Alcohol relapse is the treatment target for medications development for alcohol dependence. Aticaprant, a selective and short-acting kappa-opioid receptor (KOR) antagonist, has recently been under development for new clinical implications (depression or anhedonia). Recent studies have also found that aticaprant reduces alcohol intake and prevents stress- triggered alcohol seeking in rodents via a KOR-mediated mechanism. Here, we further investigated whether aticaprant alone or in combination with naltrexone (mu-opioid receptor [MOR] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. A long-acting and selective KOR antagonist nor-BNI was used as a reference compound for the effects of the KOR antagonism on the ADE. After 3-week intermittent-access alcohol drinking (two-bottle choice, 24-h access every other day), male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. Aticaprant alone decreased alcohol ADE in a dose- dependent manner (1-3 mg/kg) in both males and females. Aticaprant at a lower dose (0.3 mg/kg) than the effective one (3 mg/kg) combined with a low dose of naltrexone (1 mg/kg) reduced the ADE in both sexes, and the combination was effective after a multi-dosing regimen (5 daily injections during the abstinence) without development of tolerance, suggesting synergistic effects of the combination. In contrast, nor-BNI alone or with naltrexone had no effect on the ADE in either sex. Our present study suggests that a combination of clinically developed, short-acting KOR antagonist aticaprant with low-dose naltrexone has therapeutic potential in alcohol "relapse" treatment.
Objective: In the present study an effort was made to design and develop an immediate release tablet of glimepiride (as a model drug) by using the combination of two approaches i.e. conventional and innovative to enhance the dissolution rate of hydrophobic drugs. Method:In the proposed study, USP analytical method was validated for the determination of glimepiride in its formulations.The calibration curve was linear over the concentration range of 2.5-12.5 µg/ml with a regression analysis (r² = 0.9999).For getting an idea about the release of drug from its dosage form, innovator brands were picked and estimated for pharmaceutical parameters.On the basis of this information, 10 experimental batches of tablets were prepared.The optimized batch was prepared by using 2:1 ratios of tween 80 and PVP K30 by slurry technique.Pre-compression and post-compression parameters were evaluated to confirm the validity of the design and development of processes.The optimized batch was subjected to stability studies for 03 months at 40±2 °C & % RH: 75±5%. Results:The selected excipients and their proportions were found compatible with drug as well as with each other.The enhancement of dissolution indicated that the combination of Tween 80 and PVP K-30 in the slurry method made the faster release of the drug possible.The release rate of drug from optimized batch was estimated by a validated HPLC analytical method and compared with innovator results. Conclusion:It was concluded that the proposed slurry technique is a simple and easy to adopt method and could be useful for the improvement of drug release from the tablets.The results indicated that the releases of drug from formulated tablets were same as that of innovator.
SARS-coronavirus 2 is the causal agent of the COVID-19 outbreak. SARSCov-2 entry into a cell is dependent upon binding of the viral Spike (S) protein to cellular receptor and on cleavage of the spike protein by the host cell proteases such as Cathepsin L and Cathepsin B (CTSL/B). They are crucial elements of lysosomal pathway and both enzymes are almost exclusively located in the lysosomes. CTSL disruption offers potential for CoVID-19 therapies. The mechanisms of disruption include: decreasing expression of CTSL, direct inhibition of CTSL activity and modification of the CTSL environment (increase pH in the lysosome). We have conducted a high throughput drug screen gene expression analysis to identify compounds with the capacity to downregulate the expression of CTSL/CTSB. One of the most significant results shown to downregulate the expression of the CTSL gene is Amantadine(10uM). We confirmed Amantadine’s lysosmal trapping capacity in an invitro Lysosomal Trapping Assay. In addition, to downregulating CTSL, Amantadine disrupts the lysosomal pathways, hence, interferes with the capacity of the virus to replicate. It acts as a lysosomotropic agent altering the CTSL functional environment. We propose that Amantadine could decrease the viral load in SARS-CoV-2 positive patients and as such it may serve as a potent therapeutic decreasing the replication and infectivity of the virus likely leading to better clinical outcomes. Clinical studies are currently needed to examine the therapeutic efficacy of Amantadine in COVID-19 infection.
Background: The B-cell antigen CD20 is expressed on normal B-cells and almost all B-cell lymphomas. This non-modulating agent provides an excellent target for antibody-directed therapeutic regimens. IDECC2B8 (rituximab) is a monoclonal antibody (mAb) directed against the B-cell-specific antigen CD20. The monoclonal antibody mediates complement and antibody-dependent cell-mediated cytotoxicity. As its usage has surged, there have been growing concerns about rituximab-related infusion reactions. Approximately 1/4th of the patients receiving first administration show infusion reactions, and most of the time they are re-challenged safely. Since recent studies have reported the presence of serum anti-rituximab antibodies in patients who develop hypersensitivity reactions, we are evaluating the pharmacodynamic response of rituximab in patients re-challenged with it.
5,7-Dimethoxyfl avone (5,7-DMF) is a natural polymethoxyfl avone, and acts as an inhibitor of ABC efflux transporters (BCRP, MRP2 and/ or P-gp), and rosuvastatin is taken up via OATP2B1 and secreted by BCRP and MRP2. In this study, we investigated the effect of 5,7-DMF on the transport of rosuvastatin through the apical membrane and the accumulation in Caco-2 cells. Furthermore, we investigated whether the rosuvastatin accumulation is mediated by monocarboxylate transporter 1 (MCT1), in addition to OATP2B1. Coincubation with 5,7- DMF significantly increased the cellular accumulation of rosuvastatin from the apical membranes of Caco-2 cells cultured on the plastic dish. Coincubation with Ko-143 (a BCRP inhibitor) or MK-571 (an MRP inhibitor) significantly increased the rosuvastatin accumulation, whereas coincubation with verapamil (a P-gp inhibitor) did not. Coincubation with benzoic acid or pravastatin, which are substrates of both OATP2B1 and MCT1, signifi cantly decreased the rosuvastatin accumulation, whereas coincubation with estron-3-sulfate or sulfobromophthalein, which are substrates of both OATP2B1 and ABC efflux transporter, did not decrease and increased the rosuvastatin accumulation, respectively. On the other hand, the transcellular transport of rosuvastatin from basolateral to apical side (B-to-A transport) was markedly higher than that from apical to basolateral side (A-to-B transport). Coincubation with 5,7-DMF from the apical side significantly increased the A-to-B transport and the accumulation of rosuvastatin, whereas that from the basolateral side significantly decreased the B-to-A transport of rosuvastatin with increases in the accumulation. These results suggest that 5,7-DMF may increase the rosuvastatin accumulation as a result of the inhibition of rosuvastatin efflux mediated by BCRP and MRP2, and the rosuvastatin transport through the apical membrane may be mediated by not only OATB2B1 but also MCT1.
Alcohol relapse is the treatment target for medications development for alcohol dependence. Aticaprant, a selective and short-acting kappa-opioid receptor (KOR) antagonist, has recently been under development for new clinical implications (depression or anhedonia). Recent studies have also found that aticaprant reduces alcohol intake and prevents stress- triggered alcohol seeking in rodents via a KOR-mediated mechanism. Here, we further investigated whether aticaprant alone or in combination with naltrexone (mu-opioid receptor [MOR] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. A long-acting and selective KOR antagonist nor-BNI was used as a reference compound for the effects of the KOR antagonism on the ADE. After 3-week intermittent-access alcohol drinking (two-bottle choice, 24-h access every other day), male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. Aticaprant alone decreased alcohol ADE in a dose- dependent manner (1-3 mg/kg) in both males and females. Aticaprant at a lower dose (0.3 mg/kg) than the effective one (3 mg/kg) combined with a low dose of naltrexone (1 mg/kg) reduced the ADE in both sexes, and the combination was effective after a multi-dosing regimen (5 daily injections during the abstinence) without development of tolerance, suggesting synergistic effects of the combination. In contrast, nor-BNI alone or with naltrexone had no effect on the ADE in either sex. Our present study suggests that a combination of clinically developed, short-acting KOR antagonist aticaprant with low-dose naltrexone has therapeutic potential in alcohol "relapse" treatment.
Members of the adamantane family of agents in general and two such members, amantadine and memantine, in particular, have established beneficial actions across a wide range of infectious diseases including those caused by coronaviruses. Increasing evidence suggests that the protective effects of these agents is the result of actions on neurotransmitter systems namely the NMDA receptor subclass of the glutamatergic system and by the α7-nACh subclass of nicotinic cholinergic receptor. The potent NMDA receptor antagonist, memantine, prevents motor disabilities and reduces replication of the neuroinvasive/neurotropic human respiratory virus HCoV-OC43 dose-dependently. Moreover, the lysosomotrophic adamantanes amantadine and memantine also limit viral replication. Known lysomotrophic agents such as ammonium chloride inhibit cellular entry of SARS-CoV-2 on laboratory testing. Inhibiting clathrinmediated endocytosis (cellular entry) of the SARS-CoV-2/ACE2 complex by amantadine or rimantadine may block viral entry into vulnerable cellular populations, and also reduce platelet activating factor-priming of Polymorphonuclear [PMN] cells, potentially lessening PMN cell-mediated tissue damage and excess Neutrophil Extracellular Traps [NETs] seen in advanced cases of COVID-19. Rimantadine has inhibitory effects of SARS-CoV-1, a closely-related virus to SARS-CoV-2, which may indicate the need for further evaluation as a treatment for COVID-19. Amantadine increases Dopamine [DA] release and blocks its reuptake, increasing its action on DA receptors on T cells thus activating resting effector T cells and suppressing regulator T cells, which may have a beneficial immunomodulating function in infectious diseases. Proposed adverse effects of smoking on COVID-19 outcomes are attributed to the effects of nicotine via the α7-nACh receptor located on bronchial and alveolar epithelial cells. As an antagonist of this receptor, memantine has the potential to prevent the entry of SARSCoV- 2 into these cells. Independent case reports provide evidence of protective effects of amantadine and/or memantine against COVID-19. Additional epidemiologic studies however indicate a lower incidence of smoking in hospitalized patients, stimulating investigations of nicotine-related aspects, and amino acid sequence analysis indicate homologous sequences with those of neurotoxins seen in snake venoms blocking the α7-nAChR suggesting that COVID-19 may be a disease of the nicotinic cholinergic system; α7-nAChR is involved in the cholinergic anti-inflammatory pathway or reflex. COVID-19 is a biphasic disease, the initial aspect involved with the initial infection and viral replication which stimulates a prominent innate immune response. This then transitions to the adaptive immune response with suppression of infection and recovery, while the innate response is suppressed via the cholinergic anti-inflammatory pathway. Severe disease may occur when the initial innate immune response continues, the cholinergic anti-inflammatory pathway being arrested by the neurotoxin inherent in the viral amino acid sequence, causing a runaway innate immune response. Memantine, being an inhibitor of α7-nACHR, could possibly make COVID-19 worse should it be α7-nACHR inhibitor. Tilorone, a lysosomotrophic agent and α7-nACHR agonist could also have potential as a treatment for COVID-19. Further studies are necessary to determine whether repurposing of adamantanes is beneficial in COVID-19, and for further investigations of pharmacological and pathophysiological properties of SARS-CoV-2.
This article discusses the function of the SARS-Cov-2 virus E-channel and its interaction with amantadine.In this analysis it is proposed that amantadine is able to enter the E-channel of the coronavirus, inhibiting the viral content to enter the cell avoiding viral replication. Therefore, amantadine is a drug that can help decrease the symptoms of coronavirus. It is also mentioned how amantadine may be acting with the Spike protein, through a molecular docking study.
The study aim was to develop controlled-release, solid dispersion granules containing a poorly water-soluble drug, Hydrated Silicon Dioxide (HSD), and Polyvinylpyrrolidone (PVP), and to elucidate the mechanism underlyingsustained release from the soliddispersion granules.To achieve this purpose, we used the wet granulation method to prepare the first-release granules containing a poorly water-soluble drug and HSD.Then, the effect of PVP on the dissolution of the poorly water-soluble drug was estimated.Initially, the selection of a binder and contentsof drug and binder were investigated to determine the optimum formulation fora rapidly dissolving granule with HSD.Firstrelease granules containing Nifedipine (NIF) as a poorly water-soluble drug, erythritol as a binder, and HSD were developed.Differential scanning calorimetry confirmed reduced NIF crystallinity in the granules.To investigate the first-release granules' applicabilityto other drugs, six poorly water-soluble drugs (griseofulvin, indomethacin, ibuprofen, carbamazepine, progesterone, and phenytoin) were prepared.Rapid dissolutionof all tested drugs from the granule with the same NIF formulation was observed.These findings suggest that HSD is useful for improving dissolution ratesof poorly water-soluble drugs insoliddispersion granules.Next, we investigated PVP's effect on the dissolution of drug from the first-release granules.The effects of PVP on sustained release from the granules containing the seven drugs weredivided into three types: Type 1 was no effect (rapid dissolution), type 2 was a middle effect, and type 3 was a strong effect (sustained release).To elucidate the mechanism underlying sustained release from the solid dispersion granules, the intermolecular interactions between the drugs and HSD or PVP were investigated by Fourier transform infrared spectroscopy.The results suggested that the balance between the interaction of a drug and HSD and the interaction of a drug and PVP is important for sustained release of the drug.
The aim of this study was to prepare and evaluate Ibuprofen (IBU) solid dispersion tablets with improved dissolution and less sticking using Porous Calcium Silicate (PCS). Solid dispersion granules were prepared using water-based solid dispersion and water-retained PCS with the wet granulation method and a high-speed agitation granulator. We attempted to use four binders [Hydroxypropylcellulose (HPC), dextrin, maltitol, and xylitol] to prepare the granules; however, HPC could not be used. After 1h of continuous tableting using a rotary machine, sticking was estimated by a visual inspection of all tablets and photographs of the upper punches with a digital camera. All prepared tablets demonstrated quick disintegration and dissolution. From the results of DSC and PXRD studies, IBU may exist in an amorphous form in the adsorption solid dispersion and the granules. From FT-IR studies, IBU appears to interact with PCS through a salt formation between the COO-groups of IBU and the Ca2+ ions of PCS. To investigate differences in binders on the sticking problem, DSC, NIR spectra, and bulk density were measured. From these results, we speculated that the primary localization of the specific binder in the PCS pores may differ among binders, with this localization affecting the sticking property.
Author(s): Meagher, Eileen Mary; Trivedi, Mahendra Kumar; Branton, Alice; Trivedi, Dahryn; Nayak, Gopal; Mondal, Sambhu Charan; Jana, Snehasis | Abstract: The objective of the current experiment was to evaluate the potential of Consciousness Energy Healing-based test items (Vitamin D3 and DMEM) on bone parameters. Both the TI were distributed into two individual parts. One part of each samples was received Consciousness Energy Healing Treatment by Eileen Mary Meagher and those samples were labelled as the Biofield Treated (BT) samples, while the other parts of each samples were denoted as the untreated test items (UT). Cell viability data showed more than 71% viable cells signifies a safe and nontoxic profile of test items on MG-63 cell line. ALP was significantly increased by 132.18% and 126.52% in BT-DMEM+UT-TI and BT-DMEM+BT-TI, respectively at 50 µg/mL; while 139.06% (at 0.1 µg/mL) in UT-DMEM+BT-TI compared to untreated. Collagen was significantly increased by 172.76% at 1 µg/mL in UT-DMEM+BT-TI, while 89.65% in BT-DMEM+UT-TI at 10 µg/mL than untreated. Additionally, collagen was significantly increased by 111.2% in BT-DMEM+UT-TI at 50 µg/mL, while 113.16% in BT-DMEM+BT-TI at 100 µg/mL than untreated. The percent of bone mineralization was significantly increased by 206.21%, 168.74%, and 224.82% in UT-DMEM+BT-TI, BT-DMEM+UT-TI, and BT-DMEM+BT-TI, respectively at 0.1 µg/mL compared with the untreated. In addition, percent of bone mineralization data showed a significant increased by 190.63%, 181.07%, and 245.41% in UT-DMEM+BT-TI, BT-DMEM+UT-TI, and BT-DMEM+BT-TI, respectively at 1 µg/mL than untreated. Moreover, at 10 µg/mL it was significantly increased by 129.44%, 111.76%, and 109.81% in UT-DMEM+BT-TI, BT-DMEM+UT-TI, and BT-DMEM+BT-TI, respectively at 10 µg/mL with respect to untreated. Based on the study outcomes it emphasized that Biofield Energy Treatment could regulates the osteoblast function, improves bone mineralization, and calcium absorption in wide range of bone disorders along with wide range of autoimmune diseases.
Introduction: Polygonum amplexicaule (Polygonaceae) is an herbal drug used to treat fractures, rheumatism, osteoporosis, muscle injuries and pain. It has also been reported to be effective to treat atherosclerosis and its antibiotic and antivirus effects. Methods: The plant Polygonum amplexicaule including leaves, stem, and flowers were extracted by hydro distillation method for 6 hours using Clevenger apparatus. Results: Total fifty one compounds were identified constituting 96.09% of the total oil. The main compounds was Geraniol (19.91%), β-Linalool (19.63), Citronellol (16.22%), 2-Methyl-6-hepten-1-ol (7.77%), Heptan-2-ol (5.66).
Objectives: This study sought to develop controlled-release solid dispersion granules containing a poorly water-soluble drug, porous calcium silicate (PCS), and a water-soluble polymer.
Neurodegenerative disorders are the medical condition characterized by destruction in neuronal cells, abruption of neuronal activity and distinct involvement of the functional movement. The main neuronal disorders like Parkinson and Alzheimer disease are caused by environmental and genetic influences associated with accumulation of abnormal protein aggregation, which leads to inflammation as well as oxidative stress in the central nervous system. The AYUSH medication system considerably accepted by health-care professionals played a critical role since a decade to manage the elevated factors and continuously improving lifestyle for good survival of the patients. In which allopathic and ayurvedic medications have been precisely introduced for the management of disorders and regain of neuronal function. Unani and Siddha medicines have been widely used since ancient time and found as significantly reliving the sign and symptoms of neurodegenerative disorders, while yoga plays a perfect role for the management of these disorders. Regular yoga practice may relax the mind and calms the brain; reduces headache, fatigue and cures insomnia; increases blood circulation and maintain proper supply of oxygen to the lungs and detoxifies the internal organs. Thus, yoga plays a promising role in the improvement of mental health, releases stress, fatigue, depression and tension and also stimulating blood circulation in the brain. Finally it was concluded that, the AYUSH medication system ighly accepted for reliving the neuronal complications and managing all elevated parameters in patients suffering from neuronal disorders.
Hydroxypropyl β-Cyclodextrin (HPBCD) has many applications in the foods, nutraceuticals, and pharmaceuticals industries. The primary objective of this study was to evaluate the influence of the Trivedi Effect® on the physicochemical and thermal properties of HPBCD using modern analytical techniques. The HPBCD test sample was divided into two parts. One part did not receive the Biofield Energy Treatment and was called as a control sample, whereas, the other part received the Biofield Energy Treatment remotely by a renowned Biofield Energy Healer, Alice Branton and was called as a treated sample. The particle size values of the treated HPBCD were decreased by 5.32%, 1.51%, 0.36%, and 1.12% at d10, d50, d90, and D (4,3), respectively compared with the control sample. Thus, the surface area of the treated HPBCD was significantly increased by 6.67% compared with the control sample. The evaporation and melting temperature of the treated HPBCD were increased by 4.76% and 1.92%, respectively compared with the control sample. However, the latent heat of evaporation and latent heat of fusion of the treated HPBCD were significantly decreased by 7.95% and 33.85%, respectively compared to the control sample. The total weight loss in the treated HPBCD sample was decreased by 1.83% compared with the control sample. But, the residue amount was 40.55% more in the case of the treated HPBCD compared to the control sample. The Trivedi Effect®-Consciousness Energy Healing Treatment introduced a new form of HPBCD which may show better stability, solubility, dissolution rate, absorption, and bioavailability compared to the control sample. The treated would be more useful for the improvement of solubility of the lipophilic drug, stabilize volatile and unstable compounds, preparation of cholesterol free food products, weight loss supplements, and other anti-obesity medication, and also for the industry using it as a raw material.
Case description: A 4-year-old boy presented with tuberous sclerosis and symptomatic partial epilepsy of the upper right extremity. Topiramate was prescribed for the treatment of epilepsy, and seizure behavior was well controlled. However, the patient experienced a significantly increased seizure frequency immediately after the administration of clarithromycin and pranlukast treatment during topiramate treatment. Topiramate is metabolized by CYP3A4, which is inhibited by clarithromycin and pranlukast. Thus, pharmacokinetic interactions may have occurred. This is the first report of a possible drug interaction between topiramate, clarithromycin, and pranlukast.
Neurodegenerative disorders are the medical condition characterized by destruction in neuronal cells, abruption of neuronal activity and distinct involvement of the functional movement. The main neuronal disorders like Parkinson and Alzheimer disease are caused by environmental and genetic influences associated with accumulation of abnormal protein aggregation, which leads to inflammation as well as oxidative stress in the central nervous system. The AYUSH medication system considerably accepted by health-care professionals played a critical role since a decade to manage the elevated factors and continuously improving lifestyle for good survival of the patients. In which allopathic and ayurvedic medications have been precisely introduced for the management of disorders and regain of neuronal function. Unani and Siddha medicines have been widely used since ancient time and found as significantly reliving the sign and symptoms of neurodegenerative disorders, while yoga plays a perfect role for the management of these disorders. Regular yoga practice may relax the mind and calms the brain; reduces headache, fatigue and cures insomnia; increases blood circulation and maintain proper supply of oxygen to the lungs and detoxifies the internal organs. Thus, yoga plays a promising role in the improvement of mental health, releases stress, fatigue, depression and tension and also stimulating blood circulation in the brain. Finally it was concluded that, the AYUSH medication system ighly accepted for reliving the neuronal complications and managing all elevated parameters in patients suffering from neuronal disorders.
