The chemotherapeutic index

All these discoveries were made by pursuing clues which Ehrlich and his school had revealed. Indicative of the impact that chemotherapy was now making was the German State s ban on any disclosure of the constitution of suramin and mepacrine, because of the potential they lent to tropical warfare. This was a complete swing of the pendulum from the State s apathy in 1899. (Parenthetically, the secrecy was short-lived the synthesis of suramin was solved by Fourneau et al, in 1924 at the Pasteur Institute in Paris Maghidson and Grigorovski, in Moscow, published that of mepacrine in 1933.) 

The year 1932 was notable not only for the introduction of mepacrine, but for the discovery by Tatum and Cooper of a much safer arsenical drug for use in syphilis, namely oxophenarsine (6,4) ( Mapharside ) (Tatum and Cooper, 1934). This drug had been discovered by Ehrlich and his colleagues and 

Another prediction confirmed in this period was the co-operation between drug and the host s defence forces. Ehrlich had held the view that the function of a drug was to disorganize the parasite s metabolism, after which the natural defence forces of the body would complete the actual destruction of the invader. This was confirmed when Kritschewsky (1928) showed that the host s reticuloendothelial system provided such co-operation, because when this was artificially damaged, the efficiency of chemotherapeutic drugs was lowered greatly. 

That a parasite need not be harmed merely by taking up a foreign substance, followed from Ehrlich s teaching that the haptophoric (anchoring) and toxo-philic (poisoning) portions of a substance were distinct entities. Techniques of vital staining have now made this concept familiar. 

As momentous as any discovery in the period we are considering, was the first demonstration of the chemical nature of the union between a drug and a parasite. This was accomplished by Voegtlin and his colleagues in the United States Public Health Services, who showed that the toxic action of arsenicals was due to the formation of As—S bonds with essential thiol-groups in the parasites (see Section 13.0). This, too, had been predicted by Ehrlich (1909). 

2 Chemotherapeutic drugs available before 1935. The chemotherapeutic index 

Schulemann et aLy 1932), and mepacrine (6.9) ( Atebrin ) (Kikuth, 1932 Mauss and Mietzsch, I933)- They were inspired by the weak antimalarial action that Guttmann and Ehrlich (1891) had found in methylene blue (6.70), but systematic work had to await discovery of a test object, and Roehl found this in malaria-infected finches. 

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Similarly Magidson et al., in a series of 6-methoxyquinolines substituted at C by the chain. NH—[CHjJn—NEtj found in anti-malarial tests in siskins, the following changes in the chemotherapeutic index — ... 

Determination and cataloging of the chemotherapeutic index of the 600 compounds Ehrlich and Hata synthesized enabled them in 1909 to discover arsphe-mamine (Salvarsan). This drug was very toxic but safer than the then currently used Atoxyl. It was used up to the mid-1940s, when it was replaced by penicillin. 

Extracts of various Sophora species have earlier been reported to show antitumour activity, and it was therefore of interest to determine which, if any, of the alkaloidal constituents was responsible for this activity. Kojima et al.21 have now shown that matrine exhibits anti-tumour activity against Ehrlich ascites tumour in mice, and both matrine and matrine N-oxide show activity against solid Sarcoma-180 in mice. In fact, the chemotherapeutic index of matrine IV-oxide for Sarcoma-180 is estimated to be about 7.8 times that of mitomycin C. 

A measured quantity of the test compound is administered by various routes. From the activity in vivo the value of EDjq is calculated. The chemotherapeutic index is determined from the ED 50 and LDjp, which assesses the final therapeutic value of nitrofurans. 

In seeking drugs which would have a great affinity for the invader and little for the host, Ehrlich introduced the Chemotherapeutic Index which he defined as the ratio ... 

Allopurinol Metabolism In Man - There are scattered reports of the use of allopurinol at doses of 900 mg ( 12 mg/kg) per day or higher (Sweetman, 1968 Rundles, 1966). The proposed use of high doses of allopurinol to improve the chemotherapeutic index of 5-fluorouracil (Schwartz, 1980) and also to treat the parasitic disease, leishmaniasis, gave impetus to the present metabolic study. 

Alkylating Agents are contlnuii to receive attention as antlneoplastlc agents. In view of the favorable therapeutic indices of some aromatic carbamate mustards in the Walker 256 system, several new compounds were prepared, wherein the jD-phenyl N- phenylcaibamate moiety was linked to bis (1-aziridinyl)- and bis (2,2-dimethyl-l-aziridinyl)phosphinate. No improvement of the chemotherapeutic index was achieved by this modification . On the other hand, replacement of one ethyleneimine group in thio-TEPA with a methyl substituted oxypiperidine moiety 5 (Vin), furnished a compound which reportedly was... 

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