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Anxiety is one of the most common psychopathologies in the general population that often begin early in life; however, research on this disorder during early developmental stages has been poorly explored compared to adults. A better understanding of the anxiety disorder through childhood is essential to develop more effective treatments. This chapter provides a general overview of the usefulness of animal models of childhood anxiety and its neurobiological bases to discuss how the studies on animals meet the several criteria of validity to discover pathophysiological mechanisms of human disorders and new treatments for these conditions. The research methodology for this chapter consisted in using a thesaurus system such as Medical Subject Headings (MeSH) terms of the National Library of Medicine to find original articles in databases as PubMed or Web of Science about preclinical findings related to the neuropharmacology of anxiety before adulthood. The contribution of this chapter is to provide data from preclinical studies which are encouraged to a better comprehension of anxiety at young age.

Density functional theory (DFT) is a quantum mechanical approach used to investigate the electronic structure (principally the ground state) of many-body systems, in particular atoms, molecules, and the condensed phases. In this work, we have used DFT/B3LYP/6-31+G(d) level of theory to get insight into the molecular geometry and thermochemical properties of histamine H2-receptor antagonists. Histamine H2-receptor antagonists or H2 blockers are a group of pharmaceutical ingredients that reduce the amount of acid produced by the cells in the lining of the stomach. The potential H2 blockers include cimetidine, famotidine, nizatidine, and ranitidine. The detailed theoretical investigation on the listed H2 blockers in terms of their thermochemical parameters and global descriptive parameters revealed that, though famotidine is the best among them with highest Gibbs free energy, nizatidine showed higher biological activity with high softness, low hardness, and high electrophilicity index. The theoretical vibrational spectra of these four Histamine H2-receptor antagonists were analyzed and the infrared spectra of nizatidine was compared with the experimental IR spectra, and found to be good agreement with the experimental values. Further, frontier molecular orbitals especially the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were determined and the activation energy of the selected samples were calculated. In addition to this, the amorphisation technique were employed to enhance the solubility and bio availability of the best biologically active H2 blocker nizatidine using broadband dielectric spectroscopy.

Active heterocyclic compounds are one of the main topics of interest for the medicinal chemists as they display a number of pharmacological activities. Nitrogen, sulfur, and oxygen containing five- and six-membered heterocyclic compounds have occupied enormous significance in the field of medicinal chemistry. The most important six-membered heterocyclic compounds are quinazoline and quinazolinone derivatives for their biological activities. The current chapter outlined the different methods for synthesis of quinazoline and quinazolinone derivatives that possess broad spectrum of biological activities.

The treatment of chronic pain is a chronic problem for many specialities. It is generally based on an approach with antidepressants, anti-epileptics and opioids as drugs of first choice. It has been worked by many different protocols. Ketamine, which is known as a good anaesthetic, has been used for chronic pain. When the pain has a neuropathic component, ketamine is a promising treatment for pain management. Ketamine: by inhibiting the N-methyl-D-aspartate receptor and having some other effects like enhancement of descending inhibition and anti-inflammatory effects at central sites, takes part in chronic pain management. Besides having analgesic effects, there are some concerns about the side effects of ketamine. Some psychedelic symptoms as hallucinations, memory defects, panic attacks, nausea and vomiting, somnolence, cardiovascular stimulation and sometimes hepatoxicity may be seen in patients. Ketamine is generally well-tolerated in clinical settings. Close monitoring of patients receiving ketamine should be mandatory in order to be aware of central nervous system, haemodynamic, renal and hepatic symptoms as well as abuse.

4(3H)-Quinazolinone derivatives have considerable great interesting due to the diverse range of their biological properties. This review summarized the methods of preparation of 2-substituted-4(3H)-quinazolinone, 3-substituted-4(3H)-quinazolinone and 2,3-disubstituted-4(3H)-quinazolinone derivatives. Chemical reaction of 4(3H)-quinazolinone derivatives and the reactivity of the 2-methyl group, reactivity of the 3-amino group, electrophilic substitution, oxidation, reduction, reaction of 4(3H)-quinazolinones with metal ions, Mannich reaction, cycloaddition reaction as well as other reagents were discussed. Also, biological properties of 4(3H)-quinazolinone derivatives were given herein.

When treating opioid addiction, multidisciplinary treatment is highly recommended, but pharmacotherapy plays a key role. Although the ideal goal is to achieve complete abstinence, an elevated percentage of opioid addicts requires maintenance substitution therapy. In the first section of this chapter, we will focus on the current pharmacological interventions to treat opioid addiction, such as methadone, buprenorphine, and naltrexone. Thanks to these medications, people are able to go back to their normal lives, by preventing withdrawal symptoms, reducing craving, and increasing their adherence to psychotherapy. In the second section, based on the evidence that addiction induces neuroadaptive changes in several neurotransmission systems, we focus on the wide range of possible pharmacological developments at the preclinical and clinical levels, which in recent years have increased considerably.

A cross-sectional study has been conducted to detect the facts about the use of traditional herbal medicines (THMs) in South Korea. The questionnaire has been adopted from the 2017 National Survey for the usage of traditional Korean medicine (TKM) and consumption of THMs. A total number of 1346 participants have been involved in this study. Results showed that the non-decoction types of herbal medicines, which are mostly used for therapeutic purposes (89.0%), and the decoction types of herbal medicines were not only used for the purpose of treatment of diseases (62.5%) but also health improvement purposes (21.9%). Results presented that decoction types of THMs are used for musculoskeletal diseases (56.0%), digestive diseases (21.3%), and respiratory diseases (6.3%), whereas the non-decoction types of THMs are commonly used in musculoskeletal diseases (55.6%), respiratory diseases (20.5%), and digestive diseases (18.1%). Future studies are highly recommended to detect more details about the medical use of THMs in South Korea.

3-amino-2-methylquinolin-4(3H)-one on condensation with different substituted naphthanones in presence of acetic acid under classical procedure to affords novel series of Schiff bases containing quinazoline moiety. The procedure is simple and easy to obtain the resultant quinazoline Schiff bases in good yields. The product 2a–d is purified by crystallization in pure 94% ethanol and characterized by thin layer chromatography. The newly synthesized imines (Schiff bases) are confirmed on the basis of spectral techniques, 1H NMR, IR, and mass spectroscopy.

A medical product usually undergoes several clinical trials, including the testing of volunteers. Nevertheless, genomic variances in the patients cannot be considered comprehensively and adverse drug reactions (ADRs) are missed or misinterpreted during trials. Despite the relation between ADRs and human leukocyte antigen (HLA) molecules being known for several years, the fundamental molecular mechanisms leading to the development of such an ADR often remains only vaguely solved. The analysis of the peptidome can reveal changes in peptide presentation post-drug treatment and explain, for example, the severe cutaneous ADR in HLA-B*57:01-positive patients treated with the antiretroviral drug abacavir in anti-HIV therapy. However, as seen in the biophysical features of HLA-A*31:01-presented peptides, treatment with the anticonvulsant carbamazepine only induces minor changes. Since the binding of a drug to a certain HLA allelic variant is extremely distinct, the influence of the small molecule/protein complex on the proteomic content of a cell becomes clear. A sophisticated methodology elucidating the impact of drug treatment on cells is a full proteome analysis. The principal component analysis of abacavir, carbamazepine or carbamazepine-10,11-epoxid treated cells reveals clear clustering of the drug-treated and the untreated samples that express the respective HLA molecule. Following drug treatment, several proteins were shown to be significantly up- or downregulated. Proteomics and peptidomics are valuable tools to differential clinical outcomes of patients with the same HLA phenotype.

Biosynthesized silver (Ag) and gold nanoparticles (Au NPs) were synthesized by using Punica granatum and Citrus reticulata extracts and these extracts act as stabilizer. The average sizes of the Silver and Gold NPs were in the range of 8–10 nm and 30–40 nm, respectively. The confirmation of NPs was done by UV-visible absorption spectra, X-ray diffraction (XRD), transmission electron microscope (TEM), and Fourier transform infrared spectra (FTIR) techniques. The luminescence studies of europium and samarium complexes with NPs were studied. Emission intensities of complexes with the presence of silver enhanced and quenched with gold due to the reabsorption. The toxicity and antimicrobial studies of nanostructures were studied.

Drug repurposing is one of the best strategy for drug discovery. There are several examples where drug repurposing has revolutionized the drug development process, such as metformin developed for diabetes and is now employed in polycystic ovarian syndrome. Drug repurposing against breast cancer is currently a hot topic to look upon. With the continued rise in breast cancer cases, there is a dire need for new therapies that can tackle it in a better way. There is a rise of resistance to current therapies, so drug repurposing might produce some lead candidates that may be promising to treat breast cancer. We will highlight the breast cancer molecular targets, currently available drugs, problems with current therapy, and some examples that might be promising to treat it.

Danaparoid sodium is an antithrombotic isolated from porcine mucosa. Its main constituent is a mixture of heparan sulphates that inhibits thrombin generation and also possesses anti-inflammatory and immune-modulatory activity. It has shown safety and efficacy in its main indications of deep venous thrombosis prophylaxis, heparin-induced thrombocytopenia treatment and disseminated intravascular thrombosis treatment. In addition, there are reports of its off-label use for the treatment of portal vein thrombosis in adults and for prevention of the hepatic thrombotic microangiopathies haematogenous that complicate recovery after stem cell transplantation in adults and children. The results of these studies provide further support for its safety and efficacy even in subjects with cirrhosis and/or severe hepatic dysfunction. In this chapter the rationale for danaparoid use is presented and the collated results of comparative studies and case reports are compared with those of other pharmaceutical options for managing these hepatic thrombotic disorders.

With the advent of dynamical omics technology, especially the transcriptome and proteome, a huge amount of data related to various diseases and approved drugs are available under multi global projects or researches with their interests. These omics data and new machine learning technology largely promote the translation of drug research into clinical trials. We will cover the following topics in this chapter. 1) An introduction to the basic discipline of gene signature-based drug repurposing; 2) databases of genes, drugs and diseases; 3) gene signature databases of the approved drugs; 4) gene signature databases of various diseases; 5) gene signature-based methods and tools for drug repositioning; 6) new omics technology for drug repositioning; 7) drug repositioning examples with reproducible code. And finally, discuss the future trends and conclude.

A smile plays an important role in determining a person’s initial impression, and its assessment has become integral to clinical evaluation. A smile with an esthetic appearance should be symmetrical and should reveal less than 2 mm of gums when smiling. A gingival smile, gummy smile, or high smile line, is defined as the number of excess gums on the upper jaw exposed. This may have some serious psychological repercussions on the patient, which may sometimes lead them to conceal their smile to avoid “embarrassment.” One of the most common methods of treating a gingival smile resulting from an overactive lip is lip reposition as a surgical procedure and the injection of type A (Botox) toxin as an injectable inhibitor of muscle action. However, many patients refrain from surgical treatment because of fear of complications and pain. In this case, injections of botulinum toxin group A are an excellent alternative to surgery. The injection of botulinum toxin takes less time and with the correct dosage and compliance with the protocol of its administration causes much fewer complications. The study presented here is devoted to the disclosure of the potential of this tool in esthetic dentistry.

Essential oil, sent by nature, is a complex mixture of volatile secondary metabolites. Its composition varies along with many parameters that can lead to misunderstanding of its wonderful pharmacological property. In fact, from post-harvest treatment to the compound’s identification through extraction approaches, the original chemotype of essential oils can be misdescribed. The pharmacological potentials of these oils are well known in the traditional system since time immemorial. Nowadays, some chemotypes of these oils had shown the effect against WHO’s top 10 killer diseases. But the misuses of these essential oils are in part due to the lack of robust and easy analysis strategy that can allow the quality of the essential oils.

Drug metabolism or more generally, xenobiotic metabolism, is the biotransformation of exogenous compounds by living organisms, usually through specialized enzymatic systems. The metabolism of experimental therapeutics is an important aspect of pharmacology and translational medicine as the rate and the interindividual variability of drug metabolism can determine the duration and/or efficacy of a drug’s pharmacologic action. Since the introduction of metabolites in safety testing guidance by the Food and Drug Administration, major changes have occurred in the experimental methods for the identification and quantification of metabolites, evaluation of metabolites, and the timing of critical nonclinical studies to generate this information.

Gamma-amino butyric acid (GABA) is a major inhibitory neurotransmitter found in several regions of the brain and known to have various significant physiological roles as a potent bioactive compound. Malfunction of GABAergic neuronal signaling prompts to cause severe psychiatric symptoms in numerous mental disorders. Several drugs are available in clinical practice for neuropsychiatric disorders targeting through GABAergic pathway, with notable adverse effects. Interestingly, in recent years, researchers are focusing on natural compounds altering GABAergic neurotransmission for various psychiatric disorders due to its wide range of therapeutic efficacy and safety. The enormous variety of natural compounds, namely alkaloids, flavonoids, terpenoids, polyacetylenic alcohols, alkanes and fatty acids were reported to alter the GABAergic transmission through its receptors and or by influencing the transmission, synthesis and metabolism of GABA. Natural compounds are able to cross the blood brain barrier and influence the GABA functions in order to treat anxiety, mania, schizophrenia and cognitive disorders. Therefore, this current chapter describes on natural products which have the potential to alter the GABAergic neurotransmission and its therapeutical benefits in treating several neuropsychiatry disorders using various pharmacological methods.

Viruses are the major pathogenic agents that cause various diseases. Antiviral drugs are used for the treatment of viral infections. Emergent advances of antiviral drugs are focused on two different approaches: targeting the host cell factors or the viruses themselves. Antiviral drugs that directly target the viruses include virus entry inhibitors, virus attachment inhibitors, uncoating inhibitors, protease inhibitors, polymerase inhibitors, nucleoside inhibitors, integrase inhibitors, and nucleotide reverse transcriptase. The protease inhibitors, viral DNA polymerase, and integrase inhibitors are the most commonly used antiviral drugs. Still, there are no effective antiviral drugs existing for several viral infections. Coronavirus disease-2019 (COVID-19) or SARS-CoV-2 is the newest member of the coronavirus family. No specific drugs particularly antiviral drugs have been approved for the treatment of COVID-19. Thus, it is extremely crucial to identify new drugs for the treatment of the COVID-19 outbreak. Various antiviral drugs are used for COVID-19 treatment. Currently, various drugs are under investigation to treat COVID-19 patients. Promising clinical outcomes for COVID-19 can be obtained by using alpha-interferon, remdesivir, lopinavir-ritonavir, favipiravir, ribavirin, umifenovir, oseltamivir, etc. Here, we reviewed anti-COVID-19 potencies of currently available antiviral drugs, and some antiviral drugs have been effective or prevent the spread of coronavirus.

Analyses in non-aspirin takers finding salicylic acid (SA) and hydroxylated metabolites in serum also SA and salicyluric acid (SU) in urine led to a re-evaluation of dietary sources of salicylates. Fruit and vegetable sources explained higher levels found in drug-free vegetarians, which overlapped with those from patients on low dose aspirin. That drug’s chemo-protective action in cancer is, at least partially, attributable to its principal metabolite, SA—which we believe contributes to the benefits of a vegetarian diet. However, diet is unlikely to be the sole source of the circulating salicylate found in aspirin-free animals and man. We adduced evidence for its persistence in prolonged fasting and biosynthesis in vivo from labelled benzoic acid. We review the roles, defined and potential, of SA in the biosphere. Emphasis on the antiplatelet effect of aspirin in man has detracted from the likely pivotal role of SA in many potential areas of bioregulation—probably as important in animals as in plants. In this expanding field, some aspirin effects, mediated by apparently conserved receptors responding to SA, are discussed. The perspectives revealed may lead to re-evaluation of the place of salicylates in therapeutics and potentially improve formulations and drug delivery systems.

Despite the introduction of new and more expensive anticonvulsant drugs, phenytoin (PHT) is still a first-line medication for common types of epilepsy such as tonic-clonic and complex partial seizures but not for absence seizures. PHT shows a nonlinear kinetics and a narrow therapeutic range, thus a fine balance must be found between efficacy and toxic effects. Since the free (unbound) drug is responsible for producing the pharmacological effect, the concentration in a novel biological fluid more closely related to arterial free plasma drug concentration—saliva—is used in this study as part of the monitoring strategy. Therefore, in order to optimize therapy in epileptic patients under PHT treatment, plasma and saliva concentrations of PHT were measured, and adverse drug reactions were registered during a 2-year follow-up. CYP2C9, CYP2C19, and epoxide hydrolase polymorphisms (enzymes involved in PHT metabolism) were also analyzed using, in this way, pharmacogenetics for drug safety. The two PHT brands commercially available in our country and used in this study demonstrated similar pattern of efficacy and safety.

Drug discovery and development is a very time- and resource-consuming process. Comprehensive knowledge of chemistry has been integrated with information technology to streamline drug discovery, design, development, and optimization. Computer-aided drug design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, and optimize the absorption, distribution, metabolism, excretion, and toxicity profile. Regulatory organizations and the pharmaceutical industry are continuously involved in the development of computational techniques that will improve the effectiveness and efficiency of the drug discovery process while decreasing the use of animals, cost, and time and increasing predictability. The present chapter will provide an overview of computational tools, such as structure-based and receptor-based drug designing, and how the coupling of these tools with a rational drug design process has led to the discovery of small molecules as therapeutic agents for numerous human disease conditions duly approved by the Food and Drug Administration. It is expected that the power of CADD will grow as the technology continues to evolve.

Cedrus atlantica Manetti and Tetraclinis articulata (Vahl) Masters are a resinous species originated from North Africa and well known for their durable and noble timbers. This work was conducted to assess the relationship between natural durability of their woods, assessed in previous works by European standards NF EN 350 and CEN/TS 15083-1, and the bioactivity of essential oils extracted from these woods by hydrodistillation and analyzed by GC-FID and GC-MS. Bioassay of sawdust essential oils, conducted by direct contact technique on agar medium on four wood-decaying fungi strains, revealed strong antifungal inhibition especially by T. articulata root burl oil due to its richness in phenols. Natural durability classes of T. articulata and C. atlantica woods were then positively correlated with antifungal activity levels of their oils.

Chronic pain is one of the leading causes of years lost to disability, as most of the time it is refractory to conventional treatment. Recent advances in understanding the pain mechanisms have favored the use of ketamine as a rescue agent in refractory chronic pain conditions, as it has potential modulating effect on both sensory-discriminative and affective motivational components of pain. Preclinical studies also suggested the antinociceptive effect of sub anesthetic dose of ketamine against central and peripheral neuropathic pain conditions and non-neuropathic pain conditions such as inflammatory and nociceptive pain states. Subanesthetic infusion of ketamine along with adjuvants such as midazolam and clonidine is found to reduce the psychomimetic and cardiovascular side effects of ketamine. Even though the consensus guidelines for intravenous use of ketamine for chronic pain advocate the use of ketamine only for complex regional pain syndrome, various other clinical studies suggested its role in other refractory painful conditions. Hence the present topic focuses specifically on the effect of ketamine on non-neuropathic pain conditions such as complex regional pain syndrome, fibromyalgia, headache, ischemic limb pain, etc. Many studies had shown that ketamine not only reduces the pain scores but also the analgesic medications, which further improves the well-being and quality of life.

The pharmacovigilance has been evolved as a professional and ethical practice in ensuring the safety of medicines. The Adverse Drug Reactions (ADRs) associated with the use of medicines including Anti-Tuberculous Therapy (ATT) through a robust system of pharmacovigilance helps in promoting the safety of patients at large. The occurrence of ADRs associated with the use of ATT is expected, a large number of medicines are combined and used for prolonged duration. The suspected ADRs associated with first line ATT are well documented. However, the drugs used in second line or multidrug resistant to tuberculosis (TB), namely bedaquiline, reported to cause QT prolongation in electrocardiogram reading as one of the most common ADRs. Therefore, early identification and prevention of ADRs during ATT is essential for promoting the rational use and reduce the burden of anti-microbial resistance, besides achieving better treatment outcomes.

Treatment of acute postoperative pain is an essential part of perioperative care and if left untreated could complicate the healing period. Ketamine blocks nociceptive pain and pain arising from inflammation. Therefore, it is potentially beneficial in the postoperative period. After systematic review using “MEDLINE/PubMed (NLM)” database, we analyzed 18 studies published during 2011–2020 and found that 0.5 mg/kg/h ketamine bolus and 0.1–0.25 mg/kg/h ketamine infusion to be the most effective dose to alleviate postoperative acute pain. Ketamine, when compared with a placebo, did not have any impact on patients’ satisfaction with postoperative pain management and overall well-being. Only three studies revealed more frequent adverse reactions to ketamine after surgery suggesting that ketamine did not have any impact on patients’ postoperational rehabilitation. So, it is the option to recommend low-dose ketamine to be part of multimodal analgesia in acute severe postoperative pain treatment. It can be used in both opioid-dependent and opioid-tolerant patients. Ketamine bolus should be ≤0.35 mg/kg and infusion ≤1 mg/kg/h. One should avoid the use of ketamine in pregnant women, people with cardiovascular diseases, acute psychosis, impaired liver function, increased intracranial, and intraocular pressure. Intranasal ketamine may be considered for children during procedures outside of the operation room.

World Health Organization (WHO) declared on March 11, 2020, coronavirus disease, which erupted in December 19th, 2019 in Wuhan, China (COVID-19) as worldwide pandemic disease. Researchers worldwide were successful to provide a prophylactic approach via developing several vaccines, which were swiftly approved by WHO under Emergency Use Listing (EUL) status. So far, lopinavir, chloroquine, azithromycin, hydroxychloroquine, favipiravir, umifenovir, ribavirin, remdesivir, and darunavir have been tested clinically. Hydroxychloroquine, favipiravir, and chloroquine exhibited a high ratio of distribution for the lung and were reported to minimize viral tonnage in respiratory system of many COVID-19 cases. However, none of the tested drugs showed a conclusive, safe, and efficient activity against COVID-19. This prompted many experts in drug discovery to fetch in the treasure of many available old drugs of natural origin to repurpose based upon their well-studied pharmacology, pharmacodynamics, virtual screening, and artificial intelligence studies. In this review chapter, we will address the repurposing of natural products and their derivatives to be used in treatment of COVID-19 via targeting host cells machinery and viral proteins either in early stages by blocking virus entry to cells or lately through inhibition of viral replication.

The purpose of this research was to evaluate the environmental pollution originated by the excessive use of agrochemicals in the production of granadilla (Passiflora ligularis) in the Oxapampa district, Pasco – Peru. The crops of this fruit were chosen in the sectors named: Abra (Ab), Chacos (Ch), Quillazú (Qll), Acuzazú (Ac), Cañera (Ca), San Alberto (SA), Alto Río Pisco (ARP), and Paradise (Pa), where applying the nonexperimental and comparative design, the soil, water, and fruit samples were taken, which were analyzed in the specialized laboratory of the Faculty of Chemistry and Chemical Engineering, of the Universidad Nacional Mayor de San Marcos (UNMSM). A survey was also carried out by the farmers to form groups (ABC), and the results obtained were statistically analyzed by means of the comparative difference of concentration of heavy metals in three groups selected according to intensity of use of agrochemicals, which were between 0.26 and 0.36 mg of Cu/kg of fruit, between 0.001 and 0.003 mg of Cd and Pb/kg of fruit, between 0.0012 and 0.0006 mg As and Hg/kg of fruit, between 19 and 25 mg of Cu/kg of soil, between 0.02 and 0.08 mg of Cd and Pb/kg of soil, between 0.05 and 0.08 mg of As and Hg/kg of soil; between 1 and 1.12 mg of Cu/l of water, between 0.002 and 0.003 mg of Cd and Pb/l of water, between 0.002 and 0.005 mg of As and Hg/l of water; being observed high averages in some heavy metals and whose comparisons were not significant for As, Hg, Pb, Cd, Cu in fruits, soil, and water, and significant only the Cd in fruits and Hg in soils, concluding that there is a potential risk of toxicity due to ingestion of granadilla (P. ligularis).

Toxicosis is a poisoning caused by venomous animals such as snake, scorpion, honeybee, spider and wasp. Their poisons contain amino acids, peptides, proteins, enzymes and metallic ions that are responsible for neurotoxicity, hemotoxicity and myotoxicity. Because of in vivo therapeutic challenges posed by toxicosis, there is need for ideal therapeutic agents against envenomation caused by venomous animals. Findings have shown that toxicosis could be treated symptomatically. Snake and scorpion antivenins could be used for treatment of poisoning caused by snake, scorpion, honeybee, spider and wasp. The amount of antivenin is dependent on the quantity of venom injected into the affected individuals. Moreso, sympotomatic treatments are also done according to the systems affected. Hospitalization is necessary for assessment of therapeutic success.

Different studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories; corticotrophin-releasing factor (CRF) plays a critical role in reward- and aversion-driven associative learning. In the present chapter, we have evaluated whether CP-154,526, a selective CRF1 receptor (CRF1R) antagonist, or genetic deletion of CRF1R (KO mice) have comparable effects on conditioned place preference (CPP) and conditioned place aversion (CPA) learning. We also investigated CP-154,526 effects on morphine-induced CPP activation of CRF, CREB phosphorylation, and thioredoxin (Trx1) expression in dentate gyrus (DG), a brain region involved in memory consolidation, and the role of hypothalamic-pituitary-adrenocortical (HPA) axis in CPA expression and extinction. The CRF1R antagonist abolished the acquisition of morphine CPP, Trx-1 and BDNF increased expression, and pCREB/Trx-1 co-localization in the DG. The increase in adrenocorticotropic hormone (ACTH) plasma levels observed after CPA expression was attenuated in CRF1R KO mice, suggesting a role of HPA axis in aversive memories. Altogether, these results suggest a critical role of CRF, through CRF1R, in molecular changes involved in memory formation and consolidation and may facilitate the development of effective treatments for opioid addiction.

For more than 50 years, oral vitamin K antagonists were the choice of anticoagulant for the long-term treatment and prevention of arterial and venous thromboembolic events. In recent years, four direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban and edoxaban have been compared with warfarin for thromboembolism prevention. These anticoagulants directly inhibit specific proteins within the coagulation cascade; in contrast, oral vitamin K antagonists inhibit the synthesis of vitamin K-dependent clotting factors. Dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban and edoxaban, the factor Xa inhibitors, produce a more predictable, less labile anticoagulant effect. DOACs do not have limitations inherent vitamin K antagonists. DOACs have a predictable pharmacokinetic profile and are free of advers drugs reactions inherent in vitamin K antagonists. However, it is necessary to take into account the pharmacogenetic characteristics of the individual that can affect effectiveness and safety of use of DOACs. The results carried out to the present fundamental and clinical studies of DOACs studies demonstrate an undeniable the influence of genome changes on the pharmacokinetics and pharmacodynamics of DOACs. However, the studies need to be continued. There is a need to plan and conduct larger studies in various ethnic groups with the inclusion of sufficient associative genetic studies of the number of patients in each of the documented groups treatments with well-defined phenotypes.

The Republic of Suriname (South America) is among the culturally, ethnically, and religiously most diverse countries in the world. Suriname’s population of about 600,000 consists of peoples from all continents including the Javanese who arrived in the country between 1890 and 1939 as indentured laborers to work on sugar cane plantations. After expiration of their five-year contract, some Javanese returned to Indonesia while others migrated to The Netherlands (the former colonial master of both Suriname and Indonesia), but many settled in Suriname. Today, the Javanese community of about 80,000 has been integrated well in Suriname but has preserved many of their traditions and rituals. This holds true for their language, religion, cultural expressions, and forms of entertainment. The Javanese have also maintained their traditional medical practices that are based on Jamu. Jamu has its origin in the Mataram Kingdom era in ancient Java, some 1300 years ago, and is mostly based on a variety of plant species. The many Jamu products are called jamus. The first part of this chapter presents a brief background of Suriname, addresses the history of the Surinamese Javanese as well as some of the religious and cultural expressions of this group, focuses on Jamu, and comprehensively deals with four medicinal plants that are commonly used by the Javanese. The second part of this chapter continues with an equally extensive narrative of six more such plants and concludes with a few remarks on the contribution of Javanese jamus to Suriname’s traditional medicinal pharmacopeia.

Gallium-68 was applied for positron emission tomography (PET) imaging already in the early beginnings of PET imaging. Today, with the introduction of PSMA-targeting tracers (e.g. PSMA-11, PSMA-617, and PSMA-I&T), the number of clinical applications of 68Ga-radiopharmaceuticals for diagnostic imaging has grown considerably. This development was initiated and supported already in the mid-2000s by the commercial availability of 68Ge/68Ga generators designed for clinical usage. This progression was accompanied by the development of several purification methods to generator eluate as well as sophisticated 68Ga-radiopharmaceuticals. Due to the 68Ga-rush, the need for implementation of gallium-68 (depending on production route) and its certain tracers into the pharmacopeia increased. Based on the specifications given by the pharmacopeia, interest focused on the development of automated synthesis systems, 99mTc-analog kits with regard to patient as well as operator safety.

The use of synthetic dyes began in 1865 with the discoveries of researcher William Henry Perkin. Its production and use only grew due to the high demand of several industrial sectors, mainly textiles. At the same time, concerns about environmental problems arose due to the disposal of wastewater with dyes, being the textile industry’s effluents the most polluting in the world. According to their structure, dyes can be more or less harmful, whereby azo dyes are the most worrisome from an environmental point of view. Problems, such as carcinogenicity, mutagenicity, and genotoxicity, are related to dyes, as well as contamination of water, and soil, and damages to agricultural plantations. Some of the methods used in the treatment of textile industrial effluents are membrane filtration, coagulation, chemical oxidation, biodegradation, photocatalytic degradation, phytoremediation, and enzymatic remediation. Enzyme remediation is considered an efficient, ecological, and innovative technique, through which enzymes can be used in free or immobilized form. The main enzymes involved in the degradation of azo dyes are azoreductases, laccases, and peroxidases. In some cases, harmful by-products are formed during the reactions and require proper management. Thus, this chapter addresses the main aspects of enzymatic bioremediation of dyes present in effluents from the textile industry.

Chinese herbal medicines (CHMs) have been widely used to promote health and treat illnesses in daily medical care throughout Asia while mostly accepted as an alternative medical method in many nations of the western world. CHM has a unique therapeutic effect to reduce adverse effects on cancer patients caused by chemotherapy and surgery; however, we did not find any high-quality review for the claimed effects. In this review, we will summarize the history, basic theories and principles, and clinical applications of CHM for disorders, especially female cancers. Meta-analyses to evaluate the efficacy and safety of CHM in the treatment of ovarian cancer and breast cancer have been conducted. The results showed that combined CHMs and western medicines treatment (CHM-WM) had significantly relieved the symptoms and reduced the side effects after surgery and chemotherapy on both ovarian cancer and breast cancer. However, more high-quality and large-scale RCTs are necessary to confirm the efficacy and safety of CHM-WM intervention.

Endocrine-disrupting activity induced by xenobiotics might pose a possible health threat. Facing so many chemicals, there is an issue on how we detect them precisely and effectively. The whole embryo culture (WEC) test, an ex vivo exposure lasting 48 hours with rat embryos of 10.5 days old, is used to detect prenatal developmental toxicity. We extended the WEC function to detect the endocrine-disrupting activity induced by environmental chemicals. Results showed that in the development of rat embryo, basically 17ß-estradiol, triiodothyronine, triadimefon, penconazole, and propiconazole exhibited no significant effect on yolk sac circulatory system, allantois, flexion, heart caudal neural tube, hindbrain, midbrain, forebrain, otic system, optic system, olfactory system, maxillary process, forelimb, hind limb, yolk sac diameter, crown-rump length, head length, and developmental score. In the immunohistochemistry, the positive control of 17ß-estradiol showed positive effect for its receptor expressions. These three triazoles induced expressions of ERα and ERß in WEC. This result basically meets the mode of action that triazoles were designed to disrupt the synthesis of steroid hormone. Here we gave a strategy to detect possible endocrine-disrupting activity induced by xenobiotics in food. This strategy is quick to initiate the whole rat embryo culture with 10.5 days to detect the hormone receptors such as androgen, estrogen, thyroid, aromatase activity and its related receptors.

Aspirin had been introduced as a nonsteroidal anti-inflammatory molecule. As further research on aspirin started, other therapeutic effects have been revealed. Now, this molecule has become the polychrest in medical science. Aspirin has served as a drug of choice for the primary prevention of cardiovascular disease (CVD) for the last few decades. However, recent trials have raised questions on the use of aspirin for CVD prevention due to some life-threatening adverse drug events. In spite of that, outcomes of trials will surely assist to frame a guideline for anoxic administration regimen of aspirin in order to prevent CVD.

Bisphenol A (BPA) has been used in many consumer products including plastics, and food packaging. There is the evidence that Bisphenol A have potential to cause oxidative stress by disturbing the redox status in cells. We have conducted the in vivo study of BPA and Ni(II) exposure to Rattus novergicus and confirmed the formation of DNA adduct 8-OHdG as biomarker of oxidative stress and cancer risk. Subacute dose of BPA (2 mg/kg BW) and Ni (II) metals (0.1 μg/kg BW) have been exposed to animal test for 28 days. We collected the urine sample of animal samples every week. The formation of 8-OHdG found in urine of animal samples monitored by Liquid Chromatography–Mass Spectrometry (LC–MS/MS). The result of this study indicates that levels of 8-OHdG in animal samples exposed to BPA and BPA-Ni (II) increase every week. However, levels of 8-OHdG in animal samples exposed by BPA-Ni (II) is less than levels of 8-OHdG in animal samples exposed by BPA only. This can be happened because Ni (II) given to animal samples are not in the excessed levels, therefore the synergic effect of BPA and Ni (II) has not already been seen. The hydroxyl radical can cause oxidative DNA damage and interact with DNA guanine base by producing DNA adduct 8-hydroxy-2′-deoxyguanosine (8-OHdG). This book aimed to obtain information regarding in vivo study of BPA and metal ions exposure can generate hydroxyl radical as a dominant form of Reactive Oxygen Species (ROS) that can interact with macromolecules such as DNA and form DNA adduct as biomarker of oxidative stress and cancer risk.

The visualization of abnormal parathyroid glands is difficult due to their variations in number and localization. Noninvasive parathyroid imaging studies include 99mTc-sestamibi scintigraphy, ultrasonography, computed tomography scanning, magnetic resonance imaging, and positron emission tomography. There is a general consensus that the most sensitive and specific imaging modality, especially when it is combined with single-photon emission CT is the scintigraphy with 99mTc-sestamibi or 99mTc-tetrofosmin. 99mTc-sestamibi scintigraphy significantly increases the role of preoperative scintigraphy in patients with hyperparathyroidism and allows unilateral surgical approach with minimally invasive parathyroidectomy to be used. Generally, three protocols with the use of two radiopharmaceuticals, 99mTc-sestamibi or 99mTc-tetrofosmin, are most widely applied: single-phase dual-isotope subtraction, dual-phase single-isotope and combination of both. Each one of them has specific advantages and disadvantages. While single parathyroid adenomas are localized with greater precision, hyperfunctioning parathyroid hyperplastic cells represent a real challenge to the imaging modalities. Several factors can influence the radionuclide uptake in pathologically changed parathyroid cells, like the size, the level of their functional activity, the quantity of oxyphilic cells, mitochondria, P glycoprotein and other MDR gene products.

The N-methyl-D-aspartate receptor (NMDAR), a glutamate-gated ion channel, mediates various physiological functions, such as synaptic plasticity, learning, and memory. Any homeostatic dysregulation of NMDAR may cause central nervous system (CNS) disorders, such as Alzheimer’s disease, depression, and schizophrenia. The involvement of NMDA dysfunction promotes advanced research on developing NMDAR pharmaceutics for treating CNS disorders. NMDAR enhancers, by direct or indirect potentiating NMDAR functions, have been used to recover NMDAR functions for treating schizophrenia. Interestingly, NMDAR blockers, by direct or indirect inhibiting NMDAR functions, have also been utilized for CNS disorders, such as Alzheimer’s disease and depression. In this chapter, the current strategy of NMDAR modulation for CNS disorders are elaborated on to discern underlying neurophysiological mechanisms of how homeostatic regulation of NMDAR plays a vital role in the normal and pathological states, respectively.

The Gamma-aminobutyric acid (GABA) system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates and is involved in critical cellular communication and brain function. The endocannabioid system (ECS) was only recenty discovered and quickly recognized to be abundantly expressed in GABA-rich areas of the brain. The strong relationship between the GABA system and ECS is supported both by studies of the neuraoanatomy of mammalian nervous systems and the chemical messaging between neurons. The ECS is currently known to consist of two endocannabinoids, Anandamide (AEA) and 2-Arachidonyl Glycerol (2-AG), that function as chemical messengers between neurons, at least two cannabinoid receptors (CB1 and CB2), and complex synthetic and degradative metabolic systems. The ECS differs from the GABA system and other neurotransmitter systems in multiple ways including retrograde communication from the activated post-synaptic neuron to the presynaptic cell. Together, this molecular conversation between the ECS and GABA systems regulate the homeostasis and the chemical messaging essential for higher cortical functions such as learning and memory and may play a role in several human pathologies. Phytocannabinoids are synthesized in the plant Cannabis sativa (C. sativa). Within the family of phytocannabinoids at least 100 different cannabinoid molecules or derivatives have been identified and share the properties of binding to the endogenous cannabinoid receptors CB1 and CB2. The well-known psychoactive phytocannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) are just two of the many substances synthesized within C. sativa that act on the body. Although the phytocannabinoids THC and CBD bind to these endogenous receptors in the mammalian CNS, these plant derived molecules have little in common with the endocannabinoids in structure, distribution and metabolism. This overlap in receptor binding is likely coincidental since phytocannabinoids evolved within the plant kingdom and the ECS including the endocannabinoids developed within animals. The GABA and ECS networks communicate through carefully orchestrated activities at localized synaptic level. When phytocannabinoids become available, the receptor affinities for CB1 and CB2 may compete with the naturally occurring endocannabinoid ligands and influence the GABA-ECS communication. In some instances this addition of phytocannabinoids may provide some therapeutic benefit while in other circumstances the presence of these plant derived ligands for the CB1 and CB2 receptors binding site may lead to disruption of important functions within the CNS. The regulatory approval of several THC products for nausea and vomiting and anorexia and CBD for rare pediatric seizure disorders are examples of some of the benefits of phytocannabinoids. Concerns regarding cannabis exposure in utero and in the child and adolescence are shrill warnings of the hazards associated with disrupting the normal maturation of the developing CNS.

Plants have been used as a source of medicine for the treatment of different diseases from thousands of years ago. There is numerous evidences are available for use of plants as a medicine in the treatment of diseases in Indian, Egyptian, Chinese, Greek and Roman system of medicine. Pharmacognosy is the study of medicines derived from natural sources, mainly from plants which may further lead to development of new drug. The exploration, extraction and screening of biological diversity such as herbs, spices, microbes and other natural resources is the worldwide activity in recent years. Phytochemicals are the naturally available bioactive compounds which are derived from different plant parts and are primarily responsible for biological activities. The most important chemical compounds which are present in the plants are alkaloids, phenols, saponins, carbohydrates, terpenoids, steroids, flavonoids and tannins etc.

Medicinal plants, bioactive compounds, and dietary measures have been found to be effective in the treatment of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). About 463 million people have diabetes worldwide; estimates project 700 million people by 2045. While T1DM is caused by the loss of beta cells of pancreatic islets that produce insulin, resulting in the deficiency of insulin, T2DM, which constitutes over 90 to 95% of all DM cases, is caused by insulin resistance, and could relatively combine reduction in the secretion of insulin. Aloe vera, Terminalia chebula, Perilla frutescens, Curcuma longa, Zingiber zerumbet, Nigella sativa, Gongronema latifolium, Pachira aquatic, Caesalpinioideae, Azadirachta indica, Artemisia dracunculus, Artemisia herbaalba, Vachellia nilotica, Abelmoschus moschatus, Cinnamomum verum, Salvia officinalis, Tinospora cordifoli, Pterocarpus, Ocimum tenuiflorum, Mangifera indica, Syzygium cumini, Coccinia grandis, Caesalpinia bonduc, Gymnema sylvestre, Carthamus tinctorius, Allium sativum, and Trigonella foenum-graecum are among the medicinal plants shown to be effective in controlling and treating T1DM and T2DM. Bioactive compounds such as lycopene, vitamin E, vitamin D, genistein, quercetin, resveratrol, epigallocatechin-3-gallate, hesperidin, naringin, anthocyanin, etc. are useful in treating T1DM and T2DM.

Metformin is one of oldest drug in reproductive medicine era; but most of times it is equal to polycystic ovary (PCO) syndrome especially obese patients. If it is still valuable or not, could have another health benefit or new fertility roles, and could be effective as well in male reproductive system will be discussed. According to increased rate of metabolic disorders and cardiovascular problems and cancers, there are several investigations on this old used drug. Those studies had been magnified its role as “the aspirin of current century,” which might have a promising role in longevity of the life. So, the chapter will be interesting.

The authors of this chapter point out that, although liposomal vesicles are widely used in cancer drug delivery systems, their limitations are also known. Therefore, more recently, new developments in modifications of liposomes have rapidly appeared to improve their parameters, including the maintenance of drugs in their structure, accumulation in target sites, and the active mechanism of drug release. Research on the effectiveness of existing liposomal carriers through their functionalization, allowed to propose a promising candidate for multifunctional nanoplatform based on liposomes and magnetic nanoparticles called magnetoliposomes. The presence of magnetic nanoparticles makes it possible to magnetically direct the liposomal carrier to the specific site, and appropriate magnetic field parameters can lead to controlled disintegration of the vesicle and release of the drug. The increasing variety of suggested platforms constantly provides new variants in the structure and mechanism of drug release, which enable the adjustment of the carrier’s characteristics to the specific needs of cancer therapy.

Several phytochemicals have been developed as medicinal compounds. Extensive research has recently been conducted on phytochemicals such as curcumin, resveratrol, catechin, gallic acid, humulone, quercetin, rutin, diosgenin, allicin, gingerenone-A, caffeic acid, ellagic acid, kaempferol, isorhamnetin, chlorogenic acid, and others. All of these phytochemicals are metabolized in the biological system. To study the metabolic pathways of phytochemicals, studies are done using both in vitro and in vivo techniques. Metabolism is critical in determining phytochemical bioavailability, pharmacokinetics, and effectiveness. Metabolism can occur in organs such as the intestine, liver, gut, and spleen. The metabolic process is aided by a variety of enzymes, including cytochrome P450 enzymes found in the organs. This study outlines a few phytochemicals metabolic pathways. Tannic acid, ellagic acid, curcumin, quercetin, and resveratrol are selected and explained as examples.

T cell activation plays a central role in inflammation, autoimmune diseases and cancer. Cancer immunotherapies, such as immune checkpoint inhibitor, bi-specific antibody, chimeric antigen receptor T (CAR T) cell, and adoptive tumor-infiltrating lymphocyte (TIL) therapies require the characterization and monitoring of T cell activation. Here we describe a novel, multiplex immune assay platform based on high-throughput flow cytometry technology and advanced computational algorithms for data analysis. The assay simultaneously measures T cell dynamics including phenotype, time-dependent expression of activation markers, secreted effector cytokines, and proliferation. The assay screened a kinase chemogenomic library and identified 25 kinase inhibitors with distinct inhibition profiles on early (CD69) and late (CD25) activation markers and the cytokines IFNγ and TNFα. We identified 5 kinase inhibitors with dissimilar effects on CD69 and CD25 expression, and a cluster of total 4 MEK1//2 inhibitors with similar activation profiles. The screening revealed 3 kinase inhibitors for PKC, IKK2, and MEK1/2 respectively, all with a phenotypic signature similar to ruxolitinib, a Jak1/2 inhibitor used to treat myelofibrosis disease. These results suggest this multiplexed assay platform, combined with a chemogenomic library screening, may be used as primary screen for phenotypic or target-based drug discovery, target identification, and potential drug repositioning.

Sharp blood circulation disorders are known for their capability to promote such abundant and hardly treatable pathologies as myocardium infarction and the ischemic brain stroke (“insult”). Noteworthy, the stroke — related brain tissue metabolic damages involve an essential ATP deplete clash along with a suppression of brain specific nucleotide — associated kinases and ATP synthase, both Mg2+ — dependent complex enzyme “machineries”. This itself makes the latter’s a legitimate target for some advanced pharmaceuticals as long as the drug — induced overstimulation of corresponding enzymatic activity is the case. Thus, magnetic isotope effects (MIE) of the nuclear spin possessing paramagnetic 25Mg2+ ions might modulate the brain creatine kinase, alfa-glycerophosphate kinase and pyruvate kinase catalytic activities in a way of a remarkable ATP hyperproduction required to compensate the hypoxia caused acute metabolic breakdown. To realize the Magnesium-25 pharmacological potential, a low-toxic amphiphilic cationite nanoparticles were introduced lately. Particularly, the Magnesium — releasing porphyrin-fullerene nanoadduct (cyclohexyl-C60-porphyrin, PMC16) has been proposed to meet expectations dealing with a targeted delivery of 25Mg2+ towards the brain ischemia surrounding areas. In order to optimize a multi-step [25Mg2+]4PMC16 preclinical trial scenario, the In Silico algorithms are to be developed and analyzed. In this study, these algorithms are in a focus with a special emphasize on a novel combination of slightly modified Gompertzian equation systems and a non-Markov population dynamics concept. This In Silico approach takes into account some literature-available patterns of brain hypoxia pathogenesis, the resulted simulation model could be considered as a promising tool for further research on experimental nanopharmacology of the ischemic stroke.

In vivo bioavailability studies are performed for new drug to establish essential pharmacokinetic parameters including rate of absorption, extent of absorption, rates of excretion and metabolism and elimination half-life after a single and multiple dose administration. These essential pharmacokinetic parameters are useful in establishing dosage regimens. Bioequivalence used to assess the expected in vivo biological equivalence of two proprietary preparations of drug products. If two drugs are bioequivalent, it means that they are expected to be same for all intents and purposes. In determining bioequivalence between two drugs such as a reference drug or brand and potential to be test drug or marketed generic drug. Pharmacokinetic studies are conducted whereby each of the drugs is administered in a cross over study to healthy volunteer’s subjects. Plasma is obtained at regular intervals and assayed for parent drug or metabolite concentration to compare the two drugs. For comparison purpose of two formulations, the plasma concentration data are used to assess key pharmacokinetic parameters. If 90% confidence interval for the ratio of the geometric least square means of peak plasma concentration, area under curve of test and reference drugs are within 80–125%, then bioequivalence will be established.