Respective Drug Treatment Research Articles

Antiseizure Effects of Scoparone, Borneol and Their Impact on the Anticonvulsant Potency of Four Classic Antiseizure Medications in the Mouse MES Model-An Isobolographic Transformation.

Numerous botanical drugs containing coumarins and terpenes are used in ethnomedicine all over the world for their various therapeutic properties, especially those affecting the CNS system. The treatment of epilepsy is based on antiseizure medications (ASMs), although novel strategies using naturally occurring substances with confirmed antiseizure properties are being developed nowadays. The aim of this study was to determine the anticonvulsant profiles of scoparone (a simple coumarin) and borneol (a bicyclic monoterpenoid) when administered separately and in combination, as well as their impact on the antiseizure effects of four classic ASMs (carbamazepine, phenytoin, phenobarbital and valproate) in the mouse model of maximal electroshock-induced (MES) tonic-clonic seizures. MES-induced seizures were evoked in mice receiving the respective doses of the tested natural compounds and classic ASMs (when applied alone or in combinations). Interactions for two-drug and three-drug mixtures were assessed by means of isobolographic transformation of data. Polygonograms were used to illustrate the types of interactions occurring among drugs. The total brain content of ASMs was measured in mice receiving the respective drug treatments with fluorescent polarization immunoassay. Scoparone and borneol, when administered alone, exerted anticonvulsant properties in the mouse MES model. The two-drug mixtures of scoparone with valproate, borneol with phenobarbital and borneol with valproate produced synergistic interactions in the mouse MES model, while the remaining tested two-drug mixtures produced additivity. The three-drug mixtures of scoparone + borneol with valproate and phenobarbital produced synergistic interactions in the mouse MES model. Verification of total brain concentrations of valproate and phenobarbital revealed that borneol elevated the total brain concentrations of both ASMs, while scoparone did not affect the brain content of these ASMs in mice. The synergistic interaction of scoparone with valproate observed in the mouse MES model is pharmacodynamic in nature. Borneol elevated the brain concentrations of the tested ASMs, contributing to the pharmacokinetic nature of the observed synergistic interactions with valproate and phenobarbital in the mouse MES model.

Multivariate curve Resolution-Alternating least squares coupled with Raman microspectroscopy: new insights into the kinetic response of primary oral squamous carcinoma cells to cisplatin.

Raman MicroSpectroscopy (RMS) is a powerful label-free tool to probe the effects of drugs at a cellular/subcellular level. It is important, however, to be able to extract relevant biochemical and kinetic spectroscopic signatures of the specific cellular responses. In the present study, a combination of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis (PCA) is used to analyse the RMS data for the example of exposure of primary Oral Squamous Carcinoma Cells (OSCC) to the chemotherapeutic agent cisplatin. Dosing regimens were established by cytotoxicity assays, and the effects of the drug on cellular spectral profiles were monitored from 16 to 72 hours post-exposure using an apoptosis assay, to establish the relative populations of viable (V), early (EA) and late apoptotic/dead (LA/D) cells after the drug treatment. Based on a kinetic model of the progression from V > EA > D, MCR-ALS regression analysis of the RMS responses was able to extract spectral profiles associated with each stage of the cellular responses, enabling a quantitative comparison of the response rates for the respective drug treatments. Moreover, PCA was used to compare the spectral profiles of the viable cells exposed to the drug. Spectral differences were highlighted in the early stages (16 hours exposure), indicative of the initial cellular response to the drug treatment, and also in the late stages (48-72 hours exposure), representing the cell death pathway. The study demonstrates that RMS coupled with multivariate analysis can be used to quantitatively monitor the progression of cellular responses to different drugs, towards future applications for label-free, in vitro, pre-clinical screening.

Comparative evaluation of natural neuroprotectives and their combinations on chronic immobilization stress-induced depression in experimental mice.

The present study evaluates the potential of neuroprotective phytochemicals-rutin (R), resveratrol (Res), 17β-estradiol (17β-E2), and their different combinations against chronic immobilization stress (CIS)-induced depression-like behaviour in male albino mice. Here, the mice were exposed to stress via immobilization of their four limbs under a restrainer for 6h daily until 7days of the induction after 30min of respective drug treatment in different mice groups. The result found the protective effect of these phytoconstituents and their combinations against CIS-induced depression due to their ability to suppress oxidative stress, restore mitochondria, HPA-axis modulation, neurotransmitter level, stress hormones, and inflammatory markers. Also, the combination drug regimens of these phytoconstituents showed synergistic results in managing the physiological and biochemical features of depression. Thus, these neuroprotective could be utilized well in combination to manage depression-like symptoms during episodic stress. Furthermore, such results could be well justified when administered in polyherbal formulation with these neuroprotective as major components. In addition, an advanced study can be designed at the molecular and epigenetics level using a formulation based on these neuroprotective.

Combination of IRAK4 Inhibitor CA-4948 with BCL2 Inhibitor Venetoclax Induces Tumor Regression in an ABC-DLBCL Xenograft Model

IRAK4 kinase activity is required for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in a variety of myeloid and lymphoid cell types. Recruitment of IRAK4 to these receptors and its subsequent activation is facilitated by the MYD88 adaptor protein, which is mutated in ~22% of diffuse large B-cell lymphoma (DLBCL) cases. The MYD88- L265P activating mutation is found in ~30% of the activated B-cell (ABC) and ~6% of germinal center B-cell (GCB) subtypes of DLBCL and leads to constitutive activation of NF-κB signaling that is associated with worse prognosis. In Waldenstrom macroglobulinemia (WM), the MYD88- L265P activating mutation is present in >90% of cases. Thus, the development of small molecule inhibitors targeting IRAK4 is an attractive anticancer strategy for MYD88 mutation-containing cancers such as DLBCL and WM.We are developing a novel IRAK4 inhibitor, CA-4948, as a therapeutic agent for non-Hodgkin lymphoma (NHL) and hematological cancers with dysregulated TLR/MYD88/IRAK4 signaling. CA-4948 is a reversible kinase inhibitor that modulates IRAK4 function in both the toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling cascades, and demonstrates pharmacodynamic and antitumor activity in in vitro and in vivo nonclinical models. CA-4948 exhibits favorable DMPK properties, oral bioavailability, and is well tolerated in mice. Furthermore, CA-4948 was previously shown to exhibit dose-dependent efficacy in ABC-DLBCL MYD88 -L265P xenograft tumor models using cell lines OCI-LY3 and OCI-Ly10 and patient-derived tumors.Activating mutations in the B-cell receptor (BCR) signaling pathway are frequently present in various NHL subtypes, leading to activation of NF-kB signaling, and growth and survival pathways. Dysregulation of both TLR and BCR pathways suggest that targeting both pathways will be required for improved therapeutic responses in NHL. Here, we report efficacy results from combined treatment of CA-4948 and the BCL2 inhibitor venetoclax in an ABC-DLBCL xenograft tumor model.We performed an in vivo study in female SCID Beige mice implanted with the ABC-DLBCL cell line OCI-Ly10, which harbors TLR (MYD88 -L265P) and BCR (CD79A ITAM) pathway activating mutations. OCI-Ly10 tumor-bearing mice were treated with CA-4948 (50 mg/kg, qd, po), venetoclax (75 mg/kg, qd, po) or the combination for 21 continuous days. Single agent treatment of CA-4948 and venetoclax exhibited moderate tumor growth inhibition (TGI) of 63% and 71%, respectively, and the combination demonstrated tumor regression. The combination was tolerated at the end of treatment without body weight loss relative to predose weight. After the 21-day drug treatment period, the mice were given a 19-day dosing holiday. Within 5 days of the holiday rapid tumor growth occurred in the previously treated single drug-treated mice and this rapid growth continued for the remainder of the dosing holiday. In contrast, tumors from the combination drug-treated mice did not commence detectable regrowth until the 10th day of the drug holiday and proceeded with a slow growth rate for the subsequent 9 days.After the 19-day drug holiday, dosing of the respective drug treatments was reinstated to each cohort. After 7 days of re-dosing, the tumors in each cohort exhibited antitumor responses to respective drug treatments with the CA-4948 plus venetoclax combination again driving the tumors into regression. In summary, CA-4948 plus venetoclax was a well-tolerated drug combination that exhibited a much greater in vivo antitumor response as compared to the single agent treatments. These results underscore the therapeutic potential of targeted IRAK4 kinase inhibition by CA-4948 in combination with other targeted agents for the treatment of NHL. DisclosuresBooher:Curis, Inc: Employment, Equity Ownership. Dellarocca:Curis, Inc: Employment, Equity Ownership. Atoyan:Curis, Inc: Employment, Equity Ownership. Borek:Curis, Inc: Employment, Equity Ownership. Samson:Curis, Inc: Employment, Equity Ownership. Tuck:Curis, Inc: Employment, Equity Ownership.

Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders

BackgroundNonadherence to antipsychotics may cause relapse and hospitalizations in patients with psychotic disorders. The purpose was to quantify and compare the outpatient's nonadherence rates of atypical antipsychotics by objective detection in blood samples. MethodsTotally, 13,217 outpatients with therapeutic drug monitoring (TDM) data of atypical antipsychotics were included. An event of complete nonadherence was defined as an occurrence of undetectable level of a prescribed antipsychotic in the blood sample submitted for TDM. Patients with such an event(s) were defined as nonadherent of the respective drug treatment (outcome). The rates of nonadherence patients were compared between the drugs by logistic regression. ResultsIn the study population, 70.2% of the patients were prescribed doses compliant with a schizophrenia diagnosis. The mean olanzapine equivalent dose in the population was 13.4 mg (95% confidence interval (CI): 13.3, 13.6). The frequency of nonadherence patients, regardless of drug, was 3.7% (CI: 3.4–4.0). The nonadherence patient rate was lowest in clozapine-treated patients (2.2%; CI: 1.5–2.8), followed by aripiprazole (2.3%; 1.7–2.8), risperidone (2.4%; 1.6–3.0), quetiapine (2.8%; 2.3–3.2) and olanzapine (4.9%; 4.1–5.3). Users of olanzapine had significantly higher risk of complete nonadherence (Odds ratio: 1.9; CI: 1.6–2.3, p < 0.001) compared to patients treated with other antipsychotics as a group. ConclusionsIn this study, complete nonadherence of atypical antipsychotics, measured as undetectable blood level, was disclosed for ~5% of outpatients with psychotic disorders. The rate of complete nonadherence was significantly higher during olanzapine treatment compared to other atypical antipsychotics. Further studies should investigate if this reflects drug differences in tolerability or other causal relationships.

Biomechanical Effects of Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD), the Major Constituents of Cannabis, in a Sprague Dawley Rat Achilles Tendon Surgical Repair Model

Category:Sports; HindfootIntroduction/Purpose:Use of Cannabis is common amongst athletes and the U.S. population at large. Use of Cannabinoid Oil is being increasingly utilized for a number of different pathologies, injuries, and ailments due to anecdotal evidence of its efficacy. Due to the current United States Opioid crisis, Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD), the two major constituents of cannabis, are currently being evaluated as potential safer alternatives to narcotic pain medicines. The effects of recreational and/or therapeutic THC and CBD on musculoskeletal injury and healing however remain largely unknown. Our purpose was to evaluate the biomechanical effects of THC and CBD on tendon to tendon healing in a Sprague Dawley Achilles Tendon injury and surgical repair model.Methods:33 Sprague Dawley rats were randomly assigned into control (1 ml/kg/day of vehicle containing 5% Cremaphor, 5% ethanol, and 0.9% saline n=12), THC (3 mg/kg/day n = 12), or CBD (3 mg/kg/day n=9) treatment groups. Surgical transection and repair of the Achilles tendon was performed and all rats began subcutaneous administration of their respective drug treatment the day of surgery and for 4 subsequent days, followed by sacrifice. Load to failure and stiffness were calculated from load displacement data during tensile load testing on a MTS machine. One-way ANOVA with heterogeneous variance was utilized for evaluation. Means and 95% confidence intervals were also determined.Results:The CBD group demonstrated the highest mean load to failure of 17.5 N (15.1-19.8 N), with the THC group having the second highest mean load to failure at 17.3 N (15.3-19.2 N), and the control group reporting the lowest at 15.2 N (12.1-18.3 N). No statistical difference was observed between CBD/control (p = 0.25), THC/control (p = 0.29), or CBD/THC groups (p = 0.92, Figure 1A). The THC group reported the highest mean stiffness of 3.9 N/mm (2.7-5.1 N/mm). The CBD and control groups demonstrated mean stiffness values of 3.5 N/mm (2.9-4.1 N/mm) and 3.5 N (2.7-4.3 N/mm), respectively. No statistically significant differences were observed between THC/control (p = 0.51), THC/CBD (p = 0.50), or CBD/control groups (p = 0.96) for stiffness (Figure 1B).Conclusion:Our investigation demonstrates that subcutaneous administration of CBD resulted in the highest mean load to failure, while THC administration resulted in the highest mean stiffness of the three groups. This did not result however in a statistically significant difference between groups. In our small animal tendon-to-tendon repair model, use of THC or CBD did not result in decreased biomechanical characteristics, and there was a trend toward improved ultimate strength and stiffness as compared to control. Further evaluation with larger numbers of animals, and evaluating the potential synergistic effects of THC and CBD administered together are warranted.

Biomechanical Effects of Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD), the Major Constituents of Cannabis, on Tendon to Tendon Healing in a Sprague Dawley Rat Achilles Tendon Surgical Repair Model

Objectives:Use of Cannabis is common amongst athletes and the U.S. population at large. Use of Cannabinoid Oil is being increasingly utilized for a number of different pathologies, injuries, and ailments due to anecdotal evidence of its efficacy. Due to the current United States Opioid crisis, Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD), the two major constituents of cannabis, are currently being evaluated as potential safer alternatives to narcotic pain medicines. The effects of recreational and/or therapeutic THC and CBD on musculoskeletal injury and healing however remain largely unknown. Our purpose was to evaluate the biomechanical effects of THC and CBD on tendon to tendon healing in a Sprague Dawley Achilles Tendon injury and surgical repair model.Methods:33 Sprague Dawley rats were randomly assigned into control (1 ml/kg/day of vehicle containing 5% Cremaphor, 5% ethanol, and 0.9% saline n=12), THC (3 mg/kg/day n = 12), or CBD (3 mg/kg/day n=9) treatment groups. Surgical transection and repair of the Achilles tendon was performed and all rats began subcutaneous administration of their respective drug treatment the day of surgery and for 4 subsequent days, followed by sacrifice. Load to failure and stiffness were calculated from load displacement data during tensile load testing on a MTS machine. One-way ANOVA with heterogeneous variance was utilized for evaluation. Means and 95% confidence intervals were also determined.Results:The CBD group demonstrated the highest mean load to failure of 17.5 N (15.1-19.8 N), with the THC group having the second highest mean load to failure at 17.3 N (15.3-19.2 N), and the control group reporting the lowest at 15.2 N (12.1-18.3 N). No statistical difference was observed between CBD/control (p = 0.25), THC/control (p = 0.29), or CBD/THC groups (p = 0.92, Figure 1A). The THC group reported the highest mean stiffness of 3.9 N/mm (2.7-5.1 N/mm). The CBD and control groups demonstrated mean stiffness values of 3.5 N/mm (2.9-4.1 N/mm) and 3.5 N (2.7-4.3 N/mm), respectively. No statistically significant differences were observed between THC/control (p = 0.51), THC/CBD (p = 0.50), or CBD/control groups (p = 0.96) for stiffness (Figure 1B).Conclusion:Our investigation demonstrates that subcutaneous administration of CBD resulted in the highest mean load to failure while THC administration resulted in the highest mean stiffness of the three groups. This did not result however in a statistically significant difference between groups. In our small animal tendon-to-tendon repair model, use of THC or CBD did not result in decreased biomechanical characteristics, and there was a trend toward improved ultimate strength and stiffness as compared to control. Further evaluation with larger numbers of animals, and evaluating the potential synergistic effects of THC and CBD administered together are warranted.Figure 1.

Chemotherapeutic drugs negatively affect myoblast proliferation and myotube anabolism by reducing rDNA transcription

Cancer cachexia negatively affects quality of life and contributes to increased morbidity and mortality in a wide variety of cancer types. Emerging evidence suggests that, in addition to tumor derived factors, chemotherapeutic drugs may also play a role in muscle wasting. The goal of this study was to determine the cellular mechanisms underpinning skeletal muscle depletion by chemotherapy drugs. Treatment of myoblasts or myotubes with Paclitaxel (PTX) or Doxorubicin (DXR) reduced cell viability in a dose dependent manner with myoblasts displaying more susceptibility than myotubes regardless of the drug. At non‐lethal doses, PTX or DXR induced significant reductions in myoblast proliferation (47%, p&lt;0.01 and 43%, p&lt;0.05 respectively). In myoblasts, PTX and DXR caused a reduction in rDNA transcription of 24% (p&lt;0.0001) and 19% (p&lt;0.0005) relative to control and a concomitant reduction in rRNA of 16% (p&lt;0.0001) and 18% (p&lt;0.0001), respectively. In myotubes, PTX or DXR reduced rDNA transcription by 21% (p&lt;0.0001) and 30% (p&lt;0.0001) compared to control, and consequently rRNA was 20% (p&lt;0.01) and 17% (p&lt;0.05) lower after the respective drug treatments. The reduction in rRNA reduced translational capacity in myotubes as evidenced by lower global protein synthesis of 52% (p&lt;0.001) and 47% (p&lt;0.001) following exposure to PTX or DXR. These results indicate that chemotherapeutic agents may affect muscle mass by impairing the ability of myogenic cells to proliferate, and by reducing the capacity for protein synthesis in myofibers via a reduction in rDNA transcription.Support or Funding InformationSupported by NIH grant AR073385

Effects of Neuroactive Drugs in the Discharge Patterns of Microsternarchus (Hypopomidae: Gymnotiformes) Electric Organ

Considering the conserved nature of synaptic physiology among vertebrates, we tested the effects of three psychotropics (diazepam, doxapram, and nicotine) on Microsternarchus cf. bilineatus, measuring 10 parameters associated to the electric organ discharges rhythm and waveform before and after the administration of each drug and a control group. There were statistically significant differences (p < 0.005) among all the experimental groups, F (70, 22619.25) = 77.7, between the two experimental phases within their respective drug treatment, F (80, 24604.51) = 16.0, and among the six experimental hours within their respective phases and groups, F (320, 37124.15) = 4.1. We observed a common general trend of reduction in the electric organ's (EO) firing rate, regardless of the expected stimulant or depressor effect of the drugs on the central nervous system (CNS). The intensity of the response changed with the treatment. The observed changes in the fishes' behavior may be a result of the drugs' direct action on the CNS or a combination of this with systemic effects of each substance tested, also in the EO.

Antihypertensive Drugs Aliskiren, Nebivolol, and Olmesartan Reduce Hypertension by Reducing Endothelial Microparticles and Regulating Angiogenesis.

The accelerated generation of endothelial microparticles (EMPs) and impaired angiogenesis are the markers of vascular pathology during various cardiovascular and inflammatory conditions including hypertension. Because studies comparing the effects of antihypertensive agents on these 2 parameters are limited, this study was designed to compare the effects of 3 antihypertensive agents: aliskiren, nebivolol, and olmesartan, on the EMP generation and angiogenesis. Changes in the hemodynamic parameters and serum EMP count were determined after 3 weeks of the drug treatments [aliskiren (30 mg/kg), nebivolol (10 mg/kg), or olmesartan (5 mg/kg) per orally] in L-NAME-induced rat model of hypertension. The 3 drugs prevented the rise in blood pressure and EMP count to a similar extent. Furthermore, nebivolol was found to possess more potent and concentration-dependent antiangiogenic activity compared with aliskiren, whereas olmesartan was devoid of such an effect. The EMPs generated by virtue of the respective drug treatments were found to be involved in mediating the antiangiogenic effect of nebivolol and aliskiren. In addition, olmesartan treatment also resulted in the increased eNOS expression. The results of this study show that the antihypertensive drugs, viz. aliskiren, nebivolol, and olmesartan, regulate the vascular health by their differential effects on the EMP generation and angiogenesis.

Anti-Atherosclerotic Potential of Aqueous Extract of Cinnamomum Zeylanicum Bark against Glucocorticoid Induced Atherosclerosis in Wistar Rats.

Atherosclerosis is one of the major causes of disability of blood vessels which can result in development of many cardiovascular disorders. There is a strong association between atherosclerosis and insulin resistance and dyslipidemia. To study the anti-atherosclerotic potential of C. zeylanicum bark extract in insulin resistance associated atherosclerosis and worsened Atherogenic Index (AI) associated with dyslipidemia, which are the predominant complications of steroid diabetes in Wistar rats. A sum of 36 rats were categorized into five study groups and one plain control. In a 12 day study period, respective drug treatments were given every day throughout the study period whereas, dexamethasone dosage was started from day seven onwards. On day 12, fasting blood samples were collected and processed for lipid estimation and the determined values were also used to assess AI further. Animals were sacrificed under ether anaesthesia and the aorta was dissected away for its measurement and histopathological findings. One-way ANOVA was used to analyse the data and multiple comparison was done, interpreted based on Post-Hoc Scheffe test. High dose of dexamethasone (8 mg/kg/i.p) in Dexa Control (DC) group produced significant dyslipidemia, increased risk of atherogenicity (p<0.05) and caused severe thickening (78.5% compared to Plain Control (PC) of wall of aorta. Rosiglitazone (ROSI) (8 mg/kg and 16 mg/kg) and C. zelanicum (CZE) extract treatments (500 mg/kg and 250 mg/kg) significantly prevented dyslipidemia, well maintained AI compared to dexa control (p<0.05). However, both the CZE treatments protected the aorta from atherosclerosis (40.3% and 30.2% compared to DC) and significantly prevented the dyslipidemia and reduced the risk of atherogenicity compared to ROSI treatment (p<0.05). Although, the CZE did not show difference in significance in maintaining very low density lipoprotein when compared to ROSI (p>0.05). The atherosclerotic changes were completely absent in both the CZE treatments whereas, ROSI treatments did not prevented the atherosclerosis of aorta completely as they showed moderate and mild atherosclerotic changes in the aorta. The aqueous extract of C. zelanicum bark exhibited marked protection against dexamethasone induced atherosclerosis and also minimized the atherogenic risk in Wistar rats.

Evaluation of Bacopa monniera for its Synergistic Activity with Rivastigmine in Reversing Aluminum-Induced Memory Loss and Learning Deficit in Rats

The objective of this study was to evaluate the synergistic activity of Bacopa monniera with Rivastigmine against aluminum-chloride (AlCl3)-induced cognitive impairment in rats. Adult male Wistar rats were divided into ten groups (n = 10) and subjected to their assigned treatments for 42 days. On the 20th day of the respective drug treatments, all the animals were trained in the Morris water maze (retention latency) and the elevated plus maze (transfer latency). After the initial training, the retention latency (RL) and the transfer latency (TL) were evaluated on the 21st and the 42nd days of the study. Chronic administration of AlCl3 caused significant memory impairment associated with increased RL in the Morris water maze task and increased TL in the elevated plus maze test. Interestingly, animals treated with oral administration of B. monniera (100 and 200 mg/kg), Rivastigmine (5 mg/kg) or a combination of B. monniera (100 mg/kg) with Rivastigmine (5 mg/kg) showed significant protection against AlCl3-induced memory impairment compared to animal treated with AlCl3per se. Additionally, the neuroprotective effect of B. monniera (100 and 200 mg/kg) was significantly improved when supplemented with Rivastigmine (5 mg/kg). These findings suggest that treatment with a combination of B. monniera with Rivastigmine may be highly beneficial compared to their per-se treatment.

Amelioration of immobilization stress-induced biochemical and behavioral alterations and mitochondrial dysfunction by naringin in mice: possible mechanism of nitric oxide modulation

The present study was undertaken to evaluate the effects of naringin on immobilization stress-induced biochemical-behavioral changes and mitochondrial dysfunction in mice. Mice were randomized and grouped based on body weights. Respective drug treatments were given for 14 d, and on the 15th day all the animals were subjected to a 6-hour immobilization stress; then all the animals were subjected to various behavioral paradigms and were sacrificed. Various biochemical parameters and mitochondrial functions were analyzed using brain homogenate. The 6-hour acute immobilization stress significantly altered the behavioral (anxiety and memory) and biochemical parameters coupled with mitochondrial dysfunction in mice. Fourteen days pretreatment with naringin (50 and 100 mg/kg, per oral) significantly inhibited the behavioral and biochemical alterations and mitochondrial dysfunction caused by acute immobilization stress (P<0.05). Further, pretreatment with L-arginine (50 mg/kg, intraperitoneally), a nitric oxide precursor, reversed the protective effect of naringin (P<0.05). In addition, pretreatment with NG-nitro-L-arginine methyl ester (5 mg/kg, intraperitoneally) caused potentiation in the protective effect of naringin. These results suggest the possible involvement of nitrergic pathway in the protective effect of naringin against immobilization stress-induced behavioral, biochemical and mitochondrial dysfunctions in mice.

Characterization of ethylcellulose: starch-based film coatings for colon targeting

Background: The site-specific delivery of drugs to the colon can be highly advantageous for various applications, including the local treatment of inflammatory bowel diseases. The aim of this study was to provide efficient tools that can be used to easily adjust the key properties of novel polymeric film coatings allowing for colon targeting. Methods: Free films based on blends of ethylcellulose and different types of starch derivatives (partially being pregelatinized, acetylated, and/or hydroxypropylated) were prepared and characterized. Results: The key properties of the polymeric systems can effectively be adjusted by varying the polymer blend ratio and type of starch derivative. This includes the water uptake and dry mass loss kinetics as well as the mechanical properties of the films before and upon exposure to aqueous media simulating the contents of the upper GIT. Conclusion: Broad ranges of film coating properties can easily be provided, being adapted to the needs of the respective drug treatment.

Effect of Moringa oleifera Lam. Seed Extract on Toluene Diisocyanate-Induced Immune-Mediated Inflammatory Responses in Rats

Moringa oleifera Lam. is a small tree cultivated throughout India. We have investigated the effect of ethanolic extract of seeds of Moringa oleifera (MOEE, an herbal remedy) on the potential prevention of immune-mediated inflammatory responses in toluene diisocyanate (TDI as antigen)-induced asthma in Wistar rats. Rats were divided into five different groups (n = 8/group): Group-I = unsensitized control; Group-II = TDI control/vehicle; Group-III = dexamethasone (DXM) 2.5 mg/kg; and, Groups IV and V = 100 mg/kg and 200 mg/kg body weight [BW] of MOEE, respectively. All rats (except unsensitized controls) were sensitized by intranasal application of 10% TDI to induce airway hypersensitivity. Animals in Groups II–V were given their respective drug treatment per os from 1 wk prior to initiation of sensitization until the day of final provocation with 5% TDI. After this last challenge, all rats were examined for hyperreactivity symptoms and then sacrificed to determine their total and differential leucocytes in blood and bronchoalveolar (BAL) fluid and levels of TNF ∝, IL-4, and IL-6 in their BAL and serum. Homogenates of one lung lobe from each animal were utilized to assess oxidative stress; a separate lobe underwent histologic examination to assess airway inflammatory status. The results suggest that asthmatic symptoms were found in TDI control rats only, while both MOEE- and DXM-treated rats did not manifest any airway abnormality. In MOEE- and DXM-treated rats, neutrophil and eosinophil levels in the blood were decreased significantly; levels of total cells and each different cell in their BAL fluid were markedly decreased as compared to those in TDI controls. TNF α, IL-4, and IL-6 were predominant in serum as well as in BAL fluids in TDI controls, but these levels were reduced significantly by MOEE treatment. The antioxidant activity in relation to antiinflammatory activity of the extract and histopathological observations also reflected a protective effect. Based on the above findings and observations, it can be concluded that Moringa oleifera may possess some beneficial properties that act against chemically stimulated immune-mediated inflammatory responses that are characteristic of asthma in the rat.

Impact of Curcumin-Induced Changes in P-Glycoprotein and CYP3A Expression on the Pharmacokinetics of Peroral Celiprolol and Midazolam in Rats

The aim of this study was to evaluate whether curcumin could modulate P-glycoprotein (P-gp) and CYP3A expression, and in turn modify the pharmacokinetic profiles of P-gp and CYP3A substrates in male Sprague-Dawley rats. Intragastric gavage of the rats with 60 mg/kg curcumin for 4 consecutive days led to a down-regulation of the intestinal P-gp level. There was a concomitant upregulation of hepatic P-gp level, but the renal P-gp level was unaffected. Curcumin also attenuated the CYP3A level in the small intestine but induced CYP3A expression in the liver and kidney. Regular curcumin consumption also caused the C(max) and area under the concentration-time curve (AUC(0-8) and total AUC) of peroral celiprolol (a P-gp substrate with negligible cytochrome P450 metabolism) at 30 mg/kg to increase, but the apparent oral clearance (CL(oral)) of the drug was reduced. Similarly, rats treated with curcumin for 4 consecutive days showed higher AUC (AUC(0-4) and total AUC) and lower CL(oral) for peroral midazolam (a CYP3A substrate that does not interact with the P-gp) at 20 mg/kg in comparison with vehicle-treated rats. In contrast, curcumin administered 30 min before the respective drug treatments did not significantly modify the pharmacokinetic parameters of the drugs. Analysis of the data suggests that the changes in the pharmacokinetic profiles of peroral celiprolol and midazolam in the rat model were contributed mainly by the curcumin-mediated down-regulation of intestinal P-gp and CYP3A protein levels, respectively.

Organization of oligodendroglial membrane sheets: II. Galactocerebroside: Antibody interactions signal changes in cytoskeleton and myelin basic protein

Antibodies to galactocerebroside (GalC) cause patching of this surface glycolipid over internal domains of myelin basic protein (MBP), which are demarcated by a network of microtubules. The patching occurs whether or not second antibody is present, but the process is accelerated by the presence of second antibody. GalC patching results in disruption of microtubules in the lacy networks in oligodendroglial membrane sheets and in the eventual fusion of MBP domains, similar to the effects of colchicine (Dyer and Benjamins, 1989). Antibodies to GalC also disrupt F-actin in the lacy networks. Since colchicine does not alter the distribution of F-actin, anti-GalC is causing F-actin redistribution by a mechanism other than microtubule depolymerization. Extended exposure to anti-GalC results in coalescence of surface GalC patches concomitant with fusion of internal MBP domains. When anti-GalC is applied to induce GalC patching in cells previously treated with cytoskeletal inhibitors, patching is altered. After colchicine treatment, GalC surface staining is granular; i.e., patching is totally disorganized. Following cytochalasin B treatment, most membrane sheets display a few very large patches rather than the normal multiple, small patches. These GalC surface patterns are similar to the MBP distributions following the respective drug treatments (Dyer and Benjamins, 1989). Thus, the pattern of GalC distribution in the presence of antibody always reflects the organization of the underlying MBP domains; in turn, the organization of the MBP domains is determined by the lacy networks of microtubules in the oligodendroglial membrane sheets.

Effect of two formulations of a beta blocker on fibrinolytic response to maximum exercise

It has been reported that catecholamine release is associated with stressful events and that adrenaline administration induces hyperfibrinolysis. To examine the possible involvement of the adrenoreceptor mechanism in the regulation of fibrinolytic activity at rest and to maximum exercise, 12 healthy volunteers (six males and six females, age range 19-21 yr) were orally medicated with two formulations of a beta blocker. The drug treatments consisted of 1) a single dose of OM756 alpha 10 mg propranolol "Inderal" tablet, 2) a single dose of a generic 10 mg propranolol tablet, and 3) a single dose of generic placebo. The drug administrations were assigned to the subjects using a complete Latin square design and double-blind procedure and were separated by 7 d. Two hours after the administration of the respective drug treatment, subjects exercised to maximal capacity using a graded exercise protocol on a bicycle ergometer. Prior to and 2 h after the drug administration and immediately after maximum exercise, heart rate, blood pressure, and oxygen consumption were measured and venous blood was removed and analyzed for fibrinolytic activity using a standard fibrin plate method. ANOVA showed that the resting and maximum heart rates were significantly reduced (P less than 0.05) following oral premedication with either of the two formulations of beta blocker, while blood pressure and oxygen consumption were unaffected. ANOVA also showed no difference in the resting fibrinolytic activity 2 h post-administration of the drug treatments but a significant decrease (P less than 0.05) in the normal fibrinolytic response to maximum exercise. It was concluded, therefore, that the resting level of fibrinolytic activity is not mediated via an adrenergic pathway but that the enhanced fibrinolytic activity to maximum exercise is partially regulated via an adrenoreceptor mechanism.

The TSH-response to trh: a possible predictor of outcome to antidepressant and neuroleptic treatment

1. 1. This study was designed to investigate the possible common patterns of neuroendocrine mechanisms,which may be involved in the therapeutic effects of antidepressant drugs in depressive and of neuroleptic drugs in schizophrenic patients. 2. 2. Sixtythree depressed women (major depressive disorder) and 21 paranoid-hallucinatory women have been studied while on antidepressant (clomipramine) or neuroleptic (haloperidol) treatment, respectively. The neuroendocrine test (TRH-test) was performed at weekly intervals. 3. 3. The change of TSH-response to TRH during treatment, i.e. the treatment associated normalization of a former blunted TSH-response, can tentatively be regarded as a predictor of outcome for depressive and paranoid-hallucinatory patients to their respective drug treatments. 4. 4. Antidepressant and neuroleptic drugs appear to involve the normalization of the TSH-response in their therapeutic effects in that proportion of patients (40%) which showed a blunted TSH-response at admission.