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Antimalarial medication

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease ("malaria burden") is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment (e.g., new combination therapies) remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses (e.g., retinopathy with chloroquine, acute haemolytic anaemia with tafenoquine).

Specifically, antimalarial drugs may be used to treat malaria in three categories of individuals, (i) those with suspected or confirmed infection, (ii) those visiting a malaria-endemic regions who have no immunity, to prevent infection via malaria prophylaxis, and (iii) or in broader groups of individuals, in routine but intermittent preventative treatment in regions where malaria is endemic via intermittent preventive therapy. Practice in treating cases of malaria is most often based on the concept of combination therapy (e.g., using agents such as artemether and lumefantrine against chloroquine-resistant Plasmodium falciparum infection ), since this offers advantages including reduced risk of treatment failure, reduced risk of developed resistance, as well as the possibility of reduced side-effects. Prompt parasitological confirmation by microscopy, or alternatively by rapid diagnostic tests, is recommended in all patients suspected of malaria before treatment is started. Treatment solely on the basis of clinical suspicion is considered when a parasitological diagnosis is not possible.

Anti-malaria aid campaigns have a globally positive impact for health outcomes and beyond.

Medications
It is practical to consider antimalarials by chemical structure since this is associated with important properties of each drug, such as mechanism of action.

Quinine and related agents
Quinine has a long history stretching from Peru, and the discovery of the cinchona tree, and the potential uses of its bark, to the current day and a collection of derivatives that are still frequently used in the prevention and treatment of malaria. Quinine is an alkaloid that acts as a blood schizonticidal and weak gametocide against Plasmodium vivax and Plasmodium malariae. As an alkaloid, it is accumulated in the food vacuoles of Plasmodium species, especially Plasmodium falciparum. It acts by inhibiting the hemozoin biocrystallization, thus facilitating an aggregation of cytotoxic heme. Quinine is less effective and more toxic as a blood schizonticidal agent than chloroquine; however, it is still very effective and widely used in the treatment of acute cases of severe P. falciparum. It is especially useful in areas where there is known to be a high level of resistance to chloroquine, mefloquine, and sulfa drug combinations with pyrimethamine. Quinine is also used in post-exposure treatment of individuals returning from an area where malaria is endemic.

The treatment regimen of quinine is complex and is determined largely by the parasite's level of resistance and the reason for drug therapy (i.e. acute treatment or prophylaxis). The World Health Organization recommendation for quinine is 20 mg/kg first times and 10 mg/kg every eight hours for five days where parasites are sensitive to quinine, combined with doxycycline, tetracycline or clindamycin. Doses can be given by oral, intravenous or intramuscular routes. The suggested course of action is determined by the need for therapy and the available resources (i.e. sterilised needles for IV or IM injections).

Use of quinine is characterised by a frequently experienced syndrome called cinchonism. Tinnitus (a hearing impairment), rashes, vertigo, nausea, vomiting and abdominal pain are the most common symptoms. Neurological effects are experienced in some cases due to the drug's neurotoxic properties. These actions are mediated through the interactions of quinine causing a decrease in the excitability of the motor neuron end plates. This often results in functional impairment of the eighth cranial nerve, resulting in confusion, delirium and coma. Quinine can cause hypoglycaemia through its action of stimulating insulin secretion; this occurs in therapeutic doses and therefore it is advised that glucose levels are monitored in all patients every 4–6 hours. This effect can be exaggerated in pregnancy and therefore additional care in administering and monitoring the dosage is essential. Repeated or over-dosage can result in kidney failure and death through depression of the respiratory system.

Quinimax and quinidine are the two most commonly used alkaloids related to quinine in the treatment or prevention of malaria. Quinimax is a combination of four alkaloids (quinine, quinidine, cinchonine and cinchonidine). This combination has been shown in several studies to be more effective than quinine, supposedly due to a synergistic action among the four cinchona derivatives. Quinidine is a direct derivative of quinine. It is a distereoisomer, thus having similar anti-malarial properties to the parent compound. Quinidine is recommended only for the treatment of severe cases of malaria.

Warburg's tincture was a febrifuge developed by Carl Warburg in 1834, which included quinine as a key ingredient. In the 19th-century it was a well-known anti-malarial drug. Although originally sold as a secret medicine, Warburg's tincture was highly regarded by many eminent medical professionals who considered it as being superior to quinine (e.g. Surgeon-General W. C. Maclean, Professor of Military Medicine at British Army Medical School, Netley). Warburg's tincture appeared in Martindale: The complete drug reference from 1883 until about 1920. The formula was published in The Lancet 1875.

Chloroquine
Chloroquine was, until recently, the most widely used anti-malarial. It was the original prototype from which most methods of treatment are derived. It is also the least expensive, best tested and safest of all available drugs. The emergence of drug-resistant parasitic strains is rapidly decreasing its effectiveness; however, it is still the first-line drug of choice in most sub-Saharan African countries. It is now suggested that it is used in combination with other antimalarial drugs to extend its effective usage. Popular drugs based on chloroquine phosphate (also called nivaquine) are Chloroquine FNA, Resochin and Dawaquin.

Chloroquine is a 4-aminoquinolone compound with a complicated and still unclear mechanism of action. It is believed to reach high concentrations in the vacuoles of the parasite, which, due to its alkaline nature, raises the internal pH. It controls the conversion of toxic heme to hemozoin by inhibiting the biocrystallization of hemozoin, thus poisoning the parasite through excess levels of toxicity. Other potential mechanisms through which it may act include interfering with the biosynthesis of parasitic nucleic acids and the formation of a chloroquine-haem or chloroquine-DNA complex. The most significant level of activity found is against all forms of the schizonts (with the obvious exception of chloroquine-resistant P. falciparum and P. vivax strains) and the gametocytes of P. vivax, P. malariae, P. ovale as well as the immature gametocytes of P. falciparum. Chloroquine also has a significant anti-pyretic and anti-inflammatory effect when used to treat P. vivax infections, and thus it may still remain useful even when resistance is more widespread. According to a report on the Science and Development Network website's sub-Saharan Africa section, there is very little drug resistance among children infected with malaria on the island of Madagascar, but what drug resistance there is exists against chloroquinine.

Children and adults should receive 25 mg of chloroquine per kg given over three days. A pharmacokinetically superior regime, recommended by the WHO, involves giving an initial dose of 10 mg/kg followed 6–8 hours later by 5 mg/kg, then 5 mg/kg on the following two days. For chemoprophylaxis: 5 mg/kg/week (single dose) or 10 mg/kg/week divided into six daily doses is advised. Chloroquine is only recommended as a prophylactic drug in regions only affected by P. vivax and sensitive P. falciparum strains. Chloroquine has been used in the treatment of malaria for many years and no abortifacient or teratogenic effects have been reported during this time; therefore, it is considered very safe to use during pregnancy. However, itching can occur at intolerable level and Chloroquinine can be a provocation factor of psoriasis.

Hydroxychloroquine
Hydroxychloroquine was derived in the 1950s by adding a hydroxy group to existing Chloroquine, making it more tolerable than Chloroquine by itself.

Amodiaquine
Amodiaquine is a 4-aminoquinolone anti-malarial drug similar in structure and mechanism of action to chloroquine. Amodiaquine has tended to be administered in areas of chloroquine resistance while some patients prefer its tendency to cause less itching than chloroquine. Amodiaquine is now available in a combined formulation with artesunate (ASAQ) and is among the artemisinin-combination therapies recommended by the World Health Organization. Combination with sulfadoxine=pyrimethamine is not recommended.

The drug should be given in doses between 25 mg/kg and 35 mg/kg over three days in a similar method to that used in chloroquine administration. Adverse reactions are generally similar in severity and type to that seen in chloroquine treatment. In addition, bradycardia, itching, nausea, vomiting and some abdominal pain have been recorded. Some blood and hepatic disorders have also been seen in a small number of patients.

Pyrimethamine
Pyrimethamine is used in the treatment of uncomplicated malaria. It is particularly useful in cases of chloroquine-resistant P. falciparum strains when combined with sulfadoxine. It acts by inhibiting dihydrofolate reductase in the parasite thus preventing the biosynthesis of purines and pyrimidines, thereby halting the processes of DNA replication, cell division and reproduction. It acts primarily on the schizonts during the erythrocytic phase, and nowadays is only used in concert with a sulfonamide

Proguanil
Proguanil (chloroguanide) is a biguanide; a synthetic derivative of pyrimidine. It was developed in 1945 by a British Antimalarial research group. It has many mechanisms of action but primarily is mediated through conversion to the active metabolite cycloguanil. This inhibits the malarial dihydrofolate reductase enzyme. Its most prominent effect is on the primary tissue stages of P. falciparum, P. vivax and P. ovale. It has no known effect against hypnozoites therefore is not used in the prevention of relapse. It has a weak blood schizonticidal activity and is not recommended for therapy of acute infection. However it is useful in prophylaxis when combined with atovaquone or chloroquine (in areas where there is no chloroquine resistance). 3 mg/kg is the advised dosage per day, (hence approximate adult dosage is 200 mg). The pharmacokinetic profile of the drugs indicates that a half dose, twice daily maintains the plasma levels with a greater level of consistency, thus giving a greater level of protection. The proguanil- chloroquine combination does not provide effective protection against resistant strains of P. falciparum. There are very few side effects to proguanil, with slight hair loss and mouth ulcers being occasionally reported following prophylactic use. Proguanil hydrochloride is marketed as Paludrine by AstraZeneca.

Sulfonamides
Sulfadoxine and sulfamethoxypyridazine are specific inhibitors of the enzyme dihydropteroate synthetase in the tetrahydrofolate synthesis pathway of malaria parasites. They are structural analogs of p-aminobenzoic acid (PABA) and compete with PABA to block its conversion to dihydrofolic acid. Sulfonamides act on the schizont stages of the erythrocytic (asexual) cycle. When administered alone sulfonamides are not efficacious in treating malaria but co-administration with the antifolate pyrimethamine, most commonly as fixed-dose sulfadoxine-pyrimethamine (Fansidar), produces synergistic effects sufficient to cure sensitive strains of malaria.

Sulfonamides are not recommended for chemoprophylaxis because of rare but severe skin reactions experienced. However it is used frequently for clinical episodes of the disease.

Mefloquine
Mefloquine was developed during the Vietnam War and is chemically related to quinine. It was developed to protect American troops against multi-drug resistant P. falciparum. It is a very potent blood schizonticide with a long half-life. It is thought to act by forming toxic heme complexes that damage parasitic food vacuoles. Mefloquine is effective in prophylaxis and for acute therapy. It is now used solely for the prevention of resistant strains of P. falciparum (usually combined with Artesunate) despite being effective against P. vivax, P. ovale and P. marlariae. Chloroquine/proguanil or sulfa drug-pyrimethamine combinations should be used in all other plasmodia infections.

The major commercial manufacturer of mefloquine-based malaria treatment is Roche Pharmaceuticals, which markets the drug under the trade name "Lariam". Lariam is fairly expensive at around three € per tablet (pricing of the year 2000).

A dose of 15–25 mg/kg is recommended, depending on the prevalence of mefloquine resistance. The increased dosage is associated with a much greater level of intolerance, most noticeably in young children; with the drug inducing vomiting and esophagitis. It was not recommended for use during the first trimester, although considered safe during the second and third trimesters; nevertheless, in October 2011, the Centers for Disease Control and Prevention (CDC) changed its recommendation and approved use of Mefloquine for both prophylaxis and treatment of malaria in all trimesters, after the Food and Drug Administration (FDA) changed its categorization from C to B. Mefloquine frequently produces side effects, including nausea, vomiting, diarrhea, abdominal pain and dizziness. Several associations with neurological events have been made, namely affective and anxiety disorders, hallucinations, sleep disturbances, psychosis, toxic encephalopathy, convulsions and delirium. Cardiovascular effects have been recorded with bradycardia and sinus arrhythmia being consistently recorded in 68% of patients treated with mefloquine (in one hospital-based study).

Mefloquine can only be taken for a period up to six months due to side effects. After this, other drugs (such as those based on paludrine/nivaquine) again need to be taken.

Atovaquone
Atovaquone is available in combination with proguanil under the name Malarone, albeit at a price higher than Lariam. It is commonly used in prophylaxis by travelers and used to treat falciparum malaria in developed countries. A liquid oral suspension of Atovaquone is available under the name Mepron.

Primaquine
Primaquine is a highly active 8-aminoquinolone that is effective against P. falcipraum gametocytes but also acts on merozoites in the bloodstream and on hypnozoites, the dormant hepatic forms of P. vivax and P. ovale. It is the only known drug to cure both relapsing malaria infections and acute cases. The mechanism of action is not fully understood but it is thought to block oxidative metabolism in Plasmodia. It can also be combined with methylene blue.

For the prevention of relapse in P. vivax and P. ovale 0.15 mg/kg should be given for 14 days. As a gametocytocidal drug in P. falciparum infections a single dose of 0.75 mg/kg repeated seven days later is sufficient. This treatment method is only used in conjunction with another effective blood schizonticidal drug. There are few significant side effects although it has been shown that primaquine may cause anorexia, nausea, vomiting, cramps, chest weakness, anaemia, some suppression of myeloid activity and abdominal pains. In cases of over-dosage granulocytopenia may occur.

Artemisinin and derivatives
Artemisinin is a Chinese herb (qinghaosu) that has been used in the treatment of fevers for over 1,000 years. It is derived from the plant Artemisia annua, with the first documentation as a successful therapeutic agent in the treatment of malaria is in 340 AD by Ge Hong in his book Zhou Hou Bei Ji Fang (A Handbook of Prescriptions for Emergencies). Ge Hong extracted the artemesinin using a simple macerate, and this method is still in use today. The active compound was first isolated in 1971 and named artemisinin.

 * Artemisinin has a very rapid action and the vast majority of acute patients treated show significant improvement within 1–3 days of receiving treatment. It has demonstrated the fastest clearance of all anti-malarials currently used and acts primarily on the trophozoite phase, thus preventing progression of the disease. Semi-synthetic artemisinin derivatives (e.g. artesunate, artemether) are easier to use than the parent compound and are converted rapidly once in the body to the active compound dihydroartemesinin. On the first day of treatment 20 mg/kg is often given, and the dose then reduced to 10 mg/kg per day for the six following days. Few side effects are associated with artemesinin use. However, headaches, nausea, vomiting, abnormal bleeding, dark urine, itching and some drug fever have been reported by a small number of patients. Some cardiac changes were reported during a clinical trial, notably non specific ST changes and a first degree atrioventricular block (these disappeared when the patients recovered from the malarial fever).
 * Artemether is a methyl ether derivative of dihydroartemesinin. It is similar to artemesinin in mode of action but demonstrates a reduced ability as a hypnozoiticidal compound, instead acting more significantly to decrease gametocyte carriage. Similar restrictions are in place, as with artemesinin, to prevent the development of resistance, therefore it is only used in combination therapy for severe acute cases of drug-resistant P. falciparum. It should be administered in a 7-day course with 4 mg/kg given per day for three days, followed by 1.6 mg/kg for three days. Side effects of the drug are few but include potential neurotoxicity developing if high doses are given.
 * Artesunate is a hemisuccinate derivative of the active metabolite dihydroartemisin. Currently it is the most frequently used of all the artemesinin-type drugs. Its only effect is mediated through a reduction in the gametocyte transmission. It is used in combination therapy and is effective in cases of uncomplicated P. falciparum. The dosage recommended by the WHO is a five or seven day course (depending on the predicted adherence level) of 4 mg/kg for three days (usually given in combination with mefloquine) followed by 2 mg/kg for the remaining two or four days. In large studies carried out on over 10,000 patients in Thailand no adverse effects have been shown.
 * Dihydroartemisinin is the active metabolite to which artemesinin is reduced. It is the most effective artemesinin compound and the least stable. It has a strong blood schizonticidal action and reduces gametocyte transmission. It is used for therapeutic treatment of cases of resistant and uncomplicated P. falciparum. 4 mg/kg doses are recommended on the first day of therapy followed by 2 mg/kg for six days. As with artesunate, no side effects to treatment have thus far been recorded.
 * Arteether is an ethyl ether derivative of dihydroartemisinin. It is used in combination therapy for cases of uncomplicated resistant P. falciparum. The recommended dosage is 150 mg/kg per day for three days given by IM injections. With the exception of a small number of cases demonstrating neurotoxicity following parenteral administration no side effects have been recorded.

Halofantrine
Halofantrine is a relatively new drug developed by the Walter Reed Army Institute of Research in the 1960s. It is a phenanthrene methanol, chemically related to Quinine and acts acting as a blood schizonticide effective against all Plasmodium parasites. Its mechanism of action is similar to other anti-malarials. Cytotoxic complexes are formed with ferritoporphyrin XI that cause plasmodial membrane damage. Despite being effective against drug resistant parasites, halofantrine is not commonly used in the treatment (prophylactic or therapeutic) of malaria due to its high cost. It has very variable bioavailability and has been shown to have potentially high levels of cardiotoxicity. It is still a useful drug and can be used in patients that are known to be free of heart disease and that have severe and resistant forms of acute malaria. A popular drug based on halofantrine is Halfan. The level of governmental control and the prescription-only basis on which it can be used contributes to the cost, thus halofantrine is not frequently used.

A dose of 8 mg/kg of halofantrine is advised to be given in three doses at six-hour intervals for the duration of the clinical episode. It is not recommended for children under 10 kg despite data supporting the use and demonstrating that it is well tolerated. The most frequently experienced side-effects include nausea, abdominal pain, diarrhea, and itch. Severe ventricular dysrhythmias, occasionally causing death are seen when high doses are administered. This is due to prolongation of the QTc interval. Halofantrine is not recommended for use in pregnancy and lactation, in small children, or in patients that have taken mefloquine previously.

Lumefantrine
Lumefantrine is a relative of halofantrine that is used in some combination antimalarial regimens.

Doxycycline
Probably one of the more prevalent antimalarial drugs prescribed, due to its relative effectiveness and cheapness, doxycycline is a tetracycline compound derived from oxytetracycline. The tetracyclines were one of the earliest groups of antibiotics to be developed and are still used widely in many types of infection. It is a bacteriostatic agent that acts to inhibit the process of protein synthesis by binding to the 30S ribosomal subunit thus preventing the 50s and 30s units from bonding. Doxycycline is used primarily for chemoprophylaxis in areas where chloroquine resistance exists. It can also be used in combination with quinine to treat resistant cases of P. falciparum but has a very slow action in acute malaria, and should not be used as monotherapy.

When treating acute cases and given in combination with quinine; 100 mg of doxycycline should be given per day for seven days. In prophylactic therapy, 100 mg (adult dose) of doxycycline should be given every day during exposure to malaria.

The most commonly experienced side effects are permanent enamel hypoplasia (although this is only relevant during the period of tooth development during the first decade of life), transient depression of bone growth, gastrointestinal disturbances and some increased levels of photosensitivity. Due to its effect of bone and tooth growth it is not used in children under 8, pregnant or lactating women and those with a known hepatic dysfunction.

Tetracycline is only used in combination for the treatment of acute cases of P. falciparum infections. This is due to its slow onset. Unlike doxycycline it is not used in chemoprophylaxis. For tetracycline, 250 mg is the recommended adult dosage (it should not be used in children) for five or seven days depending on the level of adherence and compliance expected. Oesophageal ulceration, gastrointestinal upset and interferences with the process of ossification and depression of bone growth are known to occur. The majority of side effects associated with doxycycline are also experienced.

Clindamycin
Clindamycin is a derivative of lincomycin, with a slow action against blood schizonticides. It is only used in combination with quinine in the treatment of acute cases of resistant P. falciparum infections and not as a prophylactic. Being more toxic than the other antibiotic alternatives, it is used only in cases where the Tetracyclines are contraindicated (for example in children).

Clindamycin should be given in conjunction with quinine as a 300 mg dose (in adults) four times a day for five days. The only side effects recorded in patients taking clindamycin are nausea, vomiting and abdominal pains and cramps. However these can be alleviated by consuming large quantities of water and food when taking the drug. Pseudomembranous colitis (caused by Clostridium difficile) has also developed in some patients; this condition may be fatal in a small number of cases.

Resistance
Anti-malarial drug resistance has been defined as: "the ability of a parasite to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within tolerance of the subject. The drug in question must gain access to the parasite or the infected red blood cell for the duration of the time necessary for its normal action." Resistance to antimalarial drugs is common. In most instances this refers to parasites that remain following on from an observed treatment; thus, it excludes all cases where anti-malarial prophylaxis has failed. In order for a case to be defined as resistant, the patient in question must have received a known and observed anti-malarial therapy while the blood drug and metabolite concentrations are monitored concurrently; techniques used to demonstrate this include in vivo, in vitro, and animal model testing, and more recently developed molecular techniques.

Drug resistant parasites are often used to explain malaria treatment failure. However, they are two potentially very different clinical scenarios. The failure to clear parasitemia and recover from an acute clinical episode when a suitable treatment has been given is anti-malarial resistance in its true form. Drug resistance may lead to treatment failure, but treatment failure is not necessarily caused by drug resistance despite assisting with its development. A multitude of factors can be involved in the processes including problems with non-compliance and adherence, poor drug quality, interactions with other pharmaceuticals, poor absorption, misdiagnosis and incorrect doses being given. The majority of these factors also contribute to the development of drug resistance.

The generation of resistance can be complicated and varies between Plasmodium species. It is generally accepted to be initiated primarily through a spontaneous mutation that provides some evolutionary benefit, thus giving the anti-malarial used a reduced level of sensitivity. This can be caused by a single point mutation or multiple mutations. In most instances a mutation will be fatal for the parasite or the drug pressure will remove parasites that remain susceptible, however some resistant parasites will survive. Resistance can become firmly established within a parasite population, existing for long periods of time.

The first type of resistance to be acknowledged was to chloroquine in Thailand in 1957. The biological mechanism behind this resistance was subsequently discovered to be related to the development of an efflux mechanism that expels chloroquine from the parasite before the level required to effectively inhibit the process of haem polymerization (that is necessary to prevent buildup of the toxic byproducts formed by haemoglobin digestion). This theory has been supported by evidence showing that resistance can be effectively reversed on the addition of substances which halt the efflux. The resistance of other quinolone anti-malarials such as amodiaquine, mefloquine, halofantrine and quinine are thought to have occurred by similar mechanisms.

Plasmodium have developed resistance against antifolate combination drugs, the most commonly used being sulfadoxine and pyrimethamine. Two gene mutations are thought to be responsible, allowing synergistic blockages of two enzymes involved in folate synthesis. Regional variations of specific mutations give differing levels of resistance.

Atovaquone is recommended to be used only in combination with another anti-malarial compound as the selection of resistant parasites occurs very quickly when used in mono-therapy. Resistance is thought to originate from a single-point mutation in the gene coding for cytochrome-b.

Spread of resistance
There is no single factor that confers the greatest degree of influence on the spread of drug resistance, but a number of plausible causes associated with an increase have been acknowledged. These include aspects of economics, human behaviour, pharmacokinetics, and the biology of vectors and parasites.

The most influential causes are examined below:
 * 1) The biological influences are based on the parasites ability to survive the presence of an anti-malarial thus enabling the persistence of resistance and the potential for further transmission despite treatment. In normal circumstances any parasites that persist after treatment are destroyed by the host's immune system, therefore any factors that act to reduce the elimination of parasites could facilitate the development of resistance. This attempts to explain the poorer response associated with immunocompromised individuals, pregnant women and young children.
 * 2) There has been evidence to suggest that certain parasite-vector combinations can alternatively enhance or inhibit the transmission of resistant parasites, causing 'pocket-like' areas of resistance.
 * 3) The use of anti-malarials developed from similar basic chemical compounds can increase the rate of resistance development, for example cross-resistance to chloroquine and amodiaquine, two 4-aminoquinolones and mefloquine conferring resistance to quinine and halofantrine. This phenomenon may reduce the usefulness of newly developed therapies prior to large-scale usage.
 * 4) The resistance to anti-malarials may be increased by a process found in some species of Plasmodium, where a degree of phenotypic plasticity was exhibited, allowing the rapid development of resistance to a new drug, even if the drug has not been previously experienced.
 * 5) The pharmacokinetics of the chosen anti-malarial are key; the decision of choosing a long half-life over a drug that is metabolised quickly is complex and still remains unclear. Drugs with shorter half-life's require more frequent administration to maintain the correct plasma concentrations, therefore potentially presenting more problems if levels of adherence and compliance are unreliable, but longer-lasting drugs can increase the development of resistance due to prolonged periods of low drug concentration.
 * 6) The pharmacokinetics of anti-malarials is important when using combination therapy. Mismatched drug combinations, for example having an 'unprotected' period where one drug dominates can seriously increase the likelihood of selection for resistant parasites.
 * 7) Ecologically there is a linkage between the level of transmission and the development of resistance, however at present this still remains unclear.
 * 8) The treatment regime prescribed can have a substantial influence on the development of resistance. This can involve the drug intake, combination and interactions as well as the drug's pharmacokinetic and dynamic properties.

Prevention
The prevention of anti-malarial drug resistance is of enormous public health importance. It can be assumed that no therapy currently under development or to be developed in the foreseeable future will be totally protective against malaria. In accordance with this, there is the possibility of resistance developing to any given therapy that is developed. This is a serious concern, as the rate at which new drugs are produced by no means matches the rate of the development of resistance. In addition, the most newly developed therapeutics tend to be the most expensive and are required in the largest quantities by some of the poorest areas of the world. Therefore, it is apparent that the degree to which malaria can be controlled depends on the careful use of the existing drugs to limit, insofar as it is possible, any further development of resistance.

Provisions essential to this process include the delivery of fast primary care where staff are well trained and supported with the necessary supplies for efficient treatment. This in itself is inadequate in large areas where malaria is endemic thus presenting an initial problem. One method proposed that aims to avoid the fundamental lack in certain countries' health care infrastructure is the privatisation of some areas, thus enabling drugs to be purchased on the open market from sources that are not officially related to the health care industry. Although this is now gaining some support there are many problems related to limited access and improper drug use, which could potentially increase the rate of resistance development to an even greater extent.

There are two general approaches to preventing the spread of resistance: preventing malaria infections, and preventing the transmission of resistant parasites.

Preventing malaria infections developing has a substantial effect on the potential rate of development of resistance, by directly reducing the number of cases of malaria thus decreasing the need for anti-malarial therapy. Preventing the transmission of resistant parasites limits the risk of resistant malarial infections becoming endemic and can be controlled by a variety of non-medical methods including insecticide-treated bed nets, indoor residual spraying, environmental controls (such as swamp draining) and personal protective methods such as using mosquito repellent. Chemoprophylaxis is also important in the transmission of malaria infection and resistance in defined populations (for example travelers).

A hope for future of anti-malarial therapy is the development of an effective malaria vaccine. This could have enormous public health benefits, providing a cost-effective and easily applicable approach to preventing not only the onset of malaria but the transmission of gametocytes, thus reducing the risk of resistance developing. Anti-malarial therapy also could be diversified by combining a potentially effective vaccine with current chemotherapy, thereby reducing the chance of vaccine resistance developing.

Combination therapy
The problem of the development of malaria resistance must be weighed against the essential goal of anti-malarial care; that is to reduce morbidity and mortality. Thus a balance must be reached that attempts to achieve both goals while not compromising either too much by doing so. The most successful attempts so far have been in the administration of combination therapy. This can be defined as, 'the simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasite'. There is much evidence to support the use of combination therapies, some of which has been discussed previously, however several problems prevent the wide use in the areas where its use is most advisable. These include: problems identifying the most suitable drug for different epidemiological situations, the expense of combined therapy (it is over 10 times more expensive than traditional mono-therapy), how soon the programmes should be introduced and problems linked with policy implementation and issues of compliance.

The combinations of drugs currently prescribed can be divided into two categories: non-artemesinin-based combinations and artemesinin based combinations. It is also important to distinguish fixed-dose combination therapies (in which two or more drugs are co-formulated into a single tablet) from combinations achieved by taking two separate antimalarials.

Non-artemisinin based combinations
Artemisinin-based combination therapies should be used in preference to amodiaquine plus sulfadoxine-pyrimethamine for the treatment of uncomplicated P. falciparum malaria.

Artemisinin-based combination therapies (ACTs)
Artemesinin has a very different mode of action than conventional anti-malarials (see information above), which makes it particularly useful in the treatment of resistant infections. However, to prevent the development of resistance to this drug it is only recommended in combination with another non-artemesinin based therapy. It produces a very rapid reduction in the parasite biomass with an associated reduction in clinical symptoms and is known to cause a reduction in the transmission of gametocytes thus decreasing the potential for the spread of resistant alleles. At present there is no known resistance to Artemesinin (though some resistant strains may be emerging) and very few reported side-effects to drug usage, however this data is limited.

Other combinations
Several other anti-malarial combinations have been used or are in development. For example, Chlorproguanil-dapsone and artesunate appeared efficacious in trials from the late 90s and 2000s, but the problem of haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency is likely to prevent widespread use.

By type of malaria
Antimalarial drugs and combinations may also be sorted according to the type of malaria in which they are used.

Falciparum malaria
Artemisinin-based combination therapies (ACTs) are the recommended antimalarial treatments for uncomplicated malaria caused by P. falciparum. The choice of ACT in a country or region will be based on the level of resistance to the constituents in the combination. For pregnant women, the recommended first-line treatment during the first trimester is quinine plus clindamycin to be given for seven days. In second and third trimesters, it is recommended to give ACTs known to be effective in the country/region or artesunate plus clindamycin for seven days, or quinine plus clindamycin to be given for seven days. Lactating women should receive standard antimalarial treatment (including ACTs) except for dapsone, primaquine and tetracyclines. In infants and young children, it is recommended to give ACTs for first-line treatment, with attention to accurate dosing and ensuring the administered dose is retained.

In severe falciparum malaria, it is recommended that rapid clinical assessment and confirmation of the diagnosis is made, followed by administration of full doses of parenteral antimalarial treatment without delay with whichever effective antimalarial is first available. For adults, intravenous (IV) or intramuscular (IM) artesunate is recommended. Quinine is an acceptable alternative if parenteral artesunate is not available. Parenteral antimalarials should be administered for a minimum of 24 h in the treatment of severe malaria, irrespective of the patient's ability to tolerate oral medication earlier. Thereafter, it is recommended to complete treatment by giving a complete course of any of the following:
 * an ACT
 * artesunate plus clindamycin or doxycycline;
 * quinine plus clindamycin or doxycycline.

Vivax malaria
Chloroquine remains the treatment of choice for vivax malaria, except in Indonesia's Irian Jaya (Western New Guinea) region and the geographically contiguous Papua New Guinea, where chloroquine resistance is common (up to 20% resistance).

Malaria in poultry
No medications are approved in the United States for treatment of malaria in poultry.

title: Antimalarial medication


text:
William Rockefeller Jr.

William Avery Rockefeller Jr. (May 31, 1841 – June 24, 1922) was an American businessman and financier. Rockefeller was a co-founder of Standard Oil along with his elder brother John Davison Rockefeller. He was also a part owner of Anaconda Copper, which was the fourth-largest company in the world by the late 1920s. Rockefeller started his business career as a clerk at 16. In 1867, he joined his brother's company, Rockefeller, Andrews & Flagler, which later became Standard Oil. The company was eventually split up by the Supreme Court in 1911. Rockefeller also had a significant involvement in the copper industry. In 1899, Rockefeller and Standard Oil principal Henry H. Rogers joined with Anaconda Company founder Marcus Daly to create the Amalgamated Copper Mining Company, which later returned to the name Anaconda Copper.

He married Almira Geraldine Goodsell in 1864, and they had six children. Rockefeller died in 1922, leaving a gross estate of $102 million, significantly reduced by debts and taxes. He was a prominent member of the Rockefeller family, contributing to its reputation as a leading American business dynasty.

Early years
William Avery Rockefeller Jr. was born in Richford, New York. He was the middle son of con artist William Avery Rockefeller Sr. and Eliza Davison. In addition to elder brother John, William Jr.'s siblings were Lucy, Mary, and twins Franklin (Frank) and Frances (who died young). He also had two elder half-sisters, Clorinda (who died young) and Cornelia, through his father's affairs with mistress and housekeeper Nancy Brown. In 1853 his family moved to Strongsville, Ohio. As a young pupil in public school, he was inspired and motivated by his teacher-mentor, Rufus Osgood Mason, whom Rockefeller later named "A Rockefeller Patron."

Business career
At the age of sixteen, he began work as a clerk for a miller in Cleveland, Ohio. About two years later, he joined his older brother's produce commission business, Clark and Rockefeller, which later supplied provisions to the Union Army.

Oil business
Rockefeller was very adept in business matters. When John D. formed Rockefeller, Andrews & Flagler in 1867, he invited William to take charge of the company's export business in New York. In 1867, William Rockefeller and Co. was formed as a subsidiary to Rockefeller and Andrews. In 1870, that company became Standard Oil. In 1911 Standard Oil of New Jersey was split up by the United States Supreme Court.

Copper mining
In 1899, Rockefeller joined fellow Standard Oil principal Henry H. Rogers and Anaconda Copper Company founder Marcus Daly in forming the Amalgamated Copper Mining Company, a holding company that intended to control the copper industry. With Daly as company president and Rogers as Vice-President, Rockefeller and Rogers devised a scheme which earned them a profit of $36 million. First, they purchased Anaconda Properties from Daly for $39 million, with the understanding that the check was to be deposited in the bank and remain there for a definite time (National City Bank was run by Rockefeller's friends). Rogers and Rockefeller then set up a paper organization, known as the Amalgamated Copper Mining Company, with their own clerks as dummy directors, saying the company was worth $75 million.

They had Amalgamated Copper Company buy Anaconda from them for $75 million in capital stock, which was conveniently printed for the purpose. Then, they borrowed $39 million from the bank using Amalgamated Copper as collateral. They paid back Daly for Anaconda and sold $75 million worth of stock in Amalgamated Copper to the public. They paid back the bank's $39 million and had a profit of $36 million in cash.

After Daly died in November 1900, banker John Dennis Ryan rose to head Amalgamated's Montana operations. Amalgamated acquired two large competitors, and soon controlled all the mines of Butte, Montana. The company returned to the name Anaconda in 1915, and by the late 1920s Anaconda Copper Company was the fourth-largest company in the world.

From 1912 to 1913, the Pujo Committee investigated Rockefeller and others for allegedly earning $30 million in profit through cornering the copper market and "synchronizing with artificially enforced activity" in Amalgamated Copper stock in the New York Stock Exchange.

When the newly formed Mutual Alliance Trust Company opened for business in New York on the Tuesday after June 29, 1902, there were 13 directors, including Emanuel Lehman and Rockefeller.

Personal life
Rockefeller married Almira Geraldine Goodsell (March 19, 1844 – January 17, 1920) on May 25, 1864, in Fairfield, Connecticut. There were many connections among this and other elite families. Her sister Esther Judson Goodsell was married to Oliver Burr Jennings, who became one of the original stockholders of Standard Oil. Together, William and Almira had: William Rockefeller Jr. died of pneumonia on June 24, 1922, in Rockwood Hall. He had caught a cold during a car trip he took with brother John and nephew John Jr. to visit his childhood home in Richford, New York. He was interred in the Sleepy Hollow Cemetery, Sleepy Hollow, New York.
 * 1) Lewis Edward Rockefeller (March 2, 1865 – August 3, 1866)
 * 2) Emma Rockefeller (June 8, 1868 – August 11, 1934), who married Dr. David Hunter McAlpin
 * 3) William Goodsell Rockefeller (May 21, 1870 – November 30, 1922), who married Sarah Elizabeth "Elsie" Stillman
 * 4) John Davison Rockefeller II (March 8, 1872 – 1877)
 * 5) Percy Avery Rockefeller (February 27, 1878 – September 25, 1934), who married Isabel Goodrich Stillman
 * 6) Ethel Geraldine Rockefeller (April 3, 1882 – August 13, 1973), who married Marcellus Hartley Dodge Sr.

The New York Times, in discussing a trust that Rockefeller set up for his born and yet-to-be born great-grandchildren, stated that he "left a gross estate of $102,000,000 which was reduced to $50,000,000 principally by $30,000,000 of debts and $18,600,000 of inheritance and estate taxes."

Rockefeller was a regular attendee of the Saint Mary's Episcopal Church in Scarborough in the last few years of his life.

Family and descendants
Rockefeller and Almira's second son, William Goodsell Rockefeller, married Sarah Elizabeth "Elsie" Stillman, the elder daughter of James Jewett Stillman and Sarah Elizabeth Stillman; her father was National City Bank president. The new couple's family included James Stillman Rockefeller. He became a member of the Jekyll Island Club (aka The millionaires Club) on Jekyll Island, Georgia, along with J. P. Morgan, Joseph Pulitzer, and other business moguls of the day.

Residences
In 1886, Rockefeller bought property in Westchester County along the Hudson River from General Lloyd Aspinwall. He renovated or rebuilt the mansion Rockwood Hall.

The Rockefeller Cottage is a house on Jekyll Island, Georgia. It is also called Indian Mound and is next to the Jekyll Island Club. The house was built by Gordon McKay in 1892. McKay died in 1903 and the house was bought by William Rockefeller in 1905, who used it as a winter home. It was evacuated in 1942, along with the rest of the island. The house remained in the Rockefeller family until 1947, when the Jekyll Island Authority bought the property. It was open as a museum from 1950 until 1968, when it was closed for badly needed repairs. It is now a public museum. Decades later the former "Indian Mound" Cottage was listed on the National Register of Historic Places as Rockefeller Cottage.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: William Rockefeller Jr.


text:
Cosmic Background Explorer

The Cosmic Background Explorer (COBE ), also referred to as Explorer 66, was a NASA satellite dedicated to cosmology, which operated from 1989 to 1993. Its goals were to investigate the cosmic microwave background radiation (CMB or CMBR) of the universe and provide measurements that would help shape our understanding of the cosmos.

COBE's measurements provided two key pieces of evidence that supported the Big Bang theory of the universe: that the CMB has a near-perfect black-body spectrum, and that it has very faint anisotropies. Two of COBE's principal investigators, George F. Smoot and John C. Mather, received the Nobel Prize in Physics in 2006 for their work on the project. According to the Nobel Prize committee, "the COBE project can also be regarded as the starting point for cosmology as a precision science".

COBE was the second cosmic microwave background satellite, following RELIKT-1, and was followed by two more advanced spacecraft: the Wilkinson Microwave Anisotropy Probe (WMAP) operated from 2001 to 2010 and the Planck spacecraft from 2009 to 2013.

Mission
The purpose of the Cosmic Background Explorer (COBE) mission was to take precise measurements of the diffuse radiation between 1 micrometre and 1 cm over the whole celestial sphere. The following quantities were measured: (1) the spectrum of the 3 K radiation over the range 100 micrometres to 1 cm (2) the anisotropy of this radiation from 3 to 10 mm; and, (3) the spectrum and angular distribution of diffuse infrared background radiation at wavelengths from 1 to 300 micrometres.

History
In 1974, NASA issued an Announcement of Opportunity for astronomical missions that would use a small- or medium-sized Explorer spacecraft. Out of the 121 proposals received, three dealt with studying the cosmological background radiation. Though these proposals lost out to the Infrared Astronomical Satellite (IRAS), their strength made NASA further explore the idea. In 1976, NASA formed a committee of members from each of 1974's three proposal teams to put together their ideas for such a satellite. A year later, this committee suggested a polar-orbiting satellite called COBE to be launched by either a Delta 5920-8 launch vehicle or the Space Shuttle. It would contain the following instruments:

NASA accepted the proposal provided that the costs be kept under US$30 million, excluding launcher and data analysis. Due to cost overruns in the Explorer program due to IRAS, work on constructing the satellite at Goddard Space Flight Center (GSFC) did not begin until 1981. To save costs, the infrared detectors and liquid helium dewar on COBE would be similar to those used on Infrared Astronomical Satellite (IRAS).

COBE was originally planned to be launched on a Space Shuttle mission STS-82-B in 1988 from Vandenberg Air Force Base, but the Challenger explosion delayed this plan when the Shuttles were grounded. NASA prevented COBE's engineers from going to other space companies to launch COBE, and eventually a redesigned COBE was placed into Sun-synchronous orbit on 18 November 1989 aboard a Delta launch vehicle.

On 23 April 1992, COBE scientists announced at the APS April Meeting in Washington, D.C. the finding of the "primordial seeds" (CMBE anisotropy) in data from the DMR instrument; until then the other instruments were "unable to see the template." The following day The New York Times ran the story on the front page, explaining the finding as "the first evidence revealing how an initially smooth cosmos evolved into today's panorama of stars, galaxies and gigantic clusters of galaxies."

The Nobel Prize in Physics for 2006 was jointly awarded to John C. Mather, NASA Goddard Space Flight Center, and George F. Smoot, University of California, Berkeley, "for their discovery of the blackbody form and anisotropy of the cosmic microwave background radiation".

Spacecraft

COBE was an Explorer class satellite, with technology borrowed heavily from IRAS, but with some unique characteristics.

The need to control and measure all the sources of systematic errors required a rigorous and integrated design. COBE would have to operate for a minimum of 6 months, and constrain the amount of radio interference from the ground, COBE and other satellites as well as radiative interference from the Earth, Sun and Moon. The instruments required temperature stability and to maintain gain, and a high level of cleanliness to reduce entry of stray light and thermal emission from particulates.

The need to control systematic error in the measurement of the CMB anisotropy and measuring the zodiacal cloud at different elongation angles for subsequent modeling required that the satellite rotate at a 0.8 rpm spin rate. The spin axis is also tilted back from the orbital velocity vector as a precaution against possible deposits of residual atmospheric gas on the optics as well against the infrared glow that would result from fast neutral particles hitting its surfaces at extremely high speed.

In order to meet the twin demands of slow rotation and three-axis attitude control, a sophisticated pair of yaw angular momentum wheels were employed with their axis oriented along the spin axis. These wheels were used to carry an angular momentum opposite that of the entire spacecraft in order to create a zero net angular momentum system.

The orbit would prove to be determined based on the specifics of the spacecraft's mission. The overriding considerations were the need for full sky coverage, the need to eliminate stray radiation from the instruments and the need to maintain thermal stability of the dewar and the instruments. A circular Sun-synchronous orbit satisfied all these requirements. A 900 km altitude orbit with a 99° inclination was chosen as it fit within the capabilities of either a Space Shuttle (with an auxiliary propulsion on COBE) or a Delta launch vehicle. This altitude was a good compromise between Earth's radiation and the charged particle in Earth's radiation belts at higher altitudes. An ascending node at 18:00 was chosen to allow COBE to follow the boundary between sunlight and darkness on Earth throughout the year.

The orbit combined with the spin axis made it possible to keep the Earth and the Sun continually below the plane of the shield, allowing a full sky scan every six months.

The last two important parts pertaining to the COBE mission were the dewar and Sun-Earth shield. The dewar was a 650 L superfluid helium cryostat designed to keep the FIRAS and DIRBE instruments cooled during the duration of the mission. It was based on the same design as one used on IRAS and was able to vent helium along the spin axis near the communication arrays. The conical Sun-Earth shield protected the instruments from direct solar and Earth based radiation as well as radio interference from Earth and the COBE's transmitting antenna. Its multilayer insulating blankets provided thermal isolation for the dewar.

In January 1994, engineering operations concluded and the operation of the spacecraft was transferred to Wallops Flight Facility (WFF) for use as a test satellite.

Differential Microwave Radiometers (DMR)
The Differential Microwave Radiometer (DMR) investigation uses three differential radiometers to map the sky at 31.4, 53, and 90 GHz. The radiometers are distributed around the outer surface of the cryostat. Each radiometer employs a pair of horn antennas viewing at 30° from the spin axis of the spacecraft, measuring the differential temperature between points in the sky separated by 60°. At each frequency there are two channels for dual polarization measurements for improved sensitivity and for reliability. Each radiometer is a microwave receiver whose input is switched rapidly between the two horn antennas, obtaining the difference in brightness of two fields of view 7° in diameter located 60° apart and 30° from the axis of the spacecraft. High sensitivity is achieved by temperature stabilization (at 300 K for 31.4 GHz and at 140 K for 53 and 90 GHz), by spacecraft spin, and by the ability to integrate over the entire year. Sensitivity to large-scale anisotropies is about 3E-5 K. The instrument weighs 120 kg, uses 114 watts, and has a data rate of 500 bit/s.

Diffuse Infrared Background Experiment (DIRBE)
The Diffuse Infrared Background Experiment (DIRBE) consists of a cryogenically cooled (to 2 K) multiband radiometer used to investigate diffuse infrared radiation from 1 to 300 micrometres. The instrument measures the absolute flux in 10 wavelength bands with a 1° field of view pointed 30° off the spin axis. Detectors (photoconductors) and filters for the 8 to 100 micrometre channels are the same as for the IRAS mission. Bolometers are used for the longest wavelength channel (120 to 300 micrometres). The telescope is a well baffled, off-axis, Gregorian flux collector with re-imaging. The instrument weighs approximately 34 kg, uses 100 W and has a data rate of 1700 bit/s.

Far Infrared Absolute Spectrophotometer (FIRAS)
The Far Infrared Absolute Spectrophotometer (FIRAS) is a cryogenically cooled polarizing Michelson interferometer used as a Fourier transform spectrometer. The instrument points along the spin axis and has a 7° field of view. This device measures the spectrum to a precision of 1/1000 of the peak flux at 1.7 mm for each 7° field of view on the sky (over the range 0.1 to 10 mm). The FIRAS uses a special flared trumpet horn flux collector having very low sidelobe levels and an external calibrator covering the entire beam; precise temperature regulation and calibration are required. The instrument has a differential input to compare the sky with an internal reference at 3 K. This feature provides immunity from systematic errors in the spectrometer, and contributes significantly to the ability to detect small deviations from a blackbody spectrum. The instrument weighs 60 kg, uses 84 watts and has a data rate of 1200 bit/s.

Scientific findings

The science mission was conducted by the three instruments detailed previously: DIRBE, FIRAS and DMR. The instruments overlapped in wavelength coverage, providing consistency check on measurements in the regions of spectral overlap and assistance in discriminating signals from our galaxy, Solar System and CMB.

COBE's instruments would fulfill each of their objectives as well as making observations that would have implications outside COBE's initial scope.

Black-body curve of CMB

During the 15-year-long period between the proposal and launch of COBE, there were two significant astronomical developments:
 * First, in 1981, two teams of astronomers, one led by David Wilkinson of Princeton University and the other by Francesco Melchiorri of the University of Florence, simultaneously announced that they detected a quadrupole distribution of CMB using balloon-borne instruments. This finding would have been the detection of the black-body distribution of CMB that FIRAS on COBE was to measure. In particular, the Florence group claimed a detection of intermediate angular scale anisotropies at the level 100 microkelvins in agreement with later measurements made by the BOOMERanG experiment. However, a number of other experiments attempted to duplicate their results and were unable to do so.
 * Second, in 1987 a Japanese-American team led by Andrew E. Lange and Paul Richards of University of California, Berkeley and Toshio Matsumoto of Nagoya University made an announcement that CMB was not that of a true black body. In a sounding rocket experiment, they detected an excess brightness at 0.5 and 0.7 mm wavelengths.

With these developments serving as a backdrop to COBE's mission, scientists eagerly awaited results from FIRAS. The results of FIRAS were startling in that they showed a perfect fit of the CMB and the theoretical curve for a black body at a temperature of 2.7 K, in contrast to the Berkeley-Nagoya results.

FIRAS measurements were made by measuring the spectral difference between a 7° patch of the sky against an internal black body. The interferometer in FIRAS covered between 2- and 95-cm−1 in two bands separated at 20-cm−1. There are two scan lengths (short and long) and two scan speeds (fast and slow) for a total of four different scan modes. The data were collected over a ten-month period.

Intrinsic anisotropy of CMB

The DMR was able to spend four years mapping the detectable anisotropy of cosmic background radiation as it was the only instrument not dependent on the dewar's supply of helium to keep it cooled. This operation was able to create full sky maps of the CMB by subtracting out galactic emissions and dipole at various frequencies. The cosmic microwave background fluctuations are extremely faint, only one part in 100,000 compared to the 2.73 K average temperature of the radiation field. The cosmic microwave background radiation is a remnant of the Big Bang and the fluctuations are the imprint of density contrast in the early universe. The density ripples are believed to have produced structure formation as observed in the universe today: clusters of galaxies and vast regions devoid of galaxies.

Detecting early galaxies
DIRBE also detected 10 new far-IR emitting galaxies in the region not surveyed by IRAS as well as nine other candidates in the weak far-IR that may be spiral galaxies. Galaxies that were detected at the 140 and 240 μm were also able to provide information on very cold dust (VCD). At these wavelengths, the mass and temperature of VCD can be derived. When these data were joined with 60 and 100 μm data taken from IRAS, it was found that the far-infrared luminosity arises from cold (≈17–22 K) dust associated with diffuse H I region cirrus clouds, 15-30% from cold (≈19 K) dust associated with molecular gas, and less than 10% from warm (≈29 K) dust in the extended low-density H II regions.

DIRBE

On top of the findings DIRBE had on galaxies, it also made two other significant contributions to science. The DIRBE instrument was able to conduct studies on interplanetary dust (IPD) and determine if its origin was from asteroid or cometary particles. The DIRBE data collected at 12, 25, 50 and 100 μm were able to conclude that grains of asteroidal origin populate the IPD bands and the smooth IPD cloud.

The second contribution DIRBE made was a model of the Galactic disk as seen edge-on from our position. According to the model, if the Sun is 8.6 kpc from the Galactic Center, then it is 15.6% above the midplane of the disk, which has a radial and vertical scale lengths of 2.64 and 0.333 kpc, respectively, and is warped in a way consistent with the HI layer. There is also no indication of a thick disk.

To create this model, the IPD had to be subtracted out of the DIRBE data. It was found that this cloud, which as seen from Earth is Zodiacal light, was not centered on the Sun, as previously thought, but on a place in space a few million kilometers away. This is due to the gravitation influence of Saturn and Jupiter.

Cosmological implications
In addition to the science results detailed in the last section, there are numerous cosmological questions left unanswered by COBE's results. A direct measurement of the extragalactic background light (EBL) can also provide important constraints on the integrated cosmological history of star formation, metal and dust production, and the conversion of starlight into infrared emissions by dust.

By looking at the results from DIRBE and FIRAS in the 140 to 5000 μm we can detect that the integrated EBL intensity is ≈16 nW/(m2·sr). This is consistent with the energy released during nucleosynthesis and constitutes about 20–50% of the total energy released in the formation of helium and metals throughout the history of the universe. Attributed only to nuclear sources, this intensity implies that more than 5–15% of the baryonic mass density implied by big bang nucleosynthesis analysis has been processed in stars to helium and heavier elements.

There were also significant implications into star formation. COBE observations provide important constraints on the cosmic star formation rate, and help us calculate the EBL spectrum for various star formation histories. Observation made by COBE require that star formation rate at redshifts of z ≈ 1.5 to be larger than that inferred from UV-optical observations by a factor of 2. This excess stellar energy must be mainly generated by massive stars in yet - undetected dust enshrouded galaxies or extremely dusty star forming regions in observed galaxies. The exact star formation history cannot unambiguously be resolved by COBE and further observations must be made in the future.

On 30 June 2001, NASA launched a follow-up mission to COBE led by DMR Deputy Principal Investigator Charles L. Bennett. The Wilkinson Microwave Anisotropy Probe has clarified and expanded upon COBE's accomplishments. Following WMAP, the European Space Agency's probe, Planck has continued to increase the resolution at which the background has been mapped.

title: Cosmic Background Explorer


text:
CMB (disambiguation)

CMB is the cosmic microwave background, the thermal radiation left over from the time of recombination in Big Bang cosmology.

CMB may also refer to:

Science and technology

 * Core–mantle boundary, lying between the Earth's silicate mantle and its metallic outer core
 * Continuous marine broadcast, a type of radio station providing marine weather information to coastal areas of Canada

Arts and entertainment

 * C.M.B. (album), the debut album of American R&B and pop group Color Me Badd
 * Color Me Badd, American R&B and pop group

 * C.M.B. (manga), a detective fiction manga by Motohiro Katoui
 * CMB Televisión, a religious TV channel in Colombia
 * The Cosmic Microwave Background, the debut solo album of Shiny Joe Ryan
 * The Combine, the antagonistic alien empire from the Half-Life video game series

Organizations

 * Cavalier Marching Band, marching band of the University of Virginia, US
 * Center for Mind and Brain, cognitive neuroscience research center at the University of California, US
 * China Medical Board, organization promoting medical education and research in China
 * China Merchants Bank, bank headquartered in Shenzhen, China
 * China Motor Bus, first motor bus company in Hong Kong
 * Compagnie Maritime Belge, one of the oldest ship-owners of Antwerp, Belgium
 * Compagnie Monégasque de Banque, private bank of Monaco
 * Compagnie des Machines Bull, French computer manufacturer
 * Union of the Belgian Metal Industry, trade union in Belgium

Other uses

 * Bandaranaike International Airport (IATA code: CMB), an airport in Sri Lanka
 * Cambodia, UNDP country code
 * Cash management bills, a form of security issued by the United States Treasury
 * Christus Mansionem Benedicat (English: May Christ Bless This House), text written in chalk on house doors on the day of Epiphany
 * Certified Mortgage Banker, a certification offered by the Mortgage Bankers Association
 * Coastal Motor Boat, torpedo boats built and used by Britain in both World Wars
 * Combat Medical Badge, a decoration of the United States Army

title: CMB (disambiguation)


text:
Bearded vulture

The bearded vulture (Gypaetus barbatus), also known as the lammergeier and ossifrage, is a very large bird of prey in the monotypic genus Gypaetus. Traditionally considered an Old World vulture, it actually forms a separate minor lineage of Accipitridae together with the Egyptian vulture (Neophron percnopterus), its closest living relative. It is not much more closely related to the Old World vultures proper than to, for example, hawks, and differs from the former by its feathered neck. Although dissimilar, the Egyptian and bearded vulture each have a lozenge-shaped tail—unusual among birds of prey. It is vernacularly known as Homa, a bird in Iranian mythology.

The bearded vulture population is thought to be in decline; in 2004, it was classified on the IUCN Red List as least concern but has been listed as near threatened since 2014. It lives and breeds on crags in high mountains in Iran, southern Europe, East Africa, the Indian subcontinent, Tibet, and the Caucasus. Females lay one or two eggs in mid-winter that hatch at the beginning of spring. The bearded vulture is the only known vertebrate whose diet consists of 70–90% bone.

Taxonomy
The bearded vulture was formally described in 1758 by the Swedish naturalist Carl Linnaeus in the tenth edition of his Systema Naturae. He placed it with the vultures and condors in the genus Vultur and coined the binomial name Vultur barbatus. Linnaeus based his account on the "bearded vulture" that had been described and illustrated in 1750 by the English naturalist George Edwards. Edwards had based his hand-coloured etching on a specimen that had been collected at Santa Cruz near the town of Oran in Algeria. Linnaeus specified the type locality as Africa, but in 1914 this was restricted to Santa Cruz by the German orthithologist Ernst Hartert. The bearded vulture is now the only species placed in the genus Gypaetus that was introduced in 1784 by the German naturalist Gottlieb Storr. The genus name Gypaetus is from Ancient Greek gupaietos, a corrupt form of hupaietos meaning "eagle" or "vulture". The specific epithet barbatus is Latin meaning "bearded" (from barba, "beard"). The name "lammergeier" originates from the German word Lämmergeier, which means "lamb-vulture". The name stems from the belief that it attacked lambs.

Two subspecies are recognised:
 * G. b. barbatus (Linnaeus, 1758) (includes hemachalanus and aureus) – south Europe and northwest Africa to northeast China through the Himalayas to Nepal and west Pakistan
 * G. b. meridionalis Keyserling & Blasius, JH, 1840 – southwest Arabia and northeast, east, south Africa

Description
This bearded vulture is 94 - 125 cm long with a wingspan of 2.31 - 2.83 m. It weighs 4.5 - 7.8 kg, with the nominate race averaging 6.21 kg and G. b. meridionalis of Africa averaging 5.7 kg. In Eurasia, vultures found around the Himalayas tend to be slightly larger than those from other mountain ranges. Females are slightly larger than males. It is essentially unmistakable with other vultures or indeed other birds in flight due to its long, narrow wings, with the wing chord measuring 71.5 - 91 cm, and long, wedge-shaped tail, which measures 42.7 - 52 cm in length. The tail is longer than the width of the wing. The tarsus is relatively small for the bird's size, at 8.8 - 10 cm. The proportions of the species have been compared to a falcon, scaled to an enormous size.

Unlike most vultures, the bearded vulture does not have a bald head. This species is relatively small-headed, although its neck is powerful and thick. It has a generally elongated, slender shape, sometimes appearing bulkier due to the often hunched back of these birds. The gait on the ground is waddling and the feet are large and powerful. The adult is mostly dark gray, rusty, and whitish in color. It is grey-blue to grey-black above. The creamy-coloured forehead contrasts against a black band across the eyes and lores and bristles under the chin, which form a black beard that give the species its English name. Bearded vultures are variably orange or rust of plumage on their head, breast, and leg feathers, but this is thought to be cosmetic. This colouration comes from dust-bathing or rubbing iron-rich mud on its body. They also transfer the brown colour to the eggs. The tail feathers and wings are gray. The juvenile bird is dark black-brown over most of the body, with a buff-brown breast and takes five years to reach full maturity. The bearded vulture is silent, apart from shrill whistles in their breeding displays and a falcon-like cheek-acheek call made around the nest.

Physiology
The acid concentration in the bearded vulture's stomach has been estimated to be of pH about 1. Large bones are digested in about 24 hours, aided by slow mixing or churning of the stomach content. The high fat content of bone marrow makes the net energy value of bone almost as good as that of muscle, even if bone is less completely digested. A skeleton left on a mountain will dehydrate and become protected from bacterial degradation, and the bearded vulture can return to consume the remainder of a carcass even months after the soft parts have been consumed by other animals, larvae, and bacteria.

Distribution and habitat
The bearded vulture is sparsely distributed across a vast range. It occurs in mountainous regions in the Pyrenees, the Alps, the Arabian Peninsula, the Caucasus region, the Zagros Mountains, the Alborz,Iran, the Koh-i-Baba in Bamyan, Afghanistan, the Altai Mountains, the Himalayas, Ladakh in northern India, and western and central China. In Africa, it lives in the Atlas Mountains, the Ethiopian Highlands and south from Sudan to northeastern Democratic Republic of the Congo, central Kenya, and northern Tanzania. An isolated population inhabits the Drakensberg in South Africa. It has been reintroduced in several places in Spain, such as the Sierras de Cazorla, Segura and Las Villas Jaén, the Province of Castellón and Asturias. The resident population as of 2018 was estimated at 1,200 to 1,500 individuals.

In Israel it is locally extinct as a breeder since 1981, but young birds have been reported in 2000, 2004, and 2016. The species is extinct in Romania, the last specimens from the Carpathians being shot in 1927. However, unconfirmed sightings of the bearded vulture happened in the 2000s, and in 2016 a specimen from a restoration project in France also flew over the country before returning to the Alps.

In southern Africa, the total population as of 2010 was estimated at 408 adult birds and 224 young birds of all age classes therefore giving an estimate of about 632 birds.

In Ethiopia, it is common at garbage dumps tips on the outskirts of small villages and towns. Although it occasionally descends to 300 - 600 m, the bearded vulture is rare below an elevation of 1000 m and normally resides above 2000 m in some parts of its range. It typically lives around or above the tree line which are often near the tops of the mountains, at up to 2000 m in Europe, 4500 m in Africa and 5000 m in central Asia. In southern Armenia, it breeds below 1000 m if cliff availability permits. It has even been observed living at elevations of 7500 m in the Himalayas and been observed flying at a height of 24000 ft.

Though a rare visitor, bearded vultures occasionally travel to parts of the United Kingdom, with the first confirmed sighting taking place in 2016 in Wales and the Westcountry. A series of sightings took place in 2020, when an individual bird was sighted separately over the Channel Island of Alderney after migrating north through France, then in the Peak District, Derbyshire, Cambridgeshire, and Lincolnshire. The bird, nicknamed 'Vigo' by Tim Birch of the Derbyshire Wildlife Trust, is believed to have originated from the reintroduced population in the Alps.

Diet and feeding
The bearded vulture is a scavenger, feeding mostly on the remains of dead animals. Its diet comprises mammals (93%), birds (6%) and reptiles (1%), with medium-sized ungulates forming a large part of the diet. It usually disdains the actual meat and typically lives on 85–90% bones including bone marrow. This is the only living bird species that specializes in feeding on bones. Meat and skin only makes up a small part of what the adults eat, but scraps of meat or skin makes up a larger amount of the chicks' diet. The bearded vulture can swallow whole or bite through brittle bones up to the size of a lamb's femur and its powerful digestive system quickly dissolves even large pieces. The bearded vulture has learned to crack bones too large to be swallowed by carrying them in flight to a height of 50 - 150 m above the ground and then dropping them onto rocks below, which smashes them into smaller pieces and exposes the nutritious marrow. They can fly with bones up to 10 cm in diameter and weighing over 4 kg, or nearly equal to their own weight.

After dropping the large bones, the bearded vulture spirals or glides down to inspect them and may repeat the act if the bone is not sufficiently cracked. This learned skill requires extensive practice by immature birds and takes up to seven years to master. Its old name of ossifrage ("bone breaker") relates to this habit. Less frequently, these birds have been observed trying to break bones (usually of a medium size) by hammering them with their bill directly into rocks while perched. During the breeding season they feed mainly on carrion. They prefer the limbs of sheep and other small mammals and they carry the food to the nest, unlike other vultures which feed their young by regurgitation.

Bearded vultures sometimes attack live prey, with perhaps greater regularity than any other vulture. Among these, tortoises seem to be especially favored depending on their local abundance. Tortoises preyed on may be nearly as heavy as the preying vulture. To kill tortoises, bearded vultures fly with them to some height and drop them to crack open the bulky reptiles' hard shells. Golden eagles have been observed to kill tortoises in the same way. Other live animals, up to nearly their own size, have been observed to be predaceously seized and dropped in flight. Among these are rock hyraxes, hares, marmots and, in one case, a 62 cm long monitor lizard. Larger animals have been known to be attacked by bearded vultures, including ibex, Capra goats, chamois, and steenbok. These animals have been killed by being surprised by the large birds and battered with wings until they fall off precipitous rocky edges to their deaths; although in some cases these may be accidental killings when both the vulture and the mammal surprise each other. Many large animals killed by bearded vultures are unsteady young, or have appeared sickly or obviously injured. Humans have been anecdotally reported to have been killed in the same way. This is unconfirmed, however, and if it does happen, most biologists who have studied the birds generally agree it would be accidental on the part of the vulture. Occasionally smaller ground-dwelling birds, such as partridges and pigeons, have been reported eaten, possibly either as fresh carrion (which is usually ignored by these birds) or killed with beating wings by the vulture. When foraging for bones or live prey while in flight, bearded vultures fly fairly low over the rocky ground, staying around 2 - 4 m high. Occasionally, breeding pairs may forage and hunt together. In the Ethiopian Highlands, bearded vultures have adapted to living largely off human refuse.

Reproduction and life cycle
The bearded vulture occupies an enormous territory year-round. It may forage over 2 sqkm each day. The breeding period is variable, being December through September in Eurasia, November to June in the Indian subcontinent, October to May in Ethiopia, throughout the year in eastern Africa, and May to January in southern Africa. Although generally solitary, the bond between a breeding pair is often considerably close. Biparental monogamous care occurs in the bearded vulture. In a few cases, polyandry has been recorded in the species. The territorial and breeding display between bearded vultures is often spectacular, involving the showing of talons, tumbling, and spiraling while in solo flight. The large birds also regularly lock feet with each other and fall some distance through the sky with each other. In Europe, the breeding pairs of bearded vultures are estimated to be 120. The mean productivity of the bearded vulture is 0.43±0.28 fledgings per breeding pair per year and the breeding success averaged 0.56±0.30 fledgings per pair with clutches/year.

The nest is a massive pile of sticks, that goes from around 1 m across and 69 cm deep when first constructed up to 2.5 m across and 1 m deep, with a covering of various animal matter from food, after repeated uses. The female usually lays a clutch of 1 to 2 eggs, though 3 have been recorded on rare occasions, which are incubated for 53 to 60 days. After hatching, the young spend 100 to 130 days in the nest before fledging. The young may be dependent on the parents for up to 2 years, forcing the parents to nest in alternate years on a regular basis. Typically, the bearded vulture nests in caves and on ledges and rock outcrops or caves on steep rock walls, so are very difficult for nest-predating mammals to access. Wild bearded vultures have a mean lifespan of 21.4 years, but have lived for up to at least 45 years in captivity.

Threats
The bearded vulture is one of the most endangered European bird species as over the last century its abundance and breeding range have drastically declined. It naturally occurs at low densities, with anywhere from a dozen to 500 pairs now being found in each mountain range in Eurasia where the species breeds. The species is most common in Ethiopia, where an estimated 1,400 to 2,200 are believed to breed. Relatively large, healthy numbers seem to occur in some parts of the Himalayas as well. It was largely wiped out in Europe and, by the beginning of the 20th century, the only substantial population was in the Spanish and French Pyrenees. Since then, it has been successfully reintroduced to the Swiss and Italian Alps, from where they have spread into France. They have also declined somewhat in parts of Asia and Africa, though less severely than in Europe.

Many raptor species were shielded from anthropogenic influences in previously underdeveloped areas therefore they are greatly impacted as the human population rises and infrastructure increases in underdeveloped areas. The increase in human population and infrastructure results in the declines of the bearded vulture populations today. The increase of infrastructure includes the building of houses, roads, and power lines. A major issue with infrastructure and bird species populations is collision with power lines. The declines of the bearded vulture populations have been documented throughout their range resulting from a decrease in habitat space, fatal collisions with energy infrastructure, reduced food availability, poisons left out for carnivores and direct persecution in the form of trophy hunting.

This species is currently listed as near threatened by the IUCN Red List last accessed on 1 October 2016, and the population continues to decline.

Conservation
Mitigation plans have been established to reduce the population declines in bearded vulture populations. One of these plans includes the South African Biodiversity Management Plan that has been ratified by the government to stop the population decline in the short term. Actions that have been implemented include the mitigation of existing and proposed energy structures to prevent collision risks, the improved management of supplementary feeding sites as well to reduce the populations from being exposed to human persecution and poisoning accidents and outreach programmes that are aimed at reducing poisoning incidents.

The Foundation for the Conservation of the Bearded Vulture (Fundación para la Conservación del Quebrantahuesos), established in Spain in 1995, was created in response to the national population dropping to 30 specimens by the end of the 20th century. Focused on conserving the species in the Pyrenees, it also returned the species to other already extinct areas such as the Picos de Europa in the north of the country or the Sierra de Cazorla, in the south. After 25 years of work, the Foundation reported that they had managed to recover the species, with more than 1,000 specimens throughout the country.

Reintroduction in the Alps
Efforts to reintroduce the bearded vulture began in the 1970s in the French Alps. Zoologists Paul Geroudet and Gilbert Amigues attempted to release vultures that had been captured in Afghanistan, but this approach proved unsuccessful: it was too difficult to capture the vultures in the first place, and too many died in transport on their way to France. A second attempt was made in 1987, using a technique called "hacking", in which young individuals (from 90 to 100 days) from zoological parks would be taken from the nest and placed in a protected area in the Alps. As they were still unable to fly at that age, the chicks were hand-fed by humans until the birds learned to fly and were able to reach food without human assistance. This method has proven more successful, with over 200 birds released in the Alps from 1987 to 2015, and a bearded vulture population has reestablished itself in the Alps.

In culture
The bearded vulture is considered a threatened species in Iran. Iranian mythology considers the rare bearded vulture (lit. 'Homa') the symbol of luck and happiness. It was believed that if the shadow of a Homa fell on one, he would rise to sovereignty and anyone shooting the bird would die in forty days. The habit of eating bones and apparently not killing living animals was noted by Sa'di in Gulistan, written in 1258, and Emperor Jahangir had a bird's crop examined in 1625 to find that it was filled with bones.

The ancient Greeks used ornithomancers to guide their political decisions: bearded vultures, or ossifrage, were one of the few species of birds that could yield valid signs to these soothsayers.

The Greek playwright Aeschylus was said to have been killed in 456 or 455 BC by a tortoise dropped by an eagle who mistook his bald head for a stone—if this incident did occur, the bearded vulture is a likely candidate for the "eagle" in this story.

In the Bible/Torah, the bearded vulture, as the ossifrage, is among the birds forbidden to be eaten (Leviticus 11:13).

In 1944, Shimon Peres and David Ben-Gurion found a nest of bearded vultures in the Negev desert. The bird is called peres in Hebrew, and Shimon Persky liked it so much he adopted it as his surname.

title: Bearded vulture