56 research outputs found
Artemisia Spp. Derivatives for COVID-19 Treatment: Anecdotal Use, Political Hype, Treatment Potential, Challenges, and Road Map to Randomized Clinical Trials
The world is currently facing a novel COVID-19 pandemic caused by SARS-CoV-2 that, as of July 12, 2020, has caused a reported 12,322,395 cases and 556,335 deaths. To date, only two treatments, remdesivir and dexamethasone, have demonstrated clinical efficacy through randomized controlled trials (RCTs) in seriously ill patients. The search for new or repurposed drugs for treatment of COVID-19 continues. We have witnessed anecdotal use of herbal medicines, including Artemisia spp. extracts, in low-income countries, and exaggerated claims of their efficacies that are not evidence based, with subsequent political controversy. These events highlight the urgent need for further research on herbal compounds to evaluate efficacy through RCTs, and, when efficacious compounds are identified, to establish the active ingredients, develop formulations and dosing, and define pharmacokinetics, toxicology, and safety to enable drug development. Derivatives from the herb Artemisia annua have been used as traditional medicine over centuries for the treatment of fevers, malaria, and respiratory tract infections. We review the bioactive compounds, pharmacological and immunological effects, and traditional uses for Artemisia spp. derivatives, and discuss the challenges and controversies surrounding current efforts and the scientific road map to advance them to prevent or treat COVID-19
Optimization of Topical Therapy for Leishmania major Localized Cutaneous Leishmaniasis Using a Reliable C57BL/6 Model
When initiating the cutaneous disease named cutaneous leishmaniasis (CL), Leishmania parasites develop within the parasitophorous vacuoles of phagocytes residing in and/or recruited to the dermis, a process leading to more or less chronic dermis and epidermis-damaging inflammatory processes. Topical treatment of CL could be a mainstay in its management. Any improvements of topicals, such as new vehicles and shorter optimal contact regimes, could facilitate their use as an ambulatory treatment. Recently, WR279396, a third-generation aminoglycoside ointment, was designed with the aim to provide stability and optimal bioavailability for the molecules expected to target intracellular Leishmania. Two endpoints were expected to be reached: i) accelerated clearance of the maximal number of parasites, and ii) accelerated and stable repair processes without scars. A mouse model of CL was designed: it relies on the intradermal inoculation of luciferase-expressing Leishmania, allowing for in vivo bioluminescence imaging of the parasite load fluctuation, which can then be quantified simultaneously with the onset and resolution of clinical signs. These quantitative readout assays, deployed in real time, provide robust methods to rapidly assess efficacy of drugs/compounds i) to screen treatment modalities and ii) allow standardized comparison of different therapeutic agents
Mechanisms of intrinsic resistance and acquired susceptibility of Pseudomonas aeruginosa isolated from cystic fibrosis patients to temocillin, a revived antibiotic
The β-lactam antibiotic temocillin (6-α-methoxy-ticarcillin) shows stability to most extended spectrum β-lactamases, but is considered inactive against Pseudomonas aeruginosa. Mutations in the MexAB-OprM efflux system, naturally occurring in cystic fibrosis (CF) isolates, have been previously shown to reverse this intrinsic resistance. In the present study, we measured temocillin activity in a large collection (n = 333) of P. aeruginosa CF isolates. 29% of the isolates had MICs ≤ 16 mg/L (proposed clinical breakpoint for temocillin). Mutations were observed in mexA or mexB in isolates for which temocillin MIC was ≤512 mg/L (nucleotide insertions or deletions, premature termination, tandem repeat, nonstop, and missense mutations). A correlation was observed between temocillin MICs and efflux rate of N-phenyl-1-naphthylamine (MexAB-OprM fluorescent substrate) and extracellular exopolysaccharide abundance (contributing to a mucoid phenotype). OpdK or OpdF anion-specific porins expression decreased temocillin MIC by ~1 two-fold dilution only. Contrarily to the common assumption that temocillin is inactive on P. aeruginosa, we show here clinically-exploitable MICs on a non-negligible proportion of CF isolates, explained by a wide diversity of mutations in mexA and/or mexB. In a broader context, this work contributes to increase our understanding of MexAB-OprM functionality and help delineating how antibiotics interact with MexA and MexB
CLIMP-63 is a gentamicin-binding protein that is involved in drug-induced cytotoxicity
Aminoglycoside-induced nephrotoxicity and ototoxicity is a major clinical problem. To understand how aminoglycosides, including gentamicin, induce cytotoxicity in the kidney proximal tubule and the inner ear, we identified gentamicin-binding proteins (GBPs) from mouse kidney cells by pulling down GBPs with gentamicin–agarose conjugates and mass spectrometric analysis. Among several GBPs specific to kidney proximal tubule cells, cytoskeleton-linking membrane protein of 63 kDa (CLIMP-63) was the only protein localized in the endoplasmic reticulum, and was co-localized with gentamicin-Texas Red (GTTR) conjugate after cells were treated with GTTR for 1 h. In western blots, kidney proximal tubule cells and cochlear cells, but not kidney distal tubule cells, exhibited a dithiothreitol (DTT)-resistant dimer band of CLIMP-63. Gentamicin treatment increased the presence of DTT-resistant CLIMP-63 dimers in both kidney proximal (KPT11) and distal (KDT3) tubule cells. Transfection of wild-type and mutant CLIMP-63 into 293T cells showed that the gentamicin-dependent dimerization requires CLIMP-63 palmitoylation. CLIMP-63 siRNA transfection enhanced cellular resistance to gentamicin-induced toxicity, which involves apoptosis, in KPT11 cells. Thus, the dimerization of CLIMP-63 is likely an early step in aminoglycoside-induced cytotoxicity in the kidney and cochlea. Gentamicin also enhanced the binding between CLIMP-63 and 14-3-3 proteins, and we also identified that 14-3-3 proteins are involved in gentamicin-induced cytotoxicity, likely by binding to CLIMP-63
CLIMP-63 is a gentamicin-binding protein that is involved in drug-induced cytotoxicity
Aminoglycoside-induced nephrotoxicity and ototoxicity is a major clinical problem. To understand how aminoglycosides, including gentamicin, induce cytotoxicity in the kidney proximal tubule and the inner ear, we identified gentamicin-binding proteins (GBPs) from mouse kidney cells by pulling down GBPs with gentamicin–agarose conjugates and mass spectrometric analysis. Among several GBPs specific to kidney proximal tubule cells, cytoskeleton-linking membrane protein of 63 kDa (CLIMP-63) was the only protein localized in the endoplasmic reticulum, and was co-localized with gentamicin-Texas Red (GTTR) conjugate after cells were treated with GTTR for 1 h. In western blots, kidney proximal tubule cells and cochlear cells, but not kidney distal tubule cells, exhibited a dithiothreitol (DTT)-resistant dimer band of CLIMP-63. Gentamicin treatment increased the presence of DTT-resistant CLIMP-63 dimers in both kidney proximal (KPT11) and distal (KDT3) tubule cells. Transfection of wild-type and mutant CLIMP-63 into 293T cells showed that the gentamicin-dependent dimerization requires CLIMP-63 palmitoylation. CLIMP-63 siRNA transfection enhanced cellular resistance to gentamicin-induced toxicity, which involves apoptosis, in KPT11 cells. Thus, the dimerization of CLIMP-63 is likely an early step in aminoglycoside-induced cytotoxicity in the kidney and cochlea. Gentamicin also enhanced the binding between CLIMP-63 and 14-3-3 proteins, and we also identified that 14-3-3 proteins are involved in gentamicin-induced cytotoxicity, likely by binding to CLIMP-63
The ISoP CommSIG for Improving Medicinal Product Risk Communication: A New Special Interest Group of the International Society of Pharmacovigilance
WR279,396, a Third Generation Aminoglycoside Ointment for the Treatment of Leishmania major Cutaneous Leishmaniasis: A Phase 2, Randomized, Double Blind, Placebo Controlled Study
Cutaneous leishmaniasis is due to a small parasite (Leishmania) that creates disfiguring sores, and affects more than one million persons (mainly children) each year. Treating lesions with a cream—instead of with injections as currently done—would greatly improve the well-being of affected patients. No cream formulation that would be efficient and would not create important skin irritation has been identified yet. Here, we tested a new cream formulation (WR279,396) containing paromomycin and gentamicin, two members of a well-known family of antibacterial antibiotics (aminoglycosides). Injectable paromomycin is efficient in other forms of the disease (visceral leishmaniasis). This was a carefully monitored study (phase 2) involving mainly children in Tunisia and France. The cream was applied twice a day for 20 days. The proportion of patients treated with the paromomycin-containing cream (active formulation) that cured (94%) was higher than that observed (71%) in patients treated with a cream that did not contain the active product (placebo formulation). Local irritation affected less than one-third of the patients and was usually mild. This new cream formulation was safe and effective in treating cutaneous leishmaniasis, thereby providing a new, simple, easily applicable, and inexpensive treatment for this neglected disease
A Guide to Medications Inducing Salivary Gland Dysfunction, Xerostomia, and Subjective Sialorrhea: A Systematic Review Sponsored by the World Workshop on Oral Medicine VI
Aminoglycoside Antibiotics Induce Aggregation But Not Fusion Of Negatively-Charged Liposomes
peer reviewedThe binding of aminoglycoside antibiotics to acidic phospholipids of membranes is
an essential step in the development of both their renal and auditory toxicities,
which could be associated with critical modifications of the membrane properties.
This work examines the capacity of aminoglycosides to induce membrane aggregation
and fusion. Three techniques were used in parallel: (i) measurement of the
dequenching rate of a lipid-soluble fluorescent probe (octadecylrhodamine B)
incorporated at self-quenched concentration in membranes; (ii) measurement of the
increase in the energy transfer between two fluorescent derivatives of
phospholipids; and (iii) electron microscopy of negatively-stained replicas. The
results were compared with those obtained with spermine (an aggregating
polycation) and melittin (a fusogenic peptide). The three approaches indicate
that aminoglycosides induce liposomes aggregation, but not fusion. Aggregation is
related to the capacity of each drug studied to bind phosphatidylinositol, as
evaluated by its energy of interaction with this acidic phospholipid, and to its
toxic potential. Membrane aggregation occurring in vivo could therefore
contribute to, or be a determinant of this toxicity, which could rationally be
screened for new derivatives by the methods applied here
Aminoglycoside Antibiotics Prevent The Formation Of Non-Bilayer Structures In Negatively-Charged Membranes. Comparative Studies Using Fusogenic (Bis(Beta-Diethylaminoethylether)Hexestrol) And Aggregating (Spermine) Agents
Aminoglycoside antibiotics cause aggregation but not fusion of negatively-charged
liposomes at an extent proportional to their capacity to interact with acidic
phospholipids (Van Bambeke et al., 1995, Eur. J. Pharmacol., 289, 321-333). To
understand why aggregation is not followed by fusion, we have examined here the
influence of two aminoglycosides with markedly different toxic potential
(gentamicin > isepamicin) on lipid phase transition in negatively-charged
liposomes using 31P-NMR spectroscopy, in comparison with spermine (an aggregating
agent) and bis(beta-diethylaminoethylether)hexestrol or DEH (a fusogenic cationic
amphiphile). Gentamicin, spermine, and, to a lesser extent, isepamicin inhibit
the appearance of the isotropic signal seen upon warming of control liposomes and
denoting the presence of mobile structures. This non-bilayer signal appeared most
prominently when liposomes were incubated with DEH, a strong fusogenic agent. We
conclude that aminoglycosides, like spermine, have the potential to prevent
membrane fusion, by inhibiting the development of a critical change in membrane
organization, which is associated with fusion. We suggest that this capacity
could be a determinant in aminoglycoside toxicity
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