Potential Applications of Mitochondrial Therapy with a Focus on Parkinson's Disease and Mitochondrial Transplantation.

Purpose: Both aging and neurodegenerative illnesses are thought to be influenced by mitochondrial malfunction and free radical formation. Deformities of the energy metabolism, mitochondrial genome polymorphisms, nuclear DNA genetic abnormalities associated with mitochondria, modifications of mitochondrial fusion or fission, variations in shape and size, variations in transit, modified mobility of mitochondria, transcription defects, and the emergence of misfolded proteins associated with mitochondria are all linked to Parkinson's disease. Methods: This review is a condensed compilation of data from research that has been published between the years of 2014 and 2022, using search engines like Google Scholar, PubMed, and Scopus. Results: Mitochondrial transplantation is a one-of-a-kind treatment for mitochondrial diseases and deficits in mitochondrial biogenesis. The replacement of malfunctioning mitochondria with transplanted viable mitochondria using innovative methodologies has shown promising outcomes as a cure for Parkinson's, involving tissue sparing coupled with enhanced energy generation and lower oxidative damage. Numerous mitochondria-targeted therapies, including mitochondrial gene therapy, redox therapy, and others, have been investigated for their effectiveness and potency. Conclusion: The development of innovative therapeutics for mitochondria-directed treatments in Parkinson's disease may be aided by optimizing mitochondrial dynamics. Many neurological diseases have been studied in animal and cellular models, and it has been found that mitochondrial maintenance can slow the death of neuronal cells. It has been hypothesized that drug therapies for neurodegenerative diseases that focus on mitochondrial dysfunction will help to delay the onset of neuronal dysfunction.

Development and Optimization of Proniosomal Formulation of Irbesartan Using a Box-Behnken Design to Enhance Oral Bioavailability: Physicochemical Characterization and In Vivo Assessment.

This research work aimed to develop and evaluate proniosomes for the oral delivery of the lipophilic drug Irbesartan (IRB) to improve its solubility and bioavailability. Proniosomes of Irbesartan were formulated using a lipid, surfactant, and carrier by a slurry method. Based on the prepared preliminary trial batches and their evaluation, the formulation was optimized by employing a Box-Behnken design (BBD) in which concentrations of span 60 (X1), cholesterol (X2), and mannitol (X3) were used as three independent variables and the vesicular size (VS) (Y1), % entrapment efficiency (% EE) (Y2), and % cumulative drug release (% CDR) (Y3) were used as dependent variables. The optimized batch B1 was obtained from the BBD experiment after validation of checkpoint analysis, and their characterization was done for VS, % EE, % CDR, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) analysis. The optimized batch showed a VS of 199 ± 5.4 nm, a % EE of 99.25 ± 2.24%, and a % CDR of 97.36 ± 1.13% at 24 h. Scanning electron microscopy (SEM) study showed a smooth surface of batch B1. DSC and XRD studies indicated the amorphous nature of the proniosomal formulation. The proniosomal formulation showed increased solubility (2.65 ± 0.2 mg/mL) in phosphate buffer, pH 6.8, as compared to water (0.059 ± 0.02 mg/mL). The pharmacokinetic study in rats confirmed the increased bioavailability of the drug in optimized proniosomal formulation compared with its pure drug suspension. Cmax, Tmax, and AUC0-t of the drug also increased by 2-fold compared to those of drug suspension. Thus, in conclusion, the proniosomal formulation proved to be an efficient carrier for improved oral delivery of Irbesartan by improving the solubility and bioavailability of the drug.

A Comprehensive Review of Various Therapeutic Strategies for the Management of Skin Cancer.

Skin cancer (SC) poses a global threat to the healthcare system and is expected to increase significantly over the next two decades if not diagnosed at an early stage. Early diagnosis is crucial for successful treatment, as the disease becomes more challenging to cure as it progresses. However, identifying new drugs, achieving clinical success, and overcoming drug resistance remain significant challenges. To overcome these obstacles and provide effective treatment, it is crucial to understand the causes of skin cancer, how cells grow and divide, factors that affect cell growth, and how drug resistance occurs. In this review, we have explained various therapeutic approaches for SC treatment via ligands, targeted photosensitizers, natural and synthetic drugs for the treatment of SC, an epigenetic approach for management of melanoma, photodynamic therapy, and targeted therapy for BRAF-mutated melanoma. This article also provides a detailed summary of the various natural drugs that are effective in managing melanoma and reducing the occurrence of skin cancer at early stages and focuses on the current status and future prospects of various therapies available for the management of skin cancer.

Self-Emulsifying Drug Delivery System for Enhanced Oral Delivery of Tenofovir: Formulation, Physicochemical Characterization, and Bioavailability Assessment.

Tenofovir (TNF) is a common component of many antiretroviral therapy regimens, but it is associated with poor membrane permeability and low oral bioavailability. To improve its oral bioavailability and membrane permeability, a self-emulsifying drug delivery system (SEDDS) was developed and characterized, and its relative bioavailability was compared to the marketed tablets (Tenof). Based on solubility and ternary phase diagram analysis, eucalyptus oil was selected as an oil phase, Kolliphor EL, and Kollisolv MCT 70 were chosen as surfactant and cosurfactant, respectively, while glycerol was used as cosolvent in surfactant mixture. Optimized SEDDS formulation F6 showed an oil droplet size of 98.82 nm and zeta potential of -13.03 mV, indicating the high stability of oil droplets. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy characterization studies were also carried out to assess the amorphous and morphological states of the drug in the prepared SEDDS formulation. The in vitro dissolution profile of SEDDS shows the rapid release of the drug. SEDDS F6 demonstrates a higher drug permeability than the plain TNF and TNF-marketed tablets (Tenof). A pharmacokinetic study in rats revealed that SEDDS F6 showed significantly higher Cmax and AUC0-t than the marketed tablets and pure drug suspension. In addition, the relative bioavailability of SEDDS formulation dramatically improved by 21.53-fold compared to marketed tablets and 66.27-fold compared to pure drugs. These findings show that SEDDS composed of eucalyptus oil, glycerol, Kolliphor EL, and Kollisolv MCT 70 could be a useful tool for enhancing physiochemical properties and oral TNF absorption. Therefore, SEDDS has shown promise in improving the oral bioavailability of poorly water-soluble drugs.

Exposure to pesticide residues in honey and its potential cancer risk assessment.

Honey is the most recognized natural food by-product derived from flower nectar and the upper aero-digestive tract of the honeybees. Significance of honey for its medicinal importance are well-documented in the world's oldest medical literatures. However, the current urbanization, environmental contaminations and changes in agricultural, as well as apiculture practices has led to various types of contaminations in honey. Among all, pesticide contamination has become one of the major issues worldwide. This review focuses on the recent updates concerning pesticides occurrence in honey, as well as how the repeated use and long-term exposure to honey contaminated with pesticide residues could affect the human physiological functions, possibly leading to the development of various cancers. Our findings suggests that uncontrolled use of pesticides in farming and apiculture practices leads to the occurrence of pesticides residues in honey. Therefore, regular consumption of such honey will pose a serious threat to human health, since most of the pesticides has been reported as potential carcinogens. This review will draw the attention of honey consumers, scientific communities, apiculture farmers, as well as governing bodies to strictly monitor the pesticide usage in floriculture, agriculture as well as other related practices.

A case series of autologous platelet-rich plasma injection in treating chronic ulcers conducted in Saudi Arabia.

Objective: This is a case series study of 14 cases of chronic unhealed ulcers involving patients of 19-85 years, aimed to demonstrate the positive therapeutic outcomes of using autologous platelet rich plasma (PRP) in diabetic foot ulcer (DFU) and other chronic wound healing. Methods: This is a formal consecutive clinical case series. Patients with chronic unhealed ulcers were enrolled from the amputation prevention clinic by an interdisciplinary team includes podiatrist, general surgeon, orthopedic, vascular surgeon, and wound care nurses at Kahel Specialized Centre, a specialized center for managing foot and ankle diseases, located in Riyadh, Saudi Arabia. Those patients who presented with chronic wounds and showed no significant wound reduction despite following the standard wound care protocol were included in the study. There were no specific predetermined exclusion criteria when considering patients for treatment with this modality. Results: In this case series, majority (80%) of the patients were above 50 years of age, and 10 (66.7%) patients were male and 5 (33.3%) were female. Of all the cases presented to the amputation prevention clinic, majority (73.3%) reported suffering from type 2 diabetes mellitus (DM) and also, one reported type 1 DM [6.7%]). All the cases of DFU received a combination of hydrogel and autologous PRP treatment and were put of suitable offloading devices, except one case received a combination of Cadexomer iodine, hydrogel and PRP treatment. In the present case series involving 3-14 weeks of the treatment duration, only 2-3 doses of autologous PRP provided complete healing and or maximum wound closure. Conclusion: Autologous PRP therapy is efficacious in facilitating, enhancing wound healing and aids in complete wound closure. This case series was limited in term of the sample size which is the number patients enrolled for the study, hence, the study finding remain inconclusive to some extent and hence, further study is required with greater number of sample size. The strength of this study is that it is the first study in Saudi Arabia and gulf region, to report the beneficial effect of PRP in chronic unhealed ulcers including diabetic ulcers.

New Paradigms of Old Psychedelics in Schizophrenia.

Psychedelics such as lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), and mescaline exhibit intense effects on the human brain and behaviour. In recent years, there has been a surge in studies investigating these drugs because clinical studies have shown that these once banned drugs are well tolerated and efficacious in medically supervised low doses called microdosing. Psychedelics have demonstrated efficacy in treating neuropsychiatric maladies such as difficult to treat anxiety, depression, mood disorders, obsessive compulsive disorders, suicidal ideation, posttraumatic stress disorder, and also in treating substance use disorders. The primary mode of action of psychedelics is activation of serotonin 5-HT2A receptors affecting cognition and brain connectivity through the modulation of several downstream signalling pathways via complex molecular mechanisms. Some atypical antipsychotic drugs (APDs) primarily exhibit pharmacological actions through 5-HT2A receptors, which are also the target of psychedelic drugs. Psychedelic drugs including the newer second generation along with the glutamatergic APDs are thought to mediate pharmacological actions through a common pathway, i.e., a complex serotonin-glutamate receptor interaction in cortical neurons of pyramidal origin. Furthermore, psychedelic drugs have been reported to act via a complex interplay between 5HT2A, mGlu2/3, and NMDA receptors to mediate neurobehavioral and pharmacological actions. Findings from recent studies have suggested that serotoninergic and glutamatergic neurotransmissions are very closely connected in producing pharmacological responses to psychedelics and antipsychotic medication. Emerging hypotheses suggest that psychedelics work through brain resetting mechanisms. Hence, there is a need to dig deeply into psychedelic neurobiology to uncover how psychedelics could best be used as scientific tools to benefit psychiatric disorders including schizophrenia.

Anti-Adhesion and Antibiofilm Activity of Eruca sativa Miller Extract Targeting Cell Adhesion Proteins of Food-Borne Bacteria as a Potential Mechanism: Combined In Vitro-In Silico Approach.

Bacterial cells have the ability to form biofilm onto the surfaces of food matrixes and on food processing equipment, leading to a source of food contamination posing serious health implications. Therefore, our study aimed to determine the effect of Eruca sativa Miller (E. sativa) crude extract against biofilms of food-borne bacteria along with in silico approaches to investigate adhesion proteins responsible for biofilm activity against the identified phytochemicals. The antibacterial potential of crude extract was evaluated using agar well diffusion technique and combinations of light and scanning electron microscopy to assess the efficacy of crude extract against the developed biofilms. Our results showed that crude extract of E. sativa was active against all tested food-borne bacteria, exhibiting a rapid kinetics of killing bacteria in a time-dependent manner. MIC and MBC values of E. sativa crude extract were found to be ranging from 125 to 500 µg/mL and 250 to 1000 µg/mL respectively. Furthermore, inhibition of developed biofilm by E sativa was found to be ranging from 58.68% to 73.45% for all the tested strains. The crude extract also reduced the viability of bacterial cells within biofilms and amount of EPS (ranging 59.73-82.77%) in the biofilm matrix. Additionally, the microscopic images also revealed significant disruption in the structure of biofilms. A molecular docking analysis of E. sativa phytochemicals showed interaction with active site of adhesion proteins Sortase A, EspA, OprD, and type IV b pilin of S. aureus, E. coli, P. aeruginosa, and S. enterica ser. typhi, respectively. Thus, our findings represent the first demonstration of E. sativa crude extract's bioactivity and potency against food-borne bacteria in their planktonic forms, as well as against the developed biofilms. Therefore, a possible mechanistic approach for inhibition of biofilm via targeting adhesion proteins can be explored further to target biofilm producing food-borne bacterial pathogens.

An in-silico analysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α.

Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPß1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing -5.30 kcal/mol and -84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting -6.9 kcal/mol and -66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. In silico exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs. Communicated by Ramaswamy H. Sarma.

An insight into the implications of estrogen deficiency and transforming growth factor ß in antiepileptic drugs-induced bone loss.

There have been a number of reports that chronic antiepileptic drug (AEDs) therapy is associated with abnormal bone and calcium metabolism, osteoporosis/osteomalacia, and increased risk of fractures. Bony adverse effects of long term antiepileptic drug therapy have been reported for more than four decades but the exact molecular mechanism is still lacking. Several mechanisms have been proposed regarding AEDs induced bone loss; Hypovitaminosis D, hyperparathyroidism, estrogen deficiency, calcitonin deficiency. Transforming growth factor-ß (TGF- ß) is abundant in bone matrix and has been shown to regulate the activity of osteoblasts and osteoclasts in vitro. All isoforms of TGF- ß are expressed in bone and intricately play role in bone homeostasis by modulating estrogen level. Ovariectomised animal have shown down regulation of TGF- ß in bone that could also be a probable target of AEDs therapy associated bone loss. One of the widely accepted hypotheses regarding the conventional drugs induced bone loss is hypovitaminosis D which is by virtue of their microsomal enzyme inducing effect. However, despite of the lack of enzyme inducing effect of certain newer antiepileptic drugs, reduced bone mineral density with these drugs have also been reported. Thus an understanding of bone biology, pathophysiology of AEDs induced bone loss at molecular level can aid in the better management of bone loss in patients on chronic AEDs therapy. This review focuses mainly on certain new molecular targets of AEDs induced bone loss.

Natural Polysaccharides as Preventive and Therapeutic Horizon for Neurodegenerative Diseases.

Neurodegenerative diseases are a serious and widespread global public health burden amongst aging populations. The total estimated worldwide global cost of dementia was US$818 billion in 2015 and has been projected to rise to 2 trillion US$ by 2030. While advances have been made to understand different neurodegenerative disease mechanisms, effective therapeutic strategies do not generally exist. Several drugs have been proposed in the last two decades for the treatment of different types of neurodegenerative diseases, with little therapeutic benefit, and often with severe adverse and side effects. Thus, the search for novel drugs with higher efficacy and fewer drawbacks is an ongoing challenge in the treatment of neurodegenerative disease. Several natural compounds including polysaccharides have demonstrated neuroprotective and even therapeutic effects. Natural polysaccharides are widely distributed in plants, animals, algae, bacterial and fungal species, and have received considerable attention for their wide-ranging bioactivity, including their antioxidant, anti-neuroinflammatory, anticholinesterase and anti-amyloidogenic effects. In this review, we summarize different mechanisms involved in neurodegenerative diseases and the neuroprotective effects of natural polysaccharides, highlighting their potential role in the prevention and therapy of neurodegenerative disease.

Janus Kinase Mutations in Mice Lacking PU.1 and Spi-B Drive B Cell Leukemia through Reactive Oxygen Species-Induced DNA Damage.

Precursor B cell acute lymphoblastic leukemia (B-ALL) is caused by genetic lesions in developing B cells that function as drivers for the accumulation of additional mutations in an evolutionary selection process. We investigated secondary drivers of leukemogenesis in a mouse model of B-ALL driven by PU.1/Spi-B deletion (Mb1-CreΔPB). Whole-exome-sequencing analysis revealed recurrent mutations in Jak3 (encoding Janus kinase 3), Jak1, and Ikzf3 (encoding Aiolos). Mutations with a high variant-allele frequency (VAF) were dominated by C→T transition mutations that were compatible with activation-induced cytidine deaminase, whereas the majority of mutations, with a low VAF, were dominated by C→A transversions associated with 8-oxoguanine DNA damage caused by reactive oxygen species (ROS). The Janus kinase (JAK) inhibitor ruxolitinib delayed leukemia onset, reduced ROS and ROS-induced gene expression signatures, and altered ROS-induced mutational signatures. These results reveal that JAK mutations can alter the course of leukemia clonal evolution through ROS-induced DNA damage.

TAEO-A Thermal Aware & Energy Optimized Routing Protocol for Wireless Body Area Networks.

Wireless Body Area Networks (WBANs) are in the spotlight of researchers and engineering industries due to many applications. Remote health monitoring for general as well as military purposes where tiny sensors are attached or implanted inside the skin of the body to sense the required attribute is particularly prominent. To seamlessly accomplish this procedure, there are various challenges, out of which temperature control to reduce thermal effects and optimum power consumption to reduce energy wastage are placed at the highest priority. Regular and consistent operation of a sensor node for a long-time result in a rising of the temperature of respective tissues, where it is attached or implanted. This temperature rise has harmful effects on human tissues, which may lead to the tissue damage. In this paper, a Temperate Aware and Energy Optimized (TAEO) routing protocol is proposed that not only deals with the thermal aspects and hot spot problem, but also extends the stability and lifetime of a network. Analytical simulations are conducted, and the results depict better performance in terms of the network lifetime, throughput, energy preservation, and temperature control with respect to state of the art WBAN protocols.

Pleiotropic Effects of Melatonin.

Melatonin's pleiotropic actions begin from controlling day/night cycle and hypothalamic/pituitary axes to, for example, vasomotor effects, immunomodulation, antilipid effects, modulation of endocrine functions, direct and indirect antiapoptotic effects, interference with nitric oxide signaling, other antiexcitatory actions through ion channels and neurotransmitter systems, and most prominently the antioxidant activities which include expression of genes relevant to redox metabolism, including modulation of mitochondrial electron flux. Because of ubiquitous nature of the melatonin receptor, melatonin serves as pleiotropic molecule and its multiplicity of action goes beyond the established antioxidant activities. Melatonin exhibits pleiotropic effects essentially through four different mechanisms: binding to membrane receptors; nuclear receptors; intracellular proteins, and a receptor-independent radical scavenging function. The present review highlights some of the important pleiotropic effects of melatonin in human body.

Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect: a current preclinical & clinical perspective.

Histamine H3 receptors are present as autoreceptors on histaminergic neurons and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key neurotransmitters in the brain. H3 antagonism may be a novel approach to develop a new class of antipsychotic medications given the gathering evidence reporting therapeutic efficacy in several central nervous system disorders. Several medications such as cariprazine, lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of schizophrenia. These medications works through diverse mechanisms which include agonism at metabotropic glutamate receptor (mGluR2/3), partial agonism at dopamine D2, D3 and serotonin 5-HT1A receptors, antagonism at D2, 5-HT2A, 5-HT2B and 5-HT7 receptors, combined dopamine antagonism with GABA agonist activity, inhibition of monoamine oxidase-B, modulation of oestrogen receptor, and activation of nuclear retinoid X receptor. However, still specific safe therapy for psychosis remains at large. Schizophrenia is a severe neuropsychiatric disorder result both from hyper- and hypo-dopaminergic transmission causing positive and negative symptoms, respectively. Pharmacological stimulation of dopamine release in the prefrontal cortex has been a viable approach in treating negative symptoms and cognitive deficits of schizophrenia symptoms that are currently not well treated and continue to represent significant unmet medical challenges. Administration of H3 antagonists/inverse agonists increase extracellular dopamine concentrations in rat prefrontal cortex, but not in the striatum suggesting that antagonism via H3 receptor may be a potential target for treating negative symptoms and cognitive deficits associated with schizophrenia. Further, insights are emerging into the potential role of histamine H3 receptors as a target of antiobesity therapeutics which is one of the limiting adverse effects of second generation schizophrenia medications. The recent failures of two promising H3 compounds in clinical trial dampened the interest in seeking antipsychotic like activities of H3 receptor antagonists. However, due to the inconclusive nature of many of these studies, the development of H3 compounds via H3 antagonism/inverse agonism approach still hold lot of promises and may be developed as a novel class of drugs for schizophrenia and its related complications e.g. weight gain.

Histamine H3 receptor antagonists display antischizophrenic activities in rats treated with MK-801.

BACKGROUND: Animal models based on N-methyl-d-aspartate receptor blockade have been extensively used for schizophrenia. Ketamine and MK-801 produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia, which led to the use of PCP (phencyclidine)- and MK-801 (dizocilpine)-treated animals as models for schizophrenia. METHODS: The study investigated the effect of subchronic dosing (once daily, 7 days) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p.) on MK-801 (0.2 mg/kg, i.p.)-induced locomotor activity and also measured dopamine and histamine levels in rat's brain homogenates. The study also included clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively. RESULTS: Atypical and typical antipsychotic was used to serve as clinically relevant reference agents to compare the effects of the H3R antagonists. MK-801 significantly increased horizontal locomotor activity, which was reduced with CPX and CBP. MK-801-induced locomotor hyperactivity attenuated by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised striatal dopamine level, which was reduced in rats pretreated with CPX and CBP. CPZ also significantly lowered striatal dopamine levels, although the decrease was less robust compared to CLZ, CPX, and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increased histamine levels in the hypothalamus compared to MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.), counteracted the effect of CPX and CBP. CONCLUSIONS: The present study shows the positive effects of CPX and CBP on MK-801-induced schizophrenia-like behaviors in rodents.

Protective effects of histamine H3-receptor ligands in schizophrenic behaviors in experimental models.

Schizophrenia (SCZ) afflicts around 1% of the world's population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H(3)-receptor (H(3)R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, i.p.) and clobenpropit (15 mg/kg, i.p.), on some of the established animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apomorphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (AChE) activity. Results of the present study demonstrate that ciproxifan and clobenpropitwere able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as reduced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain AChE activity demonstrated positive results with these protypical imidazole H(3)R-antagonists/inverse agonists.

Protective effects of aliskiren in doxorubicin-induced acute cardiomyopathy in rats.

In this study, effect of aliskiren (ALK) on doxorubicin (DXR)-induced cardiomyopathy in rats was evaluated. ALK (50 and 100 mg/kg/day) was administered for 7 days and a single intraperitoneal injection of DXR (20 mg/kg) on day 5. The animals were sacrificed 48 h after DXR administration. DXR produced significant elevation in malondialdehyde (MDA) and significantly inhibited the activity of glutathione (GSH) in heart tissue, with a significant rise in the serum levels of lactate dehydrogenase (LDH), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) and reduction in high-density lipoprotein (HDL), indicating acute cardiac toxicity. ALK pretreatment significantly reduced the MDA concentration and ameliorated the inhibition of cardiac GSH activity. ALK also significantly improved the serum levels of LDH, TC, TG, LDL and reduction in HDL in DXR-treated rats. Furthermore, histological examination of the heart sections confirmed the myocardial injury with DXR administration and the near-normal pattern with ALK pretreatment. The results provide clear evidence that the ALK pretreatment offered significant protection against DXR-induced enzymatic changes and cardiac tissue damage.

Comparative evaluation of humic substances in oral drug delivery.

Major and biologically most explored components of natural organic matter (NOM) are humic acid (HA) and fulvic acid (FA). We have explored rock shilajit as a source of NOM. On the other hand carbamazepine (CBZ) is a well known anticonvulsant drug and has a limited accessibility to brain. Bioavailability and pharmacokinetic profiles of CBZ have been improved by complexation and different techniques also. Present study has assessed the comparative abilities of FA and HA as complexing agent for CBZ in order to enhance pharmacokinetic profile of CBZ and accessibility to the brain. These two complexing agents have been compared on various indices such as their abilities to cause complexation and enhance solubility, permeability and dissolution. The present study also compared pharmacodynamic and biochemical profiles after oral administration of complexes. With the help of various pharmaceutical techniques such as freeze drying, physical mixture, kneading and solvent evaporation, two molar ratios (1:1 and 1:2) were selected for complexation and evaluated for conformational analysis (molecular modeling). Complex formed was further characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), mass spectroscopy and X-ray diffraction (XRD). Preclinical study on rodents with CBZ-HA and CBZ-FA has yielded appreciable results in terms of their anticonvulsant and antioxidants activities. However, CBZ-HA (1:2) demonstrated better result than any other complex.

Comparison of antinociceptive and antidiabetic effects of sertraline and amitriptyline on streptozotocin-induced diabetic rats.

Antidepressants (ADs) are frequently used for the treatment of persistent pain associated with diabetic neuropathy. The aim of this study is to investigate the antinociceptive effects of sertraline (Ser) and amitriptyline (Ami) in diabetic rats, and additionally monitoring their effects on grip strength, blood glucose and percentage glycosylated hemoglobin (GHb%) levels. Streptozotocin (STZ; 55 mg/kg, intraperitoneal [ip]) was injected in rats to induce diabetes. After 7 days, Ser (30 mg/kg) or Ami (15 mg/kg) was administered in diabetic rats orally. After 28 days drug treatment, the antinociceptive effects were evaluated using hot plate test both in diabetic and non-diabetic rats. The effects of these drugs on grip strength, blood glucose and GHb% were also measured. Ser and Ami showed antinociceptive effects in diabetic and non-diabetic rats. Both the drugs increased the grip strength reduction in STZ-induced diabetic rats. Ser reduces and Ami increases the serum glucose levels in diabetic and normal rats. Administration of Ami per se increased GHb% levels, while Ser per se has no effects. The effects of Ser (30 mg/kg, per os [po]) on glucose, GHb% and antinociceptive action on hot plate test showed an association between improved blood glucose levels and analgesia. However, the results of Ami treatment are controversial and needs further studies.