ABSTRACT
We present investigations about the mechanism of action of a previously reported 4-anilino-2-trichloromethylquinazoline antiplasmodial hit-compound (Hit A), which did not share a common mechanism of action with established commercial antimalarials and presented a stage-specific effect on the erythrocytic cycle of P. falciparum at 8 < t < 16 h. The target of Hit A was searched by immobilising the molecule on a solid support via a linker and performing affinity chromatography on a plasmodial lysate. Several anchoring positions of the linker (6,7 and 3') and PEG-type linkers were assessed, to obtain a linked-hit molecule displaying in vitro antiplasmodial activity similar to that of unmodified Hit A. This allowed us to identify the PfPYK-1 kinase and the PfRab6 GTP-ase as potential targets of Hit A.
Subject(s)
Antimalarials , Malaria, Falciparum , Humans , Antimalarials/chemistry , Plasmodium falciparum , Structure-Activity Relationship , Malaria, Falciparum/drug therapy , ErythrocytesABSTRACT
Accidental intoxications in children are frequent but most of them are without serious consequences. We describe herein the case of a young girl who drank 100 mg of a topical hair lotion with minoxidil. On arrival, she had no symptoms except flush on the face and ears. Four and half hours after ingestion, tachycardia appeared with a pulse above 170 beats per min with hypotension at 76/24 mmHg. The heart rate remained between 170 and 190 beats per min for 12 h and then lowered to between 140 and 160 beats per min. Thirty-six hours after ingestion, the heart beat was at 140 beats per min. Minoxidil is a strong vasodilator used first in the 1970s for severe hypertension. It produces hypotension by direct arteriolar vasodilatation. Only a few cases of minoxidil intoxication have been described in the literature, including only one pediatric case. This young boy had only tachycardia of 160 beats per min for 40 h. Most serious cases have been described in adults. They suffered long-lasting tachycardia, hypotension, and ECG changes. Most patients need a bolus of normal saline fluid and some with hemodynamic problems need vasoactive drugs such as dopamine and/or phenylephrine. All patients need to be under medical supervision for a long time because of the product's very long action.
Subject(s)
Hair Preparations/poisoning , Hypotension/chemically induced , Minoxidil/poisoning , Tachycardia/chemically induced , Vasodilator Agents/poisoning , Child, Preschool , Female , Humans , Hypotension/therapy , Minoxidil/pharmacology , Monitoring, Physiologic , Tachycardia/therapy , Treatment Outcome , Vasodilator Agents/pharmacologyABSTRACT
One of the current options for reducing the morbidity and mortality of malaria are chemoprophylaxis and chemotherapy. For this reason, the increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs poses a serious problem for control of malaria. There is an urgent need to find and develop novel compounds and to identify novel chemotherapeutic targets. Different approaches to discover new compounds are presented from examples of molecules studied in the Tropical Medicine Institute of the French Army Health Service (IMTSSA) evaluation against isolates of compounds in pharmaceutical development in collaboration with pharmaceuticals (pyronaridine, benflumetol, ferrochloroquine), screening of molecules which are still registered for other pathologies (antibiotics), screening of new synthesized compounds (artemisinin derivatives) and identification of parasitical targets and essential metabolic ways for parasite, and identification of molecules acting on these targets (reversal of resistance to chloroquine, iron chelators).
