12 research outputs found
Chrysin directing an enhanced solubility through the formation of a supramolecular cyclodextrin–calixarene drug delivery system: a potential strategy in antifibrotic diabetes therapeutics
Calixarene 0118 (OTX008) and chrysin (CHR) are promising molecules for the treatment of fibrosis and diabetes complications but require an effective delivery system to overcome their low solubility and bioavailability. Sulfobutylated β-cyclodextrin (SBECD) was evaluated for its ability to increase the solubility of CHR by forming a ternary complex with OTX008. The resulting increase in solubility and the mechanisms of complex formation were identified through phase-solubility studies, while dynamic light-scattering assessed the molecular associations within the CHR-OTX008-SBECD system. Nuclear magnetic resonance, differential scanning calorimetry, and computational studies elucidated the interactions at the molecular level, and cellular assays confirmed the system’s biocompatibility. Combining SBECD with OTX008 enhances CHR solubility more than using SBECD alone by forming water-soluble molecular associates in a ternary complex. This aids in the solubilization and delivery of CHR and OTX008. Structural investigations revealed non-covalent interactions essential to complex formation, which showed no cytotoxicity in hyperglycemic in vitro conditions. A new ternary complex has been formulated to deliver promising antifibrotic agents for diabetic complications, featuring OTX008 as a key structural and pharmacological component
Anti-calmodulins and Tricyclic Adjuvants in Pain Therapy Block the TRPV1 Channel
Ca2+-loaded calmodulin normally inhibits multiple Ca2+-channels upon dangerous elevation of intracellular Ca2+ and protects cells from Ca2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca2+-uptake via the vanilloid inducible Ca2+-channel/inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced 45Ca2+-uptake at µM concentrations: calmidazolium (broad range)≥trifluoperazine (narrow range)>chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially). Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca2+ or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca2+-uptake in intact TRPV1+ cells, and suggests an extracellular site of inhibition. TRPV1+, inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca2+-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca2+-channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca2+-channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca2+-channels but not affecting motoneurons
Suprasellar pilocytic astrocytoma in an adult with hemorrhage and leptomeningeal dissemination: case report and review of literature
Pilocytic astrocytoma (PA) is a low-grade tumor. It has an excellent prognosis after total resection. Leptomeningeal dissemination and hemorrhage are very rare to be associated with PA and lead to unfavorable prognosis. A 35-year-old man was diagnosed with a hemorrhagic suprasellar PA in 2006. Subsequent examination in 2007 revealed another large subdural hemorrhagic lesion in the sacral region, which proved to be PA by histopathologic assessment. Other leptomeningeal foci were discovered mainly at the craniocervical junction. The patient underwent subtotal resection and received chemotherapy with disease control for 7 years. Progression of the disseminated disease has recently occurred; however, the patient is still alive with stable disease after radiotherapy. The radiological features, management, and relevant literature are also presented. Our report heightens the awareness of PA in the adult population and the importance of close surveillance for the leptomeningeal spread, especially for sellar region tumors
Oxygen-Ozone Therapy for Herniated Lumbar Disc in Patients with Subacute Partial Motor Weakness Due to Nerve Root Compression: the First 13 Cases
none8Intradiscal oxygen-ozone (O2-O3) chemonucleolysis
is a well-known effective treatment for
pain caused by protruding disc disease and
nerve root compression due to bulging or herniated
disc.
The most widely used therapeutic combination
is intradiscal injection of an O2-O3 mixture
(chemonucleolysis), followed by periradicular injection
of O2-O3, steroid and local anaesthetic to
enhance the anti-inflammatory and analgesic effect.
The treatment is designed to resolve pain and
is administered to patients without motor weakness,
whereas patients with acute paralysis caused
by nerve root compression undergo surgery 24-
48h after the onset of neurological deficit.
This paper reports on the efficacy of O2-O3
chemonucleolysis associated with anti-inflammatory
foraminal injection in 13 patients with
low back pain and cruralgia, low back pain and
sciatica and subacute partial motor weakness
caused by nerve root compression unresponsive
to medical treatment. All patients were managed
in conjunction with our colleagues in the Neurosurgery
Unit of Bellaria Hospital and the IRCCS
Institute of Neurological Sciences, Bologna.
The outcomes obtained are promising: 100%
patients had a resolution of motor weakness, while
84.6% had complete pain relief. Our results demonstrate
that O2-O3 therapy can be considered a
valid treatment option for this category of patients.noneMassimo Dall'Olio;Ciro Princiotta;Luigi Cirillo;Caterina Budai;Fabio de Santis;Stefano Bartolini;Elena Serchi;Marco LeonardiMassimo Dall'Olio;Ciro Princiotta;Luigi Cirillo;Caterina Budai;Fabio de Santis;Stefano Bartolini;Elena Serchi;Marco Leonard
Multimodal Pain Management in Veterinary Medicine: The Physiologic Basis of Pharmacologic Therapies
Suprasellar pilocytic astrocytoma in an adult with hemorrhage and leptomeningeal dissemination: case report and review of literature
Differential effects of the cannabinoid receptor agonist, WIN 55,212-2, on lamina I and lamina V spinal trigeminal nucleus caudalis neurons
Divalent Heavy Metal Cations Block the TRPV1 Ca(2+) Channel
Transient receptor potential vanilloid 1 (TRPV1)
is a non-selective cation channel involved in pain sensation
and in a wide range of non-pain-related physiological and
pathological conditions. The aim of the present study was to
explore the effects of selected heavy metal cations on the
function of TRPV1. The cations ranked in the following
sequence of pore-blocking activity: Co2+ [half-maximal inhibitory
concentration (IC50)013 μM]>Cd2+ (IC500
38 μM)>Ni2+ (IC50062 μM)>Cu2+(IC500200 μM). Zn2+
proved to be a weak (IC50027 μM) and only partial inhibitor
of the channel function, whereas Mg2+, Mn2+ and La3+
did not exhibit any substantial effect. Co2+, the most potent
channel blocker, was able not only to compete with Ca2+ but
also to pass with it through the open channel of TRPV1. In
response to heat activation or vanilloid treatment, Co2+
accumulation was verified in TRPV1-transfected cell lines
and in the TRPV1+ dorsal root ganglion neurons. The
inhibitory effect was also demonstrated in vivo. Co2+ applied
together with vanilloid agonists attenuated the nocifensive
eye wipe response in mice. Different rat TRPV1
pore point mutants (Y627W, N628W, D646N and E651W)
were created that can validate the binding site of previously
used channel blockers in agonist-evoked 45Ca2+ influx
assays in cells expressing TRPV1. The IC50 of Co2+ on
these point mutants were determined to be reasonably comparable
to those on the wild type, which suggests that
divalent cations passing through the TRPV1 channel use
the same negatively charged amino acids as Ca2+