associated with immune responses. If a patient who has been allergic to a drug and then uses the same drug, the second adverse drug reaction will occur more rapidly and more severely. However, the immune mechanism is very complicated, such as: HLA-A has more than 300 genotypes; HLA-B has more than 600 genotypes. Therefore, it is difficult to find the immune mechanism that causes adverse drug reactions.

拉莫三嗪(Lamotrigine,LTG)(商品名為樂命達,LamictalTM,以下簡稱為LTG)是一種目前在臨床上可供使用的抗癲癇藥物,其作用機轉是透過抑制電壓敏感性的鈉離子通道,進而減低突觸末端麩胺酸釋放,達到安定神經的功效。和傳統抗癲癇藥物相比,LTG相較是較新開發的藥物,約1980年後期上市,其結構式和傳統抗癲癇藥物有些許不同,屬於三嗪(triazine)的結構。根據 美國食品藥物管理局FDA指示,目前LTG被核准應用於治療局部性癲癇發作、全身性癲癇發作、兒童癲癇疾病(Lennox-Gastaut syndrome)及第一型雙極性躁鬱症,而其他非適應症用途包括治療減肥、偏頭痛、三叉神經痛和憂鬱症[Micomedex]。 Lamotrigine (Lamotrigine, LTG) (trade name of music life, Lamictal TM, hereinafter referred to as the LTG) is a clinically currently available antiepileptic drugs, their mechanism of action is through inhibition of voltage-sensitive The sodium ion channel, which in turn reduces the release of glutamic acid at the synaptic terminal, achieves the effect of calming nerves. Compared with traditional anti-epileptic drugs, LTG is a relatively new drug developed in the late 1980s. Its structural formula is slightly different from traditional anti-epileptic drugs and belongs to the structure of triazine. According to the US Food and Drug Administration's FDA directive, LTG is currently approved for the treatment of local seizures, generalized seizures, Lennox-Gastaut syndrome and type 1 bipolar bipolar disorder, while other non-indications use These include treatment for weight loss, migraine, trigeminal neuralgia and depression [Micomedex].

LTG雖然可應用於治療多種類型的癲癇,然而卻因為其在臨床上有較高發生不良反應的頻率而限制其被使用。在臨床上出現最嚴重的副作用即是造成嚴重皮膚藥物不良反應,包含:SJS、TEN及DRESS等病變;其中DRESS也會造成全身性的反應像是肝衰竭、貧血、顆粒球減少、血小板減少、週邊血管內凝集以及嗜伊紅性球血症等。。因此,對於LTG引起皮膚藥物不良反應的風險評估之需求仍然存在。本發明解決此需要。 Although LTG can be used to treat many types of epilepsy, it is limited because it has a high frequency of adverse reactions in the clinic. The most serious side effects in the clinic are serious skin drug adverse reactions, including: SJS, TEN and DRESS; DRESS also causes systemic reactions like liver failure, anemia, granule reduction, thrombocytopenia, Peripheral intravascular agglutination and eosinophilic globulinemia. . Therefore, there is still a need for a risk assessment of LTG-induced adverse drug reactions in the skin. The present invention addresses this need.

本發明提供一種評估患者發展出抗癲癇藥物拉莫三嗪(Lamotrigine)引發皮膚藥物不良反應風險的方法,其中皮膚藥物不良反應包括:斑丘疹(maculopapular eruption,MPE)、固定型藥疹(fixed drug eruption,FDE)及嚴重皮膚藥物不良反應(severe cutaneous adverse drug reactions,SCAR),該嚴重皮膚藥物不良反應包含:史帝文生-強生症候群(Stevens Johnson Syndrome,SJS)、毒性表皮壞死症(toxic epidermal necrolysis,TEN)或藥物疹合併嗜伊紅血症及全身症狀(drug rash with eosinophilia and systemic symptoms,DRESS)。本發明發現HLA-A*0207及/或HLA-B*1502對偶基因與抗癲癇藥物拉莫三嗪所引發之皮膚藥物不良反應有關。 The present invention provides a method for assessing a patient's development of an anti-epileptic drug, Lamotrigine, which causes a risk of adverse drug reactions in the skin, wherein the dermatological adverse reactions include: maculopapular eruption (MPE), fixed drug eruption (fixed drug eruption) , FDE) and severe cutaneous adverse drug reactions (SCAR), the severe dermal adverse drug reactions include: Stevens Johnson Syndrome (SJS), toxic epidermal necrosis (toxic epidermal necrolysis) TEN) or drug rash with eosinophilia and systemic symptoms (DRESS). The present invention found that the HLA-A*0207 and/or HLA-B*1502 dual gene is associated with an adverse drug reaction to the skin caused by the anti-epileptic drug lamotrigine.

明確言之,本發明提供一種評估患者因藥物而發展出皮膚藥物不良反應之風險的方法,包括測定HLA-A*0207及/或HLA-B*1502對偶基因之存在,其中該HLA-A*0207及/或HLA-B*1502對偶基因之存在為皮膚藥物不良反應風險之指標。在一具體實例中,該藥物為抗癲癇藥物拉莫三嗪(Lamotrigine)。皮膚藥物不良反應包括至少一種選自以下之不良反應:斑丘疹(maculopapular eruption,MPE)、固定型藥疹(fixed drug eruption,FDE)、史帝文生-強生症候群(Stevens Johnson Syndrome,SJS)、毒性表皮壞死症(toxic epidermal necrolysis,TEN)或藥物疹合併嗜伊紅血症及全身症狀(drug rash with eosinophilia and systemic symptoms,DRESS)。在一具體實例中,患者帶有HLA-A*0207對偶基因。在一具體實例中,患者帶有HLA-B*1502。在另一具體實例中,患者帶有HLA-A*0207與HLA-B*1502。 Specifically, the present invention provides a method for assessing a patient's risk of developing a skin drug adverse reaction due to a drug, comprising determining the presence of a HLA-A*0207 and/or HLA-B*1502 dual gene, wherein the HLA-A* The presence of the 0207 and/or HLA-B*1502 dual gene is an indicator of the risk of adverse drug reactions in the skin. In one embodiment, the drug is the anti-epileptic drug Lamotrigine. The dermatological adverse reaction includes at least one adverse reaction selected from the group consisting of: maculopapular eruption (MPE), fixed drug eruption (FDE), Stevens Johnson Syndrome (SJS), toxic epidermis Toxic epidermal necrolysis (TEN) or drug rash with eosinophilia and systemic symptoms (DRESS). In one embodiment, the patient carries the HLA-A*0207 dual gene. In one embodiment, the patient carries HLA-B*1502. In another embodiment, the patient carries HLA-A*0207 and HLA-B*1502.

在一具體實例中,患者帶有HLA-A*0207,皮膚藥物不良反應為史帝文生-強生症候群、毒性表皮壞死症或藥物疹合併嗜伊紅血症及全身症狀。在一具體實例中,患者帶有HLA-A*0207,皮膚藥物不良反應為斑丘疹或固定型藥疹。在一具體實例中,患者帶有HLA-B*1502,皮膚藥物不良反應為斑丘疹或固定型藥疹。在一具體實例中,患者帶有HLA-B*1502,皮膚藥物不良反應為斑丘疹、固定型藥疹或藥物疹合併嗜伊紅血症及全身症狀。在一具體實例中,患者帶有HLA-A*0207與HLA-B*1502,皮膚藥物不良反應為史帝文生-強生症候群、毒性表皮壞死症或藥物疹合併嗜伊紅血症及全身症狀。在一具體實例中,患者帶有HLA-A*0207與HLA-B*1502,皮膚藥物不良反應為斑丘疹或固定型藥疹。在另一具體實例中,患者帶有HLA-A*0207或HLA-A*0207與HLA-B*1502, 皮膚藥物不良反應包括至少一種選自以下之不良反應:斑丘疹、固定型藥疹、史帝文生-強生症候群、毒性表皮壞死症或藥物疹合併嗜伊紅血症及全身症狀。 In one embodiment, the patient has HLA-A*0207, and the dermatological adverse drug reaction is Stevenson-Strong Syndrome, toxic epidermal necrosis or drug rash with eosinophilia and systemic symptoms. In one embodiment, the patient has HLA-A*0207 and the dermatological adverse drug reaction is a maculopapular rash or a fixed drug eruption. In one embodiment, the patient has HLA-B*1502 and the dermatological adverse drug reaction is a maculopapular rash or a fixed drug eruption. In one embodiment, the patient has HLA-B*1502, and the dermatological adverse drug reaction is maculopapular rash, fixed drug eruption or drug rash with eosinophilia and systemic symptoms. In one embodiment, the patient has HLA-A*0207 and HLA-B*1502, and the dermatological adverse drug reaction is Stevenson-Strong Syndrome, toxic epidermal necrosis or drug rash with eosinophilia and systemic symptoms. In one embodiment, the patient carries HLA-A*0207 and HLA-B*1502, and the dermal adverse drug reaction is a maculopapular rash or a fixed drug eruption. In another embodiment, the patient carries HLA-A*0207 or HLA-A*0207 and HLA-B*1502, The dermatological adverse reaction includes at least one adverse reaction selected from the group consisting of maculopapular rash, fixed drug eruption, Stevenson-Johnson syndrome, toxic epidermal necrosis or drug rash with eosinophilia, and systemic symptoms.

本發明提供一種檢測HLA-A*0207及/或HLA-B*1502對偶基因的試劑在製備用於評估抗癲癇藥物拉莫三嗪(Lamotrigine)引發皮膚藥物不良反應的風險的檢測試劑中的用途。其中,此試劑檢測HLA-A*0207及/或HLA-B*1502對偶基因之存在。所述皮膚藥物不良反應包括至少一種選自以下之不良反應:斑丘疹、固定型藥疹、史帝文生-強生症候群、毒性表皮壞死症或藥物疹合併嗜伊紅血症及全身症狀。 The invention provides a reagent for detecting HLA-A*0207 and/or HLA-B*1502 dual gene in the preparation of a detection reagent for evaluating the risk of skin drug adverse reactions caused by the anti-epileptic drug Lamotrigine . Among them, the reagent detects the presence of the HLA-A*0207 and/or HLA-B*1502 dual gene. The dermatological adverse reaction includes at least one adverse reaction selected from the group consisting of maculopapular rash, fixed drug eruption, Stevenson-Johnson syndrome, toxic epidermal necrosis or drug rash with eosinophilia, and systemic symptoms.

HLA-A*0207、HLA-B*1502或HLA-A*0207與HLA-B*1502對偶基因之存在代表該患者比HLA-A*0207、HLA-B*1502或HLA-A*0207與HLA-B*1502對偶基因不存在之患者具有高於一倍以上、高於二倍以上、高於三倍以上、高於四倍以上、高於五倍以上、高於六倍以上、高於七倍以上、高於八倍以上、高於九倍以上、高於十倍以上、高於三倍至高於四倍或高於一倍至高於四倍皮膚藥物不良反應之風險。 The presence of HLA-A*0207, HLA-B*1502 or HLA-A*0207 and HLA-B*1502 dual genes represents the patient's ratio to HLA-A*0207, HLA-B*1502 or HLA-A*0207 and HLA. -B*1502 patients with non-existent genes have more than one-fold, more than two-fold, more than three-fold, more than four-fold, more than five-fold, more than six-fold higher than seven More than eight times, more than eight times, more than nine times, more than ten times, more than three times to more than four times or more than one time to more than four times the risk of adverse drug reactions in the skin.

對偶基因之存在可採用相關技術上已知任何方法檢測,例如(但不限於):使用與編碼該對偶基因之核酸專一性雜化之寡核苷酸測定,血清定型法或顯微細胞毒性法來測定對偶基因之cDNA、RNA或蛋白質產物[Kenneth D.McClatchey.Clinical Laboratory Medicine.2002]。在一具體實例中,核酸專一性雜化之寡核苷酸測定使用來自患者周邊血液所製成之DNA進行測定。其中具專一性之寡核苷酸可針對HLA-A*0207及/或HLA-B*1502對偶基因中最具變異性之序列進行設計,如:第1圖顯示之HLA-A*0207對偶基因及HLA-B*1502對偶基 因之exon2或外顯子2(序列2)及exon3或外顯子3序列(序列1)。在一具體實例中,檢測HLA-A*0207存在所使用的正向引子(forward primer)寡核苷酸序列為5’-TCCGGAGTATTGGGACGGGGAGACACGGAAA-3’(序列3),反向引子序列(reverse primer)為5’-TCAACTGCTCCGCCACATGGGCCGCCT-3’(序列4),探針(probe)序列為5’-TCCAGAGGATGTGTGGCT-3’(序列5)及5’-TCCAGAGGATGTATGGCT-3’(序列6)。在另一具體實例中,檢測HLA-B*1502存在所使用的正向引子寡核苷酸序列為5’-ATGGCGCCCCGGG-3’(序列7),反向引子序列為5’-TAGTAGCCGCGCAGGTTCC-3’(序列8),探針序列為5’-AACACACAGATCTACAAGG-3’(序列9)及5’-AACACACAGATCTCCAAGA-3’(序列10)。在另一具體實例中,血清定型法或顯微細胞毒性法使用來自患者周邊血液之RNA、蛋白質、細胞或血清進行測定。 The presence of the dual gene can be detected by any method known in the art, such as, but not limited to, using an oligonucleotide assay specific to the nucleic acid encoding the dual gene, serotyping or microcytotoxicity. To determine the cDNA, RNA or protein product of the dual gene [Kenneth D. McClatchy. Clinical Laboratory Medicine. 2002]. In one embodiment, the nucleic acid-specific hybridization oligonucleotide assay is performed using DNA prepared from blood surrounding the patient. The specific oligonucleotides can be designed for the most variegated sequences of HLA-A*0207 and/or HLA-B*1502 dual genes, such as: HLA-A*0207 dual gene shown in Figure 1. And HLA-B*1502 dual base Because of exon2 or exon 2 (sequence 2) and exon3 or exon 3 sequence (sequence 1). In a specific example, the forward primer oligonucleotide sequence used to detect the presence of HLA-A*0207 is 5'-TCCGGAGTATTGGGACGGGGAGACACGGAAA-3' (sequence 3), and the reverse primer sequence is 5'-TCAACTGCTCCGCCACATGGGCCGCCT-3' (SEQ ID NO: 4), the probe sequence is 5'-TCCAGAGGATGTGTGGCT-3' (SEQ ID NO: 5) and 5'-TCCAGAGGATGTATGGCT-3' (SEQ ID NO: 6). In another embodiment, the forward primer oligonucleotide sequence used to detect the presence of HLA-B*1502 is 5'-ATGGCGCCCCGGG-3' (sequence 7), and the reverse primer sequence is 5'-TAGTAGCCGCGCAGGTTCC-3' (SEQ ID NO: 8), the probe sequences are 5'-AACACACAGATCTACAAGG-3' (SEQ ID NO: 9) and 5'-AACACACAGATCTCCAAGA-3' (SEQ ID NO: 10). In another embodiment, the serotyping method or microcytotoxicity method is performed using RNA, protein, cells or serum from the peripheral blood of the patient.

本發明提供用於評估抗癲癇藥物拉莫三嗪引發皮膚藥物不良反應的風險的檢測試劑,此檢測試劑包含一試劑可檢測HLA-A*0207及/或HLA-B*1502對偶基因之存在,其中HLA-A*0207及/或HLA-B*1502對偶基因之存在代表皮膚藥物不良反應之風險,其中,所述皮膚藥物不良反應包括至少一種選自以下之不良反應:斑丘疹、固定型藥疹、史帝文生-強生症候群、毒性表皮壞死症或藥物疹合併嗜伊紅血症及全身症狀。 The present invention provides a detection reagent for assessing the risk of an anti-epileptic drug lamotrigine-induced skin drug adverse reaction, the detection reagent comprising a reagent for detecting the presence of HLA-A*0207 and/or HLA-B*1502 dual genes, Wherein the presence of the HLA-A*0207 and/or HLA-B*1502 dual gene represents a risk of adverse drug reactions in the skin, wherein the dermal adverse drug reaction comprises at least one adverse reaction selected from the group consisting of maculopapular rash and fixed drug eruption. , Stevenson - Johnson & Johnson syndrome, toxic epidermal necrosis or drug rash with eosinophilia and systemic symptoms.

使用於本發明的用語「發明」及「本發明」旨在廣泛地指本發明的所有申請目標,以及權利要求書。含有這些術語的陳述應被理解為不限於本 文所述的申請目標或限於發明的權利要求書的含義或範疇。被本發明所涵蓋的發明之實施例藉由權利要求書而非本發明內容所定義。本發明內容為本發明的各種態樣的高層次概述,並介紹在下面的實施方式部分中進一步描述的一些概念。本發明內容並不旨在確認所要求保護的申請目標之關鍵或必要特徵,也不旨在單獨地使用以決定所要求保護的申請目標之範疇。申請目標應藉由參照整份說明書任何或所有圖式及每項權利要求的適當部分而理解。 The terms "invention" and "the invention" as used in the present invention are intended to broadly refer to all of the application objects and the claims of the invention. Statements containing these terms should be understood as not limited to this The application of the application is intended to be limited to the meaning or scope of the claims of the invention. Embodiments of the invention encompassed by the invention are defined by the claims rather than the invention. This Summary of the Invention is a high level overview of various aspects of the invention and is a description of some of the concepts that are further described in the section below. This Summary is not intended to identify key or essential features of the claimed subject matter, and is not intended to be used solely to determine the scope of the claimed application. The application should be understood by reference to any or all of the drawings and the appropriate parts of each claim.

第1圖係為HLA-A*0207及HLA-B*1502對偶基因之外顯子(exon)exon 2及exon3序列。其中小寫序列為連接exon2及exon3之內含子(intron)。 Figure 1 shows the exon exon 2 and exon3 sequences of the HLA-A*0207 and HLA-B*1502 dual genes. The lowercase sequence is an intron connecting exon2 and exon3.

本發明提供一種評估患者發展出抗癲癇藥物拉莫三嗪(Lamotrigine)皮膚藥物不良反應的方法,該皮膚藥物不良反應包括至少一種選自以下之不良反應:斑丘疹(maculopapular eruption,MPE)、固定型藥疹(fixed drug eruption,FDE)及嚴重皮膚藥物不良反應(severe cutaneous adverse drug reactions,SCAR),該嚴重皮膚藥物不良反應包含至少一種選自以下之嚴重皮膚藥物不良反應:史帝文生-強生症候群(Stevens Johnson Syndrome,SJS)、毒性表皮壞死症(toxic epidermal necrolysis,TEN)或藥物疹合併嗜伊紅血症及全身症狀(drug rash with eosinophilia and systemic symptoms,DRESS)。本發明發現HLA 對偶基因HLA-A*0207、HLA-B*1502或HLA-A*0207與HLA-B*1502與抗癲癇藥物拉莫三嗪所誘發之皮膚藥物不良反應有關。 The present invention provides a method for assessing a patient's development of an anti-epileptic drug, Lamotrigine, a skin drug adverse reaction comprising at least one adverse reaction selected from the group consisting of: maculopapular eruption (MPE), fixation Severe cutaneous adverse drug reactions (SCAR), which contain at least one serious skin drug adverse reaction selected from the following: Stevenson-Johnson syndrome (Stevens Johnson Syndrome, SJS), toxic epidermal necrolysis (TEN) or drug rash with eosinophilia and systemic symptoms (DRESS). The present invention finds HLA The dual gene HLA-A*0207, HLA-B*1502 or HLA-A*0207 and HLA-B*1502 are associated with an adverse drug reaction to the skin induced by the anti-epileptic drug lamotrigine.

在以下實施例中,我們收集26位抗癲癇藥物拉莫三嗪皮膚藥物不良反應之患者(包括SCAR、MPE和FDE患者)進行HLA定型並與755位一般健康人對照組進行比較分析。結果顯示HLA-A*0207、HLA-B*1502或HLA-A*0207與HLA-B*1502對偶基因與拉莫三嗪引起之皮膚藥物不良反應具有相關性(如表1)。在HLA-A*0207對偶基因分布情形中,26位皮膚藥物不良反應(CADR)患者中有11位帶有此基因型(42.31%),755位一般健康人對照組(Control)中只有200位帶有此基因型(16.82%),顯示HLA-A*0207與拉莫三嗪引起之皮膚藥物不良反應具有關聯性(皮膚藥物不良反應vs.健康人對照組:P=2.48×10-3,勝算比(Odds Ratio or OR)=3.63(1.63-8.08),敏感度:42.31%,特異性:83.18%)。在HLA-B*1502對偶基因分布情形中,26位皮膚藥物不良反應(CADR)患者中有7位帶有此基因型(26.92%),755位一般健康人對照組中只有73位帶有此基因型(10.70%),顯示HLA-B*1502與拉莫三嗪引起之皮膚藥物不良反應具有關聯性(皮膚藥物不良反應vs.健康人對照組:P=1.2×10-2,勝算比=3.44(1.40-8.46),敏感度:26.92%,特異性:90.33%)。若進一步將HLA-A*0207及HLA-B*1502合併分析,結果顯示HLA-A*0207及HLA-B*1502結合後與拉莫三嗪引起皮膚藥物不良反應的相關性及敏感性顯著提高(皮膚藥物不良反應vs.健康人對照組:P=4.32×10-4,勝算比=4.44(1.98-9.45),敏感度:61.54%,特異性:73.51%)。由以上結果得知檢測HLA-A*0207、HLA-B*1502或HLA-A*0207與HLA-B*1502對偶基因存在與否可以被用來評估抗癲癇藥物拉莫三嗪引發皮膚藥物不良反應之風險。 In the following examples, we collected 26 patients with anti-epileptic drug lamotrigine dermatological adverse drug reactions (including SCAR, MPE, and FDE patients) for HLA typing and comparative analysis with 755 normal healthy controls. The results showed that HLA-A*0207, HLA-B*1502 or HLA-A*0207 and HLA-B*1502 dual genes were associated with dermatological adverse drug reactions caused by lamotrigine (see Table 1). In the case of HLA-A*0207 dual gene distribution, 11 of 26 skin drug adverse drug reaction (CADR) patients had this genotype (42.31%), and only 755 of the 755 normal healthy controls (Control) With this genotype (16.82%), it was shown that HLA-A*0207 was associated with dermatological adverse drug reactions caused by lamotrigine (dermatological adverse drug reaction vs. healthy person control group: P=2.48×10 -3 , Odds Ratio or OR = 3.63 (1.63-8.08), sensitivity: 42.31%, specificity: 83.18%). In the case of HLA-B*1502 dual gene distribution, 7 of 26 patients with dermal adverse drug reaction (CADR) had this genotype (26.92%), and only 73 of the 755 normal healthy controls had this Genotype (10.70%), showing that HLA-B*1502 is associated with dermatological adverse drug reactions caused by lamotrigine (dermatological adverse drug reaction vs. healthy person control group: P = 1.2 × 10 -2 , odds ratio = 3.44 (1.40-8.46), sensitivity: 26.92%, specificity: 90.33%). If HLA-A*0207 and HLA-B*1502 were further analyzed, the results showed that the correlation and sensitivity of HLA-A*0207 and HLA-B*1502 combined with lamotrigine caused adverse reactions to skin drugs were significantly improved. (Skin adverse drug reaction vs. healthy person control group: P = 4.32 × 10 -4 , odds ratio = 4.44 (1.98-9.45), sensitivity: 61.54%, specificity: 73.51%). From the above results, it is known that the presence or absence of HLA-A*0207, HLA-B*1502 or HLA-A*0207 and HLA-B*1502 dual genes can be used to evaluate the anti-epileptic drug lamotrigine-induced skin dysfunction. The risk of reaction.

因此,本發明提供一種評估患者在服用藥物後發展出皮膚藥物不良反應之風險的方法,包括測定HLA-A*0207及/或HLA-B*1502對偶基因之存在,其中HLA-A*0207及/或HLA-B*1502對偶基因之存在為皮膚藥物不良反應危險性之指標。該藥物為抗癲癇藥物拉莫三嗪(Lamotrigine)。皮膚藥物不良反應包括至少一種選自以下之不良反應:斑丘疹(MPE)、固定型藥疹(FDE)、史帝文生-強生症候群(SJS)、毒性表皮壞死症(TEN)或藥物疹合併嗜伊紅血症及全身症狀(DRESS)。 Accordingly, the present invention provides a method for assessing the risk of a patient developing a dermatological adverse drug reaction after taking a drug, comprising determining the presence of a HLA-A*0207 and/or HLA-B*1502 dual gene, wherein HLA-A*0207 and / or the presence of the HLA-B*1502 dual gene is an indicator of the risk of adverse drug reactions in the skin. The drug is the anti-epileptic drug Lamotrigine. Dermatological adverse effects include at least one adverse reaction selected from the group consisting of maculopapular rash (MPE), fixed drug eruption (FDE), Stevenson-Strong Syndrome (SJS), toxic epidermal necrosis (TEN), or drug rash combined with eosinophilia Redness and systemic symptoms (DRESS).

前文係針對本發明之較佳實施例為本發明之技術特徵進行具體之說明;惟,熟悉此項技術之人士當可在不脫離本發明之精神與原則下對本發明進行變更與修改,而該等變更與修改,皆應涵蓋於如下申請專利範圍所界定之範疇中。 The present invention has been described with reference to the preferred embodiments of the present invention. However, those skilled in the art can change and modify the present invention without departing from the spirit and scope of the invention. Such changes and modifications shall be covered in the scope defined by the following patent application.

<110> 長庚醫療財團法人林口長庚紀念醫院 國立陽明大學 <110> Chang Gung Medical Foundation Corporation Linkou Chang Gung Memorial Hospital National Yang Ming University

<120> 評估抗癲癇藥物拉莫三嗪引發皮膚藥物不良反應風險的方法、其檢測試劑和其用途 <120> A method for evaluating the risk of skin drug adverse reactions caused by the anti-epileptic drug lamotrigine, a test reagent thereof and use thereof

<130> F17W1277 <130> F17W1277

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Claims (9)

一種評估患者發展出皮膚藥物不良反應風險之方法,包括測定來自患者周邊血液樣本中的HLA-A*0207或HLA-A*0207與HLA-B*1502對偶基因之存在,其中HLA-A*0207或HLA-A*0207與HLA-B*1502對偶基因之存在代表患者比HLA-A*0207或HLA-A*0207與HLA-B*1502對偶基因不存在之患者具有較高皮膚藥物不良反應之風險,其中該藥物為抗癲癇藥物拉莫三嗪(Lamotrigine)。 A method for assessing a patient's risk of developing a skin drug adverse reaction, including determining the presence of HLA-A*0207 or HLA-A*0207 and HLA-B*1502 dual genes from a peripheral blood sample of a patient, wherein HLA-A*0207 Or the presence of HLA-A*0207 and HLA-B*1502 dual genes represents a higher dermatological adverse reaction in patients than patients with HLA-A*0207 or HLA-A*0207 and HLA-B*1502 dual genes. Risk, where the drug is the anti-epileptic drug Lamotrigine. 如申請專利範圍第1項所述之方法,其中該皮膚藥物不良反應包括至少一種選自以下之不良反應:斑丘疹(maculopapular eruption,MPE)、固定型藥疹(fixed drug eruption,FDE)、史帝文生-強生症候群(Stevens Johnson Syndrome,SJS)、毒性表皮壞死症(toxic epidermal necrolysis,TEN)或藥物疹合併嗜伊紅血症及全身症狀(drug rash with eosinophilia and systemic symptoms,DRESS)。 The method of claim 1, wherein the dermatological adverse reaction comprises at least one adverse reaction selected from the group consisting of: maculopapular eruption (MPE), fixed drug eruption (FDE), and Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) or drug rash with eosinophilia and systemic symptoms (DRESS). 如申請專利範圍第1項所述之方法,其中HLA-A*0207、或HLA-A*0207與HLA-B*1502對偶基因之測定係採用來自患者周邊血液之DNA、RNA、蛋白質、細胞或血清製備之樣品進行測定。 The method of claim 1, wherein the HLA-A*0207, or HLA-A*0207 and HLA-B*1502 dual genes are determined by using DNA, RNA, protein, cells or cells derived from peripheral blood of the patient. Samples prepared by serum were assayed. 一種評估患者發展出皮膚藥物不良反應風險之檢測試劑,包括測定HLA-A*0207或HLA-A*0207與HLA-B*1502對偶基因之存在之一試劑,其中HLA-A*0207或HLA-A*0207與HLA-B*1502對偶基因之存在代表患者比HLA-A*0207或HLA-A*0207與HLA-B*1502對偶基因不存在之患者具有較高皮膚藥物不良反應之風險,其中該藥物為抗癲癇藥物拉莫三嗪(Lamotrigine)。 A test reagent for assessing a patient's risk of developing an adverse drug reaction to the skin, including one of the reagents for determining the presence of HLA-A*0207 or HLA-A*0207 and HLA-B*1502 dual genes, wherein HLA-A*0207 or HLA- The presence of the A*0207 and HLA-B*1502 dual genes represents a higher risk of adverse dermal reactions in patients than patients with HLA-A*0207 or HLA-A*0207 and HLA-B*1502 dual genes. The drug is the anti-epileptic drug Lamotrigine. 如申請專利範圍第4項所述之檢測試劑,其中該皮膚藥物不良反應包括至少一種選自以下之不良反應:斑丘疹、固定型藥疹、史帝文生 -強生症候群、毒性表皮壞死症、藥物疹合併嗜伊紅血症及全身症狀。 The detection reagent according to claim 4, wherein the dermatological adverse reaction comprises at least one adverse reaction selected from the group consisting of maculopapular rash, fixed drug eruption, and Stevenson - Johnson & Johnson syndrome, toxic epidermal necrosis, drug rash with eosinophilia and systemic symptoms. 如申請專利範圍第4項所述之檢測試劑,其中該試劑包含與編碼HLA-A*0207或HLA-A*0207與HLA-B*1502對偶基因之核酸專一性雜化之一寡核苷酸。 The detection reagent according to claim 4, wherein the reagent comprises an oligonucleotide specific for hybridization with a nucleic acid encoding HLA-A*0207 or HLA-A*0207 and HLA-B*1502 dual gene. . 一種檢測HLA-A*0207或HLA-A*0207與HLA-B*1502對偶基因的試劑在製備用於評估抗癲癇藥物拉莫三嗪(Lamotrigine)引發皮膚藥物不良反應的風險的檢測試劑的用途。 Use of an agent for detecting HLA-A*0207 or HLA-A*0207 and HLA-B*1502 dual gene for preparing a detection reagent for evaluating the risk of skin drug adverse reactions caused by the anti-epileptic drug Lamotrigine . 如申請專利範圍第7項所述之用途,其中該試劑包含與編碼HLA-A*0207或HLA-A*0207與HLA-B*1502對偶基因的核酸專一性雜化的一寡核苷酸。 The use of claim 7, wherein the reagent comprises an oligonucleotide that is specifically hybridized to a nucleic acid encoding HLA-A*0207 or HLA-A*0207 and HLA-B*1502 dual genes. 如申請專利範圍第7項所述之用途,其中該皮膚藥物不良反應包括至少一種選自以下之不良反應:斑丘疹、固定型藥疹、史帝文生-強生症候群、毒性表皮壞死症、藥物疹合併嗜伊紅血症及全身症狀。 The use according to claim 7, wherein the dermatological adverse reaction comprises at least one adverse reaction selected from the group consisting of maculopapular rash, fixed drug eruption, Stevenson-Johnson syndrome, toxic epidermal necrosis, drug rash merger Eosinophilia and systemic symptoms.
TW106137259A 2017-10-27 2017-10-27 Risk assessment for lamotrigine-induced cutaneous adverse drug reactions and detecting agent thereof and use thereof TWI650423B (en)

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WO2012174723A1 (en) * 2011-06-23 2012-12-27 Chang Gung Medical Foundation Chang Gung Memorial Hospital at Keelung Risk assessment for phenytoin-induced adverse drug reactions
CN106399503A (en) * 2016-09-20 2017-02-15 深圳荻硕贝肯精准医学有限公司 Primers, kit and method for detection of SJS/TEN caused by AEDs

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Publication number Priority date Publication date Assignee Title
WO2012174723A1 (en) * 2011-06-23 2012-12-27 Chang Gung Medical Foundation Chang Gung Memorial Hospital at Keelung Risk assessment for phenytoin-induced adverse drug reactions
CN106399503A (en) * 2016-09-20 2017-02-15 深圳荻硕贝肯精准医学有限公司 Primers, kit and method for detection of SJS/TEN caused by AEDs

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