| Neues antivirales Medikament |
Lamivudin ist ein neues antivirales Medikament, gehören zu den nukleosidischen Reverse-Transkriptase-Inhibitoren, hat in vitro und im Tierversuch eine starke Hemmwirkung auf die Infektion mit dem Hepatitis-B-Virus (HBV), kann die Synthese des HIV-Virus hemmen; das von der GlaxoSmithKline Co. hergestellte Medikament. In den frühen 90ern, Sie werden zur Behandlung von AIDS-Medikamenten in Europa und nordamerikanischen Ländern eingesetzt. Mitten in der 1990 Medizinische Experten stellten fest, dass sie eine Hemmung der Hepatitis-B-Virus-DNA aufweisen, In 1998 der US-amerikanischen Food and Drug Administration (FDA) hat das erste Medikament zur Behandlung von Hepatitis B zugelassen. In China, Die staatliche Lebensmittel- und Arzneimittelbehörde genehmigte den Import von Arzneimitteln, die hauptsächlich als Arzneimittel zur Behandlung von Hepatitis B eingesetzt werden, Chinesischer Produktname als “Er Puding”. In 1999, offiziell auf dem Festland begonnen. Chinesen danach verkauft 10 Jahre der klinischen Verifizierung, Lamivudin ist das einzige Arzneimittel, das nachweislich das Fortschreiten einer Hepatitis-Zirrhose verzögert, weniger Nebenwirkungen, weniger Kosten für Medikamente, derzeit hat 2 Millionen der Hepatitis-B-Patienten des Landes verwenden.
Lamivudin kann in HBV-Infektionszellen und normalen Zellen zu Lamivudin-drei-Phosphat metabolisiert werden, es ist die aktive Form von Lamivudin, beides Inhibitoren der HBV-Polymerase, und ist Polymerasesubstrat. Einbau von Lamivudin drei Phosphaten in die virale DNA-Kette, kann die Synthese viraler DNA blockieren, und stört den normalen Desoxynukleosidstoffwechsel der Zelle nicht, Es weist eine schwache Hemmung der Säugetier-DNA-Polymerase Alpha und Beta auf, nahezu keine Auswirkung auf den DNA-Gehalt von Säugetierzellen, und ohne offensichtliche Toxizität für die Struktur der Mitochondrien, Inhalt und Funktion der DNA. Die Ergebnisse des Serum-HBV-DNA-Nachweises der meisten Hepatitis-B-Patienten zeigten, dass Lamivudin die Replikation von HBV schnell hemmen kann, seine hemmende Wirkung hielt während des gesamten Behandlungsprozesses an. Gleichzeitig sank die Serumtransaminase auf den Normalwert, Eine langfristige Anwendung kann die Lebernekrose und entzündlichen Veränderungen deutlich verbessern und Leberfibrose lindern oder verhindern. |
| Produktionsmethoden |
Wählen Sie eine 6-o-Sulfo-Acylierungsreaktion für die Verbindungen aus (ICH), dann acetyliert, um die Verbindung zu erhalten (II), Die Ausbeute war 96.7%. Die Verbindung (II) verwendet Essigsäure als Lösungsmittel, und 3 molL Bromwasserstoff/L Säure (45%, W/V) Reaktion, Bromierung, um eine Verbindung zu erhalten (III), Die Ausbeute war 99%. Bromid (III) und 3.3 mol Ethylkaliumxanthat, in Aceton unter Rückfluss kochen, Thio und Cyclisierung; dann in Methanol mit Ammoniak hydrolysiert, um die Verbindung zu erhalten (IV), Die Ausbeute des zweiten Schritts beträgt 72%. Verbindungen (IV) wird durch Säulenchromatographie gereinigt, ist kristalliner Feststoff. Verbindung (IV) verwendet 1.4 Mol-Natriumperiodat-Behandlung, um 2,3-CIS-Glykol zu öffnen; Anschließend folgt die Reduktion von Natriumborhydrid zu Aldehyden und die Schrumpfung der Ketoform, um das Glykol zu schützen, und Verbindung erhalten (V), der Ertrag ist 60%. Die Verbindung (V) Silan zum Schutz des restlichen Primäralkohols, und dann Ketal abtrennen, um die Verbindung zu erhalten (VI) und die Ausbeute beträgt 63 %. Verwenden Sie Bleitetraacetat, um Glykolverbindungen zu oxidieren (VI), and then to use dichromic acid pyridine salt to further oxidation, und Verbindung erhalten (VII), the oxidation method does not affect the sulfur. compounds (VII) is oxidized by using lead acetate to obtain compounds (VIII), der Ertrag ist 66%[ according to compounds (VI)]. Verbindungen (VIII) und (IX) are in the dichloroethane,and TMSOTf as a Lewis acid catalyst, condensated to compound (X), der Ertrag ist 64%. And the amount of isomers of compounds (X) is half of the compounds (X) and their available silica gel chromatography to isolate. Verbindungen (X) in ammonia-methanol and acetyl, der Ertrag ist 73% ; with Tetrabutylammonium fluoride solution to remove the silylation to obtain lamivudine and yield of 75%. |
| What kind of patients suitable for use Lamivudine |
Not all patients with hepatitis B are suitable for the use of lamivudine. Lamivudine should be applied in the following cases according to the action characteristics of lamivudine and clinical summary of the experience in the application of lamivudine:
(1) HBVDNA quantitative detection of moderate positive; HBeAg positive; ALT increased 2~10 times.
(2) HBeAg negative, but HBVDNA was moderately positive (do not take the qualitative PCR results as the standard, to do quantitative measurement), ALT increased 2~10 times. The majority of this situation may be the virus gene mutations in the C region.
Not suitable for the use of lamivudine is the main:
(1) HBVDNA negative or quantitative determination of <105copies/ml;
(2)with normal ALT (mainly refers to the virus asymptomatic HBV carriers (ASC); for the past elevated ALT, but now ALT and AST normal patients, can be temporary not treatment, elevated ALT and treated. The patient was not suitable for use, not because lamivudine is harmful to the people, but because of the low effective rate of these patients, does not meet the pharmaceutical economics principle.
Lamivudin, like any other drugs, can be used properly to benefit most patients, and inappropriate use will not produce the desired effect, and inappropriate withdrawal may even lead to exacerbations.
The above information is Chemicalbook Hanya edited. |
| Zidovudine |
Zidovudine (azidothymidine, AZT) is a thymidine analogue. Within the virus-infected cell, the 3′-azido group is used by retroviral reverse transcriptase and incorporated into DNA transcription, preventing viral replication. The shared mechanism of action is inhibition of RNA-dependent DNA polymerase (reverse transcriptase). This enzyme is responsible for conversion of the viral RNA genome into double-stranded DNA before it is integrated into the cell genome. Because these actions occur early in replication, the drugs tend to be effective for acute infections but are relatively ineffective for chronically infected cells. Cellular α-DNA polymerases are inhibited only at concentrations 100-fold greater than those necessary to inhibit reverse transcriptase, thus rendering this drug relatively safe to host cells. Cellular γ-DNA polymerase, jedoch, is inhibited at lower concentrations. AZT is effective against a variety of retroviruses at low concentrations. Resistance to AZT is associated with point mutations resulting in amino acid substitutions in the reverse transcriptase. Prolonged use of AZT can facilitate viral resistance. The risk of resistance also appears to correlate with CD4 cell count and the state of infection. Viral susceptibility to AZT may return after the drug has been discontinued for a period of time. |
| Pharmakokinetik |
After oral administration of lamivudine, it is well absorbed. And about 0.1 g of adult oral about 1hr reached peak plasma concentration Cmax 1.1-1.5 u g/ml, bioavailability is 80-85%. and at the same time of food taking, the Tmax delayed 0.25-2.5 HR and lower 10-40% of Cmax, but the bioavailability is unchanged. Intravenous administration research results table Ming lamivudine average distribution capacity is 1.3 L/Kg, system average clearance rate of 0.3 L/h/kg, seventy percent by organic cation transport system and renal clearance and elimination half-life is 5-7hr. within the therapeutic dose range and lamivudine pharmacokinetics showed a linear relationship, the plasma protein binding rate is low. In vitro studies have shown that with serum albumin binding rate is <16-36%. It can pass through the blood brain barrier into the cerebrospinal fluid. Mainly the prototype drug excretion by the kidneys, renal excretion accounted for about total removal of 70% oder so, nur 5-10% is metabolized into Anti sulfur oxide derivatives. For patients with renal insufficiency can affect lamivudine excretion, and for creatinine clearance rate <30mL/ points in patients, does not recommend the use of this product. Liver damage does not affect the metabolism of drugs, due to increased age and decreased renal excretory function in elderly patients, lamivudine metabolism without significant changes, Only in creatinine clear except rate <30mL/ time-sharing, there is influence. |
| drug withdrawal |
Lamivudine is not hepatitis b curative drugs, can only make it better, and easy to rebound after discontinuation of lamivudine treatment. So how long is more appropriate, should according to the therapeutic effect and It differs from man to man. The most accepted standard of withdrawal is: before treatment, HBVDNA positive, HBeAg positive, ALT increased more than 1 mal; treatment after HBVDNA seroconversion, HBeAg seroconversion (“big Sanyang” zu “small Sanyang”), ALT normalization, maintain the effect of the above 6 months can be stopped. Of course in this standard withdrawal is not only without recurrence, the recurrence rate is low. It is reported that this group of patients discontinued 21 months still maintain curative effect. The recurrence rate of 81%. Asians is slightly higher, but in a year when the recurrence rate is lower than that of 40%. For example not up to this effect and withdrawal, while the majority of cases in a short period of time to recurrence, even some patients because of inappropriate drug withdrawal and lead to illness. So stoping the drug is a great event, I hope the patients in the decision to stop the medicine to go to the hospital to consult an experienced specialist, and not to stop the medicine. |
| Adverse reactions and side effects |
Lamivudine is a kind of nucleoside drugs, by inhibiting or blocking synthesis of the hepatitis B virus DNA to restrain replication of hepatitis B virus, thus gradually clear hepatitis B virus, often are used by doctors to treat acute and chronic hepatitis B.
Common side effects are easy to produce drug resistance, Nebenwirkungen, withdrawal difficult, Fieber, upper respiratory tract infection symptoms, Kopfschmerzen, Bauchschmerzen, physical discomfort, diarrhea and other symptoms, but the symptoms are generally mild and in a short time the ego recede. At the same time the State Food and Drug Administration released Thirtieth phase drug adverse reaction information bulletin also alert our medical workers and drug producers wary of lamivudine and telbivudine may cause the risk of rhabdomyolysis, myalgia, Schwäche, elevated creatine kinase, blood creatinine rise higher.
Long-term use is easily virus mutates, more performance is after discontinuation of hepatitis B virus DNA positive rotation or is in a cycle of treatment occurs when the hepatitis B virus positive turn, this is the hallmark of virus mutates, indicating that more serious illness, more difficult to treat. Recent studies also suggest, the side effects of lamivudine is also reflected on the damage to the kidney, the majority of patients will have different degrees of renal toxicity, serious and even renal failure. |
| Disabling condition |
1.Chronic asymptomatic hepatitis B virus carriers were normal and no symptoms, whatever virus replication index or not (both “big Sanyang” und “small Sanyang”), are not taking lamivudine. But it is understood that at present this part of patients taking this medicine is a common phenomenon, which wasted drugs and money. At present the treatment of hepatitis B virus is not resolved, medical scientists is also exploring, the existing methods are not mature. The important reason of lamivudine in treatment of hepatitis B virus are invalid, someone after taking HBVDNA may drop to 103 copies/ml, once the withdrawal and we immediately rebound. We found that people taking more than half a year after discontinuation of HBVDNA negative, weniger als 1 months back, and HBeAg cannot be negative. Deshalb, can’t use this medicine to treat hepatitis B virus, unless the liver puncture biopsy confirmed chronic liver. The application can only be considered when the inflammatory pathological changes.
2. Acute severe hepatitis or acute liver failure are in critical condition, the ferocious. At this time the patient’s main contradiction is not virus replication, some patients even without virus replication index, threatening the patient’s life is liver failure, according to “the government ease the emergency treatment of the subject”, then the most important is supportive therapy, such as the input of fresh plasma, albumin, artificial liver support therapy.
3. Acute exacerbation of chronic hepatitis B, if the transaminase is greater than the upper limit of the normal value of 10 mal, there are obvious jaundice, or serum bilirubin than 85.5 mmol/L, temporarily not to take lamivudine and other antiviral drugs, and liver, jaundice and reducing enzyme treatment is given priority to, When remission can apply a small amount. Although lamivudine on immune function has strongly influenced not the same interferon but in the acute exacerbation of hepatitis, prevent damage on the immune system. No use is the best policy.
4. Chronic hepatitis B in pregnancy or pregnancy after HBV infection, do not use this product, the main reasons of the effect of lamivudine on the fetus are yet to be elucidated. As both at home and abroad, There are application reports and relatively safe, but experts in China has not yet reached a consensus, as a precaution, temporarily application is a wise choice. |
| Chemische Eigenschaft |
White solid obtained from methanol-ethyl acetate. [A]D21-132°(C=1.08, Methanol). Or from the boiling ethanol crystallization, melting point is 160~162℃. [A]D21-135°(C=0.38, Methanol). |
| Verwendet |
1. Antiviral drugs for hepatitis B.
2. Antiviral drugs for the treatment of liver and gallbladder diseases.
3. Medicine for liver and gallbladder diseases. |
| Chemische Eigenschaften |
White Powder Muscle Building Steroide Epiandrosteron |
| Verwendet |
A reverse transcriptase inhibitor. Antiviral. |
| Definition |
Chebi: A monothioacetal that consists of cytosine having a (2R,5S)-2-(Hydroxymethyl)-1,3-oxathiolan-5-yl moiety attached at position 1. An inhibitor of HIV-1 reverse transcriptase. |
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