: they can interfere with ...- oxidative status, by producing R.O.S.
-
artemisinin
/ qinghaosu(a
molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane
heterocycle) : is a compound based on qinghaosu, or sweet wormwood. 1st
isolated in 1965 by Chinese military researchers while seeking a new antimalarial
treatment for Vietnamese troops fighting American forces, it cut the death
rate by 97% in a malaria epidemic in Viet Nam in the early 1990's. It is
rapidly replacing quinine derivatives and later drugs against which the
disease has evolved into resistant strains. To protect artemisinin from
the same fate, it will be given as part of multidrug cocktails. Unicef,
the United Nations Children's Fund, which procures drugs for the world's
poorest countries, opposed its use during an Ethiopian epidemic in 2003,
saying that there was too little supply and that switching drugs in mid-outbreak
would cause confusion. Until recently, big donors like the United States
and Britain had opposed its use on a wide scale, saying it was too
expensive, had not been tested enough on children and was not needed in
areas where other malaria drugs still worked. In 2004 the new Global Fund
for AIDS, Tuberculosis and Malaria has given 11 countries grants to buy
artemisinin and has instructed 34 others to drop requests for 2 older drugs
-- chloroquine and sulfadoxine-pyrimethamine -- and switch to the new one.
The price of artemisinin cocktails has fallen from $2 per treatment to
< 90 cents as more companies in China, India and Viet Nam have begun
making them (older drugs cost only 20 cents)
- dihydroartemisin (DHA)
- dihydroartemisinin with napthoquine and trimethoprim (DNP)
- b-artemether (Artenam®; co-artemether / CGP 56697 / A-L in combination with lumefantrine (Coartem® (sold by Novartis to poor countries for 10 cents less than it costs to make), Riamet® (sold to European travelers for about $20))
- artether
- artesunate (Arenax®, Arsumax®, Falcigo®, Plasmotrim®)
- although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Saccharomyces cerevisiae has been engineered to produce high titres (up to 100 mg/l) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a 3-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current pricesref.
- RBx-11160, is a synthetic, slightly altered version of artemisinin. It only needs to be taken for around 3 days, and its simple structure means it should be at least 5 times cheaper to produce. Better solubility means the drug can be given orally or injected intravenously. Added stability means that less of the compound is broken down as it travels to the blood plasma, where the parasite lives. The new version is also more potent. When infected mice are given the drug, 95-100% of parasites disappear within four days. Conventional artemisinin drugs take a week to clear 95% of parasites. The drug entered preliminary human safety trials in Britain in July 2004. If the drug works well in people, it would probably be given in combination with a second drug, which would kill any parasites missed by RBx-11160ref.
- nitrofurans
- mitochondrial electron transport
- hydroxynaphtoquinones
- atovaquone (Mepron®) : usually administered in combination with proguanil (ATQ/PG) (Malarone®)
- heme polymerization to hemozoin
- 4-aminoquinolines
-
quinine
and its optical isomer quinidine.
- chloroquine (Aralen® in combination with primaquine; once called Resochin®) phosphate, diphosphate or sulfate.
- hydroxychloroquine (Plaquenil®)
- amodiaquine (Basoquin®, CAM-AQ1®, Camoquin®, Camoquinal®, Flavoquin®, Fluroquine®, Miaquin®, SN-10,751®; Camoprima Infatabs® in combination with primaquine)
- pyronaridine, a hydroxyanilino-benzonaphthyridine synthesized in China in 1970, which has been used for the treatment of P. vivax and P. falciparum for more than 20 years and has been shown to be effective in the treatment of falciparum malaria in children in Cameroon. It has more gastrointestinal side effects than chloroquine. There are insufficient data at present to recommend the use of pyronaridine for the treatment of malaria in non-immune travellers.
- bisquinoline
- piperaquine phosphate is an orally active bisquinoline discovered in the early 1960s and developed for clinical use in China in 1973. In vitro testing in several laboratories has shown that piperaquine approximates chloroquine’s effects against sensitive parasites and is significantly more effective than chloroquine in treating resistant P. falciparum. In China, Vietnam and Cambodia, piperaquine is now available as a fixed combination with
- dihydroartemisinin (Artekin®, Duo-Cotecxin®)
-
trimethoprim
and primaquine
-
dihydroartemisinin, trimethoprim
and primaquine (China-Vietnam 4 (CV4®),
which was followed by CV8® (the same components as CV4 but
in increased quantities)
-
dihydroartemisinin and trimethoprim
(Artecom®)P
- 8-aminoquinolines
- primaquine phosphate (Primaquine®; Aralen® in combination with chloroquine)
- compound 80/53 / bulaquin (Aablaquine® in combination with chloroquine)
- tafenoquine / WR 238605 (Etaquine®) (long-acting : half-life measured in weeks rather than hours)
- sitamaquine / WR6026ref
- NPC1161Cref
- 8-hydroxyquinolines
- iodoquinol / diiodohydroxyquin (Yodoxin®)
-
clioquinol / iodochlorhydroxyquin (nowadays
used only as Zn chelator)
- 4-quinoline-methanols
- mefloquine chlorhydrate (Falcitab®, Lariam®) was isolated at the Walter Reed Army Institute of Research in 1963 for American troops in the Vietnamese conflict. In combination with pyrimethamine-sulfadoxine in Fansimef®
- antimetabolites
- protozoal dihydropteroate synthetase
- sulfones
- dapsone / 4,4'-diaminodiphenylsulfone (Lapdap® in combination with chlorproguanil)
- sulfonamides
- protozoal DHF reductase (at concentrations far lower than those required to produce comparable inhibition of the mammalian enzymes) (antifols) work poorly against P. vivax
- 2,4-diaminopyrimidines
- pyrimethamine (Daraprim®). In combination with sulfadoxine in Fansidar®, in combination with dapsone in Maloprim®)
- aminopterin (4-aminofolate)
-
amethopterin
(4-amino-10-methylfolate) / methotrexate (MTX)
-
trimethoprim
- aryl aminoalcohols
- halofantrine (Halfan®)
- lumefantrine / benflumetol (a fluorene derivative) (co-artemether / CGP 56697 / A-L (Coartem®, Riamet®) in combination with artemether)
- proguanil / chloroguanide (Paludrine®) chlorhydrate => cycloguanil; usually administered in combination with atovaquone (Malarone®)
- chlorproguanil (Lapudrine®; Lapdap® in combination with dapsone)
- trypanothione reductase
- melarsoprol / Mel B (Arsobal®) : binding to trypanothione (a glutathione analog) results in formation of melarsen oxide-trypanothione adduct (Mel T), a compound that is a potent competitive inhibitor of trypanothione reductase, thus affecting defenses against oxidative stress.
- ornithine decarboxylase (ODC)
- suramin sodium (Germanin® / Bayer 205®) is a polysulfonated derivative of urea and has been widely used both to treat trypanosome infections and as a chemotherapeutic drug. Suramin has been shown to inhibit growth factor signaling pathways and inhibits death receptor-induced apoptosis in hepatoma and lymphoma cells in vitro and fulminant apoptotic liver damage in mice. It also inhibits the proapoptotic effect of chemotherapeutic drugsref
-
farnesyl diphosphate
synthase (FPPS) inhibitors
from Trypanosoma bruceiref
- diamidines
- pentamidine isethionate or methylate (Pentacarinate®, Pentam® or NebuPent®)
- pafuramidine maleate / DB-289 : an oral diamidoxime prodrug of DB-75ref (source : Immtech Pharmaceuticals, Inc)
- stilbamidine
- dibromo propamidine isethiaote (Brolene®)
- diminazine (Berenil®)
- cell membrane stability
- polyene macrolides
-
amphotericin
B
(AmB) deoxycholate (DAMB) (Amphocil®,
Amphocin®,
Fungilin®, Fungizone®, Intralipid®)
: parenteral administration of amphotericin B (AMB), a polyene antibiotic
with strong antifungal activity, at 0.6-1.0 mg/kg daily remains the therapy
of choice for systemic mycoses. It is highly hydrophobic and is commonly
administrated as desoxycholate amphotericin (DAMB), a detergent micelle
complex. AMB binds preferentially to ergosterol in fungal plasma membranes,
although it also interacts with animal cell sterols such as cholesterol,
which accounts for known toxicityref1,
ref2.
DAMB therapy is associated with nephrotoxicity, central nervous system
and liver damage, and side effects such as nausea and feverref1,
ref2,
ref3.
AMB, with its inherent low solubility in water and many organic solvents,
shows relatively poor bioavailabilityref1,
ref2.
In order to increase the therapeutic index of AMB and reduce its associated
toxicity, new lipid-based formulations have been developedref1,
ref2,
ref3.
These drug delivery systems, such as liposomal formulations, lipid complexes,
lipid emulsions, and colloidal dispersions, have been introduced into clinical
practice. But their use remains limited by cost, stability, and toxicityref1,
ref2,
ref3,
ref4,
ref5,
ref6.
Despite the improvement in therapeutic index for liposomal AMB formulations,
the overall prognosis for patients with severe candidemia remains poor
due to the inadequacy of treatments. The development of new, effective
antifungal delivery systems for acute and prophylactic application remains
an important objective. AMB is not significantly absorbed across the gastrointestinal
tract in either detergent-solubilized form or in liposomal preparationsref.
- amphotericin B lipid complex (ABLC) (Abelcet®). Posology : 5 mg/kg daily i.v.
- amphotericin B colloidal dispersion (ABCD) (Amphotec®)
- liposomal amphotericin B (LAMB) (AmBisome®, Fujisawa Healthcare, Inc.). Posology : 3 mg/kg daily i.v.. Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate.
- cochleates containing amphotericin B (CAMB)are a novel lipid-based delivery vehicle that have an advantage over existing formulations due to the stability of cochleates and their resistance to degradation in the gastrointestinal tract. Thus, cochleate preparations have the potential to delivery AMB orally. Cochleates are stable phospholipid-calcium precipitates comprised mainly of phosphatidylserine. They have a defined multilayered structure consisting of a continuous, solid, lipid bilayer sheet rolled up in a spiral, with no internal aqueous space. Papahadjopoulos et al. first described cochleates in 1975 as an intermediate in the preparation of large unilamellar vesiclesref. Cochleates have been used to deliver protein, peptide, and DNA for vaccine and gene therapy applications and have been used recently as a drug delivery systemref. CAMB have been shown to be highly protective in a mouse candidiasis model following parenteral administration. Because of the hydrophobic nature of AMB molecules, it was hypothesized that AMB would be localized in the unique, rigid lipid bilayers of the cochleates. This unique association should provide protection for AMB from degradation when exposed to harsh environmental conditions or enzymes. CAMB should be an ideal system to deliver amphotericin B orally. Initial biodistribution studies of CAMB administered orally in a mouse model showed that cochleates delivered therapeutic levels of AMB to target organsref
- protein synthesis
-
tetracyclines,
azithromycin
and clindamycin
also have antiplasmodial activity, although in general their action is
slow for malaria treatment (as opposed to prophylaxis); they are recommended
only in combination with other antimalarial drugs
- acridine derivatives
- quinacrine hydrochloride
- antimonial compounds
- antimony (Sb)
- stibine (SbH3)
- lead sibocaptate
- antimony trioxide (Sb2O3)
- potassium antimony tartrate / antimony potassium tartrate (tartar emetic)
- sodium antimony tartrate
- sodium stibogluconate / sodium antimony gluconate (Pentostam®) (i.v.)
- sodium antimony bis(pyrocatechol)-2,4-disulfate (C12H12Na5O23S4Sb)
- meglumine antimonate (Glucantime®)
Pharmacodynamics : intraparasitic heme of infected erythrocytes irreversible catalyzes cleavage of the endoperoxide bridge. This is followed by intramolecular rearrangement to produce carbon-centered radicals that covalently modify (alkylation) and damage haem and proteins. Further artemisins interfere with the function of the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 that generates energy in the malaria parasite.
Semi-synthetic derivatives :
Side effects : acute psychiatric syndrome (=> suicide
)
and post-malaria
neurological syndrome (PMNS).
The Pentagon is studying 21 suicides committed in Iraq and Kuwait during
Operation Iraqi Freedom (plus 5 more deaths in Iraq as possible suicides,
and six deaths among soldiers in Iraq who killed themselves after returning
to the United States). 4 of the 21 soldiers who committed suicide in Iraq
or Kuwait came from units that took Lariam and 1 tested positive for Lariam
in the bloodSide effects : QTc prolongation
|
|
|
|
|
| body as a whole | abdominal pain | 19,8 | 21.8 |
| asthenia | 13.1 | 10.8 | |
| back pain | 12 | 7.3 | |
| blood product transfusion reaction | 18.4 | 18.6 | |
| chills | 47.5 | 75.9 | |
| infection | 11.1 | 9.3 | |
| pain | 14 | 12.8 | |
| sepsis | 14 | 11.3 | |
| cardiovascular system | chest pain | 12 | 11.6 |
| hypertension | 7.9 | 16.3 | |
| hypotension | 14.3 | 21.5 | |
| tachycardia | 13.4 | 21.9 | |
| digestive system | diarrhea | 30.3 | 27.3 |
| gastrointestinal hemorrhage | 9.9 | 11.3 | |
| nausea | 39.7 | 38.7 | |
| vomiting | 31.8 | 43.9 | |
| metabolic and nutritional disorders | alkaline phosphatase increased | 22.2 | 19.2 |
| ALT (SGPT) increased | 14.6 | 14 | |
| AST (SGOT) increased | 12.8 | 12.8 | |
| bilirubinemia | 18.1 | 19.2 | |
| BUN increased | 21 | 31.1 | |
| creatinine increased |
22.4 | 42.2 | |
| edema | 14.3 | 14.8 | |
| hyperglycemia |
23 | 27.9 | |
| hypernatremia | 4.1 | 11 | |
| hypervolemia | 12.2 | 15.4 | |
| hypocalcemia | 18.4 | 20.9 | |
| hypokalemia |
42.9 | 50.6 | |
| hypomagnesemia | 20.4 | 25.6 | |
| peripheral edema | 14.6 | 17.2 | |
| nervous system | anxiety | 13.7 | 11 |
| confusion | 11.4 | 13.4 | |
| headache | 19.8 | 20.9 | |
| insomnia | 17.2 | 14.2 | |
| respiratory system | cough increased | 17.8 | 21.8 |
| dyspnea | 23 | 29.1 | |
| epistaxis | 14.9 | 20.1 | |
| hypoxia | 7.6 | 14.8 | |
| lung disorder | 17.8 | 17.4 | |
| pleural effusion | 12.5 | 9.6 | |
| rhinitis | 11.1 | 11 | |
| skin and appendages | pruritus | 10.8 | 10.2 |
| rash | 24.8 | 24.4 | |
| sweating | 7 | 10.8 | |
| urogenital system | hematuria | 14 | 14 |
- diloxanide furoate (Amoebyl®, Furamide®)
-
paromomycin
sulfate (Humatin®) (nonabsorbed aminoglycoside)
- fosmidomycin inhibits DOXP reductoisomerase (part of the 1-deoxy-D-xylulose 5-
-
emetine
- dehydroemetine (Mebadin®)
- furazolidone (Furoxone®)
- polyhexamethylene biguanide
- nitroimidazoles
- azomycin / 2-nitro-imidazole
- benznidazole (Rochagan®)
- metronidazole (1-(b-hydroxyethyl)-2-methyl-5-nitroimidazole) (Deflamon®, Flagyl®, Metrocream®, Metronidazolo®, Metrogel®, Noritate®, Protostat®, Vagilen®; Meclon 100® in combination with clotrimazole)
- nimorazole (Naxogin®)
- ornidazole (Tiberal®)
- tinidazole (Fasigyn®)
- secnidazole (Seczol-DS®)
-
Ru, Rh, and Pt complexes with azoles and Cu2+
and Au+ clotrimazole and ketoconazole
complexes are currently in development for therapy of Trypanosoma
cruzi
-
Cola acuminata
proanthocyanidins: a class of anti-trypanosomal compounds effective against
Trypanosoma
bruceiref
phosphate / 2-C-methyl-D-erythritol 4-phosphate pathway (DOXP/MEP pathway) for non-mevalonate isoprenoid biosynthesis) in Mycobacterium tuberculosis
and Plasmodium falciparum.
ref1,
ref2
: they can interfere with ...- ... cell wall
- pneumocandins / echinocandins are noncompetitive inhibitors of the synthesis of b-glucan, which is an essential constituent of the candida cell wall
- anidulafungin / LY303366 (Eraxis®). Posology : initial dose of 200 mg i.v., followed by 100 mg i.v. daily
- caspofungin acetate (Cancidas®, MK-0991®) is a semisynthetic lipopeptide derivative of pneumocandin B0 that inhibits b(1,3)-glucan synthase, preventing formation of b(1,3)-D-glucans in the fungal cell wall. Posology : 70 mg i.v. in 1 hour on the first day of treatment, followed by 50 mg daily (70 mg daily if body weight > 80 kg, concurrent administration of efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine; monitor tacrolimus if administered concurrently). No dose adjustements in renal failure, mild liver failure (in moderate liver failure = Child-Pugh score 7-9, administer 35 mg i.v. daily), and age > 65 years.
- micafungin / FK463 (Mycamine®, Funguard®). Posology : 100 mg i.v. daily
- polyene macrolides : bind to ergosterol (affinity is greater than for cholesterol) and create pores or channels.
- tetraenes
-
nystatin
(Mycostatin®, Nilstat®) active against Candida
- liposomal nystatin (Nyotran®, Aronex Ltd., EE.UU.)
- pentaenes
- pentamycin
- hexaenes
- endomycin
- heptaenes
- candicidin
-
partricin
- methylpartricin / mepartricin : a methyl ester of partricin, used chiefly in the treatment of vaginal and cutaneous candidiasis, applied topically.
- azoles inhibit sterol 14-a-demethylase, a microsomal cytochrome P450-dependent enzyme system necessary for synthesis of ergosterol from lanosterol. Accumulation of 14-a-methylsterols lead to disruption of close packing of acyl chains of phospholipids, impairing the functions of membrane-bound enzymes.
- imidazoles
- bifonazole (Azolmen®, Bifazol®, Micospor®)
- butoconazole nitrate (Femstat 3®)
- clotrimazole (Antimicotico Same®, Canesten®, Lotremin®, Lotrimin®, Mycelex®, Gynelotrimin®, Gyno-canesten®, Mycelex-G®; Meclon®, Meclon 100® in combination with metronidazole)
- econazole (Ganazolo®, Ifenec-Derm®, Ifenec-Ginec.®, Micos®, Pevaryl®, Pevaryl Gel®; Pevisone® in combination with triamcinolone)
- econazole nitrate (Chemionazolo®, Chemionazolo Topic®, Dermazol®, Ecodergin®, Ecostatin®, Eco Mi®, Econazolo Gnr®, Econazolo Merck Generics®, Econazolo Pliva®, Ecorex®, Ecosteril®, Ganazolo®, Gyno-Pevaryl®, Ifenec Derm®, Ifenec Ginec.®, Micos®, Pevaril®, Pevaryl Lipogel®, Polinazolo®, Spectazole®)
- enilconazole / imazalil (IMZ) (Clinafarm®, Imaverol®, Imazalil®)
- fenticonazole (Falvin®, Fenzol®, Lomexin®)
-
isoconazole nitrate (Icaden®,
Isogyn®, Travogen® cream, Gyno-Travogen®cream;
Travocort® in combination with diflucortolone
valerate)
-
ketoconazole (Nizoral®,
Nizoral® Scalp Fluid, Nizoral® Shampoo, Extina®,
silvadeneTriatop®). It also inhibits CYP11A1,
CYP11B2,
CYP17A1,
and CYP51A1
- miconazole (Pivanazolo®)
- miconazole nitrate (Conofite®, Daktarin®, Daktarin Gel Orale®, Femeron®, Gyno-Daktarin®, Micatin®, Miconal®, Micotef 0.2% soluzione vaginale, Micotef 2% crema cutanea®, Micotef 2% gel orale®, Micreme®, Miderm®, Monistat-Derm®, Nizacol®, Surolan®)
- oxiconazole nitrate (Oxistat®)
- sertaconazole (Ertaczo®, Sertacream®, Sertaderm®, Sertadie®, Sertagyn®)
- sulconazole nitrate (Exelderm®)
- tioconazole (Gyno-Trosyd®, Trosyd®, Trosyd Soluzione Unguele®Vagistat 1®)
- triazoles
- 'first-generation' triazoles
- fluconazole (Diflucan®, Diflucan Gel®, Elazor®). Posology : initial dose of 800 mg i.v., followed by 400 mg i.v. Antifungal prophylaxis with fluconazole reduces morbidity and mortality among recipients of allogeneic hematopoietic stem-cell transplantsref1, ref2. Fluconazole prophylaxis is also used in other patient populations with neutropenia, although fewer data support its efficacy in these patientsref. Fluconazole has an acceptable adverse-event profile but lacks efficacy against filamentous fungi, which have become increasingly frequent causes of infection in patients with neutropenia.
- itraconazole (Sporanox®, Sporonox®, Triasporin®) : dilute in water, make oral cavity washings and then swallow. It has a wider spectrum of activity than fluconazole, including activity against aspergillus species. A meta-analysis of trials involving patients with neutropenia and hematologic cancers showed that prophylaxis with itraconazole is more effective than prophylaxis with fluconazoleref. However, the clinical usefulness of itraconazole is limited by the poor tolerability of the cyclodextrin-containing oral solution and the erratic bioavailability of the oral-capsule formulation. Thus, early-generation oral azole agents have limitations related to the spectrum of antifungal activity and tolerability.
- terconazole (Terazol®)
- 'second-generation' triazoles
- posaconazole / SCH 56592 (Noxafil®) is an extended-spectrum triazole with in vitro activity against a broad spectrum of fungiref1, ref2, ref3 and clinical activity against various fungal pathogens, including aspergillus species, candida species, zygomycetes, and fusarium speciesref1, ref2, ref3. Posaconazole was similar to fluconazole for prophylaxis against fungal infections among patients with GVHD. It was superior in preventing invasive aspergillosis and reducing the rate of deaths related to fungal infections who were receiving immunosuppressive therapyref. In patients undergoing chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome, posaconazole prevented invasive fungal infections more effectively than did either fluconazole or itraconazole and improved overall survival. There were more serious adverse events possibly or probably related to treatment in the posaconazole groupref
- ravuconazole
- voriconazole / UK-109,496 (Vfend®)
- allylamines and other nonazole ergosterol biosynthesis inhibitors : fungal squalene epoxidase inhibitors
- amorolfine (Loceryl®)
- butenafine hydrochloride (Mentax®)
- naftifine hydrochloride (Exoderil®, Naftin®, Suadian®) inhibits squalene-2,3-epoxidase and so fungal biosynthesis of ergosterol
- terbinafine (Lamisil®)
- praziquantel (Azinox®, Biltricide®, Cesol®, Distocide®, Pikiton®) : a pyrazinoisoquinoline that alters membrane permeability
-
myriocin / thermozymocidin / ISP-I from Isaria
sinclarii or
Myriococcum albomyces is a serine palmitoyltransferase
inhibitor. Inhibition of ceramide synthesis leads to a rapid and specific
reduction in the rate of transport of glycosylphosphatidylinositol (GPI)-anchored
proteins to the Golgi apparatus without affecting transport of soluble
or transmembrane proteins. Inhibition of ceramide biosynthesis also quickly
blocks remodelling of GPI anchors to their ceramide-containing. See also
the derivative fingolimod
-
flavovirin
- flucytosine or 5-fluorocytosine (Ancobon®) : it crosses blood-brain barrier ==deamination (not in mammalian cells !!)==> 5-fluorouracil ==UMP pyrophosphorylase==> 5-fluorouridylic acid
- metronidazole
-
fusidic acid
inhibits eEF2
- puromicin
- polyoxorim
- sparsomicin
- cycloheximide (CHX)
- blasticidin-S
- anisomicin
-
Corynebacterium
diphtheriae
toxin
- protease 2A in Enterovirus and Rhinovirus
- protease L in Aphtovirus
- protease E in Picornaviridae
-
griseofulvin
(Fulcin®, Fulvicin P/G®, Grisactin®,
Grifulvin V®, Grisovin®, Likuden®)
inhibits microtubule formation in mitotic spindle by binding to tubulin
and MAPs. It may acts as a photosensitizer.
- mebendazole disrupts microtubules
- tunicamicin inhibits the reaction between dolichol-P and UDP-GlcNAc, preventing all O-glycosylations.
- hydroxypyridone
- ciclopiroxolamine (ciclopirox olamine) (systemic : Loprox®; topical : Dafnegin®, Penloc®; Batrafen) has a high affinity for trivalent metal cations. Ciclopirox olamine can be used to synchronize mammalian cells, but its mechanism of action is not understood well. The targets of ciclopirox olamine in S. cerevisiae appear to include multiple proteins that participate in various components of cellular metabolism, including DNA replication, DNA repair, and cellular transport. Three genes were cloned: a Fe/Cu reductase (FRE1/COS107), an oxidative stress response gene (YAP1/COS110), and a gene involved in signal transduction (YBR203W/COS111)ref.
- thiocarbamates
- haloprogin (Halotex®)
- undecylenic acid (Caldesene®, Cruex®, Desenex®, Dr Scholl's®, Egomycol®, Mycota®)
- zinc undecenoate (Tineafax®)
- benzoic acid (6%) and salicylic acid (3%) (Whitfield's ointment)
- propionic acid and caprylic acid
- natamycin (Natacyn®)
- K+I-
- miltefosine / hexadecylphosphocholine (Impavido®, Miltex®) (p.o.) inhibits CTP:PC cytidylyltransferase
- diminazene (Berenil®)
- chlordantoin : an antifungal agent effective against various fungi, including Candida albicans; used topically in the treatment of fungal infections of the vulvovaginal region and of the skin
- lufenuron, a chitin synthetase inhibitor
- Whitfield's ointment : benzoic acid 6%, salicylic acid 3%
- Castellani's paint : carbol-fuchsin topical solution
- ==> 5-fluoroUTP ==> incorporated into RNA
==> 5-fluorodeoxyuridylic acid, an inhibitor of thymidylate synthase
or
dewormers (including helminthicides / helminthagogues and nematicides)- praziquantel (Biltricide® or Distocide®) a pyrazinoisoquinoline that increases membrane permeability of calcium and has a selective effect on the tegument of trematodes
- clorsulon is a selective antagonist of fluke phosphoglycerate kinase and mutase
- b-tubulin inhibitors => inhibit microtubule formation
- benzimidazoles
- albendazole (Albenza®, Valbazen®)
- fenbendazole (Panacur®, Safeguard®)
- mebendazole (Telmin®, Vermox®)
- oxfendazole (Benzelmin®)
-
thiabendazole
(Mintezol®, Ominzole®,
Thiabendazole®) (E233)
- triclabendazole (Fascinex®) is a fasciolicide
- pro-benzimidazoles / prebenzimidazoles
- febantel (Rintel®)
-
GABA-R
agonist on nematode muscles => causes flaccid paralysis.
- piperazine citrate (Multifuge®)
- piperazine derivatives
- paralysis of pharyngeal pumping
- HC110R blockers
- cyclooctadepsipeptides
- PF1022A, the first anthelmintically active member, is a natural compound from the fungus Mycelia sterilia that belongs to the microflora of the leaves of the Camellia japonica. PF1022A contains 4 N-methyl-L-leucines, 2 D-lactic acids and 2-D-phenyllactic acids arranged as a cyclic octadepsipeptide with an alternating L-D-L-configuration
- emodepside is a semisynthetic derivative of PF1022A with a morpholine ring at each of the 2 D-phenyllactic acids in para position
- glutamate-gated chloride (GluCl) channels activators =>
- 16-membered macrocyclic lactons
- abamectin (Endecto®)
- milbemycins
- moxidectin (Cydectin®, Equest Oral Gel®, ProHeart®, ProHeart 6®, Quest®)
- milbemycin oxime (Interceptor®, Sentinel®)
- doramectin (Dectomax®)
-
AChE
inhibitors :
- metrifonate / trichlorfon (Bilarcil®) => dichlorvos / 2,2-dichlorovinyl dimethyl phosphate (DDVP)
- haloxon (Loxon®)
-
N AChR
agonists => spastic paralysis
- imidazothiazoles
-
levamisole (LMS)
/ (--)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole
(Decaris®, Levasol®, Tramisole®,
Ripercol®, Ergamisol®) is also an immunomodulator
- tetramisole / 2,3,5,6-tetrahydro-6-phenyl-imidazole[2,1-b]thiazole
- tetrahydropyrimidines
- proton ionophores
- salicylanilides
- rafoxanide
- oxyclozanide
- brotianide
- closantel
- substituted phenol
- nitroxynil
- niclosamide (Niclocide®)
- oxamniquine (Vansil®)
- isometamidium (Samorin®)
- homidium (Ethidium®, Novidium®)
- ectoparasiticides (pediculocides and miticides / acaricides)
- hexachlorophene (HCP)
-
lindane /
g
isomer of benzene hexachloride / hexachlorobenzene (HCB) / hexachlorocyclohexane
(HCH)
(Kwell®, Scabene®,
...)
- bithionol (Lorothidol®, Bitin®)
- pyrethroids are used in insecticide treated net (ITN) and in "zampirone" spirals (from the inventor's name Zampironi)
-
permethrin
(Acticin®, Ambush®, Elimite®,
Imperator/Peripel® (EC : 200-500 mg/m2), Nix®,
Pounce®), a synthetic derivative of
pyrethrins
- alphacyano pyrethroids : more reported side effects than permethrin, but far more active, can be used at lower doses and last longer than permethrin.
- alphacypermethrin (Alphacypermethrin TG®, Alphacypermethrin 95% TG®, Alphaguard 10 EC®, Alphaguard TG®, Bitin®, Fendona® (SC : 20-40 mg/m2), Prabal 100®, Renegade®) is a racemic mixture of 2 isomers (1R cis S and 1Scis R isomers) out of the 8 cypermethrin isomers. It is 2-3 times more active than cypermethrin under field conditions. It is effective on a wide range of insects in a variety of crops at dosage of 7-30g a.i./ha. Alphacypermethrin has contact and stomach action and can be used on cereals, cotton, fruits, vegetables, flower crops, oilseeds, sugar beet, tea, tobacco, vines, etc. for the control of a variety of insects.
- bifenthrin (SC) (Talstar®)
- cyfluthrin (Solfac® (EW : 30-50 mg/m2))
- deltamethrin (K-Othrine® (SC : 15-25 mg/m2), K-O Tab® (tablet : 1 per net), SPOTON® (1% S.C.))
- lambdacyhalothrin (Hallmark®, ICON® (CS : 10-20 mg/m2))
- etofenprox (Vectron® (EW : 200 mg/m2)) is completely different from the pyrethroids. Activity similar to permethrin, but far less toxic than any of the pyrethoids.
- flumethrin (Bayticol & Drastic Deadline®) 1% S.C.
- zetacypermethrin (Fury 10EW®)
- piperonyl butoxide
- bioresmethrin
- esfenvalerate (Sumi-alpha®)
- fenvalerate
- remethrin
- suspension concentrate (SC) : active ingredient is in the form of crystalline particles mixed with solvents. Because the active ingredient is in particles, it is less easily absorbed by net fibers or by the skin - this means that the insecticide is not only more readily available to kill mosquitoes, but is less toxic to people.
- capsule suspension (CS) : microencapsulated formulation. The active ingredient is encased in microscopic plastic capsules suspended in water. Capsule suspension formulation are more pleasant to handle than emulsifiable concentrates, have almost no smell and remain effective for a longer period of time - they are however usually more expensive.
- emulsifiable concentrate (EC) : insecticide is mixed with a solvent to give a clear solution that turns milky when mixed with water. Because the solvent allows the insecticide to more easily penetrate the skin they can be significantly more toxic. Many agricultural pesticides are EC. Except for permethrin, EC formulations of the others should not be used for treating nets.
- emulsion in water (EW) : the active ingredient is dissolved in a synthetic oil mixed with water so the insecticide is in fine oil phase droplets suspended in water. The synthetic oil helps the active ingredient to adhere to the net fibers. It also masks the smell and irritancy of the active ingredient.
- wettable powder (WP) : the pesticide is mixed with a carrier plus a wetting agent. Commonly used for indoor spraying (e.g. ICON), but flakes off too easily when applied to a net. Only deltamethrin is effective in WP formulations - but because the other formulations are so much better, this should only be used in an emergency.
-
malathion
- benzyl benzoate
- crotamiton / N-ethyl-o-crotonotoluidide (Eurax®)
- crotamiton (Eurax®)
- 5% sulfur in petrolatum
- thiabendazole
- soil fumigants
-
cyanide / hydrocyanic acid (HCN) / prussic acid
==mt
rhodanese / thiosulfate sulfurtransferase==> thiocyanate. Therapy
for cyanide intoxications.
-
methyl bromide (MBr) : chloropicrin
(CCl3NO2), a powerful stimulator of lacrimation,
is added to fumigants as a warning of methyl bromide exposure. Side
effects : prostate
adenocarcinoma.
- D-D (a mixture of 1,3-dichloropropene and 1,2-dichloropropane)
- 1,2-dibromo-3-chloropropane (DBCP) (ClCH2CHBrCH2Br)
- ethylene dibromide / 1,2-dibromoethane (EDB)
- phosphine (PH3)
- organo phosphorous
- phorate
- fensulphothion
- thionazin
- dichlofenthion
- disulfoton
- diazinon
- fenamiphos
- carbamates
- aldicarb
- carbofuran
- methomyl
- nydate
- diethylcarbamazine
(DEC) citrate (Filaribits®, Hetrazan®)
blocks host, and possibly parasite, enzymes involved in arachidonic acid
metabolism, and enhances the innate, nonspecific immune system.
