Sensitivity of Mycobacterium leprae to Telacebec.

The treatment of leprosy is long and complex, benefiting from the development of sterilizing, rapidly-acting drugs. Reductive evolution made Mycobacterium leprae exquisitely sensitive to Telacebec, a phase 2 drug candidate for tuberculosis. The unprecedented potency of Telacebec against M. leprae warrants further validation in clinical trials.

Telacebec: an investigational antibacterial for the treatment of tuberculosis (TB).

INTRODUCTION: Tuberculosis is an infectious disease that affected more than 50 million people and killed 6.7 million patients in the past 5 years alone. Additionally, rising incidence of treatment resistance threatens the global effort to eradicate this disease. With limited options available, additional novel antibiotics are needed for the treatment of multidrug-resistant tuberculosis (MDR-TB). Telacebec is a first-in-class antibiotic that targets the pathogen's energy metabolism. AREAS COVERED: This paper provides an overview of the recent progress in the development and testing of telacebec. We discuss published clinical data and examine the design and setup of its clinical trials. We also offer insights on the therapeutic potential of telacebec and aspects of which should be evaluated in the future. EXPERT OPINION: The first phase 2a trial showed a correlation between dosage and bacterial load in patient sputum, which should be confirmed using a direct measurement method such as colony-forming unit counting. Its clinical efficacy, favorable pharmacokinetic properties, low arrhythmogenic risk, and activity against MDR-TB strains make telacebec a suitable candidate for further development. Future clinical testing in combination with approved second-line drugs will reveal its full potential against MDR-TB. Considering recent preclinical studies, we also recommend initiating clinical trials for Buruli ulcer and leprosy.

Effect of lyophilization on the bacterial cellulose produced by different Komagataeibacter strains to adsorb epicatechin.

Bacterial cellulose (BC) has been widely used as a model system to investigate the interaction of polyphenols with the polysaccharides of cell walls. In this study, the water absorption ability and the adsorption ability of epicatechin of the never-dried and freeze-dried BC produced by a high-yield Komagataeibacter hansenii strain ATCC 53582 was compared with two normal-yield strains. The structural characteristics of BC were investigated via microscopy observation and mechanical/rheological tests. The 1-butyl-3-methylimidazolium acetate/dimethyl sulfoxide ([BMIM]Ac/DMSO) co-solvent was used to dissolve BC to calculate the degree of polymerization (DP). Results showed that compared with the other two strain, the BC synthesised by ATCC 53582 had a higher cellulose concentration (1.2 wt%) but lower epicatechin adsorption (29 µg/mg under 4 mM, pH 7). Its fibril network collapsed and led to a reduced recovery ratio (86 %) in the compression-relaxation test, which may be due to large DP (2856).

Practical Determination of the Solubility Parameters of 1-Alkyl-3-methylimidazolium Bromide ([CnC1im]Br, n = 5, 6, 7, 8) Ionic Liquids by Inverse Gas Chromatography and the Hansen Solubility Parameter.

The physicochemical properties of four 1-alkyl-3-methylimidazolium bromide ([CnC1im]Br, n = 5, 6, 7, 8) ionic liquids (ILs) were investigated in this work by using inverse gas chromatography (IGC) from 303.15 K to 343.15 K. Twenty-eight organic solvents were used to obtain the physicochemical properties between each IL and solvent via the IGC method, including the specific retention volume and the Flory⁻Huggins interaction parameter. The Hildebrand solubility parameters of the four [CnC1im]Br ILs were determined by linear extrapolation to be δ 2 ( [ C 5 C 1 im ] Br ) = 25.78 (J·cm-3)0.5, δ 2 ( [ C 6 C 1 im ] Br ) = 25.38 (J·cm-3)0.5, δ 2 ( [ C 7 C 1 im ] Br ) =24.78 (J·cm-3)0.5 and δ 2 ( [ C 8 C 1 im ] Br ) = 24.23 (J·cm-3)0.5 at room temperature (298.15 K). At the same time, the Hansen solubility parameters of the four [CnC1im]Br ILs were simulated by using the Hansen Solubility Parameter in Practice (HSPiP) at room temperature (298.15 K). The results were as follows: δ t ( [ C 5 C 1 im ] Br ) = 25.86 (J·cm-3)0.5, δ t ( [ C 6 C 1 im ] Br ) = 25.39 (J·cm-3)0.5, δ t ( [ C 7 C 1 im ] Br ) = 24.81 (J·cm-3)0.5 and δ t ( [ C 8 C 1 im ] Br ) = 24.33 (J·cm-3)0.5. These values were slightly higher than those obtained by the IGC method, but they only exhibited small errors, covering a range of 0.01 to 0.1 (J·cm-3)0.5. In addition, the miscibility between the IL and the probe was evaluated by IGC, and it exhibited a basic agreement with the HSPiP. This study confirms that the combination of the two methods can accurately calculate solubility parameters and select solvents.

A randomized, double-blind trial of amorolfine 0.25% cream and sertaconazole 2% cream in limited dermatophytosis.

BACKGROUND: Dermatophytosis is becoming increasingly unresponsive to conventional antifungals. Newer topical antifungals may be more effective in these patients. AIMS: To evaluate and compare the efficacy and safety of amorolfine 0.25% cream and sertaconazole 2% cream in limited tinea cruris/corporis. METHODS: A single-center, randomized (1:1), double-blind, parallel group, active-controlled trial (CTRI/2014/12/005246) was performed. Sixty-six untreated adults with acutely symptomatic tinea cruris/corporis were included in the study. All patients had limited cutaneous involvement and were KOH mount positive. Group A received amorolfine 0.25% cream, and group B received sertaconazole 2% cream twice daily application to the lesions for 4 weeks. After the baseline visit, four follow-up visits were carried out. The outcome measures for effectiveness were clinical and mycological cure. Safety parameters studied were treatment-emergent adverse events and changes in routine laboratory parameters. RESULTS: Both sertaconazole and amorolfine significantly reduced symptoms (P < 0.001) in both groups. However, improvement in symptoms (pruritus, burning sensation, erythema, scaling and crusting) was significantly greater in the sertaconazole group at every follow-up visit. Sertaconazole cream was also more effective than amorolfine cream in reducing the number of lesions (P = 0.002 at 12 weeks) and improving the Dermatology Life Quality Index (P < 0.001) at all the follow-up visits. Adverse events were similar in the two groups (P = 0.117). Fungal cultures became negative in 92.3% of the sertaconazole group as compared to 80% in the amorolfine group (P = 0.010). LIMITATIONS: Antifungal susceptibility testing could not be done. CONCLUSION: Sertaconazole 2% is superior to amorolfine 0.25%, both in terms of effectiveness and tolerability. Improvement can be appreciated from second week onwards.

Poly(N-vinylimidazole/ethylene glycol dimethacrylate) for the purification and isolation of phenolic acids.

In this study we report the novel polymeric resin poly(N-vinyl imidazole/ethylene glycol dimethacrylate) for the purification and isolation of phenolic acids. The monomer to crosslinker ratio and the porogen composition were optimized for isolating phenolic acids diluted in acetonitrile at normal phase chromatography conditions, first. Acetonitrile serves as polar, aprotic solvent, dissolving phenolic acids but not interrupting interactions with the stationary phase due to the approved Hansen solubility parameters. The optimized resin demonstrated high loading capacities and adsorption abilities particularly for phenolic acids in both, acetonitrile and aqueous solutions. The adsorption behavior of aqueous standards can be attributed to ion exchange effects due to electrostatic interactions between protonated imidazole residues and deprotonated phenolic acids. Furthermore, adsorption experiments and subsequent curve fittings provide information of maximum loading capacities of single standards according to the Langmuir adsorption model. Recovery studies of the optimized polymer in the normal-phase and ion-exchange mode illustrate the powerful isolation properties for phenolic acids and are comparable or even better than typical, commercially available solid phase extraction materials. In order to prove the applicability, a highly complex extract of rosemary leaves was purified by poly(N-vinyl imidazole/ethylene glycol dimethacrylate) and the isolated compounds were identified using UHPLC-qTOF-MS.

Lignin dissolution in dialkylimidazolium-based ionic liquid-water mixtures.

Lignin dissolution in dialkylimidazolium-based ionic liquid (IL)-water mixtures (40wt%-100wt% IL content) at 60°C was investigated. The IL content and type are found to considerably affect lignin solubility. For the IL-water mixtures except 1-butyl-3-methylimidazolium tetrafluoroborate ([C4C1im]BF4), the maximum lignin solubility can be achieved at 70wt% IL content. Lignin solubility in IL-water mixtures with different cations follows the order 1-butyl-3-methylimidazolium ([C4C1im](+))>1-hexyl-3-methylimidazolium ([C6C1im](+))>1-ethyl-3-methylimidazolium ([C2C1im](+))>1-octyl-3-methylimidazolium ([C8C1im](+))>1-butyl-3-ethylimidazolium ([C4C2im](+))>1-butyl-3-propylimidazolium ([C4C3im](+)). For IL mixtures with different anions, lignin solubility decreases in the following order: methanesulfonate (MeSO3(-))>acetate (MeCO2(-))>bromide (Br(-))>dibutylphosphate (DBP(-)). Evaluation using the theory of Hansen solubility parameter (HSP) is consistent with the experimental results, suggesting that HSP can aid in finding the appropriate range of IL content for IL-water mixtures. However, HSP cannot be used to evaluate the effect of IL type on lignin solubility.

Leukocytoclastic vasculitis due to thalidomide in multiple myeloma.

Thalidomide is successfully used in the treatment of multiple myeloma, leprosy and various autoimmune diseases due to its anti-angiogenic, immunomodulatory and anti-inflammatory effects. Thalidomide's most common side effects are constipation, neuropathy, fatigue, sedation, rash, tremor and peripheral edema. We achieved complete response with a 400 mg/day dose thalidomide therapy in a 58-year-old male patient diagnosed with relapsing refractory multiple myeloma. While continuing thalidomide for sustainable response, the therapy was terminated at the ninth month due to development of leukocytoclastic vasculitis. We describe the case and discuss the place of thalidomide in the treatment of multiple myeloma and the rare occurrence of leukocytoclastic vasculitis during thalidomide therapy in multiple myeloma, since only one such case has been reported in the literature thus far.

Nucleotide sequence of the rol region of the mikimopine-type root-inducing plasmid pRi1724.

The rol genes of root-inducing plasmids (pRi) are essential for tumorigenesis on various dicotyledonous plants. The nucleotide sequences of the rol genes together with their flanking regions from the mikimopine-type pRi1724 were analyzed and compared with the corresponding portions of the agropine-type pRiA4 and the mannopine-type pRi8196 that were previously reported [Slightom et al., J. Biol. Chem., 261, 108-121 (1986); Hansen et al., Proc. Natl. Acad. Sci. U.S.A., 88, 7763-7767 (1991)]. The sequenced region of 8967 bp contained seven ORFs, five on the upper strand and two on the lower one. These ORFs resembled the ORFs 8, 10 (rolA), 11 (rolB), 12 (rolC), 13, 13a, and 14 of pRiA4 and pRi8196. However, the similarity of the rolABC genes, particularly rolA, among the three plasmids, was considerably lower than that of other ORFs. The spacer regions between the ORFs were also conserved, but to a smaller extent than ORFs, among the three plasmids.

Progress in antimycotic chemotherapy 1945-1980

Before 1950 no reliable or safe therapy existed for systemic and invasive mycoses, and only traditional and empirical topical preparations were available for dermatomycoses. Two distinct eras of rapid progress in antifungal therapy followed: first, in the 1950's came the introduction of the polyenes, nystatin and pimaricin for cutaneous, vaginal and intestinal candidiasis, and amphotericin B for the treatment of severe systemic mycoses. The second phase saw the successful introduction and clinical use of 5-fluorocytosine and several imidazole derivatives some twenty years later, at a time when the vast increase in iatrogenic systemic mycoses caused by opportunistic fungi had created an urgent and pressing need for new agents in addition to those still effective.

Regulation of macromolecular synthesis in reovirus-infected L-929 cells I. Effect of L-histidinol.

The histidine analogue L-histidinol, reported by Vaughan and Hansen (1973) to establish a potent, readily reversible inhibition of eukaryotic protein synthesis in vivo, was used to investigate the regulation of macromolecular synthesis in reovirus-infected L-929 cells. The addition of L-histidinol to normal L cells led to a total inhibition of protein synthesis. The inhibition appeared to be a consequence neither of isotope dilution resulting from elevated endogenous amino acids nor of an inability of treated cells to accumulate exogenous amino acids. Addition of L-histidine to histidinol-arrested cells resulted in a complete recovery of protein synthesis. Similarly, protein synthesis in reovirus-infected L cells examined 17 h postinfection (31 C) was totally inhibited by histidinol treatment and was readily reversed by the addition of histidine. Reovirus-infected cells treated with histidinol had an essentially unaltered capacity to synthesize reovirus single-stranded RNA relative to unperturbed cultures but a diminishing ability to maintain genome RNA synthesis. Addition of L-histidine to arrested cultures led to a complete recovery of genome RNA synthesis. The L-histidinol-mediated arrest of protein synthesis was both very effective and easily reversed, suggesting the general applicability of this novel inhibitor to investigations of regulation of macromolecular synthesis in both normal and virus-infected eukaryotic cells.