WHO ONCHO 78 142 Eng.Pdf

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WHO ONCHO 78 142 Eng.Pdf Page 3.2 Anti-inflammatory effect .......................... 3.2.1 Anaphylaxis ............................. 3.2.1.1 In calves ......................... 3.2.1.2 In rats and monkeys .................... 3.2.1.3 Cutaneous anaphylaxis ................... 3.2.2 Rat peritonea1 cells ........................ 3.2.3 Experimental eosinophilia ...................... 3.2.4 Pros taglandins ........................... 3.2.5 Effect on skin tests ........................ 3.2.6 Sumaery of anti-inflanrmatory action ................. 3.3 Bronchial asthma .............................. 4. Antifilarial activity ............................... 4.1 Actiononmicrofilariae. .......................... 4.1.1 In vitro .............................. 4.1.2 In vivo ............................... 4.1.3 Mode of action on microfilariae ................... 4.1.3.1 Experimental evidence ................... 4.1.3.2 Theoretical conclusions .................. 4.1.4 Mobilization of microfilariae by diethylcarbamazine ......... 4.1.4.1 W. bancrofti ....................... 4.1.4.2 0. volvulus ........................ 4.1.5 Other actions of diethylcarbamazine upon microfilariae ....... 4.2 Actiononadultworms.,.......................... 4.2.1 In vitro .............................. 4.2.2 In vivo ............................... 4.2.3 Action of piperazine upon Ascaris .................. 4.3 Action on forms in the insect vector .................... 4.4 Action on infective larvae and immature worms ................ 4.5 Development of drug resistance ....................... 4.6 Action on other worms ............................ 5. Toxicity ..................................... 5.1 Animals. .................................. 5.2 Man - uninfected .............................. 5.3 Man - infected with filariae ........................ 5.3.1 O.volvulus...................... ....... 5.3.1.1 Clinical ......................... 5.3.1.2 Histology of diethylcarbamazine reaction in onchocerciasis ...................... 5.3.2 Other filariae ........................... 5.3.3 Local reactions ........................... 5.4 Deaths reported as due to diethylcarbamazine treatment ........... 5.4.1 Discussion of evidence ....................... 5.4.2 Encephalitis ............................ 6. Clinical use ................................... 6.1 Individual patients ............................. 6.1.1 Patients with W. bancrofti . 30 6.1.2 Patients with B. malayi and L. loa . 30 6.1.3 Patients with 0. volvulus . 30 6.1.3.1 Treatment of light infections . 30 6.1.3.2 Treatment for ocular onchocerciasis . 31 6.1.3.3 Local application for ocular onchocerciasis . 31 6.2 Mass therapy . 3 2 6.2.1 Bancroftian and malayan filariasis . 32 6.2.1.1 Mass treatment with diethylcarbamazine . 32 6.2.1.2 Review of nmss therapy . 33 6.2.2 Diethylcarbamazine in cooking salt . 34 6.2.3 Mass therapy of other filarial infections . .. 35 6.3 Treatment of tropical eosinophilia . 35 7. Recommendations for research on diethylcarbamazine . 35 RI~~uuI~.......................................... 37 References quoted in text . 39 References consulted but not quoted in text . 51 Recommendations for research on diethylcarbamazine 1. Mode of action of DEC upon microfilariae 2. Mansonella ozzardi 3. Skin test for onchocerciasis with DEC 4. Radioactive diethylcarbamazine 5. Action of DEC on adult worms 6. Therapeutic so-called allergic reactions to DEC in patients with onchocerca or other filarial infections 7. Local application of DEC to the eyes 8. Methods of mass administration 9. Toxicity of arsenical compounds INTRODUCTION Difficulties encountered from toxic reactions during treatment of onchocerciasis patients with diethylcarbamazine and suramin - the only two drugs at present considered suitable for treatment - necessitated a thorough search of the literature in an attempt to throw light on the pharmacodynamics and toxicity of these drugs, both of which are used experimentally in other fields of pharmacology, biochemistry, etc. A literature search was done on Medline and with the assistance of Professor Lammler (suramin). It was stimulated as a result of recommendations of a Scientific Advisory Panel Working Group on the Chemotherapy of Onchocerciasis, Drug Efficacy and Toxicity (Geneva, 28-29 November 19741, and of the Scientific and Technical Advisory Committee of the Onchocer- ciasis Control Programme in the Volta River Basin (OCP) at its second and third sessions (Geneva, 3-5 June 1975 and 3-4 March 1976), and was financed by OCP (UNDP Project No. RAF/~~/ 004). The literature revealed by the search was studied and retrieved by Dr F. Hawking in two papers, one dealing with diethylcarbamazine and the other with suramin. This led to recom- mendations for future investigations; all possible sources of information in the literature to date have now been tapped. 1.1 Chemical and physical propertiks Name l-die thylcarbamyl-4-methyl-piperazine Formula Synonyms Hetrazan, Banocide, Notezine, Caricide, Carbilazine, Supatonin, 3799 R.P. Diethylcarbamazine was first issued as the chloride, but is now produced as the dihydrogen citrate which contains only half its weight as base. In reporting doses it is important to indicate whether the doses refer to a specific salt or to the base; unless otherwise stated, it can generally be assumed that the dose refers to the citrate. Diethylcarbamazine is a white powder, freely soluble in water with a slightly unpleasant sweetish taste. It is stable under all ordinary laboratory conditions and is fully stable to autoclaving, when mixed with diet. 1.2 Relation of structure to activity The piperazine ring is of fundamental importance as was shown during the original investi- gations of Hewitt et al. (1948) although piperazine itself has no antifilarial activity. Piperazine is, however, active against Ascaris and other round worms in the intestine, and its ring structure may have specific action on parasitic newodes in general. Various compounds with slightly different rings, e.g. N, N-diethyl-4-methyl-l, 4-diazacycloheptane-l-carbamaxide hydrochloride (JGS-110), have some antifilarial activity, but diethylcarbamazine remains the most effective known antifilarial agent (Reinertson & Thompson, 1955). In the piperazine series, a carbethoxy radical in position 1 of the ring, with various substitutions in position 4, produced high antimicrofilarial activity; but as the alkyl chain was increased the toxicity became greater and the activity less. If the alkyl group is greater than -C4Hg, activity is lost. The alkyl group in position 4 is not particularly significant, however, since high activity continues after it is removed. The only compounds lacking the carbethoxy group, which show marked activity against microfilariae, contain an ethyl, diisopropyl, dimethyl, or diethyl carbamyl group in position 1. A compound with the formula: is also active (patra et al., 1969). Apparently for the above compounds to be effective there must be two aliphatic amines connected by a saturated carbon framework; one amine must be basic and the other must be modified by some type of carbonyl function. The spatial separation of these amines in diethylcarbamazine is optimal; compounds with wider separation are less active. A modification of the diethylcarbamazine structure has been described by Saxena et al. (1970) and studied further by Thompson et al. (1973) and by Sturm et al. (1974). It is named "compound 11" for convenience, and will be described in more detail belcu. In this compound, the terminal carbon of one ethyl group is connected to the piperazine ring at the 2 carbon position as follows: The essential structure is similar to that of diethylcarbamazine but the change makes the molecular structure rigid and locks the urea moiety into a single rotational conformation. In contrast, the diethylcarbamyl group of diethylcarbamazine can rotate on all its single bonds. The new compound is approximately planar with the carbon-oxygen bond of the carbamyl and all the nitrogens lying in the same plane. There are 2.8~" between N1 and Nq of the piperazine ring and 3~"between N4 and N2. Since the compound is as active or perhaps more active than diethyl- l carbamazine, this configuration is apparently optimum. In addition to this modification, various linkages across the piperazine ring by -CH2 - CH2 - have been investigated by Stum et al. (1974). Linkage between positions 3 and 5 on the piperazine ring does not diminish activity. Other linkages between positions 1 and 6 and 2 and 6 diminish activity moderately. 1.3 Analogues of diethylcarbamazine 1.3.1 Compound I1 (Centperazine) - This campound was first reported by Saxena et al. (1970); a brief description as well as its chemical formula has been given above. Its action is almost identical to that of diethyl- carbamazine. When tested by Saxena et al. (1970) and by Thompson et al. (1973) in cotton rats and jirds infected with Litomosoides, the antifilarial rksponse was not closely propottional to the dose, a situation which made accurate conparison difficult. Saxena et al. claimed that it was five times more active than diethylcarbamazine and Thompson et al. agreed that it was as active or slightly more active than diethylcarbamazine upon the microfilariae. Like diethyl- carbamazine it had no action on the adult worms of Litomosoides. The acute toxicity in mice was slightly less than diethylcarbamazine. This compound should be investigated further and tested in man against Wuchereria bancrofti and against Onchocerca volvulus. Although similar in behaviour to diethylcarbamazine
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