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If so, does it provide incentive to Directors or prospective Directors not to want to serve with the best and brightest, but with the dumb and dimmest. Their products are sold exclusively online and are located in Santa Monica, California. Frank Zarb left Nasdaq in , Mr. Archived from the original PDF on 27 May Chief Executive Officer David Wittig and another executive guilty of looting the electric utility of millions of dollars.
Metformin use among women with PCOS before they are pregnant does not appear to reduce abortion risk. Several observational studies and randomized, controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes.
Nonetheless, several concerns were raised and evidence on the long-term safety of metformin for both mother and child is lacking. Metformin is safe in pregnancy and women with gestational diabetes treated with metformin have less weight gain during pregnancy than those treated with insulin. Metformin appears to be safe and effective in counteracting the weight gain caused by the antipsychotic medications olanzapine and clozapine.
Metformin may reduce the insulin requirement in type 1 diabetes. According to the prescribing information , heart failure in particular, unstable or acute congestive heart failure increases the risk of lactic acidosis with metformin. Metformin is recommended to be temporarily discontinued before any radiographic study involving iodinated contrast agents, such as a contrast-enhanced CT scan or angiogram , as the contrast dye may temporarily impair kidney function, indirectly leading to lactic acidosis by causing retention of metformin in the body.
The most common adverse effect of metformin is gastrointestinal irritation, including diarrhea , cramps, nausea, vomiting, and increased flatulence ; metformin is more commonly associated with gastrointestinal side effects than most other antidiabetic medications. Metformin has also been reported to decrease the blood levels of thyroid-stimulating hormone in people with hypothyroidism.
In a clinical trial of subjects, Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose 1. Long-term use of metformin has been associated with increased homocysteine levels  and malabsorption of vitamin B The most serious potential adverse effect of biguanide use is metformin-associated lactic acidosis MALA.
Though the incidence for MALA is about nine per , person-years,  this is similar to the background incidence of lactic acidosis in the general population. A systematic review concluded no data exists to definitively link metformin to lactic acidosis.
Phenformin , another biguanide, was withdrawn from the market because of an increased risk of lactic acidosis rate of per , patient-years. Lactate uptake by the liver is diminished with metformin administration because lactate is a substrate for hepatic gluconeogenesis , a process that metformin inhibits.
In healthy individuals, this slight excess is cleared by other mechanisms including uptake by unimpaired kidneys , and no significant elevation in blood levels of lactate occurs. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication.
Metformin has been suggested as increasing production of lactate in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors. Lactic acidosis is initially treated with sodium bicarbonate , although high doses are not recommended, as this may increase intracellular acidosis.
A review of metformin overdoses reported to poison control centers over a five-year period found serious adverse events were rare, though the elderly appeared to be at greater risk. The most common symptoms following overdose include vomiting, diarrhea , abdominal pain, tachycardia , drowsiness, and, rarely, hypoglycemia or hyperglycemia.
Extracorporeal treatments are recommended in severe overdoses. Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or assist in a forensic death investigation.
Chromatographic techniques are commonly employed. The H 2 -receptor antagonist cimetidine causes an increase in the plasma concentration of metformin by reducing clearance of metformin by the kidneys;  both metformin and cimetidine are cleared from the body by tubular secretion , and both, particularly the cationic positively charged form of cimetidine, may compete for the same transport mechanism. Metformin also interacts with anticholinergic medications, due to their effect on gastric motility.
Anticholinergic drugs reduce gastric motility, prolonging the time drugs spend in the gastrointestinal tract. This impairment may lead to more metformin being absorbed than without the presence of an anticholinergic drug, thereby increasing the concentration of metformin in the plasma and increasing the risk for adverse effects. Metformin's main effect is to decrease liver glucose production.
Metformin decreases high blood sugar , primarily by suppressing liver glucose production hepatic gluconeogenesis. Multiple potential mechanisms of action have been proposed, including; inhibition of the mitochondrial respiratory chain complex I , activation of AMP-activated protein kinase AMPK , inhibition of glucagon-induced elevation of cyclic adenosine monophosphate cAMP with reduced activation of protein kinase A PKA , inhibition of mitochondrial glycerophosphate dehydrogenase , and an effect on gut microbiota.
Activation of AMPK was required for metformin's inhibitory effect on liver glucose production. In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake by inducing the phosphorylation of GLUT4 enhancer factor , decreases insulin-induced suppression of fatty acid oxidation ,  and decreases absorption of glucose from the gastrointestinal tract.
Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors. AMPK probably also plays a role in increased peripheral insulin sensitivity, as metformin administration increases AMPK activity in skeletal muscle. The usual synthesis of metformin, originally described in , involves the one-pot reaction of dimethylamine hydrochloride and 2-cyanoguanidine over heat. According to the procedure described in the Aron patent,  and the Pharmaceutical Manufacturing Encyclopedia ,  equimolar amounts of dimethylamine and 2-cyanoguanidine are dissolved in toluene with cooling to make a concentrated solution, and an equimolar amount of hydrogen chloride is slowly added.
Steady state is usually reached in one or two days. Metformin has acid dissociation constant values pKa of 2. The metformin pKa values make metformin a stronger base than most other basic medications with less than 0. Furthermore, the lipid solubility of the nonionized species is slight as shown by its low logP value log 10 of the distribution coefficient of the nonionized form between octanol and water of These chemical parameters indicate low lipophilicity and, consequently, rapid passive diffusion of metformin through cell membranes is unlikely.
As a result of its low lipid solubility it requires the transporter SLC22A1 in order for it to enter cells. More lipophilic derivatives of metformin are presently under investigation with the aim of producing prodrugs with superior oral absorption than metformin.
Metformin is not metabolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; metformin is undetectable in blood plasma within 24 hours of a single oral dose. The biguanide class of antidiabetic medications, which also includes the withdrawn agents phenformin and buformin , originates from the French lilac or goat's rue Galega officinalis , a plant used in folk medicine for several centuries. Metformin was first described in the scientific literature in , by Emil Werner and James Bell, as a product in the synthesis of N , N -dimethylguanidine.
Interest in metformin resumed at the end of the s. In , metformin, unlike some other similar compounds, was found not to decrease blood pressure and heart rate in animals.
Garcia  used metformin he named it Fluamine to treat influenza; he noted the medication "lowered the blood sugar to minimum physiological limit" and was not toxic.
Garcia believed metformin to have bacteriostatic , antiviral , antimalarial , antipyretic and analgesic actions. Instead he observed antiviral effects in humans. French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine , an alkaloid isolated from Galega officinalis , which is related in structure to metformin and had seen brief use as an antidiabetic before the synthalins were developed.
Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" glucose eater for the medication and published his results in Metformin became available in the British National Formulary in It was sold in the UK by a small Aron subsidiary called Rona. Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the s. Metformin was approved in Canada in ,  but did not receive approval by the U.
Liquid metformin is sold under the name Riomet in India. Metformin IR immediate release is available in , , and mg tablets. All of these are available as generic medications in the U. Metformin SR slow release or XR extended release was introduced in It is available in , , and mg strengths, mainly to counteract common gastrointestinal side effects, as well as to increase compliance by reducing pill burden.
No difference in effectiveness exists between the two preparations. When used for type 2 diabetes, metformin is often prescribed in combination with other medications. Several are available as fixed-dose combinations , to reduce pill burden and simplify administration. A combination of metformin and rosiglitazone was released in and sold as Avandamet by GlaxoSmithKline. By it had become the most popular metformin combination. In , the stock of Avandamet was removed from the market, after inspections showed the factory where it was produced was violating good manufacturing practices.
However, following a meta-analysis in that linked the medication's use to an increased risk of heart attack ,  concerns were raised over the safety of medicines containing rosiglitazone. In September the European Medicines Agency EMA recommended that the medication be suspended from the European market because the benefits of rosiglitazone no longer outweighed the risks. In November , the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the RECORD clinical trial a six-year, open label randomized control trial , which failed to show elevated risk of heart attack or death associated with the medication.
Dipeptidyl peptidase-4 inhibitors inhibit dipeptidyl peptidase-4 and thus reduce glucagon and blood glucose levels. In Europe, Canada, and elsewhere metformin combined with linagliptin is marketed under the trade name Jentadueto. Sulfonylureas act by increasing insulin release from the beta cells in the pancreas. Metformin is available combined with the sulfonylureas glipizide Metaglip and glibenclamide US: Meglitinides are similar to sulfonylureas.
The combination of metformin with pioglitazone and glibenclamide  is available in India as Triformin.
From Wikipedia, the free encyclopedia. B No risk in non-human studies. S4 Prescription only CA: Pharmacy and pharmacology portal Medicine portal. Clinical Pharmacology and Therapeutics. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus".
Archived from the original on 24 December Retrieved 2 January A Systematic Review and Meta-analysis". Annals of Internal Medicine. Archived from the original on Archived PDF from the original on First choice for monotherapy: Analogue-based Drug Discovery II. Herb, nutrient, and drug interactions: Archived PDF from the original on 13 December The Sichuan Giant Panda Sanctuaries , located in the southwest province of Sichuan and covering seven natural reserves, were inscribed onto the World Heritage List in Not all conservationists agree that the money spent on conserving pandas is well spent.
Chris Packham has argued that the breeding of pandas in captivity is "pointless" because "there is not enough habitat left to sustain them".
In , Earthwatch Institute , a global nonprofit that teams volunteers with scientists to conduct important environmental research, launched a program called "On the Trail of Giant Panda". This program, based in the Wolong National Nature Reserve, allows volunteers to work up close with pandas cared for in captivity, and help them adapt to life in the wild, so that they may breed, and live longer and healthier lives. Pandas have been kept in zoos as early as the Western Han Dynasty in China, where the writer Sima Xiangru noted that the panda was the most treasured animal in the emperor's garden of exotic animals in the capital Chang'an present Xi'an.
Not until the s were pandas again recorded to have been exhibited in China's zoos. Chi Chi at the London Zoo became very popular. This influenced the World Wildlife Fund to use a panda as its symbol.
A New York Times article  outlined the economics of keeping pandas, which costs five times more than that of the next most expensive animal, an elephant.
San Diego's contract with China was to expire in , but got a five-year extension at about half of the previous yearly cost. Cryptozoologists use Giant Pandas as an example of an animal recently discovered by science. Skeptical cryptozoologist Joe Nickell , notes that since Giant Pandas were known to local people, they qualify as cryptids. Also, fossil evidence shows that pandas were once widespread, including the two million year old skull of Ailuropoda microta .
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Small-toothed palm civet A. Sulawesi palm civet M. Masked palm civet P. Golden wet-zone palm civet P. Owston's palm civet C. Hose's palm civet D. Banded palm civet H. Malabar large-spotted civet V. Small Indian civet V. Broad-striped Malagasy mongoose G. American black bear U. Molina's hog-nosed skunk C. Sunda stink badger M.
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