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

Abstract

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

Assessing the risk of skin drug adverse reactions induced by the anti-epileptic drug lamotrigine Method, its detection reagent and its use

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.

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.

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.

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].

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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> Chang Gung Medical Foundation Corporation Linkou Chang Gung Memorial Hospital National Yang Ming University

<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

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Claims (9)

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. 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). 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. 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. 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. 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. . 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 . 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. 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.