Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies

2020 ◽  
Vol 21 (7) ◽  
pp. 548-561
Author(s):  
Anna Furgała-Wojas ◽  
Magdalena Kowalska ◽  
Alicja Nowaczyk ◽  
Łukasz Fijałkowski ◽  
Kinga Sałat
Keyword(s):  
Neuropathic Pain ◽  
Molecular Docking ◽  
Active Metabolite ◽  
Late Phase ◽  
Repeated Dose ◽  
Tactile Allodynia ◽  
Strong Inhibitor ◽  
Cold Hyperalgesia ◽  
Pharmacologically Active

Background: Painful peripheral neuropathy is a dose-limiting adverse effect of the antitumor drug oxaliplatin. The main symptoms of neuropathy: tactile allodynia and cold hyperalgesia, appear in more than 80% of patients on oxaliplatin therapy and are due to the overexpression of neuronal sodium channels (Navs) and neuroinflammation. Objective: This study assessed antiallodynic and antihyperalgesic properties of two repurposed drugs with antiinflammatory and Nav-blocking properties (bromhexine and its pharmacologically active metabolite - ambroxol) in a mouse model of neuropathic pain induced by oxaliplatin. Using molecular docking techniques, we predicted targets implicated in the observed in vivo activity of bromhexine. Methods: Oxaliplatin (a single intraperitoneal dose of 10 mg/kg) induced tactile allodynia and cold hyperalgesia in CD-1 mice and the effectiveness of single-dose or repeated-dose bromhexine and ambroxol to attenuate pain hypersensitivity was assessed in von Frey and cold plate tests. Additionally, Veber analysis and molecular docking experiments of bromhexine on mouse (m) and human (h) Nav1.6-1.9 were carried out. Results: At the corresponding doses, ambroxol was more effective than bromhexine as an antiallodynic agent. However, at the dose of 150 mg/kg, ambroxol induced motor impairments in mice. Repeated-dose bromhexine and ambroxol partially attenuated the development of late-phase tactile allodynia in oxaliplatin-treated mice. Only 7-day administration of bromhexine attenuated the development of late-phase cold hyperalgesia. Bromhexine was predicted to be a strong inhibitor of mNav1.6, mNav1.7, mNav1.9, and hNav1.7-hNav1.9. Conclusion: The conversion of bromhexine to other than ambroxol active metabolites should be considered when interpreting some of its in vivo effects. Nav-blocking properties of bromhexine (and previously also predicted for ambroxol) might underlie its ability to attenuate pain caused by oxaliplatin.

scholarly journals The Microglial Activation Inhibitor Minocycline, Used Alone and in Combination with Duloxetine, Attenuates Pain Caused by Oxaliplatin in Mice

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3577
Author(s):  
Kinga Sałat ◽  
Anna Furgała-Wojas ◽  
Robert Sałat
Keyword(s):  
Neuropathic Pain ◽  
Sodium Channels ◽  
Microglial Activation ◽  
Channel Blocker ◽  
Tactile Allodynia ◽  
Sodium Channel Blocker ◽  
Cold Pain ◽  
Noradrenaline Reuptake ◽  
Cold Hyperalgesia

The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.

scholarly journals A new class of potential antidiabetic acetohydrazides: Synthesis, in vivo antidiabetic activity and molecular docking studies

2017 ◽  
Vol 12 (3) ◽  
pp. 319 ◽  
Author(s):  
Mubeen Arif ◽  
Furukh Jabeen ◽  
Aamer Saeed ◽  
Irfan Zia Qureshi ◽  
Nadia Mushtaq
Keyword(s):  
Molecular Docking ◽  
Video Clip ◽  
Docking Studies ◽  
Antidiabetic Activity ◽  
Molecular Docking Studies ◽  
H Nmr ◽  
New Class ◽  
Full Screen ◽  
Pharmacologically Active

<p class="Abstract">Two new pharmacologically active series of tetrazolopyridine-acetohydrazide conjugates [9 (a-n), 10 (a-n)] were synthesized by reacting a variety of suitably substituted benzaldehydes and isomeric 2-(5-(pyridin-3/4-yl)-2H-tetrazol-2-yl)acetohydrazides (7, 8). The synthesized compounds were analyzed through FTIR, <sup>1</sup>H NMR, <sup>13</sup>C NMR and elemental techniques. These acetohydrazides were screened for their in vivo antidiabetic activity and molecular docking studies. An excellent agreement was obtained as the best docked poses show-ed important binding features mostly based on interactions due to an oxygen atom and aromatic moieties of the series. The compounds 9a, 9c and 10l were found to be the most active in lowering blood glucose, having the potential of being good antidiabetic agents.</p><p><strong>Video Clip of Methodology</strong>:</p><p>Synthesis of 3/4-(2H-tetrazole-5-yl)pyridine: 1 min 57 sec   <a href="https://www.youtube.com/v/CHp8HxlEa2M">Full Screen</a>   <a href="https://www.youtube.com/watch?v=CHp8HxlEa2M">Alternate</a></p>

scholarly journals The Mechanism of Action of Cyclophosphamide and Its Consequences for the Development of a New Generation of Oxazaphosphorine Cytostatics

2020 ◽  
Vol 88 (4) ◽  
pp. 42
Author(s):  
Georg Voelcker
Keyword(s):  
Mechanism Of Action ◽  
Active Metabolite ◽  
Dna Alkylation ◽  
In Vivo Metabolism ◽  
Pharmacologically Active ◽  
New Generation ◽  
Anti Tumor Activity ◽  
Oxazaphosphorine Cytostatics

Although cyclophosphamide (CP) has been used successfully in the clinic for over 50 years, it has so far not been possible to elucidate the mechanism of action and to use it for improvement. This was not possible because the basis of the mechanism of action of CP, which was found by lucky coincidence, is apoptosis, the discovery of which was honored with the Nobel Prize only in 2002. Another reason was that results from cell culture experiments were used to elucidate the mechanism of action, ignoring the fact that in vivo metabolism differs from in vitro conditions. In vitro, toxic acrolein is formed during the formation of the cytotoxic metabolite phosphoreamidemustard (PAM), whereas in vivo proapoptotic hydroxypropanal (HPA) is formed. The CP metabolites formed in sequence 4-hydroxycyclophosphamide (OHCP) are the main cause of toxicity, aldophosphamide (ALDO) is the pharmacologically active metabolite and HPA amplifies the cytotoxic apoptosis initiated by DNA alkylation by PAM. It is shown that toxicity is drastically reduced but anti-tumor activity strongly increased by the formation of ALDO bypassing OHCP. Furthermore, it is shown that the anti-tumor activity against advanced solid P388 tumors that grow on CD2F1 mice is increased by orders of magnitude if DNA damage caused by a modified PAM is poorly repairable.

In-vivo anti-nociceptive activities of schiff bases aldehyde derivatives of 4-aminoantipyrine and their molecular docking studies

2021 ◽  
pp. 1-13
Author(s):  
Muhammad Bilal Afridi ◽  
Haroon Khan ◽  
Syed Wadood Ali Shah ◽  
Muhammad Zafar ◽  
Abdulraheem SA Almalki ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Schiff Bases ◽  
Drug Targets ◽  
Late Phase ◽  
Test Dose ◽  
Docking Studies ◽  
Dependent Manner ◽  
Molecular Docking Studies ◽  
Derivatives Of

In this study, the anti-nociceptive potential of Schiff bases derivatives of 4-aminoantioyrine, (Z)-4-(4-hydroxy-3-methoxybenzylideneamino)-2, 3-dimethyl-1-phenyl-1, 2dihydropyrazol-5-one 1 and (Z)-4-(2-nitrobenzylideneamino)-2, 3-dimethyl-1-phenyl-1-2-dihydropyrazol-5-one 2 were tested in various mice pain models and their binding affinities with different drug targets were evaluated through molecular docking studies. The binding scores were calculated through molecular docking techniques for receptor sensitivity. Acute toxicity test suggests the safety of both compounds up 200 mg/kg. In the righting test, compound 1 and 2 had a significant effect in a dose-dependent manner and showed 59.46% and 48.40% blockade of pain at 150 mg/kg, respectively. In the formalin test, dose-dependently compound 1 showed 52.95% and 62.02% of inhibition in the early and late phase at 150 mg/kg. Similarly, Compound 2 showed 45.74% and 55.95% inhibition in the early and late phases at 150 mg/kg, respectively. In the tail immersion test, both compounds caused significant pain inhibition during various assessment times with maximum effects at 74.94% and 66.80% for 1 and 2 respectively at 150 mg/kg after 120 min. In molecular docking studies, compounds 1 and 2 showed a greater affinity for LOX with a docking score of –6.50 and 6.57 respectively. Similarly, for compounds 1 and 2 the docking was –4.94 and –4.83 with COX-1 while –5.10 and –4.85 with COX-2, respectively. Taken together, both the compounds exhibited marked antinociceptive effects in various pain-induced models possibly mediated by inhibition of LOX and COX pathways.

Inhibition of Fibrinolysis and Fibrinogenolysis in Man: Comparison of ε-Aminocaproic Acid and Kallikrein Inhibitor

1963 ◽  
Vol 10 (01) ◽  
pp. 106-119 ◽  
Author(s):  
E Beck ◽  
R Schmutzler ◽  
F Duckert ◽  
Keyword(s):  
Aminocaproic Acid ◽  
Side Reactions ◽  
In Vitro Tests ◽  
Factor V ◽  
Clinical Use ◽  
Strong Inhibitor ◽  
Kallikrein Inhibitor ◽  
Therapeutic Possibilities

SummaryInhibitor of kallikrein and trypsin (KI) extracted from bovine parotis was compared with ε-aminocaproic acid (EACA): both substances inhibit fibrinolysis induced with streptokinase. EACA is a strong inhibitor of fibrinolysis in concentrations higher than 0, 1 mg per ml plasma. The same amount and higher concentrations are not able to inhibit completely the proteolytic-side reactions of fibrinolysis (fibrinogenolysis, diminution of factor V, rise of fibrin-polymerization-inhibitors). KI inhibits well proteolysis of plasma components in concentrations higher than 2,5 units per ml plasma. Much higher amounts of KI are needed to inhibit fibrinolysis as demonstrated by our in vivo and in vitro tests.Combination of the two substances for clinical use is suggested. Therapeutic possibilities are discussed.

Promising Anti-stroke Signature of Voglibose: Investigation through In- Silico Molecular Docking and Virtual Screening in In-Vivo Animal Studies

2020 ◽  
Vol 20 (3) ◽  
pp. 223-235
Author(s):  
Pooja Shah ◽  
Vishal Chavda ◽  
Snehal Patel ◽  
Shraddha Bhadada ◽  
Ghulam Md. Ashraf
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
In Silico ◽  
Reductase Activity ◽  
Infarct Volume ◽  
Docking Studies ◽  
Serum Glucose ◽  
In Vivo Studies ◽  
In Silico Molecular Docking

Background: Postprandial hyperglycemia considered to be a major risk factor for cerebrovascular complications. Objective: The current study was designed to elucidate the beneficial role of voglibose via in-silico in vitro to in-vivo studies in improving the postprandial glycaemic state by protection against strokeprone type 2 diabetes. Material and Methods: In-Silico molecular docking and virtual screening were carried out with the help of iGEMDOCK+ Pymol+docking software and Protein Drug Bank database (PDB). Based on the results of docking studies, in-vivo investigation was carried out for possible neuroprotective action. T2DM was induced by a single injection of streptozotocin (90mg/kg, i.v.) to neonates. Six weeks after induction, voglibose was administered at the dose of 10mg/kg p.o. for two weeks. After eight weeks, diabetic rats were subjected to middle cerebral artery occlusion, and after 72 hours of surgery, neurological deficits were determined. The blood was collected for the determination of serum glucose, CK-MB, LDH and lipid levels. Brains were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, ROS parameters, NO levels, and aldose reductase activity. Results: In-silico docking studies showed good docking binding score for stroke associated proteins, which possibly hypotheses neuroprotective action of voglibose in stroke. In the present in-vivo study, pre-treatment with voglibose showed a significant decrease (p<0.05) in serum glucose and lipid levels. Voglibose has shown significant (p<0.05) reduction in neurological score, brain infarct volume, the difference in brain hemisphere weight. On biochemical evaluation, treatment with voglibose produced significant (p<0.05) decrease in CK-MB, LDH, and NO levels in blood and reduction in Na+-K+ ATPase, oxidative stress, and aldose reductase activity in brain homogenate. Conclusion: In-silico molecular docking and virtual screening studies and in-vivo studies in MCAo induced stroke, animal model outcomes support the strong anti-stroke signature for possible neuroprotective therapeutics.

Sign in / Sign up

Export Citation Format

Share Document