Cinchona alkaloids toxicity

The actual catalyst is a complex formed from osmium tetroxide and a chiral ligand, e.g. dihydroquinine (DHQ) 9, dihydroquinidine (DHQD), Zj -dihydroqui-nine-phthalazine 10 or the respective dihydroquinidine derivative. The expensive and toxic osmium tetroxide is employed in small amounts only, together with a less expensive co-oxidant, e.g. potassium hexacyanoferrate(lll), which is used in stoichiometric quantities. The chiral ligand is also required in small amounts only. For the bench chemist, the procedure for the asymmetric fihydroxylation has been simplified with commercially available mixtures of reagents, e.g. AD-mix-a or AD-mix-/3, ° containing the appropriate cinchona alkaloid derivative ... 

Concerns over toxicity have also been raised for the Cinchona alkaloids, which have been described as dangerous to handle and highly toxic by Federsel [59], who recommended linkage to a solid support as a means of preventing toxic effects. At the present time, there is no indication of what effect the many substituents that have been linked to the quinudidine nitrogen in Cinchona alkaloids could have on toxicity and, until this problem is solved, they will be viewed with caution by industry. 

Dihydroxylation. Besides the enormously popular and effective cinchona alkaloid-based chiral auxiliaries several C2-symmetrical diamines (13), (14) and (15) have been developed to direct alkene dihydroxylation with OSO4. These efforts are probably overwhelmed by the Sharpless protocols because the approaches are not catalytic with respect to the most expensive and toxic reagent. 

The cinchona alkaloids are metabolized extensively, especially by hepatic CYP3A4, so only -20% of a dose is excreted unaltered in the urine. The major metabolite of quinine, 3-hydroxyquinine, retains some antimalarial activity and can accumulate and possibly cause toxicity in patients with renal failure. Renal excretion of quinine itself is more rapid when the urine is acidic. 

The distribution of quinine and other cinchona alkaloids in blood and tissues following oral or intravenous administration of these drugs has been studied by many workers in a variety of animal species. It is generally agreed by all workers that peak concentrations of the drugs in plasma are reached within 2 to 4 hours of oral dosage and decline rapidly thereafter. At relatively low or therapeutic doses of the alkaloids, there is httle localization of any of the compounds in the erythrocytes (70). For example, plasma contains 6 to 12 times as much quinine as erythrocytes. At toxic doses, however, these distribution ratios are badly distorted until at lethal doses there are essentially equal concentrations of quinine in cells and plasma (70). 

As would be expected from a history of several hundred years of unsupervised use, the cinchona alkaloids and especially quinine produce few toxic reactions in man when consumed in conventional therapeutic doses. There have been documented instances of quinine hypersensitivity, but these are exeedingly rare. The most common symptoms of quinine intoxication in man are tinnitus and amblyopia. In most instances these result from frank overdosage. In some cases, however, these toxic symptoms occur in individuals who are receiving generally tolerated doses. The intolerance in these special cases probably results from faulty metabolism of the alkaloid. 

Cinchona A genus of rubiaceous South American trees that yields the toxic cinchona alkaloids from their bark quinine, quinidine, chinconine, cinchonidine and others are used to treat malaria and cardiac arrhythmias. [NIH]... 

Carlson, W.W., and L.H. Cretcher. 1951. The blood distribution and toxicity of several cinchona alkaloid derivatives. /. Am. Pharm. Assoc. 40(9) 471-473. 

Recycling of Osmium by Immobilization of Osmium Tetroxide. Several groups have been actively searching for immobilized forms of osmium tetroxide in order to overcome the problems of toxicity and volatility associated with this reagent. The following are some representative examples of immobilization methods for a catalytic system (OSO4 and/or cinchona alkaloid ligand). 

The mechanism of action of quinine is not perfectly understood. It is generally assumed, on the basis of several model stodies [231, 232], that Cinchona alkaloids prevent the polymerization of the toxic hematin ([aquaFe(lll)protoporphyrin IX]) formed by the degradatimi of hemoglobin in erythrocytes to hemozoin (p-hematin). 

Quinine is an alkaloid produced by various Cinchona species (e.g. Cinchona pubescens or fever tree), which are mainly native to South America. The bark of these trees were initially used to treat malaria. Quinine itself was subsequently isolated in 1820 and found to be toxic not only to the protozoan Plasmodium (which causes malaria) but also to several other protozoan species. 

Quinine is derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America. The alkaloid quinine was purified from the bark in 1820, and it has been used in the treatment and prevention of malaria since that time. Quinidine, the dextrorotatory stereoisomer of quinine, is at least as effective as parenteral quinine in the treatment of severe falciparum malaria. After oral administration, quinine is rapidly absorbed, reaches peak plasma levels in 1-3 hours, and is widely distributed in body tissues. The use of a loading dose in severe malaria allows the achievement of peak levels within a few hours. The pharmacokinetics of quinine varies among populations. Individuals with malaria develop higher plasma levels of the drug than healthy controls, but toxicity is not increased, apparently because of increased protein binding. The half-life of quinine also is longer in those with severe malaria (18 hours) than in healthy controls (11 hours). Quinidine has a shorter half-life than quinine, mostly as a result of decreased protein binding. Quinine is primarily metabolized in the liver and excreted in the urine. 

Quinine sulfate, the classic drug, the salt of an alkaloid obtained from cinchona bark, has been superseded by newer drugs in most parts of the world. It is only a fairly good suppressant, even in toxic dosage, and is so rapidly eliminated that it must be given at very frequent intervals to maintain its effects. When used to check an established attack, it achieves the control of parasitemia in 96 h that chloroquine accomplishes in little more than 72 h, and its effects on fever and most other symptoms also lag (Figure 22.3). 

Quinine is a naturally occurring alkaloid obtained from Cinchona bark, with a mechanism of action similar to that of chloroquine. Quinine is very useful in treating chloroquine-resistant Plasmodium falciparum. In toxic doses, it may cause cinchonism characterized by tinnitus, headache, nausea, and visual disturbances. 

Quinine The antimalarial agent quinine is derived from the bark of the cinchona tree along with several other alkaloids and salicylate (aspirin). Many of these agents produce similar toxic features (cinchon-ism) in patients with excessive intake, but only quinine produces blindness. Cinchonism consists of abdominal pain and vomiting, ringing in the ears (tinnitus), and confusion. Visual loss after quinine overdose is due to direct retinal toxicity, although until recently it was believed to be due to spasm of the arterial blood supply to the retina. Treatment is difficult, but limited evidence suggests charcoal hemoperfusion may be beneficial (hemoperfusion is similar to hemodialysis, except in place of a semi-permeable membrane to filter the toxin from the blood, charcoal is used to bind the toxin). 

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