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"ABSTRAKSiklofosfamid (CPA) merupakan obat sitotoksik golongan agen pengalkilasi yang telah terbukti efektif penggunaannya dalam kemoterapi kanker payudara dan berbagai jenis limfoma. Sebagai prodrug, siklofosfamid harus dimetabolisme terlebih dahulu oleh enzim sitokrom P450, salah satunya adalah CYP2B6 yang bersifat sangat polimorfik. Selain itu, siklofosfamid juga dapat menyebabkan efek samping berupa sistitis hemoragik yang ditandai dengan hematuria dan dapat berkembang menjadi kanker kandung kemih. Efek samping tersebut disebabkan oleh salah satu metabolit dari siklofosfamid, yaitu akrolein. Akrolein akan dimetabolisme kembali menjadi beberapa metabolit, salah satunya adalah asam 3-hidroksipropil merkapturat (3-HPMA) yang berada di urin dengan kelimpahan yang paling banyak. Oleh karena itu, sifat toksik akrolein dapat dimonitor dari kadar 3-HPMA dalam urin. Namun, polimorfisme enzim CYP2B6 juga perlu dianalisis karena enzim tersebut merupakan salah satu enzim pertama yang mengubah siklofosfamid menjadi metabolitnya, yaitu 4-hidroksisiklofosfamid, yang nantinya akan diubah menjadi metabolit turunan lain. Skripsi ini memuat hubungan antara kadar 3-HPMA dalam urin, polimorfisme CYP2B6, dan kejadian hematuria setelah pemberian siklofosfamid beserta metode bioanalisisnya. Berdasarkan penelusuran literatur yang dilakukan, diperoleh bahwa KCKUT-SM/SM tipe ESI positif dengan metode preparasi sampel pengasaman dan dilusi menghasilkan hasil analisis kadar 3-HPMA dalam urin setelah pemberian siklofosfamid yang optimal. Selain itu, terdapat tipe polimorf CYP2B6 yang dapat meningkatkan hidroksilasi siklofosfamid sehingga kadar 3-HPMA juga dapat meningkat. Risiko kejadian hematuria turut bertambah tinggi seiring meningkatnya kadar 3-HPMA dalam urin. Skripsi ini dapat digunakan sebagai pertimbangan tenaga medis dalam pemberian siklofosfamid untuk meningkatkan efektivitas dan keamanan terapi.

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ABSTRACT

Cyclophosphamide (CPA) is an alkylating agent cytotoxic drug that has been proved effective in breast cancer and many types of lymphoma chemotherapy. As a prodrug, cyclophosphamide needs to be metabolized by cytochromes P450 enzymes, like CYP2B6 which is a very polymorphic one. Cyclophosphamide can also cause hemorrhagic cystitis that defined by hematuria that can lead to bladder cancer. That adverse effect is caused by one of the metabolites of cyclophosphamide that is acrolein. Acrolein will be metabolized into some other metabolites, one of them is 3-hydroxypropyl mercapturic acid (3-HPMA) that has the biggest abundance in the urine. Thus, acrolein toxicity can be monitored from 3-HPMA concentration in urine. However, CYP2B6 polymorphisms also must be analyzed because CYP2B6 is one of the first enzymes that breakdowns cyclophosphamide into its metabolite, which is 4-hydroxycyclophosphamide, that also will be metabolized into some other derivatives. This thesis informs the correlation between 3-HPMA urine concentration, CYP2B6 polymorphisms, and hematuria occurrences after cyclophosphamide administration and its bioanalysis methods. After the literature review, I found that positive ESI mode LC-MS/MS with acidification and dilution sample preparation method produces an optimal result for the 3-HPMA urine concentration after cyclophosphamide administration. Also, there is a type of CYP2B6 polymorph that increases CPA 4-hydroxylation which can lead to the rising of 3-HPMA concentration. The risk of hematuria also increases with the rising of 3-HPMA concentration in urine. This thesis can be used by medical personnel as a consideration in cyclophosphamide administration to increase the effectiveness and safety of the therapy.

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"ABSTRAK

Siklofosfamid merupakan obat antikanker yang umum digunakan dalam regimen kemoterapi untuk penyakit kanker payudara. Namun, penggunaan siklofosfamid dapat menyebabkan efek samping yaitu sistitis hemoragik yang dapat menyebabkan pendarahan saat berkemih dan berkembang menjadi kanker kandung kemih. Efek samping tersebut disebabkan oleh hasil samping dari metabolisme siklofosfamid yaitu akrolein. Akrolein akan diekskresikan melalui urin dalam bentuk metabolit yaitu 3-HPMA. Pada penelitian ini, dilakukan pengukuran kadar 3-HPMA dalam urin pasien kanker. Sampel urin diambil 4 jam setelah pemberian siklofosfamid dan urinalisis dilakukan untuk melihat resiko terjadinya hematuria. Analisis dilakukan secara KCKUT-SM/SM fase terbalik yang dilengkapi dengan sistem deteksi spektrometri massa triple quadrupole ESI positif. Preparasi sampel dilakukan dengan pengasaman dan dilusi. Metode analisis yang digunakan linier dengan rentang analisis 40-10000 ng/mL untuk 3-HPMA. Hasil analisis kadar 3-HPMA dalam 40 pasien kanker menunjukkan hasil yang sangat bervariasi, dengan konsentrasi terukur berkisar antara 113-9495 ng/mL dan kadar ternormalisasi kreatinin berkisar antara 650-5596 ng/mg kreatinin.

Pasien dengan hasil positif hematuria menunjukkan rata-rata kadar 3-HPMA yaitu 4839 ng/mg kreatinin, sementara untuk pasien dengan hasil negative hematuria menunjukkan rata-rata kadar yaitu 2419,431 ng/mg kreatinin.

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ABSTRACT

Cyclophosphamide is an alkylating agent commonly used in chemotherapy regimens for breast cancer, non-Hodgkins lymphoma, leukemia, and lung cancer. However, the use of cyclophosphamide can cause toxic side effects on the bladder, namely hemorrhagic cytitis which can cause hematuria and can later develop into bladder cancer. These side effects are caused by the byproduct of cyclophosphamide metabolism, acrolein. 3-HPMA is a stable metabolite of acrolein found in urine that serves as biomarker of acrolein. In this study, we developed a method to quantify 3-Hydroxy Propyl Mercapturic Acid (3-HPMA) in cancer patients urine. Urine samples were taken 4 hours after cyclophosphamide administration and urin alysis was done to observe the risk of hematuria. Analysis of 3-HPMA was performed by reversed phase UPLC-MS/MS equipped with triple quadrupole mass spectrometer positive ESI mode detection. The mobile phase used for analysis is 0,1% formic acid in water and in acetonitrile (90:10 v/v). The MRM was set at m/z 222.10>90.97 for 3-HPMA and 164.10 > 122.02 for the internal standard NAC. Sample preparation was done by acidification and simple dilution. The analytical method used is linear within the consentration range of 40-10000 ng/mL. The results showed varied levels of 3-HPMA in 40 cancer patients urine, with measured concentrations ranging from 113-9495 ng/mL and creatinine-adjusted levels ranging from 650-5596 ng/mg creatinine. Patients with positive results of hematuria showed 3-HPMA levels that were relatively high with mean level of 4839 ng/mg creatinine."

"Reaksi esterifikasi antara glukosa dengan asam lemak dapat menghasilkan ester asam lemak-glukosa. Pada penelitian ini, asam lemak diperoleh dari reaksi hidrolisis minyak kelapa sawit yang dijual dipasaran. Reaksi esterifikasi dilakukan secara enzimatik menggunakan katalis lipase Candida rugosa E.C.3.1.1.3 terimobilisasi pada nanopartikel Fe3O4-Kitosan. Nanopartikel Fe3O4- Kitosan disintesis dengan metode kopresipitasi kemudian dilakukan karakterisasi dengan FTIR (Fourier Transform Infra Red), XRD (X-Ray Diffraction), dan EDS (Energy Dispersive X-Ray Spectroscopy). Imobilisasi lipase Candida rugosa pada nanopartikel Fe3O4-Kitosan menggunakan metode ikat silang dengan glutaraldehida sebagai agen pengikat silang. Hasil imobilisasi dilakukan uji aktivitas dan persen loading. Persen loading imobilisasi lipase yang diperleh adalah 62,20% dan aktivitas hidrolisis lipase terimobilisasi sebesar 6,18 U/mL dan aktivitas spesifiknya sebesar 2,65 U/mg serta efisiensi imobilisasi sebesar 34,54%. Dari hasil optimasi esterifikasi diperoleh persen konversi optimum sebesar 3,70 % dengan kondisi reaksi pada suhu 35°C , ratio glukosa : asam lemak 1 : 90, dan waktu reaksi selama 16 jam dan 40% massa enzim terimobilisasi.

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Esterification reaction between glucose and fatty acid could produce glucose-fatty acid esters. In this study, fatty acid was synthesized from hydrolysis reaction of palm oil. Esterification reaction was carried out enzymatically using immobilized Candida rugosa lipase EC.3.1.1.3 on Fe3O4-chitosan nanoparticles. Fe3O4-chitosan nanoparticles was synthesized using co-precipitation method and was characterized using FTIR (Fourier Transform Infra Red), XRD (X-Ray Diffraction), and EDS (Energy Dispersive X-Ray Spectroscopy). Candida rugosa lipase was immobilized on Fe3O4-chitosan nanoparticles using cross-linking method with glutaraldehyde as cross linker. Loading percentage of immobilized lipase was 62,20%. Hydrolysis activity of immobilized lipase was 6,81 U/mL, the specific activity was 2,65 U/mg and the immobilization efficiency was 34,54%. From this optimization study of esterification, the highest fatty acid conversion percentage was obtained using 1 : 90 ratio of glucose : fatty acid, 16 hours reaction time, immobilized lipase 40% of substrate’s mass, and at temperature 35°C. The highest fatty acid conversion percentage was 3,70%."

"Kitosan adalah salah satu contoh polimer yang memiliki bobot molekul besar dengan gugus amina dan gugus hidroksil, yang merupakan gugus reaktif. Gugus hidroksil ini terikat secara primer pada atom karbon nomor 6 dan secara sekunder terikat pada atom karbon nomor 3 sehingga dapat dimanfaatkan dalam proses modifikasi. Pada penelitian ini, kitosan direaksikan dengan anhidrida suksinat untuk dilihat selektivitasnya terhadap gugus-gugus reaktif tersebut, dengan memvariasikan massa anhidrida suksinat dan suhu reaksi. Hasil sintesis ini dikarakterisasi menggunakan FTIR (Fourier Transform Infra Red) dan 1H-NMR (Nuclear Magnetic Resonance). Analisis menggunakan FTIR pada perbandingan massa kitosan dengan suksinat 1 : 0,2 g hanya menunjukkan puncak serapan karbonil amida pada bilangan gelombang 1681 cm-1 dan hasil karakterisasi menggunakan 1H-NMR menunjukkan puncak pergeseran kimia pada rentang 2,5ppm-2,7ppm. Hasil analisis keduanya mengindikasikan anhidrida suksinat bereaksi dengan gugus amina. Pada perbandingan inilah reaksi kitosan dengan anhidrida suksinat selektif pada gugus amina.

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Chitosan is one example of polymer with large moleculer weight. It has amino groups and hydroxyl groups which are primarily bound to carbon atom number 6 and secondary hydroxyl group in carbon atom number 3, they are reactive groups. They can also be used in the modification process. In this research, chitosan is reacted with succinic anhydride to observe the selectivity of these reactive groups by varying masses of succinic anhydride and the temperatur of reaction. The product of this synthesis is characterized with FTIR (Fourier Transform Infra Red ) and 1H-NMR (Nuclear Magnetic Resonance). Based on the result obtained with FTIR, when the mass ratio 1: 0,2 g, carbonyl peak appears only in the 1681 cm-1. Results of 1H-NMR characterization shows chemical shift at 2.4 to 2.8 ppm indicates that succinic anhydride reacts with the amine group. So in this ratio, chitosan which is reacted with succinic anhydride selective in amino groups.;Chitosan is one example of polymer with large moleculer weight. It has amino groups and hydroxyl groups which are primarily bound to carbon atom number 6 and secondary hydroxyl group in carbon atom number 3, they are reactive groups. They can also be used in the modification process. In this research, chitosan is reacted with succinic anhydride to observe the selectivity of these reactive groups by varying masses of succinic anhydride and the temperatur of reaction. The product of this synthesis is characterized with FTIR (Fourier Transform Infra Red ) and 1H-NMR (Nuclear Magnetic Resonance). Based on the result obtained with FTIR, when the mass ratio 1: 0,2 g, carbonyl peak appears only in the 1681 cm-1. Results of 1H-NMR characterization shows chemical shift at 2.4 to 2.8 ppm indicates that succinic anhydride reacts with the amine group. So in this ratio, chitosan which is reacted with succinic anhydride selective in amino groups."

"PENGARUH REGENERASI KOLOM ALUMINA ASAM TERHADAP RECOVERY DAN KUALITAS 99mTc HASIL EKSTRAKSI PELARUT MEK DARI 99Mo HASIL AKTIVASI NEUTRON. Melalui kerjasama antara PTRR-BATAN, Chiyoda dan JAEA Jepang telah dilakukan pemurnian 99mTc dari 99Mo hasil aktivasi neutron dengan menggunakan metode kromatografi kolom alumina asam terhadap hasil ekstraksi MEK (Metil Etil Keton). Pemurnian 99mTc dengan metode kolom alumina asam hanya dapat digunakan satu kali dan pemurnian berikutnya harus diganti dengan kolom baru. Hal ini dinilai kurang praktis dan juga memerlukan biaya yang mahal. Dalam penelitian ini dicoba penggunaan kolom alumina asam untuk pemurnian 99mTc lebih dari satu kali dengan melakukan proses regenerasi dengan cara melewatkan larutan HNO3 0,1N setiap kali proses pemurnian selesai. Penelitian ini bertujuan untuk mendapatkan larutan 99mTc yang dapat digunakan untuk penandaan kit radiofarmaka. Parameter yang diamati dalam penelitian ini adalah recovery, profil elusi, pH, kemurnian radiokimia dan kemurnian radionuklida (lolosan 99Mo). Hasil penelitian yang dilakukan selama 5 hari telah diperoleh pH ~5, recovery > 60 %, kemurnian radiokimia > 95 % dan lolosan 99Mo tidak terdeteksi. Dari hasil perlakuan terhadap kolom alumina asam dengan larutan HNO3 0,1 N disimpulkan bahwa kolom alumina asam tidak perlu diganti setiap hari.Purification of 99mTc from 99Mo activation using acidic alumina column chromatography system from MEK (Methyl Ethyl Keton) extraction has been carried out through cooperation between PTRR - BATAN, Chiyoda and JAEA Japan. This method has a limitation that acidic alumina column for purification of 99mTc can be used only once, for the next purification acidic alumina column should be replaced with new column, so it is less practical and also requires high cost. This study aims to obtain a 99mTc solution can be use for labelling of a radiopharmaceutical kit. In this study, the used of acidic alumina column for 99mTc purification was tried more than once by regeneration using 0.1N HNO3 solution after purification process is completed. Parameters observed in this study are the percent recovery, elution profile, pH, radiochemical purity and radionuclida purity. The results of observational studies conducted over 5 days has been obtained pH ~ 5,% recovery > 60%, radiochemical purity of > 95% and 99Mo leakage not detected. The treatment of acidic alumina column with 0,1 N HNO3 solution concluded that acidic alumina column does not need to be replaced every day."