Malaria is vector born infection blood diseases. It is strong dependent from the presence of suitable vector and infected host. The detailed geographic distribution of malaria and types of malaria vector (carriers) described in [1] -[3] .

Before discovery of synthetic antimalarial drugs quinine was a single remedy against malaria diseases. About 1630, Jesuits, working in South America (Peru) received the knowledge that the bark from cinchona trees was used by the native people as drug against malaria. A variety of alkaloids, including cinchonine, cinchonidine, quinine, quinidine, dihydroquininidine, and dihydroquinine were discovered later in the bark of these trees.

Jesuit Cardinal John de Lugo (1583 - 1660) [1] received the honor for introduction of the bark of cinchona in Europe. The alkaloids present in the bark of cinchona shown in Figure 2.

These alkaloids were a long time an only medication against malaria. As it was presented above malaria strong depends on presence of three factors: malaria parasite, suitable vector and host organism in biosphere. The first factor is a parasite. There are several types of parasites cause malaria in humans: Plasmodium vivax, P. ovale, P. malariae and P. falciparum. There are many subtypes and local variants for every type of this parasite. The second factor is a vector. The main vector for these parasites is Anopheline mosquitoes [1] [3] . When humans were bitten by Anopheline mosquitoes infected with malaria parasite they became ill with malaria, but in the same time they became a part of malarial biosphere as a carrier of a pool of parasites in their blood [1] . The third factor is the presence of humans as natives, tourists, migrant workers or foreign military personal in malaria endemic arias, the humans who are carrier of a pool of parasites in their blood.

Humans infected in one endemic aria by malaria can by traveling to the other aria which was before free from malaria or free from particular type or subtype of parasite introduce or reintroduce in this aria a new type or sub-type of parasite [1] [2] and expose the entire population of this aria for malarial infection. Especially significance of this dangerous situation present when large contingents of troopers return home from infected by malaria endemic aria. The sanitation from malaria of return home contingent of troopers is a priority for health authorities.

Prevention of introduction of malaria parasite strains from Korea was first used on large scale when US troops returned home from Korea war by ships. More than 330,000 men and women each received a single 15 mg daily dose of primaquine during the 14-day Pacific Ocean crossing [4] .

As it was mentioned in paragraph 1.3. of this paper the needs for substituents of quinine and bark from cinchona trees was grate and acute in Germany already during the World War I. Robert B. Woodward and William von Doering reported a successful synthesis of quinotoxine and conversion of quinotoxine into quinine in time

of World War II; however, it was a very poorly documented procedure, never successfully realized. A method for preparation of chloroquine an antimalarial drug by the condensation of 4,7-dichloroquinoline with 1-diethyl- amino-4-aminopentane was patented in Germany, patent 683, 692 in 1939. The structure of chloroquine is depicted in Figure 3.

Chloroquine is quite toxic drug. The need for synthetic substances with antimalarial properties persisted also after discovery of chloroquine. In 1946 Elderfield et al., [5] reported successful synthesis of long list of sub- stances with antimalarial activity; the primaquine was chosen as the more suitable and active substance in this series of aminoquinoline analogs. Elderfield et al., also reported the substance later known in USSR as Quino- cide. Quinocide is more toxic than primaquine. Table 1 shows the analogs of aminoquinoline synthesized and tested by Elderfield et al.

Despite of the fact that nearly 70 years got from the first successful use of primaquine this drug do not lost its importance in the struggle against malaria [1] . However, the drug is quite toxic and its therapeutic dose is not fare from toxic and for some of people the therapeutic dose is a toxic dose [1] . Tolerance to primaquine of some people is quite low.

Tolerance to primaquine in Caucasians to the usual therapeutic doses of primaquine is quite good. However, the tolerance to primaquine in Negroes is essentially lover [1] [6] . The incidence and degree of anemia and intra- vascular hemolysis are greater in Negroes at a daily dose level of 20 mg (base) and higher [6] . In some Cauca- sian ethnic groups, including Sardinians, Sephardic Jews, Greeks and Iranians, in whom the tolerance to prima- quine is even, lower than in the Negro so that the hemolytic reaction from a given dose of drug may be more severe [6] . The main disadvantage of primaquine and all 8-aminoquinolines is that the drugs cause methemoglo-

binemia, however the other toxic effects of primaquine and 8-aminoquinolines should not been overseen [1] . It should be mentioned that pure primaquine as pro analyses grade never was biologically tested out, the substance always was contaminated with quinocide [1] [7] -[22] .

Primaquine and all 8-aminoquinolines strong differ from natural antimalarial present in bark of cinchona trees. Quinine has a number of abilities; it kills mono- and multi-cellular organisms like bacteria, fungi, protozoa, in- sects, parasites, germs, reduces fever, reduces spasms, calms nerves, relieves pain, stimulates digestion and re- gulates the heartbeat [1] . Quinine is moderate toxic for humans’. The structure of primaquine is shown on Figure 4.

Some of batches of primaquine are heavily contaminated with quinocide [1] , [7] -[22] . Quinocide is more tox- ic than primaquine [1] the structure of quinocide is shown on Figure 5.

Contamination of primaquine with 6% of quinocide elevates the toxicity of this mixture twice in comparison to primaquine with 0.5% quinocide [7] -[8] .Primaquine is inducing methemoglobinemia [23] -[26] , effects on the red blood cell membrane [27] . Some of polyamines are involved in the development of hepatic encephalopathy

and cerebral edema [28] . The neurotoxicity of the 8-aminoquinolines [29] [30] is characteristic for these substances. In most of described neuropsychiatric disturbances after malaria prophylaxis were notified with use of mefloquine, plasmocid, clioquinol, plasmochine and rhodoquine [31] -[58] . However, already in 1951 appears that primaquine can exhibit the similar effects in animal models [53] . Later in 1981 Lee et. al., in the Bulletin of World Health Or- ganization [59] supported the observations: “In the present study, the subacute toxicity of primaquine was studied in beagle dogs, rhesus monkeys, and albino rats. ... Certain derivatives of the 8-aminoquinolines have been shown to affect some blood constituents and haemopoiesis, to induce functional changes in the central nervous system, and to cause other organ lesions”, and “gliosis of the cerebral cortex in some monkeys”.

Despite very broad use of primaquine in curative medicine, more than several hundred million cases per year, the description of neurotoxicity of this drug is very poor presented in literature. The description of neurotoxicity of quinocide is not presented at all; however it is known that combination of different 8-aminoquinolines poten- tiate toxic effects. In experiments described in [7] and [8] were clear shown that elevation of contamination of primaquine from 0.5% to 6.0% doubles the toxicity. In this model the disruption of electron transport chain was studied. Peripheral and central nerve systems are very sensitive to the biochemistry of the disruption of electron transport chain.

It is unbelievable that the drug used in about of seventy year was presented on the market to these extends con- taminated [1] [7] [8] Figure 6.

In Figure 7 shown the document published in [60] which give evidence that batches of primaquine contami- nated with more than 8% were used in productions of medical forms.

The samples even more contaminated were often found. In these circumstances the intoxication could happen.

It is obvious that all 8-aminoquinolines have numerous toxic effects and one of these is neurotoxicity, the mix-

ture of several 8-aminoquinolines is more toxic than pure substance. The neuropsychiatric adverse effects of mefloquine is best studied among the 8-aminoquinolines, however the absence of data do not suggests that primaquine or mixture of primaquine with quinocide are harmless. All evidences gathered up to date are suggest that primaquine contaminated with quinocide is a potential neurotoxic drug and can lead to psychotic conditions. The art of these is difficult to predict and the physical and psychical stress can aggravate the situation.