90-89-1 Usage
Description
N,N-DIETHYL-4-METHYL-1-PIPERAZINECARBOXAMIDE, also known as diethylcarbamazine (DEC), is a filaricide agent discovered in the 1940s. It was found to be particularly effective in treating filariasis, a parasitic disease that was prevalent among American troops during World War II. DEC is chemically similar to piperazine, but its activity against helminths is quite different. While piperazine is active against nematodes, DEC is specifically active against filarial worms and microfilariae.
Uses
Used in Pharmaceutical Industry:
N,N-DIETHYL-4-METHYL-1-PIPERAZINECARBOXAMIDE is used as a filaricide agent for the treatment of filariasis, a parasitic disease caused by filarial worms and microfilariae. It is effective in eliminating these parasites from the human body, thus reducing the incidence and severity of the disease.
Used in Public Health Initiatives:
N,N-DIETHYL-4-METHYL-1-PIPERAZINECARBOXAMIDE is used in public health initiatives aimed at controlling and eradicating filariasis in affected regions. Mass drug administration programs involving DEC have been implemented to reduce the prevalence of the disease and prevent its transmission.
Used in Research and Development:
N,N-DIETHYL-4-METHYL-1-PIPERAZINECARBOXAMIDE is also used in research and development for the discovery of new drugs and therapies targeting filarial worms and other parasitic infections. Its unique activity and mechanism of action provide valuable insights for the development of novel treatments and interventions.
Pharmacology and mechanism of action
Diethylcarbamazine (DEC) is a piperazine derivative which was introduced in clinical medicine in 1947. The drug is active against adult and microfilariae forms of Wuchereria bancrofti, Brugia malayi, Brugia timori and Loa loa. Against Onchocerca volvulus, the drug is only effective against the microfilariae. Soon after its administration, it causes rapid disappearance of microfilariae from the blood (lymphatic filariasis) or from the skin (onchocerciasis). Its effect against microfilariae in nodules or in hydroceles and in advanced elephantiasis is minimal [1].
The mechanism of action of DEC is not well understood. The drug has no microfilaricidal effect in vitro [2]. In vivo, the microfilariae is first immobilized by the drug due to a possible hyperpolarization of the worm. This is followed by changes on the outer surface of the microfilariae making them more susceptible to the host’s defence system[3]. More recently, the drug has been reported to inhibit microtubule polymerization and disrupt preformed microtubule protein prepared from porcine brain in vitro [4]. The relevance of this action in the living parasite remains to be studied. A similar?mechanism of action has been described for benzimidazoles (see Mebendazole, p. 78).
Indications
DEC is used for the treatment of individual cases infected by Wuchereria bancrofti, Brugia malayi, B. timori andLoa loa. It may also be used for large scale chemotherapeutic control of filariasis. DEC is also used in Acanthocheilonema streptocerca infestations and in tropical eosinophilia.
In onchocerciasis, DEC should only be used when ivermectin is not available.
Indications
Diethylcarbamazine citrate (Hetrazan) is active against
several microfilaria and adult filarial worms. It interferes
with the metabolism of arachidonic acid and
blocks the production of prostaglandins, resulting in
capillary vasoconstriction and impairment of the passage
of the microfilaria. Diethylcarbamazine also increases
the adherence of microfilariae to the vascular
wall, platelets, and granulocytes.
Diethylcarbamazine is absorbed from the gastrointestinal
tract, and peak blood levels are obtained in 4
hours; the drug disappears from the blood within 48
hours. The intact drug and its metabolites are excreted
in the urine.
Diethylcarbamazine is the drug of choice for certain
filarial infections, such as Wuchereria bancrofti, Brugia
malayi and Loa loa. Since diethylcarbamazine is not
universally active against filarial infections, a specific diagnosis
based on blood smears, biopsy samples, and a
geographic history is important. Dosage should be adjusted
in patients with renal impairment.
Caution is necessary when using this agent, particularly
when treating onchocerciasis.The sudden death of
the microfilariae can produce mild to severe reactions
within hours of drug administration. These are manifested
by fever, lymphadenopathy, cutaneous swelling,
leukocytosis, and intensification of any preexisting
eosinophilia, edema, rashes, tachycardia, and headache.
If microfilariae are present in the eye, further ocular
damage may result. Other side effects are relatively
mild and range from malaise, headache, and arthralgias
to gastrointestinal symptoms.
Side effects
Side effects related to DEC are usually mild and include headache, general weakness, joint pains, anorexia, nausea and vomiting. They are dose-dependent. There are specific side effects seen only in patients with filariasis. They are assumed to be caused by antigens released by dying microfilariae. In lymphatic filariasis, the side effect; are usually mild. However, in onchocerciasis, the reaction to treatment with DEC may become quite severe. The reaction is known as the ‘Mazzotti’ after its original descriptior and has been used as a diagnostic test for the disease [5]. It occurs in two phases. A primary phase which commences within 24 hours and manifests as a variable combination of increased itching of the skin and eyes, photophobia, lacrimation, erythema and oedema of the skin and conjunctiva, lymphangitis, chills, anxiety, sweating and syncope. Respiratory distress, hyperpyrexia, hypotension, tachycardia and headache can also occur. Reversible proteinuria may be seen. A second phase may follow 2–6 days later with severe symmetrical acute polyarthritis predominantly in the knees, ankles, wrists, the interphalangeal joints and the shoulders. It is usually accompanied by a recrudescence of fever. The severity of Mazzotti reaction is related chiefly to the number of microfilariae killed [6].
To be able to quantify the severity of the reaction a scoring system has been developed [7]. Using this scoring system, the suppressive effects of cyproheptadine, indomethacin, prednisolone, and their combinations on the reaction were evaluated. A marked suppression of the mean total reaction score occurred only in the group treated with the full course of prednisone.
Prednisone, however, had little effect on the severity of the itching and did not prevent the occurrence of the acute febrile polyarthritis of the secondary reaction. Prednisone has also significantly impaired the therapeutic effect of DEC [8-10].
Treatment may aggravate ocular lesions and precipitate blindness as a result of the reaction against the dead and dying microfilariae. A pre-treatment eye examination is advisable in cases with a high microfilarial density in a biopsyfrom epicanthus or from other locations.
Encephalitis and retinal damage may occur in patients with loaiasis. Periarticular swellings (‘Calabar swelling’) due to a local reaction around the dying worm are also frequently seen in such patients.
Side effects
In uninfected people, diethylcarbamazine has virtually no
side effects, but in those with various forms of filariasis it
has unpleasant effects primarily due to the death of bloodor
skin-dwelling microfilariae. Severe reactions (‘Mazzotti
reactions’), most frequently of the skin, occur in patients
with onchocerciasis and may also be systemic with fever,
headache, prostration, nausea, joint and muscle pain, vertigo,
tachycardia, cough and respiratory distress, hypotension
and ocular signs. In patients with L. loa who harbor
very large numbers of microfilariae in their blood, neurological
problems may be very severe. Cardiological damage
has also been reported. In patients with W. bancrofti and
B. malayi high fever occurs in the first few days after treatment.
Reversible proteinuria may occur.
Contraindications and precautions
There are no known contraindications to the drug. Dosage should be reduced in patients with renal impairment[11] or in strict vegetarians with high urinary pH[12] since renal function and pH are important factors for the excretion of the drug. Dosage may also be reduced in patients in poor general condition or who are heavily infected.
Preparations
Available as diethylcarbamazine citrate: 100 mg citrate is approximately equivalent to 50 mg base.
? Banocide? (Wellcome) Oral solution 10 mg/ml and 24 mg/ml; tablets 50 mg, 100 mg.
? Hetrazan? (Lederle) Tablets 50 mg.
? Notezine? (Specia) Tablets 50 mg.
References
1. Webster LT (1990). Chemotherapy of parasitic infections. In: Goodman & Gilman’s The Pharmacological basis of Therapeutics, 8th edn, edited by A.G.Gilman, T.W.Rall, A.S.Nies and P. Taylor (New York: Pergamon Press) pp. 960–961.
2. Langham ME, Kramer TR (1980). The in vitro effect of diethylcarbamazine on the motility and survival of Onchocerca volvulus microfilariae. Tropenmed Parasitol, 31, 155–158.
3. Allen GD, Goodchild TM, Weatherley BC (1979). Determination of 1-diethylcarbamoyl-4methylpiperazine in human plasma and urine. J Chromatogr, 164, 521–526.
4. Edwards G, Awadzi K, Breckenridge AM, Gilles HM, L’E Orme M, Ward SA (1981). Diethylcarbamazine disposition in patients with onchocerciasis. Clin Pharmacol Ther, 30, 551–557.
5. Mazzotti L (1948). Posibilidad de utilizar como medio diagnóstico auxiliar en la oncocercosis las reacciones alérgicas consecutivas a la administración del ‘Heterzán’. Revista del Instituto Salubridad Enfermedades Tropicales, 9, 235–237.
6. Awadzi K, Gilles HM (1992). Diethylcarbamazine in the treatment of patients with onchocerciasis. Br J Clin Pharmacol, 34, 281–288.
7. Awadazi K (1980). The chemotherapy of onchocerciasis. II. Quantification of the clinical reaction to microfilaricides. Ann Trop Med Parasitol, 74, 189–197.
8. Awadzi K, Orme ML’E, Breckenridge AM, Gilles HM (1982). The chemotherapy of onchocerciasis VI. The effects of indomethacin and cyproheptadin on the Mazzotti reaction. Ann Trop Med Parasitol, 76, 323–330.
9. Awadzi K, Orme ML’E, Breckenridge AM, Gilles HM (1982). The chemotherapy of onchocerciasis VII. The effect of prednisone on the Mazzotti reaction. Ann Trop Med Parasitol, 76, 331–338.
10. Awadzi K, Orme ML’E, Breckenridge AM, Gilles HM (1982). The chemotherapy of onchocerciasis IX: The effect of prednisone plus cyproheptadine on the Mazzotti reaction. Ann Trop Med Parasitol, 76, 547–555.
11. Adjepon-Yamoah KK, Edwards G, Breckenridge AM, Orme ML’E, Ward SA (1982). The effect of renal disease on the pharmacokinetics of diethylcarbamazine in man. Br J Clin Pharmacol, 13, 829–834.
12. Edwards G, Breckenridge AM, Adjepon-Yamoah KK, Orme ML’E, Ward SA (1981). The effect of variations in urinary pH on the pharmacokinetics of diethylcarbamazine. Br J Clin Pharmacol, 12, 807–812.
Synthesis Reference(s)
The Journal of Organic Chemistry, 13, p. 144, 1948 DOI: 10.1021/jo01159a019Diethylcarbamazine
Antimicrobial activity
Useful activity is restricted to filarial worms. It is adulticidal
and microfilaricidal against Loa loa. Against Wuchereria bancrofti
and Brugia malayi it is predominantly microfilaricidal,
but slowly kills adult worms. It kills microfilariae, but not
adults, of Onchocerca volvulus.
Pharmaceutical Applications
A carbamyl derivative of piperazine formulated as the citrate.
It is readily soluble in water and slightly hygroscopic.
Mechanism of action
Although studied extensively, the mechanism of action of DEC remains unknown.
Diethylcarbamazine appears to be the active form of the drug, with a very rapid onset of action
(within minutes), but of interest is the fact that the drug is inactive in vitro, suggesting that
activation of a cellular component is essential to the filaricidal action. Three mechanisms have
been suggested. The first is involvement of blood platelets triggered by the action of filarial
excretory antigens. A complex reaction is thought to occur between the drug, the antigen, and
platelets. Although these authors were unable to show a direct action of the drug on the
microfalaria, a more recent study showed that DEC produced morphological damage to the
microfalaria. The damage consisted of the loss of the cellular sheath, exposing antigenic
determinants to immune defense mechanisms. Severe damage then occurred to microfalaria
organelles, leading to death. The second is inhibition of microtubule polymerization and
disruption of preformed microtubules. The third is interference with arachidonic acid
metabolism. Diethylcarbamazine is known to have anti-inflammatory action, which appears to
involve blockage at cyclooxygenase and leukotriene A4 synthase (leukotriene synthesis). This
action appears to alter vascular and cellular adhesiveness and cell activation. This latter action
would suggest a possible relationship between the first and third mechanism.
Pharmacokinetics
Oral absorption: >90%
Cmax 200 mg: 1.5–2 mg/L after 2 h
Plasma half-life: c. 6–12 h
Volume of distribution: 107–371 L
Plasma protein binding: Very low
Like piperazine (to which it is related), diethylcarbamazine
is rapidly and completely absorbed. About half the dose is
excreted unchanged in the urine; the rest is metabolized and
eliminated by renal and extrarenal routes.
Clinical Use
Filariasis
It has also been used for visceral larva migrans, but experience
is limited and there is little evidence of its efficacy.
Safety Profile
Poison by
intraperitoneal route. Human systemic
effects by ingestion: allergc dermatitis. An
experimental teratogen. Mutation data
reported. When heated to decomposition it
emits toxic fumes of NOx and HCl. An
additive permitted in the food and drinking
water of animals and/or for the treatment of
food-producing animals.
Synthesis
Diethylcarbamazine, N, N-diethyl-4-methyl-1-piperazincarboxamide
(38.1.13), is made by acylating 1-methylpiperazine with diethylcarbamoylchloride.
Metabolism
The metabolism of DEC leads to the compounds shown in Figure 39.18 plus trace amounts of
methylpiperazine and piperazine. Nearly all of the metabolites appear in the urine. As much as 10
to 20% of the drug is excreted unchanged. As indicated by the rapid action of the drug, it would
appear that none of the metabolites are involved in the therapeutic action of DEC.
Check Digit Verification of cas no
The CAS Registry Mumber 90-89-1 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 9 and 0 respectively; the second part has 2 digits, 8 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 90-89:
(4*9)+(3*0)+(2*8)+(1*9)=61
61 % 10 = 1
So 90-89-1 is a valid CAS Registry Number.
InChI:InChI=1/C10H21N3O/c1-4-12(5-2)10(14)13-8-6-11(3)7-9-13/h4-9H2,1-3H3
90-89-1Relevant articles and documents
Use of disulfonyl methanes for the control of parasites
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, (2008/06/13)
The present invention is directed to the use of disulfonyl methane compounds for the control of parasites in vertebrate animals.
