Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore.

An antileishmanial structure−activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L. infantum and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC50 > 100 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 µM versus 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T1/2 > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model.

Stability Studies of Fludrocortisone Acetate Capsules and Fludrocortisone Acetate Titrated Powders (Powder Triturates).

Fludrocortisone acetate is a drug used to treat adrenal insufficiencies which can be prescribed to hospitalized or ambulatory pediatric patients at dosages not commercially available. For these patients, 10-µg fludrocortisone capsules are currently compounded from a pre-compounded titrated powder (powder triturate). Fludrocortisone stability studies were carried out to ensure a valid beyond-use date. First, a stability-indicating fludrocortisone acetate dosing method was validated. Then fludrocortisone acetate 10-µg capsules and 1% fludrocortisone acetate titrated powders (powder triturates) were realized. Finally, stability studies were performed. The fludrocortisone acetate titrated powders (powder triturates) were stable for one year at controlled ambient temperature and protected from light, whereas 10-µg fludrocortisone acetate capsules were stable for six months. One year after, even if the fludrocortisone content remained conformed, an increase in product degradation was noted. Our work allowed us to determine a six-month beyond-use date for fludrocortisone acetate titrated powder (powder triturate) with the three most commonly used excipients for capsule compounding. We also confirmed the sixmonth theoretical stability for capsules.

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.

8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi.

An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC50 amastigotes = 1.2 µM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (-0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.

Development and evaluation of an elective course of pharmacist's roles in disaster management in France.

PURPOSE: To describe Faculty of Pharmacy experience in the development of an elective course of pharmacist's roles in disaster management for third-year pharmacy students and to evaluate the effectiveness of this innovative teaching module in students' knowledge and their perception of the introduction of this specific course into their curriculum. METHODS: An expert team of physicians, surgeons and pharmacists of the Service de Santé des Armées, pharmacists teaching at the Faculty and pharmacists of Bataillon des Marins Pompiers de Marseille defined the program of a 30-hour module in disaster response in line with previously published recommendations, literature analysis and international guidelines on disaster response training. Students' knowledge of key competencies was assessed after each teaching session through a multiple-choice questionnaire. Assessment of self-perceived students' knowledge, teaching quality and students' degree of satisfaction was carried out using a volunteer survey just after the last teaching, the November 15th. RESULTS: The creation of the final curriculum resulted in a course of 6 modules. Concerning the students' knowledge of key competencies, a mean score of 19/25 for the multiple-choice questionnaire was obtained. 98.3% of students reported that this teaching allowed them to improve their knowledge in the field of pharmacist's roles in disaster management. 79.3% of them will recommend this optional course. CONCLUSION: This teaching represents a potential to increase the number of pharmacists prepared to respond to disasters. It also expands students' understanding of pharmacist's roles and stimulates their interest in emergency preparedness. Further formation, including emergency simulation in mass triage will be conducted next year.

Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity.

Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 µM) alongside good antileishmanial activities (IC50 = 1-2.1 µM) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 µM) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 µM). Molecule 5, presenting a low reduction potential (E° = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies.

8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases.

Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 µM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 µM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 µM), slightly lower than the one of miltefosine (IC50 = 4.3 µM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 µM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 µM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.

In Vitro Screening of the Antibacterial and Anti-Candida Properties of Crushed Nonantimicrobial Drugs Frequently Prescribed in Nursing Homes.

Frail older adults often experience swallowing disorders, prompting nursing staff to crush tablets, open capsules, and mix drugs into their meals or gelled water. However, crushing drugs can lead to pharmacological and gustatory problems. As crushed drugs can stay in prolonged contact with oral microbial biofilm, the current study aimed to investigate their antimicrobial properties. Crushed drugs were diluted in 1 mL of isotonic water and assayed in vitro for: (a) growth inhibition of five bacterial strains and Candida albicans by the diffusion method; (b) inhibition of Streptococcus salivarius and C. albicans biofilm formation; and (c) elimination of a preformed biofilm of S. salivarius and C. albicans after 5-minute contact. Eight of 29 crushed drugs inhibited bacterial and/or fungal growth on agar plates. Twenty-eight of 29 crushed drugs reduced the total biomass when incubated with S. salivarius, and 28 of 29 crushed drugs inhibited C. albicans biofilm formation. Preformed biomass was reduced by ≥25% by seven of 29 drugs. Crushed drugs may unbalance oral ecosystems and contribute to oral inflammation. [Res Gerontol Nurs. 2018; 11(2):82-90.].

Factors limiting adherence to antiepileptic treatment: A French online patient survey.

WHAT IS KNOWN AND OBJECTIVE: There are various reasons why antiepileptic treatment can fail. One is drug-resistant epilepsies, but non-adherence, or poor adherence, to treatment may make some patients' treatment ineffective. The consequences of poor adherence include treatment failure or introduction of more complex treatments involving greater toxicity with uncertain prognosis. This study contributes to a critical research area focused on antiepileptic drug adherence and aims to assess the main factors limiting adherence, as well as psychosocial factors influencing on risk of non-adherence. METHODS: An opinion survey was conducted among patients and parents of children treated for epilepsy and members of a French online support group. RESULTS AND DISCUSSION: A total of 263 questionnaires were collected. Of the patients, 79% said they never forget their medication, whereas 21% admitted occasional or frequent omissions. The main treatment-related factors that can limit adherence were adverse effects (limiting factors reported for 70% of patients) and number of tablets or number of intake per day (limiting factors reported for 32% of patients). Galenic (liquid) formulation (18%), drug taste (18%), tablet size (14%) and concern about the perception of others (17%) were cited in roughly equivalent terms as limiting adherence to treatment. Among the 55 patients who were genuinely non-adherent to their treatment, the occupational difficulties induced by following the treatment were a main cause of non-adherence. WHAT IS NEW AND CONCLUSION: Improving adherence in patients with epilepsy is a difficult and complex problem. Community pharmacists could play a major role in the determination of patients' adherence and should be aware of the risk of non-adherence.

Body image and psychological distress in women with breast cancer: a French online survey on patients' perceptions and expectations.

BACKGROUND: Altered body image caused by alopecia, loss of eyebrows or eyelashes, or mastectomy is a major source of psychological distress in women with breast cancer. OBJECTIVE: To identify and to assess patients' perceptions and expectations regarding altered body image. METHOD: Opinion survey conducted among patients treated for breast cancer and member of French online support groups. Anonymous online self-administered survey sent to women with breast cancer. RESULTS: 85% of the women interviewed experienced alopecia during treatment and 67% of them loss of eyebrows or eyelashes. About half of patients suffering alopecia and loss of eyebrows or eyelashes reported fearing what others think. Mastectomy was experienced by 84% of the women in our study, but only 32% of them reported fearing what others think. 87% of our study cohort received information about the possibility of adverse events. 70, 56, and 60% of women felt helped by information they received for the management of alopecia, loss of eyebrows or eyelashes, or mastectomy, respectively. CONCLUSION: This study confirms that altered body image is a critical psychosocial issue for women with breast cancer. Effective information can be a source of reassurance and may constitute one of the most important sources of emotional support.

Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold.

From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I - V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies. SARs first showed that thienopyrimidines and quinolines were globally more cytotoxic, while quinoxaline analogs appeared as active as- and less cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC50 = 0.4 µM, selectivity index = 100), but also highlighted an active (IC50 = 0.4 µM) and quite selective (SI = 265) synthesis intermediate.

[Pertinence of Off-label Prescriptions of Innovating and Expensive Drugs in a University Hospital]. / Pertinence des prescriptions « hors AMM/RTU ¼ des molécules onéreuses dans un hôpital universitaire.

OBJECTIVES: Pertinence of off-label prescriptions of innovative and expensive drugs needs a strict scientific appraisal to prevent adverse reaction risks and financial drift. METHODS: Pertinence of such prescriptions has been analyzed in a University Hospital by bibliometric methods. Scientific publications issued from this clinical activity have been also evaluated. RESULTS: Oncology differed from other clinical specialties by a better pertinence in justifying off-label prescriptions (good evidence level in 46% vs. 21%, scientific publications issued from A/B ranked journals: 51% versus 41%). Quality of scientific production from oncologists was also better (publication impact factor [IF] mean: 4.571 versus 2.245). CONCLUSIONS: The better pertinence of off-label prescriptions by oncologists in comparison to others clinicians' ones was mainly due to a shorter field of indications but also to a more efficient organisation such as systematic prescription by seniors, dedicated computerized provider order entry, multidisciplinary team meetings and collaborative culture.

Antileishmanial pharmacomodulation in 8-nitroquinolin-2(1H)-one series.

An antileishmanial pharmacomodulation at position 4 of 8-nitroquinolin-2(1H)-one was conducted by using the Sonogashira and Suzuki-Miyaura coupling reactions. A series of 25 derivatives was tested in vitro on the promastigote stage of Leishmania donovani along with an in vitro cytotoxicity evaluation on the human HepG2 cell line. Only the derivatives bearing a phenyl moiety at position 4 of the quinoline ring displayed interesting biologic profile, when the phenyl moiety was substituted at the para position by a Br or Cl atom, or by a CF3 group. Among them, molecules 17 and 19 were the most selective and were then tested in vitro on the intracellular amastigote stage of both L. donovani and Leishmania infantum, in parallel with complementary in vitro cytotoxicity assays on the macrophage cell lines THP-1 and J774A.1. Molecule 19 showed no activity on the amastigote stages of the parasites and some cytotoxicity on the J774A.1 cell line while molecule 17, less cytotoxic than 19, showed anti-amastigote activity in L. infantum, being 3 times less active than miltefosine but more active and selective than pentamidine. Nevertheless, hit-molecule 17 did not appear as selective as the parent compound.

Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium.

A preliminary in vitro screening of compounds belonging to various chemical families from our library revealed the thieno[3,2-d]pyrimidin-4(3H)-one scaffold displayed a promising profile against Plasmodium falciparum. Then, 120 new derivatives were synthesized and evaluated in vitro; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC50 35-344 nM) and resistant (IC50 45-800 nM) P. falciparum strains. They were neither cytotoxic (CC50 15-50 µM) toward HepG2 and CHO cells, nor mutagenic. Structure-activity relationships were defined. The lead-compound also appeared active against the Plasmodium liver stages (Plasmodium yoelii IC50 = 35 nM) and a preliminary in vivo evaluation indicated the in vitro activity was preserved (45% reduction in parasitemia compared to untreated infected mice). A mechanistic study demonstrated these molecules do not involve any of the pathways described for commercial drugs and exert a specific activity on the ring and trophozoite stages.

Looking for new antileishmanial derivatives in 8-nitroquinolin-2(1H)-one series.

From a recently identified antileishmanial pharmacophore, a structure-activity relationship study was conducted by introducing various aminated, phenoxy or thiophenoxy moieties at position 4 of the 8-nitroquinolin-2(1H)-one scaffold, using SNAr reactions. Thus a series of 47 derivatives was synthesized and evaluated in vitro on the promastigote stage of Leishmania donovani. In parallel, the cytotoxicity of the active molecules was tested on the human HepG2 cell line. The results we obtained showed that the introduction of a substituent at position 4 of the antileishmanial pharmacophore can either lead to inactive or active derivatives, depending on the nature of the substituent. Aminated moieties appear as very unfavorable toward antileishmanial activity, while phenoxy or thiophenoxy moieties were shown to maintain the in vitro antileishmanial profile, especially when the phenyl ring of these moieties was substituted at the para or ortho position by a halogen atom (except fluorine), a trifluoromethyl group or a methyl group. Most of these derivatives showed a lack of solubility in the culture media which hindered the in vitro determination of both their cytotoxicity and activity against the intracellular amastigoste stage of L. donovani.

Synthesis and in vitro evaluation of 4-trichloromethylpyrrolo[1,2-a]quinoxalines as new antiplasmodial agents.

Thanks to a preliminary in vitro screening of several CCl3-substituted-nitrogen containing heterocycles belonging to our chemical library, the 2-trichloromethylquinoxaline scaffold appeared to be of potential interest for developing new antiplasmodial agents. Then, combining these experimental results to the antimalarial properties reported for various pyrrolo[1,2-a]quinoxaline derivatives, an original series of fifteen 7-substituted-4-trichoromethylpyrrolo[1,2-a]quinoxalines was synthesized in a 4 to 5 reaction steps pathway. All molecules were evaluated in vitro toward both their antiplasmodial activity on the K1 multi-resistant Plasmodium falciparum strain and their cytotoxicity on the HepG2 human cell line. Thus, 3 hit molecules were identified, displaying IC50 values in the micromolar range and low cytotoxicity values, reaching good selectivity indexes, in comparison with the reference drugs chloroquine and doxycycline. Structure-activity relationship studies showed that the pyrrolo[1,2-a]quinoxaline scaffold can support selective antiplasmodial activity when substituted at position 4 by a CCl3 group. However, substitution at position 7 of the same scaffold is neither beneficial for cytotoxicity nor favourable for the solubility in the biological media.

[mediEVAL: a new evaluating tool for the medication-use system]. / mediEVAL : un nouvel outil d'évaluation de la prise en charge médicamenteuse.

PURPOSES: A new methodology to evaluate the medication-use system based on a risk cartography tool, has been developed. This work has been promoted by the Observatoire du médicament et des dispositifs médicaux stériles et de l'innovation thérapeutique (OMEDIT) from Provence-Alpes-Côte d'Azur (PACA)-Corse regions. METHODS: This new methodology has been developed with Excel (Microsoft(®)) and has led to the mediEVAL tool. It consists in two categories of Excel files: evaluating Excel files (1 for each job of the medication-use system) and synthesis Excel files which allow to compile a group of evaluating files for a defined area (department, hospital…). RESULTS AND CONCLUSION: mediEVAL is a new tool to evaluate quality and risk management of the entire medication-use system which has to be used by private or public hospitals of PACA and Corsica areas in their appropriate medication-use contract. Then, the OMEDIT can get data to provide an inventory of fixtures of the PACA-Corse area medication-use system situation.

Targeting the human parasite Leishmania donovani: discovery of a new promising anti-infectious pharmacophore in 3-nitroimidazo[1,2-a]pyridine series.

We report herein the discovery of antileishmanial molecules based on the imidazo[1,2-a]pyridine ring. In vitro screenings of imidazopyridines belonging to our chemical library, toward the promastigotes stage of Leishmania donovani, J774A.1 murine and HepG2 human cells, permitted to identify three selective hit-compounds (12, 20 and 28). New derivatives were then synthesized to allow structure-activity and -toxicity relationships analyses, enabling to characterize a lead-compound (44) displaying both a high potency (IC50=1.8 µM) and a good selectivity index, in comparison with three antileishmanial reference drug-compounds (amphotericin B, miltefosine and pentamidine). Moreover, lead-compound 44 also exhibits good in vitro activity against the intracellular amastigote stage of L. donovani. Thus, the 6-halo-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridine scaffold appears as a new promising selective antileishmanial pharmacophore, especially when substituted at position 8 by a bromine atom.

Efficacy and toxicity of factor Xa inhibitors.

Venous thromboembolism (VTE) is a serious disease that is often neglected, and effective and safe antithrombotic treatments are a public health priority. New antithrombotics such as rivaroxaban, apixaban, betrixaban, edoxaban, darexaban, TAK-442, LY517717, eribaxaban, otamixaban are being developed to overcome current therapeutic limitations. The new oral anticoagulants and parenteral otamixaban are under evaluation in clinical trials for VTE treatment, for VTE prevention in orthopedic surgery, for stroke prevention in patients with atrial fibrillation and for cardiovascular event prevention in patients with acute coronary syndrome. These antithrombotic agents directly and selectively inhibit factor Xa, and do not require coagulation monitoring and dose adjustment. Several of these drugs have shown promising results and have the potential to either replace or act as alternatives to traditional anticoagulants (heparins, vitamin K antagonists).

[Targeted based therapies in metastatic breast cancer: future evolution]. / Perspectives des thérapies ciblées dans le cancer du sein métastatique.

Research on molecular alteration process mechanisms leading to cancerogenesis permitted the elaboration of many targeted therapies. Some therapeutic classes appeared recently and are currently being tested, including HER-2 dimerization inhibitors. However, most of these therapies are mostly ineffective with monotherapy. Clinical trials are ongoing, testing their efficiency in association with other molecules of the therapeutic arsenal which is available in oncology. Nevertheless, breast cancer remains a pathology life-threatening, most of the time. Within this review will be introduced the most efficient of these targeted therapies, including their eventual association with other cytotoxic molecules.