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Date Posted: 21:32:35 02/28/02 Thu
Author: Anonymous
Subject: clinical trials progress reports info

REVERSE TRANSCRIPTASE INHIBITORS
These drugs stop HIV from multiplying by blocking the reverse transcriptase enzyme. This enzyme changes HIV's genetic material (RNA) into the form of DNA. This step has to occur before HIV's genetic code gets combined with an infected cell's own genetic codes. There are two types of reverse transcriptase inhibitors:

Nucleoside analogs (often called "nukes"). These drugs mimic the building blocks used by reverse transcriptase to make copies of the HIV genetic material. These fake building blocks disrupt the copying.
Non-nucleoside reverse transcriptase inhibitors, called NNRTIs, physically prevent the reverse transcriptase enzyme from working.

A. NUCLEOSIDE ANALOGS (NUKES)
Nucleoside analogs (nukes) in development include DAPD, and FTC. Tenofovir is a closely-related nucleotide analog.

DAPD by Triangle Pharmaceuticals is being studied in twice-daily doses. It appears to be effective against HIV that is resistant to other nukes and against hepatitis B. DAPD is in Phase I/II trials.

Emtricitabine (Coviracil�, formerly FTC) by Triangle Pharmaceuticals is closely related to the drug 3TC. FTC was much stronger than 3TC in the laboratory but is not stronger in humans. It is taken once a day and is in Phase II/III trials.

NUCLEOTIDE ANALOGS

Tenofovir (bis-poc PMPA) is being developed by Gilead. Phase II trials showed good results in patients whose virus was already resistant to some nukes. A mutation that gives HIV resistance to 3TC makes it more sensitive to tenofovir. It is in Phase III trials with once-daily dosing. Gilead has started an expanded access program.

B. NON-NUKES (NNRTIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development include Calanolide A, Capravirine, DPC083, Emivirine, PNU142721, and TMC120.

(+)-Calanolide A by Sarawak MediChem Pharmaceuticals was derived from a rain forest plant. It can easily cross the blood-brain barrier, and seems to stay in the bloodstream for a long time. It is in Phase I human trials.

Capravirine (AG1549, formerly S-1153) by Agouron Pharmaceuticals appears to be about 10 times stronger than nevirapine or delavirdine against wild type virus. HIV needs 2 or 3 mutations to develop resistance to capravirine, compared to just one mutation for current NNRTIs. The dose will probably be two 700 mg tablets twice a day. It is in Phase II/III trials.

DPC083 by DuPont Pharmaceuticals is closely related to Efavirenz (Sustiva�). It has a very long half-life, so it will probably be dosed once a day. It can suppress HIV with some resistance to NNRTIs. It is in Phase I/II trials.

Emivirine (MKC-442, Coactinon�) by Triangle Pharmaceuticals is actually a nucleoside analog molecule, but it works like the non-nucleoside analogs: by binding directly to the reverse transcriptase enzyme. It appears to be fairly difficult to tolerate and to not be very effective in patients with viral loads over 100,000. It is in Phase II/III human trials.

PNU142721 by Pharmacia & Upjohn is in very early (Phase I) trials. It appears to work against HIV that is resistant to delavirdine.

TMC120 by Tibotec is active against some strains of HIV that are resistant to other NNRTIs. It is in Phase I/II trials.

DRUGS NO LONGER IN DEVELOPMENT
The following drugs are no longer being developed for use against HIV:

Nukes:
Adefovir dipivoxil (bis POM PMEA) by Gilead Sciences
DOTC (BCH-10652) by BioChem Pharma
FddA (Beta-fluoro-ddA,
Lodenosine�) by US Bioscience
Lobucavir by Bristol-Myers Squibb

NNRTIs:
Atevirdine by Upjohn
GW420867X by GlaxoSmithKline
Loviride by Janssen Pharmaceuticals
HBY-097 by Hoechst-Bayer
New Mexico AIDS InfoNet Fact Sheet Number 402

LOS INHIBIDORES DE TRANSCRIPTASA REVERSA
Estas drogas inhiben al VIH de multiplicarse porque bloquean la enzima de transcriptasa reversa. Esta enzima cambia el material gen�tico del VIH (ARN) en la forma de ADN. Esto tiene que ocurrir antes de que el c�digo gen�tico del VIH se combine con los propios c�digos gen�ticos de una c�lula infectada. Hay dos tipos de inhibidores de transcriptasa reversa:

Los an�logos de los nucle�sidos (a menudo llamado "nukes"). Estos medicamentos imitan los ladrillos usados por la transcriptasa reversa para hacer copias del material gen�tico del VIH. Estos ladrillos falsos rompen el proceso de copiar.
Los inhibidores no nucle�sidos de transcriptasa reversa, llamados NNRTIs funcionan impidiendo f�sicamente a la enzima de transcriptasa reversa trabajar.

A. ANALOGOS DE LOS NUCLEOSIDOS (NUKES)
Los an�logos de los nucle�sidos (nukes) en v�a de desarrollo incluyen DAPD y FTC. Tenofovir es un an�logo de los nucle�tidos estrechamente relacionado a los nucle�sidos.

DAPD por Triangle Pharmaceuticals se estudia en una dosificaci�n de dos veces al d�a. Parece funcionar contra VIH ya resistente a otros "nukes" y contra la hepatitis B. DAPD se estudia in ensayos de Fase I/II.

Emtricitabine (Coviracil�, antes FTC) por Triangle Pharmaceuticals se relaciona estrechamente al medicamento 3TC. FTC parec�a mucho m�s fuerte que 3TC en el laboratorio pero no es mucho m�s fuerte en humanos. Se toma una vez por d�a y se estudia en ensayos de Fase II/III.

ANALOGOS DE LOS NUCLEOTIDOS
Tenofovir (bis-poc PMPA) se desarrolla por Gilead. Ensayos de Fase II han mostrado resultados buenos en pacientes con un virus ya resistente a algunos nukes. Una mutaci�n que da al virus resistencia a 3TC lo pone m�s sensible a tenofovir. Se estudia en ensayos de Fase III con una sola dosis al d�a. Gilead ha empezado un programa de acceso extendido.

B. INHIBIDORES NO NUCLEOSIDOS (NNRTIs)
Los inhibidores no nucle�sidos de la transcriptasa reversa (NNRTIs) en desarrollo son Calanolide A, Capravirine, DPC083, Emivirine, PNU142721 y TMC120.

(+)-Calanolide A por Sarawak MediChem Pharmaceuticals se deriv� de una planta del bosque de lluvia. Puede cruzar f�cilmente la barrera entre la sangre y el cerebro. Se estudia en ensayos de Fase I.

Capravirine (AG1549, anteriormente S-1153) por Agouron Pharmaceuticals parece ser 10 veces m�s fuerte que nevirapina o delavirdina contra el virus salvaje. El VIH necesita 2 o 3 mutaciones para desarrollar la resistencia a capravirine en lugar de una sola mutaci�n para los otros NNRTIs. La dosificaci�n probablemente ser� dos pastillas de 700 mg dos veces al d�a. Se
estudia en ensayos de Fase II/III.

DPC083 por DuPont Pharmaceuticals es estrechamente relacionado a Efavirenz (Sustiva�). Tiene una mitad de la vida muy larga as� que probablemente se tomara solamente una vez al d�a. Puede suprimir VIH con alguna resistencia a los NNRTIs. Se estudia en ensayos de Fase I/II.

Emivirine (MKC-442, Coactinon�) por Triangle Pharmaceuticals realmente es una mol�cula an�loga de los nucle�sidos pero funciona como los no nucle�sidos por atarse directamente a la enzima de transcriptasa reversa. Parece ser bastante dif�cil para tolerar y no parece funcionar para las personas con cargas virales encima de 100,000. Se estudia en ensayos humanos de Fase I/II.

PNU142721 por Pharmacia & Upjohn se estudia en estudios iniciales de Fase I. Parece funcionar contra el VIH ya resistente a delavirdina.

TMC120 por Tibotec funciona contra versiones de VIH ya resistentes a otros NNRTIs. Se estudia en ensayos de Fase I/II. por DuPont Pharmaceuticals es estrechamente relacionado a Efavirenz (Sustiva�). Tiene una mitad de la vida muy larga as� que probablemente se tomara solamente una vez al d�a. Puede suprimir VIH con alguna resistencia a los NNRTIs. Se estudia en ensayos de Fase I/II.

MEDICAMENTOS QUE NO SE DESARROLLAN MAS
Los siguientes medicamentos no se desarrollan m�s para el uso contra el VIH:

Nukes:
Adefovir dipivoxil (bis POM PMEA) por Gilead Sciences
dOTC (BCH-10652) por BioChem Pharma
FddA (Beta-fluoro-ddA, Lodenosine�) por US Bioscience
Lobucavir por Bristol Myers-Squibb

NNRTIs:
Atevirdine por Pharmacia & Upjohn
Loviride por Janssen Pharmaceuticals
GW420867 por GlaxoSmithKline
HBY-097 por Hoechst-Bayer

InfoRed SIDA Nuevo M�xico Hoja N�mero 402E

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