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Movements, leaders, victories and the continuing fight for equality.
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In 1968 Shirley Chisholm became the first Black woman elected to the United States Congress. In 1972 she launched a campaign for the Democratic presidential nomination, breaking another political barrier.
MORE →Reflects the personal views, recollections, and perspective of the author, Mike Davis.
This is a personal recollection on the Move fire on May 13, 1985
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The first pass effect (FPE), also known as first-pass metabolism (FPM) or presystemic metabolism, is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the site of action or systemic circulation.[1][2] The effect is most associated with orally administered medications, but some drugs still undergo first-pass metabolism even when delivered via an alternate route (e.g., IV, IM, etc.).[3] During this metabolism, drug is lost during the process of absorption which is generally related to the liver and gut wall. The liver is the major site of first pass effect; however, it can also occur in the lungs, vasculature or other metabolically active tissues in the body.
Notable drugs that experience a significant first pass effect are buprenorphine, chlorpromazine, cimetidine, diazepam, ethanol (drinking alcohol), imipramine, insulin, lidocaine, midazolam, morphine, pethidine, propranolol, and tetrahydrocannabinol (THC).
First-pass metabolism is not to be confused with phase I metabolism, which is a separate process.
First-pass metabolism may occur in the liver (for propranolol, lidocaine, clomethiazole, and nitroglycerin) or in the gut (for benzylpenicillin and insulin).[4] The four primary systems that affect the first pass effect of a drug are the enzymes of the gastrointestinal lumen,[5] gastrointestinal wall enzymes,[6][7][8] bacterial enzymes[5] and hepatic enzymes.[6][7][9]
After a water-soluble drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver thus may greatly reduce the bioavailability of the drug.
An example of a drug where first-pass metabolism is a complication and disadvantage is in the antiviral drug remdesivir. Remdesivir cannot be administered orally because the entire dose would be trapped in the liver with little achieving systemic circulation or reaching target organs and cells (for example, cells infected with SARS-CoV-2).[10][11] For this reason, remdesivir is administered by IV infusion, bypassing the portal vein. However, significant hepatic extraction still occurs because of second pass metabolism, whereby a fraction of venous blood travels through the hepatic portal vein and hepatocytes.
In drug design, drug candidates may have good druglikeness but fail on first-pass metabolism because it is biochemically selective.[ambiguous] Physiologically based pharmacokinetic models (PBPK) are used to predict first-pass metabolism, although they require compound-specific adjustments due to variability in intestinal mucosal permeability and other factors.[12][13][14] Enzyme expression also varies between individuals, which may influence the efficiency of first-pass metabolism and thus the bioavailability of the drug.[6]
Cytochromes P450, especially CYP3A4, play a crucial role in first-pass metabolism, affecting the bioavailability of drugs.[15][12][14]
Converting a drug into a prodrug can help avoid first-pass metabolism, thereby improving its bioavailability.[16] In in vitro models, such as the use of microfluidic chips that simulate the gut and liver, allow first-pass metabolism to be studied more accurately, facilitating the development of drugs with better absorption profiles.[17][18][19]
Alternative routes of administration, such as insufflation, rectal administration,[20][21]: 5 intravenous,[21]: 4–5 intramuscular, inhalational aerosol, transdermal, or sublingual, avoid or partially avoid the first pass effect because they allow drugs to be absorbed directly into the systemic circulation.[22]
Drugs with high first pass effect typically have a considerably higher oral dose than sublingual or parenteral dose. There is marked individual variation in the oral dose due to differences in the extent of first-pass metabolism, frequently among several other factors. Oral bioavailability of many vulnerable drugs appears to be increased in patients with compromised liver function. Bioavailability is also increased if another drug competing for first-pass metabolism enzymes is given concurrently (e.g., propranolol and chlorpromazine).
Source: Wikipedia. Article content is retrieved live through the MediaWiki API.
The first pass effect (FPE), also known as first-pass metabolism (FPM) or presystemic metabolism, is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the site of action or systemic circulation. The effect is most associated with orally administered medications, but some drugs still undergo first-pass metabolism even when delivered via an alternate route (e.g., IV, IM, etc.). During this metabolism, drug is lost during the process of absorption which is generally related to the liver and gut wall. The liver is the major site of first pass effect; however, it can also occur in the lungs, vasculature or other metabolically active tissues in the body. Notable drugs that experience a significant first pass effect are buprenorphine, chlorpromazine, cimetidine, diazepam, ethanol (drinking alcohol), imipramine, insulin, lidocaine, midazolam, morphine, pethidine, propranolol, and tetrahydrocannabinol (THC). First-pass metabolism is not to be confused with phase I metabolism, which is a separate process.
The first-dose phenomenon is a sudden and severe fall in blood pressure that can occur when changing from a lying to a standing position the first time that an alpha blocker drug is used or when resuming the drug after many months off. This postural hypotension usually happens shortly after the first dose is absorbed into the blood and can result in syncope (fainting). Syncope occurs in approximately 1% of patients given an initial dose of 2 mg prazosin or greater. This adverse effect is self-limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration. The alpha blocker prazosin (Minipress) is most notorious for producing a first dose phenomenon. Other drugs of the same family, doxazosin (Cardura) and terazosin (Hytrin), can also cause this phenomenon, though less frequently. The cause is not clear. It occurs more commonly in patients who are salt and fluid volume depleted (as happens due to the use of diuretics), or were using beta blockers. Diuretics and beta blockers are frequently used to control hypertension. For this reason, treatment with prazosin (Minipress) should always be initiated with a low dose and should be taken at bedtime to avoid standing position.
Misoprostol is a synthetic prostaglandin medication used to prevent and treat stomach and duodenal ulcers, induce labor, cause an abortion, and treat postpartum bleeding due to poor contraction of the uterus. It is taken by mouth when used to prevent gastric ulcers in people taking nonsteroidal anti-inflammatory drugs (NSAID). For abortions it is typically used in conjunction with mifepristone or methotrexate, but can be used alone. By itself, effectiveness for abortion is between 82% and 100%. Its efficacy with mifepristone is higher, but varies based on gestational age. The misoprostol-only abortion regimen is typically recommended only when mifepristone is not available. For labor induction or abortion, it is taken by mouth, dissolved in the mouth, or placed in the vagina. For postpartum bleeding it may also be used rectally. Common side effects include diarrhea and abdominal pain. It is in pregnancy category X, meaning that it is known to result in negative outcomes for the fetus if taken during pregnancy. In rare cases, uterine rupture may occur. It is a prostaglandin analogue—specifically, a synthetic prostaglandin E1 (PGE1). Misoprostol was developed in 1973 and first created for the treatment of gastric ulcers. Its first uses for abortion emerged in Latin America in the 1980s, as women noticed miscarriage was a side effect of the medication. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.
Buccal administration is a topical route of administration by which particular drugs held or applied in the buccal () area (in the cheek) will diffuse through the oral mucosa—(tissues that line the mouth)—and will thereby enter directly into the bloodstream. Buccal administration may provide better bioavailability of some drugs and a more rapid onset of action compared to oral administration because the medication does not pass through the digestive system and thereby avoids first pass metabolism. The forms of drugs suitable for buccal administration include tablets and thin films. As of May, 2014, those medications commercially available in buccal forms included the following: the psychiatric drug asenapine; the opioid drugs buprenorphine, naloxone, and fentanyl; the cardiovascular drug nitroglycerin; the nausea medication prochlorperazine; the hormone replacement therapy testosterone; and nicotine as a smoking cessation aid; as was midazolam, an anticonvulsant used to treat acute epileptic seizures. Buccal administration of vaccines has been studied, but there are challenges to this approach due to immune tolerance mechanisms that prevent the body from overreacting to immunogens encountered in the course of daily life.
Before the 1921 destruction of Tulsa’s Greenwood District, Black residents had created a remarkable center of business and community life. The district included stores, professional offices, entertainment venues and homes owned by Black citizens. Understanding Greenwood means learning what was built—not only what was burned.
MORE →Mae Jemison, aboard Space Shuttle Endeavour in 1992.