1. TBA-354 was a promising antitubercular compound with activity against both replicating and static Mycobacterium tuberculosis (M.tb), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research. 2. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LCMS/MS) and mass spectrometric imaging (MSI), respectively. Healthy female Sprague-Dawley rats received intraperitoneal (i.p.) doses of TBA-354 (20 mg/kg bw). 3. The concentrationtime profiles showed a gradual absorption and tissue penetration of TBA-354 reaching the C at 6 h post dose, followed by a rapid elimination. MSI analysis showed a time-dependent drug distribution, with highest drug concentration mainly in the neocortical regions of the brain. 4. The distribution of TBA-354 provides a possible explanation for the motor dysfunction observed in clinical trials. These results prove the importance of MSI as a potential tool in preclinical evaluations of suspected neurotoxic compounds.
Bedaquiline (BDQ) was administered to healthy Sprague-Dawley rats in order to determine its localisation in the brain using mass spectrometry imaging (MSI). This study shows that BDQ has the potential for targeting TB reservoirs in the CNS.
HIV in the central nervous system (CNS) contributes to
the development
of HIV-associated neurological disorders (HAND), even with chronic
antiretroviral therapy. In order for antiretroviral therapy to be
effective in protecting the CNS, these drugs should have the ability
to localize in brain areas known to be affected by HIV. Consequently,
this study aimed to investigate the localization patterns of three
first-line antiretroviral drugs, namely, efavirenz, tenofovir, and
emtricitabine, in the rat brain. Liquid chromatography–tandem
mass spectrometry (LC–MS/MS) and matrix-assisted laser desorption
ionization mass spectrometry imaging (MALDI-MSI) were utilized to
assess the pharmacokinetics and brain spatial distribution of the
three drugs. Each drug was administered (50 mg/kg) to healthy female
Sprague–Dawley rats via intraperitoneal administration. LC–MS/MS
results showed that all three drugs could be delivered into the brain,
although they varied in blood–brain barrier permeability. MALDI-MSI
showed a high degree of efavirenz localization across the entire brain,
while tenofovir localized mainly in the cortex. Emtricitabine distributed
heterogeneously mainly in the thalamus, corpus callosum, and hypothalamus.
This study showed that efavirenz, tenofovir, and emtricitabine might
be a potential drug combination antiretroviral therapy for CNS protection
against HAND.
Rationale
The complexity of central nervous system (CNS) drug delivery is the main obstacle with the blood–brain barrier (BBB) known to restrict access of most pharmaceutical drugs into the brain. Mass spectrometry imaging (MSI) offers possibilities for studying drug deposition into the CNS.
Methods
The deposition and spatial distribution of the two antiretroviral drugs elvitegravir and tenofovir in the brain were investigated in healthy female Sprague–Dawley rats following a single intraperitoneal administration (50 mg/kg). This was achieved by the utilization of quantitative liquid chromatography/tandem mass spectrometry (LC/MS/MS) and matrix‐assisted laser desorption/ionization (MALDI) MSI.
Results
LC/MS/MS showed that elvitegravir has better BBB penetration, reaching maximum concentration in the brain (Cmaxbrain) of 976.5 ng/g. In contrast, tenofovir displayed relatively lower BBB penetration, reaching Cmaxbrain of 54.5 ng/g. MALDI‐MSI showed the heterogeneous distribution of both drugs in various brain regions including the cerebral cortex.
Conclusions
LC/MS/MS and MALDI‐MSI provided valuable information about the relative concentration and the spatial distribution of the two common antiretroviral drugs. This study has also shown the capability of MALDI‐MSI for direct visualization of pharmaceutical drugs in situ.
The recent surge in beta-lactamase resistance has created superbugs which pose a current and significant threat to public healthcare. This has created an urgent need to keep pace with the discovery of inhibitors that can inactivate these beta-lactamase producers. In this study, the in vitro and in vivo activity of 1,4,7-triazacyclononane-1,4,7 triacetic acid (NOTA)—a potential metallo-beta-lactamase inhibitor was evaluated in combination with meropenem against metallo-beta-lactamase producing bacteria. Time-kill studies showed that NOTA restored the efficacy of meropenem against all bacterial strains tested. A murine infection model was then used to study the in vivo pharmacokinetics and efficacy of this metal chelator. The co-administration of NOTA and meropenem (100 mg/kg.bw each) resulted in a significant decrease in the colony-forming units of K. pneumoniae NDM-1 over an eight-hour treatment period (> 3 log10 units). The findings suggest that chelators, such as NOTA, hold strong potential for use as a metallo-beta-lactamase inhibitor in treating carbapenem-resistant Enterobacterale infections.
Overdose
is the main cause of mortality among heroin users. Many
of these overdose-induced deaths can be prevented through the timely
administration of naloxone (NLX), a nonselective mu (μ)-, kappa
(κ)-, and delta (δ)-opioid receptor antagonist. NLX competitively
inhibits opioid-overdose-induced respiratory depression without eliciting
any narcotic effect itself. The aim of this study was to investigate
the antagonistic action of NLX by comparing its distribution to that
of 6-monacetylmorphine (6-MAM), heroin’s major metabolite,
in a rodent model using mass spectrometric imaging (MSI) in combination
with liquid chromatography–tandem mass spectrometry (LC–MS/MS). Male
Sprague–Dawley rats (n = 5) received heroin
(10 mg kg–1) intraperitoneally, NLX (10 mg kg–1) intranasally, and NLX injected intranasally 5 min
after heroin administration. The animals were sacrificed 15 min after
dose and brain tissues were harvested. The MSI image analysis showed
a region-specific distribution of 6-MAM in the brain regions including
the corpus callosum, hippocampal formation, cerebral cortex, corticospinal
tracts, caudate putamen, thalamus, globus pallidus, hypothalamus,
and basal forebrain regions of the brain. The antagonist had a similar
biodistribution throughout the brain in both groups of animals that
received NLX or NLX after heroin administration. The MSI analysis
demonstrated that the intensity of 6-MAM in these brain regions was
reduced following NLX treatment. The decrease in 6-MAM intensity was
caused by its displacement by the antagonist and its binding to these
receptors in these specific brain regions, consequently enhancing
the opioid elimination. These findings will contribute to the evaluation
of other narcotic antagonists that might be considered for use in
the treatment of drug overdose via MSI.
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