APIGENIN

APIGENIN

         

Apigenin is a flavonoid compound. Apigenin in celery is an aglycone of Apiin. The physical properties of chemical Apigenin is as follows:

        Apigenin Physical properties:
1. Hold Warming
2. Melting point of 345-3500C
3. Unstable against light, oxidation and chemical changes
4. Because many are polar-OH groups
5. High solubility with warm alcohol
          

Apigenin Chemical properties:
1. Molecular formula C15H10O5
2. BM 270.23 g / mol
3. 5.7 dihydroxy-2-(4-hydroxyphenyl)-4H-1-​​Benzopiran-4-ON

In public life today are increasingly aware of the health, antioxidant therapy to overcome the influence of radicals increasingly feel important. Antioxidants obtained either synthetic or natural. Synthetic antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluen (BHT), tertiary-butylated hydroquinone (TBHQ), and propyl error has been widely added to the lipid-containing foods. However, synthetic antioxidants have the risk of carcinogenesis. Therefore, the development of natural antioxidants as alternatives to synthetic antioxidants continues. Natural antioxidants from plants are generally classified as vitamins, phenolic compounds including flavonoids and phenolic acids and volatile compounds. Natural antioxidants has become very important not only in food but also is a source for tackling the diseases caused by degenerative damage.

One of the natural antioxidants that can be used is honey. The chemical content of honey such as flavonoids, ascorbic acid, tocopherol, catalase enzyme, phenolic compounds and Maillard reaction products (MRP) works synergistically as antioxidants. To demonstrate the potential of honey as a source of antioxidants so in this study to test the antioxidant activity of honey in vitro by free radical capture method 1,1-diphenyl-2-pikrilhidrazin (DPPH) with UV spectrophotometry. Methods to capture free radicals DPPH is a method that is fast, easy and inexpensive compared to other methods. This study aimed to compare the antioxidant activity of some types of honey on the market. Honey is tested antioxidant activity in this study are forest honey from South Sumatra, honey and honey imported forestry (honey Australia).

Overview covers chemical literature regarding the chemical content of honey. Chemical constituents of honey including flavonoids, ascorbic acid, enzymes catalase, phenol compounds and Maillard reaction products (MRP), which work synergistically as antioxidants. In addition, the sugar content is as high as fructose 38.38% w / w, glucose 30.31% w / w, reducing sugar 76.65% w / w, 1.31% sucrose, 3-4% oligosaccharides (erlose, theanderose, and panose) and disaccharides (NHB). Gluconic acid, other acids, a little protein, enzymes, amino acids, and minerals are also present in the honey. Potassium is the largest mineral contained in honey. Some of the vitamins found in honey include vitamin B1, vitamin B2, B3, B6, and vitamin C.
Flavonoids are found in honey is a type of flavonoids that Apigenin (Gradolatto, et al., 2005), hesperetin, kaempferol, quercetin and chrysin.

A solution to inspection flavonoids, quinones, saponins and tannins were made in the following way: a 1 gram of extract added to 100 mL of hot water, boiled for 15 minutes, then filtered. The filtrate is called solution C. To a 5 mL solution C added Mg powder and 1 mL of concentrated hydrochloric acid. Colors can be drawn with amyl alcohol, if there is a red purple orange to red indicate flavonoids

 

 

Apigenin Derivatives Biosynthesis

 

MORPHINE

MORPHINE

Synonyms:
morphinum
morphia
MS contin
duramorph
oramorph

 Data Relevant Physicochemical:
MW: 285.3 morphine, 461.5 morphine glucuronide
Formula: C17H19NO3 morphine, C23H27NO9 morphine glucuronide
Chemical Name: (5a,6a)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol
Solubility: drug usually contains 5 molecules of water, soluble in water and organic solvents
Appearance: white, crystalline powder

  Images:

See //drugs.com// for additional images

General Relevancy:
Morphine is a primary constituent of opium and is used primarily in the relief of severe pain. Morphine may also be present as a metabolite after heroin administration. It is metabolized in the body to morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G) and other minor metabolites. The metabolites, M3G and M6G, possess pharmacological activity. Research has indicated that M6G is effective as an analgesic and M3G possesses neuroexcitatory activity. Studies suggest M3G may play a role in the development of tolerance in individuals chronically exposed to morphine. Both metabolites are eliminated primarily via the kidney. Changes in renal function can result in the accumulation of M6G and M3G with little change in the blood concentration of free morphine. The resultant increase in M6G may be contributory to toxicity in patients.

(Morfin merupakan konstituen utama dari opium dan digunakan terutama dalam menghilangkan rasa sakit yang parah. Morfin juga dapat hadir sebagai metabolit setelah pemberian heroin. Hal ini dimetabolisme dalam tubuh menjadi morfin-3-glukuronat (M3G), morfin-6-glukuronat (M6G) dan metabolit kecil lainnya. Metabolit, M3G dan M6G, memiliki aktivitas farmakologis. Penelitian telah menunjukkan bahwa M6G efektif sebagai analgesik dan M3G memiliki aktivitas neuroexcitatory. Studi menunjukkan M3G mungkin memainkan peran dalam perkembangan toleransi pada individu terpajan terhadap morfin. Kedua metabolit dieliminasi terutama melalui ginjal. Perubahan fungsi ginjal dapat mengakibatkan akumulasi M6G dan M3G dengan sedikit perubahan dalam konsentrasi darah morfin bebas. Peningkatan yang dihasilkan di M6G mungkin iuran untuk toksisitas pada pasien.)

 Mechanism of Action:
Morphine produces its analgesic and sedating effects primarily through stimulation of the m opioid receptor (MOR). Receptor sites throughout the central nervous system and gastrointestinal tract mediate pain, respiratory rate, euphoria, constipation and other effects associated with morphine and the opioid drugs. Glucuronidation at the 6-hydroxyl site of morphine and codeine does not interfere with binding to MOR. This explains why M6G possesses activity comparable to morphine. On the other hand, glucuronidation at the 3-hydroxyl site interferes with MOR recognition of opioids including morphine and hydromorphone. Despite less activity at MOR, these metabolites are not devoid of physiological effects. Instead, M3G and hydromorphone-3-glucuronide produce neuro-excitatory effects, possibly through activation of N-methyl-D-aspartic acid (NMDA) receptors 

Morfin menghasilkan efek analgesik dan penenang terutama melalui stimulasi dari reseptor opioid m (MOR). Reseptor situs di seluruh sistem saraf pusat dan saluran gastrointestinal nyeri menengahi, laju napas, euforia, sembelit dan efek lain yang berhubungan dengan morfin dan obat opioid. Glucuronidation di situs-6 hidroksil morfin dan kodein tidak mengganggu mengikat MOR. Hal ini menjelaskan mengapa M6G memiliki aktivitas sebanding dengan morfin. Di sisi lain, glucuronidation di situs 3-hidroksil mengganggu pengakuan MOR opioid termasuk morfin dan hidromorfon. Meskipun aktivitas kurang MOR, metabolit tidak bebas dari efek fisiologis. Sebaliknya, M3G dan hidromorfon-3-glukuronida menghasilkan neuro-rangsang efek, mungkin melalui aktivasi N-methyl-D-aspartic acid (NMDA) reseptor

 
Metabolism and Pharmacokinetics:
t1/2 morphine: 1.3-6.7 hr [1]
t1/2 M6G: 2.5-4.7 hr [12]
t1/2 M3G: 2.4-3.8 hr [12]

To make sense of morphine metabolism the structure-activity relationships must be understood. Alterations to the structure change the pharmacological activity and may have important clinical sequelae. The basic principles have been known for some time, and were well summarised in a WHO Bulletin published as long ago as 1955 [BRAENDEN et al, 1955].

The most important positions on the morphine molecule, because of their implications for both activity and morphine metabolism, are the phenolic hydroxyl at position 3, the alcoholic hydroxyl at position 6, and at the nitrogen atom (Figure 1).

Both hydroxyl groups can be converted to ethers or esters (e.g. heroin, diacetylmorphine) and these changes alter clinical effect. Changes on the hydroxyl groups are opposite in direction; additions at the phenolic 3-hydroxyl group reduce pharmacological activity considerably, by perhaps more than 90%. By contrast, modification at the alcoholic 6-hydroxyl position results in an activation of the molecule, with the resulting compound being 2-4 times more potent as an analgesic than morphine after parenteral dosing in standard tests.

These rules are not absolute, however, and some substitutions at the 6-hydroxyl (e.g. conjugation with long aliphatic acids) reduce activity because of steric and other considerations. Short chain fatty acid substitutions (such as 3,6-dibutanoylmorphine) have been used to increase the lipophilicity and potency of morphine [OWEN & NAKATSU, 1984; TASKER AND NAKATSU, 1984].

The tertiary character of the nitrogen atom is crucial for morphine's analgesic activity. Chemical modifications which make the nitrogen quaternary (as with N -oxide) greatly diminish analgesic potency because of reduced penetration into the central nervous system. Changes to the methyl substituent on the nitrogen are also important; replacement of the methyl group with 3-carbon alkyl groups not only reduces the analgesic action, but actually produces compounds which antagonise the actions of morphine, such as nalorphine.

 The majority (~65%) of a dose of morphine is excreted as glucuronide conjugates. Both glucuronides are formed by the 2B7 isoform of uridine-5’-diphosphate glucuronosyltransferase (UGT2B7) in the liver, with M3G predominating. About 5% of a dose is demethylated to normorphine, which is also mostly glucuronidated. Normorphine and its conjugate are readily detected in urine. The excretion of M3G is through bile, feces, and urine. Extensive enterohepatic recirculation causes much of the biliary M3G to be excreted in urine. In fact, the 72-hour urine includes about 87% of a morphine dose, excreted as free morphine (10% of dose) and various metabolites. The figure below describes the relationship between morphine and its glucuronide metabolites in plasma after iv administration.
(Untuk memahami metabolisme morfin struktur-aktivitas hubungan harus dipahami. Perubahan pada struktur mengubah aktivitas farmakologi dan mungkin memiliki gejala sisa klinis yang penting. Prinsip-prinsip dasar telah dikenal selama beberapa waktu, dan baik diringkas dalam Buletin WHO diterbitkan sejak tahun 1955 [et al BRAENDEN, 1955].

Posisi yang paling penting pada molekul morfin, karena implikasi mereka untuk aktivitas dan metabolisme morfin, adalah hidroksil fenolik pada posisi 3, yang hidroksil beralkohol pada posisi 6, dan pada atom nitrogen (Gambar 1).
Kedua kelompok hidroksil dapat dikonversi ke eter atau ester (misalnya heroin, diacetylmorphine) dan perubahan ini mengubah efek klinis. Perubahan pada gugus hidroksil yang berlawanan arah, penambahan pada kelompok 3-hidroksil fenolik mengurangi aktivitas farmakologi cukup, oleh mungkin lebih dari 90%. Sebaliknya, modifikasi pada 6-hidroksil hasil beralkohol posisi dalam aktivasi molekul, dengan senyawa yang dihasilkan menjadi 2-4 kali lebih kuat sebagai analgesik dari morfin setelah dosis parenteral dalam tes standar.)
Aturan-aturan ini tidak mutlak, bagaimanapun, dan beberapa substitusi di (konjugasi misalnya dengan asam alifatik panjang) 6-hidroksil mengurangi aktivitas karena pertimbangan sterik dan lainnya. Pendek rantai substitusi asam lemak (seperti 3,6-dibutanoylmorphine) telah digunakan untuk meningkatkan lipofilisitas dan potensi morfin [Owen & Nakatsu, 1984; Tasker DAN Nakatsu, 1984].

Karakter tersier dari atom nitrogen sangat penting untuk aktivitas analgesik morfin itu. Modifikasi kimia yang membuat nitrogen kuartener (seperti N-oksida) sangat mengurangi potensi analgesik karena mengurangi nilai penetrasi ke dalam sistem saraf pusat. Perubahan substituen metil pada nitrogen yang juga penting, penggantian kelompok metil dengan 3-karbon gugus alkil tidak hanya mengurangi tindakan analgesik, tapi benar-benar menghasilkan senyawa yang memusuhi tindakan morfin, seperti nalorphine.

(Mayoritas (~ 65%) dari dosis morfin diekskresikan sebagai konjugat glukuronat. Kedua glucuronides dibentuk oleh isoform 2B7 dari uridin difosfat-5'-glucuronosyltransferase (UGT2B7) dalam hati, dengan M3G mendominasi. Sekitar 5% dari dosis yang demethylated untuk normorphine, yang juga sebagian besar glucuronidated. Normorphine dan konjugat yang dapat segera dideteksi dalam urin. Ekskresi M3G adalah melalui empedu, feses, dan urin. Resirkulasi enterohepatik yang luas menyebabkan banyak M3G empedu akan diekskresikan dalam urin. Bahkan, urin 72 jam mencakup sekitar 87% dari dosis morfin, diekskresikan sebagai morfin bebas (10% dari dosis) dan metabolit berbagai. Gambar di bawah ini menggambarkan hubungan antara morfin dan metabolit glukuronat dalam plasma setelah iv administrasi.)

            There does not appear to be any genetic variation in glucuronide formation by UGT2B7. However, ethanol, naltrexone, naloxone and ranitidine may interfere with UGT2B7 activity. In addition, steroid hormones and bilirubin in newborn infants are metabolized by UGT2B7. Genetic differences in other glucuronosyl transferase enzymes (e.g., Gilbert’s syndrome) do not appear to alter morphine pharmacokinetics. The ratios of free morphine, M6G and M3G have been investigated as predictive markers for a variety of physiological outcomes including effectiveness of analgesia and acute overdose with heroin (see Critical Concentrations below). Levels of M3G peak around 2 hours after morphine administration, exceeding the concentration of free morphine remaining in serum. M6G is slow to cross the blood brain barrier during both the absorptive and elimination phases.

(Ada tampaknya tidak akan ada variasi genetik dalam pembentukan glukuronat oleh UGT2B7. Namun, etanol, naltrexone, nalokson dan ranitidine dapat mengganggu aktivitas UGT2B7. Selain itu, hormon steroid dan bilirubin pada bayi baru lahir yang dimetabolisme oleh UGT2B7. Perbedaan genetik pada enzim transferase glucuronosyl lainnya (misalnya, sindrom Gilbert) tidak muncul untuk mengubah farmakokinetik morfin. Rasio morfin bebas, M6G dan M3G telah diteliti sebagai penanda prediktif untuk berbagai hasil fisiologis termasuk efektivitas analgesia dan overdosis akut dengan heroin (lihat Konsentrasi Kritis bawah). Tingkat M3G puncak sekitar 2 jam setelah pemberian morfin, melebihi konsentrasi morfin kosong yang tersisa dalam serum. M6G lambat untuk melewati sawar darah otak selama kedua serap dan fase eliminasi.)

 

Adverse Effects:
Morphine is available in a variety of dosage forms including oral (immediate and controlled release), rectal, intravenous, epidural, and intramuscular. Morphine is well known for its ability to induce sedation and euphoria, often described as a dreamlike state. The euphoric effects are believed to contribute to reinforcement and abuse of morphine. Morphine is currently a schedule II controlled substance and package inserts include a warning that the drug may be habit forming. Morphine and M6G are central nervous system (CNS) depressants and both inhibit respiration. Patients are also warned that morphine may impair abilities necessary for the safe operation of a motor vehicle.

The most common adverse effects in patients treated with morphine are sedation, dizziness, nausea, vomiting, sweating, and constipation. Morphine may also cause visual disturbances, transient hallucinations, circulatory depression and allergic reactions. Drugs that act as CNS depressants (including alcohol, benzodiazepines, anesthetics, antipsychotics and tricyclic antidepressants) may produce at least additive effects in combination with morphine. 

(Morfin tersedia dalam berbagai bentuk sediaan, termasuk oral (pembebasan segera dan dikendalikan), rektal, intravena, epidural, dan intramuskular. Morfin adalah terkenal karena kemampuannya untuk menginduksi sedasi dan euforia, sering digambarkan sebagai negara mimpi. Efek euforia diyakini berkontribusi pada penguatan dan penyalahgunaan morfin. Morfin saat jadwal II bahan yang dikendalikan dan menyisipkan paket termasuk peringatan bahwa obat tersebut dapat membentuk kebiasaan. Morfin dan M6G adalah sistem saraf pusat (SSP) depresi dan keduanya menghambat respirasi. Pasien juga memperingatkan bahwa morfin dapat mengganggu kemampuan yang diperlukan untuk operasi yang aman dari kendaraan bermotor.

Efek samping yang paling umum pada pasien yang diobati dengan morfin adalah sedasi, pusing, mual, muntah, berkeringat, dan sembelit. Morfin juga dapat menyebabkan gangguan penglihatan, halusinasi sementara, depresi peredaran darah dan reaksi alergi. Obat yang bertindak sebagai depresan SSP (termasuk alkohol, benzodiazepin, anestesi, antipsikotik dan antidepresan trisiklik) dapat menghasilkan setidaknya efek aditif dalam kombinasi dengan morfin.)

 Methods of Analysis:

There are published GC, HPLC, GC/MS, LC/MS and LC/MS/MS methods for the determination of morphine and its glucuronide metabolites. Morphine and its glucuronide metabolites may be collected during solid phase extraction from the same column, however differences in polarity of these compounds may require separate elution solvents. Hydrolysis may be performed with heat and acidic conditions or enzymatically (b-glucuronidase). Glucuronidated metabolites are likely to elute as a group separate from their free opioid counterparts depending on the type of column used for chromatography.

(Ada diterbitkan GC, HPLC, GC / MS, LC / MS dan LC / MS / MS metode untuk penentuan morfin dan metabolit glukuronat nya. Morfin dan metabolit glukuronat yang dapat dikumpulkan selama ekstraksi fase padat dari kolom yang sama, namun perbedaan polaritas senyawa ini mungkin memerlukan pelarut elusi terpisah. Hidrolisis dapat dilakukan dengan panas dan kondisi asam atau enzimatik (b-glukuronidase). Metabolit Glucuronidated cenderung mengelusi sebagai kelompok terpisah dari rekan-rekan mereka gratis opioid tergantung pada jenis kolom yang digunakan untuk kromatografi.)

Antemortem Levels – Chronic Pain Patients, Serum/Plasma
In one reported case study, three patients with renal failure exhibited respiratory failure following morphine administration. M6G plasma levels ranged from 130 to 1,100 ng/mL with morphine levels less than 4 ng/mL. Following ingestion of 5 grams of sustained release morphine, M3G, M6G and morphine plasma levels at 60 hours post ingestion were 6,200 ng/mL, 11,000 ng/mL and 620 ng/mL respectively.

Based on observations that M3G concentrations exceed free morphine within 2 hours post-dose, several methods have been proposed to estimate survival time by comparing morphine and metabolite concentrations. This technique often uses the free/total ratio, comparing morphine levels before and after hydrolysis. If the free morphine is less than some percentage of the total, it is assumed that the individual had time to metabolize the dose. However, if the free morphine constitutes the majority of the total, the death was probably acute and the individual did not have time for metabolism to take place. Since hydrolysis introduces an additional source of uncertainty to the analysis, many recent reports are using specific measurements of morphine, M3G and M6G to determine total morphine. In two cases of heroin overdose, blood levels were 360 ng/mL morphine, 82 ng/mL M3G and 5 ng/mL M6G in an acute death and 110 ng/mL morphine, 1900 ng/mL M3G and 120 ng/mL M6G in a delayed deat.

(Dalam satu studi kasus yang dilaporkan, tiga pasien dengan gagal ginjal dipamerkan kegagalan pernafasan setelah pemberian morfin. M6G kadar plasma berkisar antara 130 sampai 1.100 ng / mL dengan tingkat morfin kurang dari 4 ng / mL. Setelah mengkonsumsi 5 gram morfin rilis berkelanjutan, M3G, M6G dan morfin tingkat plasma pada 60 jam pasca konsumsi yang 6.200 ng / mL, 11.000 ng / mL dan 620 ng / mL masing-masing.

Berdasarkan pengamatan bahwa konsentrasi M3G melebihi morfin gratis dalam 2 jam pasca-dosis, beberapa metode telah diusulkan untuk memperkirakan waktu kelangsungan hidup dengan membandingkan konsentrasi morfin dan metabolit. Teknik ini sering menggunakan rasio bebas / total, membandingkan tingkat morfin sebelum dan sesudah hidrolisis. Jika morfin bebas kurang dari beberapa persentase dari total, diasumsikan bahwa individu memiliki waktu untuk memetabolisme dosis. Namun, jika morfin bebas merupakan mayoritas dari total, kematian mungkin akut dan individu tidak punya waktu untuk metabolisme berlangsung. Karena hidrolisis memperkenalkan tambahan sumber ketidakpastian untuk analisis, laporan terakhir banyak yang menggunakan pengukuran spesifik morfin, M3G dan M6G untuk menentukan morfin total. Dalam dua kasus overdosis heroin, tingkat darah adalah 360 ng / mL morfin, 82 ng / mL M3G dan 5 ng / mL M6G dalam kematian akut dan 110 ng / mL morfin, 1900 ng / mL M3G dan 120 ng / mL M6G di sebuah DEAT tertunda.)