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Human epidermal growth factor receptor 2 (HER2) amplification or activating mutations are found in 1.6%–4% of non-small cell lung cancer (NSCLC). Pyrotinib has been reported to have better potency in NSCLC patients with HER2 exon 20 insertion (ex20ins) mutations; however, more clinical evidence is urgently needed to guide pyrotinib-based therapy in NSCLC with HER2 amplification or heterogeneous mutations. We retrospectively analyzed advanced NSCLC patients with HER2 amplification or mutations who were treated with pyrotinib-based therapy between September 25, 2018 and October 30, 2020 in our hospital. Molecular dynamics simulation was used to explore the bioactive conformation and binding mechanisms of pan-ErbB tyrosine kinase inhibitors (TKIs) including pyrotinib for different HER2 ex20ins variants. In this study, 79 eligible patients were included with 70 ex20ins variants, 6 missense mutations and 3 primary HER2 amplifications identified. A775_G776insYVMA insertion was the most common observed subtype. The median progression-free survival (mPFS) was 5.8 (95% CI: 4.1–7.4) months. Use of pyrotinib-based therapy in first-/second-line settings showed a significantly better prognosis than that observed in third-line settings or above (mPFS: 9.1 vs. 4.4 months; P = 0.0003). Compared with HER2 amplification and exon 20 non-YVMA insertion variants, patients with HER2 missense mutations had a visible mPFS benefit (12.2 vs. 6.8 vs. 5.2 months). Computational docking simulations revealed that pyrotinib failed to interact with the specific insertion variant P780_Y781insGSP. These results indicated that pyrotinib-based therapy exhibited good anti-tumor activity and acceptable safety profile in HER2-altered advanced NSCLC.

Gene editing via homology-directed repair (HDR) currently comprises the best strategy to obtain perfect corrections for pathogenic mutations of monogenic diseases, such as the severe recessive dystrophic form of the blistering skin disease epidermolysis bullosa (RDEB). Limitations of this strategy, in particular low efficiencies and off-target effects, hinder progress toward clinical applications. However, the severity of RDEB necessitates the development of efficient and safe gene-editing therapies based on perfect repair. To this end, we sought to assess the corrective efficiencies following optimal Cas9 nuclease and nickase-based COL7A1-targeting strategies in combination with single- or double-stranded donor templates for HDR at the COL7A1 mutation site. We achieved HDR-mediated correction efficiencies of up to 21% and 10% in primary RDEB keratinocytes and fibroblasts, respectively, as analyzed by next-generation sequencing, leading to full-length type VII collagen restoration and accurate deposition within engineered three-dimensional (3D) skin equivalents (SEs). Extensive on- and off-target analyses confirmed that the combined treatment of paired nicking and single-stranded oligonucleotides constituted a highly efficient COL7A1-editing strategy, associated with a significantly improved safety profile. Our findings, therefore, represent a further advancement in the field of traceless genome editing for genodermatoses.

The premise of the pharmacology of natural product is to explore benefits of natural resources for the mankind. Medicines extracted from natural resources are considered as primary source for drug discovery. Thus, the current study was designed to evaluate the safety profile and explore the analgesic and anti-inflammatory activity of ethanol extract of Cucurbita maxima (C. maxima) and Cucumis sativus (C. sativus) seeds. These seeds are edible, good in taste and have been used for several therapeutic purposes. Acute toxicity of the seeds was evaluated by Lorke's method while Eddy's hot plate and tail immersion methods were used to assess analgesic activity in mice. Anti-inflammatory activity was evaluated by rat hind paw edema method. The seed extracts of C. maxima and C. sativus were found to be safe and showed significant analgesic and anti-inflammatory activity in comparison with the control group. The therapeutic effects of these extracts were almost comparable to aspirin and brufen. Therefore, the seeds can be used as effective analgesic and anti-inflammatory agents.

Background: The quality of catheter-tissue contact is one of the most important determinants of catheter ablation (CA) success. The absence of catheter-tissue contact feedback has been regarded a major limitation of remote magnetic navigation (RMN)-guided CA. The e-Contact module (ECM) is a novel feature designed for RMN that measures the quality of catheter-tissue contact.Objective: The purpose of this study was to describe the first clinical experience with this feature and to test its effect on procedural parameters and interference with other ablation equipment during CA procedures as well as its safety.Methods: This was a prospective, single-center, 2-phase study investigating ECM use during complex RMN procedures in 30 patients. Impact of ECM on procedural parameters was evaluated in the feasibility phase (FP), and its interference with other equipment was tested in the interference phase (IP) using pacing maneuvers at 3 randomly selected right atrial sites. Intracardiac electrograms were evaluated for disturbances by 2 independent electrophysiologists.Results: For FP, mean procedural time was 162 ± 66 minutes, fluoroscopy time 21 ± 9 minutes, and ablation time 34 ± 21 minutes. For IP, no significant differences in pacing capture or thresholds were found (ECM- vs ECM+: site 1: 2.05 vs 2.21 mA; P = .320; site 2: 2.15 vs 2.12 mA; P = .873; site 3: 2.51 vs 2.50 mA; P = .976). Electrogram disturbances did not significantly differ between ECM- and ECM+. No adverse events were reported.Conclusion: The ECM is a novel catheter-tissue contact technology designed for RMN-guided CA. Our study suggests that this feature is feasible and does not interfere with other electrophysiology equipment while maintaining an excellent safety profile.

Ginseng products on the market show high variability in their composition and overall quality. This becomes a challenge for both consumers and health-care professionals who are in search of high-quality, reliable ginseng products that have a proven safety and efficacy profile. The botanical extract standardization is of crucial importance in this context as it determines the reproducibility of the quality of the product that is essential for the evaluation of effectiveness and safety. This review focuses on the well-characterized and standardized ginseng extract, G115, which represents an excellent example of an herbal drug preparation with constant safety and efficacy within the herbal medicinal products. Over the many decades, extensive preclinical and clinical research has been conducted to evaluate the efficacy and safety of G115. In vitro and in vivo studies of G115 have shown pharmacological effects on physical performance, cognitive function, metabolism, and the immune system. Furthermore, a significant number of G115 clinical studies, most of them double-blind placebo-controlled, have reinforced the findings of preclinical evidence and proved the efficacy of this extract on blood glucose and lipid regulation, chronic obstructive pulmonary disease, energy, physical performance, and immune and cognitive functions. Clinical trials and 50 years of presence on the market are proof of a good safety profile of G115. Keywords: Blood glucose and lipid regulation, Chronic obstructive pulmonary disease, Energy and physical performance, G115 standardized ginseng extract, Immune and cognitive functions

Plant-based therapy has been used and accepted globally for a plethora of human ailments. While the basis of acceptance of herbal drugs lies in its safety profile, recent research in the field of complicated diseases has led to the fact that herbal biomolecules are equally potent for the treatment of such diseases in both acute and chronic cases. Besides, stringent policies regulating the standardization, manufacture, and sale of herbal products have been formulated so that the use of such products can be ascertained with surety and safety. Knowledge about herb–drug interactions, possible adverse effects, and mechanism of drug action are other important considerations to be kept in mind. Factors such as pharmacovigilance, pharmacokinetic, and bioavailability parameters have to be sufficiently validated and updated for better patient compliance and acceptability. The field of phytopharmacology is rapidly emerging with increasing focus on the targeted herbal phytomolecules. This chapter deals with such important plant biomolecules that have been found to be effective against important diseases pertaining to cardiovascular, central nervous system, antimicrobial, antiinflammatory, oncology, and hepatic ailments.

Aim Doxorubicin/Cyclophosphamide (AC) is one of the standard adjuvant anthracycline-containing regimens that is still in use for breast cancer treatment. Cancer cell resistance and AC-induced side effects make treatment suboptimal and worsen patients’ quality of life. This study aimed to improve trans-ferulic acid’s (TFA) efficiency via loading into folate-receptor-targeted-poly lactic-co-glycolic acid nanoparticles (FA-PLGA-TFA NPs). Also, investigating both the antitumor efficacy of Doxorubicin (Dox)/FA-PLGA-TFA NPs combination against dimethylbenz[a]anthracene (DMBA)-induced breast cancer and its safety profile. Methods FA-PLGA-TFA NPs were optimally fabricated and characterized. Levels of Notch1, Hes1, Wnt-3a, β-catenin, MMP-9, cyclin D1, Permeability-Glycoprotein (P-gp), ERα, PR, and HER2 were assessed as a measure of the antitumor efficacy of different treatment protocols. Histopathological examination of heart and bone, levels of ALT, AST, ALP, CK-MB, and WBCs count were evaluated to ensure the combination’s safety profile. Key findings Dox/FA-PLGA-TFA NPs not only inhibited Notch signaling but also suppressed Notch synergy with Wnt, estrogen, progesterone, and HER2 pathways. Interestingly, Dox/FA-PLGA-TFA NPs decreased P-gp level and preserved heart, bone, and liver health as well as WBCs count. Significance Dox/FA-PLGA-TFA NPs reduced the side-effects of each single drug, and at the same time exerted excellent antitumor activity that surpass the AC regimen in evading cancer cell resistance and having a superior safety profile.

Vaccination against viral and bacterial pathogens represents a challenging issue in allergic subjects, mainly concerning patients undergoing allergen immunotherapy (AIT). For this reason, an international survey has been performed involving a panel of experts who responded to a series of questions, also concerning the COVID-19 impact on allergen immunotherapy and vaccinations. The results showed that co-administration of vaccines and AIT requires caution, mainly during the pandemic era. Moreover, the choice of AIT product should be oriented considering also the safety profile.

Purpose Previous studies suggest that stereotactic body radiation therapy (SBRT) is associated with higher toxicity rates for central lung tumors relative to peripheral tumors when using 3 fraction SBRT. The initial results from Radiation Therapy Oncology Group study 0813 suggest a safe toxicity profile of SBRT administered in 5 fractions for central non-small cell lung cancer (NSCLC). We reviewed our institutional data to evaluate the safety and efficacy of SBRT for central NSCLC. Methods and materials We reviewed our prospectively collected SBRT database for patients with central NSCLC who received SBRT between 2008 and 2014. The most frequent dose and fractionations were 50 Gy in 5 fractions (59%) and 48 Gy in 4 fraction (30%). Local control (LC), regional control, metastasis-free survival, and overall survival were calculated using Kaplan-Meier estimates. The National Cancer Institute Common Terminal Criteria for Adverse Events were used for toxicity grading. Results A total of 110 central lung tumors in 103 patients were included. The median age was 74 years (range, 40-95 years), and the median follow-up time of living patients was 50 months. The mean tumor size was 20 mm (range, 5-70 mm). The 5 year rate of LC, regional control, and distant control was 89%, 77%, and 82%, respectively. The median and 5-year overall survival were 3.5 years and 35%, respectively. No treatment variables were associated with tumor control or other clinical outcomes. A single patient experienced grade 3 radiation pneumonitis (0.97%). The rate of late toxicity grade ≥3 was 9.7% (grade 3, 7.7%; grade 4, 0.97%; grade 5, 0.97%) and included pneumonitis (3.9%), bronchial necrosis (2.9%), myocardial dysfunction (1.9%), and worsening heart failure (0.97%). Conclusions SBRT for central NSCLC provides high rates of LC. Despite excellent LC, patients remain at risk for regional and distant failure. The rate of grade 3 pneumonitis was consistent with that of prior reports. We observed low rates of grade 4-5 toxicity potentially attributable to SBRT. Our results contribute to the growing body of data in support of the safety of SBRT for central NSCLC.

Pyrolytic carbon (PyC) is a form of elemental carbon. Its favourable mechanical and biochemical properties mean it is well suited for a number of medical applications from cardiac valves to a bearing surface for joint arthroplasty. In this chapter we examine the material properties of PyC including its manufacture, safety profile and biocompatibility, structural characteristics, the bone prosthesis interface, and the articulating surface. An understanding of the material properties can help us to evaluate benefits as well as the potential shortcomings of PyC for use in joint arthroplasty.

Psoralen plus ultraviolet A (PUVA) photochemotherapy refers to the use of psoralen and ultraviolet A (320–400 nm) radiation for treatment. This is administered either orally or topically. Both are administered 2 to 3 times weekly, with dosing dependent on skin phototype or minimal phototoxic dose. The primary indication for PUVA is psoriasis and cutaneous T-cell lymphoma, in addition to numerous other papulosquamous dermatoses, vitiligo, pruritus, and some photodermatoses. Over the last few decades, narrow-band ultraviolet B (UVB) has emerged as the standard of care and preferred method of phototherapy because of equal or superior clinical efficacy, ease of administration, and short- and long-term safety profile. Excimer laser/lamp (308 nm) and ultraviolet A (UVA)-1 are other less commonly used forms of phototherapy, primarily indicated for smaller body surface areas of less than 10% and sclerodermoid dermatoses, respectively.

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Major depressive disorder is one of the leading causes of disability in the world with the emergent need for newer strategies of treatment. Repetitive transcranial magnetic stimulation (rTMS) is one of the newer strategies to manage resistant depression. Theta-burst stimulation (TBS) is a new protocol to deliver the pulses of transcranial magnetic stimulation, either intermittently (iTBS) or continuously (cTBS). Studies suggest that the effectiveness of theta-burst stimulation is non-inferior to conventional rTMS with a comparable tolerability profile. In 2018, the FDA has approved the use of TBS in treating depression. TBS provides the added advantage of less time needed for its administration. TBS seems to be a promising treatment strategy for depression with the need for proper guidelines for its administration, stimulation parameters, and safety profile.

The favorable physicochemical properties and excellent safety profile of biopolymers have enabled their extensive applications in biomedical applications, specifically in drug delivery. Smart biopolymers have especially gained a lot of attention because of their programmable drug release capacity in response to specific stimuli or alterations in their surrounding environment. The stimuli-responsive element of these smart biopolymers undergoes structural or conformational changes in response to physical, biological stimuli, or signals that arise from pathological abnormalities, enabling targeting and self-controlled release of therapeutics under desired physiological conditions. Although slow response time to stimulus is one of the major drawbacks of these polymers, fine-tuning can be done using a combinational approach due to their varying adaptability and source of origin. Therefore in this chapter, we have discussed several types of smart polymeric systems, including thermosensitive, pH-sensitive, phase-sensitive, light-sensitive, and bioresponsive polymers. We have also highlighted recent applications of these systems in controlled drug delivery.

Chemotherapy resistance is a common occurrence in women who have undergone treatment for epithelial ovarian cancer. Combination chemotherapy, while helpful in delaying the development of resistance, carries increased toxicity and a poorer safety profile. As a result, numerous studies are investigating additional pharmacological targets, combination therapies, and repurposed agents for ovarian cancer treatment. This chapter summarizes clinical studies investigating novel combination therapies and targeted treatments that may hold promise in future clinical applications.

Drug-induced toxicity poses a significant challenge for late-stage attrition of drugs. Potential drug candidate safety profile needs to be monitored closely to avoid adverse drug reactions. As of 2020, pharmaceutical companies and regulators in many countries rely on in vitro and in vivo testing. Although this approach provides researchers with necessary data, it has certain disadvantages. Certain types of toxicity remain undetected in the nonclinical phase due to physiological and metabolic variability between humans and other species and synergistic effects. Sitaxentan is an example of a drug that is not hepatotoxic in animal trials but causes significant liver injury in humans.

Intracranial dural arteriovenous fistulas (dAVFs) can be divided into aggressive and nonaggressive subtypes by their presentation and venous outflow. Stereotactic radiosurgery is a minimally invasive treatment option for cerebral dAVF with an excellent safety profile and moderately high eventual obliteration rates for appropriately chosen patients. Radiosurgery is predominantly utilized for cases of nonaggressive dAVF or for patients in whom endovascular or surgical treatment is at an unacceptably high risk; however, the main limitation of radiosurgery is the latency period. This chapter reviews stereotactic radiosurgery for cerebral dAVFs including common indications and considerations.

Herbal remedies have long been used to treat or alleviate symptoms in several pathologies or disorders. As stated by the World Health Organization, almost 80% of Asian and African populations use herbal products against various diseases. In addition, isolation of bioactive compounds/secondary metabolites has led to introduction of several novel candidates with interesting pharmacological properties. In this overview, acute and subchronic toxicities of medicinal plants and secondary metabolites are presented, based on the main chemical constituents of the examined extracts, namely flavonoids, polyphenols, and terpenes. A literature review showed that very few studies have investigated exposure periods longer than 90 days. Extract characterization was conducted in the vast majority of the reviewed studies and toxicological evaluations were performed in both sexes only in one species (mostly in rats). Toxic effects were mostly attributed to the presence of secondary metabolites. One of the main limitations of the present review is that in most cases, it was not clearly mentioned whether the examined part of the plant was the one used by the traditional medicines of the region, and the tested doses are not directly correlated with those of real-life exposure, while the solvents/methods of extracts preparation in the reviewed studies are not necessarily the same with those employed by the traditional medicine practitioners. It seems that, despite the general conception, herbal medicine should be practiced more cautiously. On the other hand, well-designed studies are required to assess the safety profiles of such herbal products in other species and with the appropriate animal protocols, for longer periods and in combination with chemicals to which humans are daily exposed as scarce data is available on chemical interactions of herbal products with other daily consumer products.

Pleural infection is a common clinical condition leading to hospitalisation. In the last decade, advances in pleural research have led to a paradigm shift in the treatment of complex effusion from a surgical approach to a less invasive non-surgical approach using a combination of intrapleural fibrinolytics and pulmozyme (DNase). We report 3 patients with pleural infection. Intercostal chest catheter failed to drain the complex effusion. They were subsequently treated with a modified short-course regimen of alteplase and DNase. They received 3 cycles of 16 mg alteplase with 5 mg DNase each within 24 hours and all three had a favourable outcome with no adverse effects. This modified regimen appears effective with good safety profile and adds to the current literature on the safety and effectiveness of different dose combinations of alteplase and DNase.

Introduction: Compared to surgery there is no evidence on bronchoscopic lung volume reduction (LVR) in patients with fading benefit after LVR surgery. CASE REPORT: We present a case of 64-year old female patient who was successfully treated with bronchial thermal vapor ablation (BTVA) after previous ineffective lung volume reduction (LVR) surgery several months earlier. CONCLUSIONS: Bronchoscopic LVR, in particular BTVA, might be considered in patients with fading or missing effects after previous LVRS. At least, the safety profile of BTVA seems not be adversely affected by previous LVRS, when proper patient selection and procedure planning are ensured.

Psoriasis, a chronic inflammatory skin disease, is characterized by abnormal differentiation and hyperproliferation of epidermal keratinocytes, inflammatory infiltration and increased skin vascularization. Despite their clinical efficacy, the current antipsoriatic drugs have a poor safety profile as they are responsible for a wide range of side effects such as skin irritation, teratogenicity, hepatotoxicity, nephrotoxicity, myelosuppression and even disease rebound after cessation. Recent studies highlighted that natural products derived from plants and marine organisms contain scaffold structures that can be exploited for the development of novel antipsoriatic drugs. Pure constituents isolated from plants and marine sponges, belonging to different chemical classes: alkaloids, cyclopeptides, flavonoids, furanocoumarins, organic acid derivatives, polyphenols, sphingolipids and terpenoids, and their analogues have been investigated for their antipsoriatic activity in different experimental models. The chapter reviews natural products derived from plants and marine organisms and their analogues which, based on their bioactivities and virtual screening studies, appear to be potential candidates for the development of novel antipsoriatic drugs.

Acalypha integrifolia Willd (Euphorbiaceae) is a monoecious shrub. The species is endemic to the Mascarenes, and this subspecies is endemic to the Mascarenes islands of Reunion and Mauritius. The leaves are used as part of alternative medicine on both islands. Herbalists recommend a decoction of the leaf for their anthelmintic and depurative properties but also for various dermatological pathologies. However, although the leaf is commonly administered orally, scientific evaluation of its efficacy, phytochemical, and safety profile for human consumption is scarce. The reported biological activity has focused on the in vitro antibacterial and antifungal properties. This chapter presents a general view of the botanical description, ethnomedicinal uses, and antimicrobial properties of the Indian Ocean A. integrifolia subspecies.

Natural cyclodextrins (CDs) and their chemically modified derivatives are used nowadays as enabling pharmaceutical excipient capable to increase aqueous solubility of lipophilic drugs, enhance drug chemical stability, reduce volatility, mask unpleasant taste, reduce side effects, and enhance bioavailability, thereby further enabling therapeutic potential and the efficiency of drugs. This chapter provides a brief overview of the CDs chemistry, safety profile, and regulatory status. The mechanism of inclusion complex formation and its fate upon administration to the body is concisely described. The examples of CD-based products in clinical practice and development aimed for parenteral, ocular, nasal, oral, oromucosal, and (trans)dermal administration are presented, critically discussing the benefits and limitations related to CD application in the dosage form development. Finally the use of CDs as novel therapeutically active agents is presented.

More than 100 types of autoimmune disorders have been identified so far, and most of them are usually chronic in nature. Multiple agents are known to have a role in causing autoimmunity, including genetic, epigenetic, immunologic, hormonal, and environmental factors. The available therapies for autoimmune disorders are associated with low efficacy, unfavorable safety profile, and high cost; thus there is always a need for a better drug in this respect. Epigenetics has been a novel target for drug discovery since the past few years. Altering expression of noncoding RNAs, DNA methylation, and histone modifications are prime targets for epigenetic drug development. Drugs with epigenetic targets are already in widespread use. Natural and synthetic compounds have been extensively studied for their ability to regulate epigenetics as their therapeutic targets, and they could be ideal sources for the development of epigenetic drugs in the future for the treatment of autoimmune disorders. This chapter focuses on the translational evidence for the role of histone modifications in disease prevention and treatment.

Pulmonary vein isolation is the cornerstone of atrial fibrillation ablation and is effective for preventing arrhythmias recurrences, especially in patients with paroxysmal atrial fibrillation. During the last years, cryoballoon ablation has emerged as an unquestionable alternative approach to radiofrequency ablation. Many non-randomized and randomized trials have proven undoubtedly that cryoballoon ablation displays similar efficacy and overall safety profile, when compared to radiofrequency ablation for the treatment of patients with drug-refractory paroxysmal atrial fibrillation. These results have been obtained in all types of pulmonary veins anatomical subsets, which confirms that there is no need to select patients according to the latter. The value of cryoablation in the setting of short persistent atrial fibrillation still needs more evidence. Importantly, cryoballoon ablation seems to be less operator-dependent and more reproducible than radiofrequency for the isolation of pulmonary veins. Keywords: Atrial fibrillation, Ablation, Cryoablation

Mucormycosis are a group of infections that affect principally immunocompromised host and have a high mortality. Liposomal amphotericin B is the first-line treatment with combined surgical removal of the infectious focus. We report the case of 67-year-old man with idiopathic granulocytic aplasia and a cutaneous lesion caused by Rhizopus arrhizus treated with isavuconazole. Its safety profile and spectrum of activity make it an important therapeutic option. Keywords: Mucormycosis, Cutaneous, Immunocompromised, Isavuconazole

Lung cancer is the leading cause of cancer-related death in both men and women. Several types of nanocarriers have succeeded in delivering both chemotherapeutic agents and genes to lung tumor sites. Among them, solid lipid nanoparticles (SLNs) are newly emerging surrogates to traditional colloidal delivery systems which hold great promise in achieving drug localization at the site of action via both passive and active targeting based on their unique features to incorporate hydrophilic or hydrophobic payloads in addition to proteins and nucleic acids. SLNs open novel frontiers for prolonged and site-specific drug and gene delivery. This chapter emphasizes the role of SLNs in drug and gene delivery via different routes of administration (intravenous, oral, or inhalation). In addition, it highlights the safety profile of biocompatible SLNs that are highly tolerable by the lungs for lung cancer management.

Most cardiovascular magnetic resonance (CMR) examinations use a gadolinium-based contrast agent. This chapter provides a broad overview of MR contrast agents in the context of cardiovascular imaging. The effect of an MRI contrast agent on T1 and T2 relaxation and the biophysical mechanisms that underpin paramagnetically induced nuclear relaxation are described. There are nine FDA-approved MR contrast agents, and this chapter describes these contrast agents and how they are used in CMR applications. The chapter also provides an overview of the state of the art in newly emergent contrast agents for cardiovascular molecular imaging. Finally, the safety of MR contrast agents is reviewed with a discussion of the established and newly emergent toxicity concerns associated with gadolinium, a comparison of the relative safety profile of the commercially available agents, and a review of known adverse drug reactions.

Osteoarthritis is the most common form of joint disease and the cause of pain and disability. Management of osteoarthritis primarily focuses on the relief of symptoms, using analgesics and nonsteroidal antiinflammatory drugs. These drugs, however, are associated with significant side effects and fail to slow the progression of osteoarthritis. There is currently no disease-modifying osteoarthritis drug. Several dietary nutrients have been shown to play a role in reducing the symptomatic and/or structural progression of osteoarthritis. A number of dietary supplements have been tested in clinical trials and shown to be more effective than placebos and at least as effective as nonsteroidal antiinflammatory drugs at relieving the symptoms of osteoarthritis. Preliminary evidence suggests that several dietary supplements may have a role in affecting the course of osteoarthritis. The safety profile of dietary supplements makes them an attractive treatment for osteoarthritis. This chapter reviews the available literature on the efficacy and safety of dietary nutrients and supplements for the management of osteoarthritis.

The objective of this chapter is to provide an overview of safety planning and monitoring along with the analysis and communication of clinical trial safety data. Safety planning requires an assessment of the available information relevant to the safety of the product including epidemiology data, nonclinical and clinical data, and information on related products. Ongoing benefit risk assessments of the investigational medical product are achieved through the frequent evaluation of data from all available sources. Quantitative and qualitative analyses are performed using statistical methodologies and medical judgment on data at the level of individual clinical trial as well as aggregate data level of product. These analyses aim to distinguish adverse drug reactions from adverse events and to determine the important risks for the product. Regulatory reporting and communication of safety information to the health authorities, institutional review boards, ethics committees, clinical trial investigators and subjects are also discussed. A systematic approach to product safety monitoring throughout clinical development is critical to characterizing the evolving safety profile of an investigational medical product.

Gastrointestinal (GI) adverse events are one of the most common adverse drug reactions in humans, often affecting patient quality of life and compliance and having the potential to impede drug development. Although the GI system is not listed as one of the core safety pharmacology organ systems in the S7A International Conference on Harmonization guidelines, the effect(s) of new pharmaceuticals on the GI system should still be characterized. This chapter begins by providing an overview of some assays that can be used to screen and rank order compounds to enable selection of a lead molecule with a favorable GI profile. It then explains how nonclinical observations of drug-induced emesis (vomiting) and diarrhea can interfere with characterizing the safety profile of other organ systems. Potential mitigation strategies for managing GI issues and a high-level overview of future directions of the field for safety pharmacologists will be discussed.

Biomolecule separation is critical to the field of biotechnology. Biomolecules include a broad diversity of primary and secondary metabolites with distinct structures and functionalities that provide an excellent platform for production of pharmaceuticals, fine chemicals, food additives, cosmetics, and advanced materials. However, efficient isolation and purification of biomolecules from natural matrices and fermentation broths represent the bottleneck of the downstream production process. Common methods involve solvent-based extractions, including conventional liquid–liquid or solid–liquid extraction and more advanced microwave- and ultrasound-assisted extraction. In this context, solvent selection remains the key factor in developing cost-effective and environmentally friendly separation processes for biomolecule recovery. Traditionally, extraction techniques rely on harmful volatile organic compound solvents subject to increasing regulations in the chemical, food, and consumer goods industries. Recently, neoteric solvents with improved environmental, health, and safety profile have emerged as promising alternatives for sustainable processing in biotechnological applications. This chapter provides a critical overview of recent advances and future trends in green solvents for bioseparations, focusing on ionic liquids, deep eutectic solvents, and biobased solvents for extraction of representative biomolecules. Furthermore, modern solvent selection tools will be reviewed to provide a comprehensive framework toward designing the next generation of sustainable bioseparation processes.

Phytotherapeutics with their multitarget mode of action and a generally favorable safety profile offer valuable options in an integrative diabetes management. This includes diabetes prevention and glycemic control as well as prevention and treatment of diabetes-associated diseases. The pathogenic processes, especially in the development of secondary diabetic complications, are discussed and examples of single plant phytotherapeutics as well as multiherbal formulations are presented according to their use in different stages of diabetes and its complications.

Past two decades have witnessed a rapid progress in medical therapy for ulcerative colitis (UC), particularly availability and wide application of antitumor necrosis factor and anti-integrin biological agents for the treatment of moderate-to-severe UC. While corticosteroids are used as induction agents and immunomodulators are administered as maintenance agents, the biological agents have been applied for both induction and maintenance therapy. For mild UC, mesalamine agents, which carry a favorable safety profile, are routinely used for both induction and maintenance therapy. In addition to the conventional therapy, a variety of “alternative” agents have been explored and used for the treatment of mild, moderate, or severe UC, including calcineurin inhibitors, nicotine, probiotics, antibiotics, and fecal microbiota transplantation. In addition, a list of small molecule, pathway-targeted agents are being investigated.

For both malignant and benign intracranial lesions, laser thermal interstitial therapy is considered a safe treatment option. In the difficult treatment of patients who are not candidates for open surgery due to deep inaccessible tumors, medical comorbidities, or extensive prior intracranial treatment placing them at higher risk for postoperative complications, minimally invasive treatment strategies such as laser thermal ablation are considered. Novel technological innovations in real-time magnetic resonance imaging-based temperature and ablation monitoring have enhanced the effectiveness and safety profile of laser interstitial thermal therapy (LITT). Such enhanced safety measures have made viable the use of LITT in the treatment of varying pathologies such as glioma, brain metastases, radiation necrosis, dural-based lesions, and epilepsy. This chapter examines the technological underpinings, described indications, imaging qualities, and limitations of laser thermal ablation in the treatment of malignant gliomas.

In a clinical setting, where multiple administrations of the therapeutic agent are usually required to improve the therapeutic outcome, it is crucial to assess the immunogenicity of the administered nanoparticles. In this data work, we investigated the safety profile of the repeated intravenous administration of brain-targeted stable nucleic acid lipid particles (RVG-9r-targeted SNALPs). To evaluate local activation of the immune system, we performed analysis of mouse tissue homogenates and sections from cerebellum. To investigate peripheral activation of the immune system, we used serum of mice that were intravenously injected with RVG-9r-targeted SNALPs. These data are related and were discussed in the accompanying research article entitled “Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado–Joseph disease neurological phenotype” (Conceição et al., in press) [1].

Introduction: Country-specific information on paediatric GH therapy is available from multi-national studies. Methods: A total of 1294 children in Spain enrolled in the observational Genetics and Neuroendocrinology of Short-stature International Study (GeNeSIS). Adverse events were assessed in all GH-treated patients (n = 1267) and effectiveness in those with GH deficiency (GHD, 78%). Results: Mean age at time of entry to the study was 9.8 years. GH was initiated at a median (Q1–Q3) 0.22 (0.20−0.25) mg/kg/week and administered for 2.8 (1.6–4.4) years. For 262 patients with GHD and 4-year data, mean (95% CI) height velocity was 4.3 (4.1–4.6) cm/year at baseline, 9.0 (8.7–9.4) cm/year at 1-year, and 5.5 (5.2–5.8) cm/year at 4-years. Height standard deviation score (SDS) was −2.48 (−2.58 to −2.38) at baseline and −1.18 (−1.28 to −1.08) at 4 years. Final height SDS minus target height SDS (n = 241) was −0.09 (−0.20 to 0.02). In 1143 GH-treated patients with ≥1 year follow-up, 93 (8.1%) reported treatment-emergent adverse events. Serious events were reported for 7 children, with 2 considered GH-related. Conclusion: These data confirm the benefit of GH replacement therapy on height gain for the patients in Spain. The safety profile was consistent with that already known for GH therapy. Resumen: Introducción: La información específica de cada país sobre el tratamiento pediátrico con hormona de crecimiento (GH) proviene de estudios multinacionales. Métodos: En España, 1.294 niños participaron en el estudio internacional y observacional sobre genética y neuroendocrinología de la talla baja (GeNeSIS). En los pacientes tratados con GH (n = 1.267) se evaluaron los acontecimientos adversos. En aquellos con deficiencia de GH (DGH, 78%) también se evaluó la efectividad. Resultados: La media de edad al inicio del estudio fue 9,8 años. La mediana (Q1-Q3) de duración del tratamiento fue 2,8 (1,6-4,4) años y la dosis inicial de GH 0,22 (0,20-0,25) mg/kg/semana. En 262 pacientes con DGH con datos a 4 años, la velocidad media (IC 95%) de crecimiento fue 4,3 (4,1 a 4,6) cm/año al inicio; 9,0 (8,7 a 9,4) cm/año tras un año y 5,5 (5,2 a 5,8) cm/año a los 4 años. La puntuación de desviación estándar (SDS) de talla fue —2,48 (—2,58 a —2,38) al inicio y −1,18 (−1,28 a −1,08) a los 4 años. La SDS de talla final menos la SDS de talla diana (n = 241) fue −0,09 (−0,20 a 0,02). De 1.143 pacientes tratados con GH con seguimiento ≥1 año, 93 (8,1%) comunicaron acontecimientos adversos surgidos durante el tratamiento. En 7 niños se comunicaron acontecimientos adversos graves, que en 2 casos se consideraron posiblemente relacionados con GH. Conclusión: La terapia de sustitución con GH fue efectiva para el aumento de talla en los pacientes españoles. El perfil de seguridad fue acorde con el ya conocido para el fármaco.

Nutritional iron deficiency anemia is the most common deficiency disorder, affecting more than two billion people worldwide. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia, but in many conditions, oral iron is less than ideal mainly because of gastrointestinal adverse events and the long course needed to treat the disease and replenish body iron stores. Intravenous iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell made of polymers such as dextran, sucrose or gluconate. The first iron product for intravenous use was the high molecular weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to use intravenous iron for the treatment of iron deficiency anemia over many years. Intravenous ferric carboxymaltose is a stable complex with the advantage of being non-dextran-containing and a very low immunogenic potential and therefore not predisposed to anaphylactic reactions. Its properties permit the administration of large doses (15mg/kg; maximum of 1000mg/infusion) in a single and rapid session (15-minute infusion) without the requirement of a test dose. The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, and safety profile of ferric carboxymaltose in the treatment of patients with iron deficiency anemia.

Plants with healing properties have long been used in different traditional medicinal systems worldwide. The everlasting interest in medicinal plants for curing various ailments evolved out of necessity and experience. Plants exemplify a rich source of a wide variety of secondary metabolites and conspicuously many of the conventional drugs that are currently used are from herbs. Regardless of their consistent use, the stringent challenge faced by phytomedicines is the lack of scientific evidence for their mode of action and safety profile in vivo. This necessitates the conduct of meticulously planned toxicity studies based on stipulated guidelines to claim the safety of medicinal plants used in various traditional practices. In addition, those herbal drugs prepared from combinations of different medicinal plants must be proved for their nontoxic outcomes. Hence there is an impending requirement to compile information on the probable adverse reactions of medicinal plants before formulating and marketing them as herbal drugs.

A single multifunctional gold nanoparticle (NP)–based platform incorporating multiple receptor targeting, multimodality imaging, and multiple therapeutic entities in a close interaction with near-infrared (NIR) laser technologies is able to revolutionize cardiology and provides the ultimate “magic bullet” for interventional vascular biomedicine. The certain progress of the photothermal technologies through the last 12 years allows us to dream about the new horizons in the research and development of new approaches for theranostics of atherosclerosis. First scientific achievements of Prof. Naomi Halas from Rice University (Houston, TX) released in 1998–99 and then in 2003 have developed new solutions to research and engineering problems beyond traditional disciplinary boundaries with a focus on infrared properties of gold and NIR thermal therapy of tumors with the noble metal NP under magnetic resonance guidance. Then Prof. Zahi Fayad (Mount Sinai, New York, NY) in 2010 tried to explore the plaque composition with the targeted gold NP and multicolor computed tomography. The successful results of the bench and clinical studies of the plasmonic photothermal therapy of atherosclerosis with the acceptable safety and efficacy profile were published in 2012–17 by the group of Dr. Alexander Kharlamov (De Haar Research Foundation, Rotterdam, The Netherlands—New York, NY; Ural Federal University, Yekaterinburg, Russia; Ural Institute of Cardiology, Yekaterinburg, Russia) and then validated by the team of Prof. Stanislav Emelianov (The University of Texas at Austin, Austin, TX) in 2013 simultaneously testing intravascular photoacoustics. The similar idea of the photoangioplasty of atherosclerosis or correctly photodynamic therapy with motexafin lutetium was announced in 2000 by the group of Dr. Stanley G. Rockson (Stanford University, Stanford, CA) without further development. The bioresorbable NPs have a chance to upgrade the field and solve concerns of nanotoxicity. The photothermal theranostics with the optimal safety profile was examined in experiments of both Tucker-Schwartz's (Vanderbilt University, Nashville, TN) and Wang's team (Soochow University, Suzhou, Jiangsu, China) of 2012 with the noble metal coated single-walled carbon nanotubes for applications in surface-enhanced Raman scattering imaging, optical coherence tomography, magnetic resonance tomography, and therapy as well as in the developments of bioresorbable electronic stent/scaffold in 2015 (Son D et al., Institute for Basic Science, Seoul, Republic of Korea). Recently, conducting polymers (e.g., polyaniline, PEDOT:PSS—poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, polypyrrole) have emerged as a new type of NIR photothermal therapy and imaging agent. The intravenously injected sugar-based amphiphilic NPs at the experiments of Dr. Lewis DR (Rutgers University, Piscataway, NJ) in 2015–16 showed a pronounced increase in lesion association compared with the control NPs, causing a significant reduction in neointimal hyperplasia, lipid burden, cholesterol clefts, and overall plaque occlusion. A statin-loaded reconstituted high-density lipoprotein (HDL) NP can inhibit atherosclerotic plaque inflammation. Dr. Duivenvoorden R et al. (Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands) in 2014 developed a reconstituted HDL NP as a vehicle to deliver statins directly to atherosclerotic plaques. So, the number of achievements and developments in nanomedicine is rocketing today, but without clear destination for the real-world cardiovascular medicine. The tools of the systems in biomedicine reveal the lack of the proper multifunctional nanoformulations and medical devices to reach all the expectations of the real clinical practice. The new wave of the discoveries heralding the achievements of the running fourth industrial revolution promises to solve these options with the combination of the approaches such as transient scaffolding, sensing, and multifunctional NPs detecting vulnerable lesions and degrading atherosclerotic plaques with the highest efficacy and safety for a patient.

© Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved., Left ventricular endomyocardial biopsy (LV-EMB) may offer a superior diagnostic yield compared with right ventricular endomyocardial biopsy (RV-EMB) in conditions predominantly affecting the LV but is underused compared with RV-EMB. Despite the steep uptake of radial approach in coronary interventions, LV-EMB is usually performed via the femoral artery in contemporary practice. Therefore, the aim of this study was to assess the safety and feasibility of LV-EMB via a transradial approach in a multicentre registry., Contexte La biopsie endomyocardique du ventricule gauche (BEM-VG) peut offrir un rendement diagnostique supérieure à celui de la BEM du ventricule droit (BEM-VD) dans des troubles qui touchent principalement le ventricule gauche (VG), mais est sous-utilisée par rapport à la BEM-VD. Malgré l’augmentation rapide de l’utilisation de la voie radiale dans les interventions coronariennes, la BEM-VG s’effectue en général par l’artère fémorale dans la pratique contemporaine. Par conséquent, l’objectif de cette étude était d’évaluer, à partir d’un registre multicentrique, la sûreté et la faisabilité de la BEM-VG par la voie transradiale. Méthodologie Cent deux patients qui avaient subi une BEM-VG par l’approche transradiale ont été inclus. Les caractéristiques cliniques et les données relatives à l’intervention, à l’innocuité et à la faisabilité ont été analysées. Résultats La BEM-VG a été effectuée avec succès par la voie transradiale chez 101 (99 %) patients. Spasme radiale légère ou modérée s’est produit chez 12 (12 %) patients, mais la conversion en voie fémorale n’a été nécessaire que chez 1 (0,98 %) patient en raison d’un spasme sévère. Au total, 80 (78 %) patients ont subi une BEM-VG au moyen d’un cathéter guide sans gaine d’introducteur (sheathless). Pour ces interventions, le diamètre externe du guide sans gaine d’introducteur inséré était de 7,5 French chez 77 (96,3 %) patients et de 8,5 French chez 3 (3,8 %) patients. Un introducteur radiale a été utilisé chez les 22 autres patients, d’un diamètre externe de 5 French chez 21 de ces derniers. Une dose médiane de 5000 (3000–5000) unités internationales (UI) d’héparine a été administrée à 93,1 % des patients. Pour les autres patients, une stratégie provisoire a été appliquée en fonction de l’obtention d’une hémostase manifeste. Aucune complication liée à la voie d’accès n’a été rapportée. Il n’y a eu aucune complication majeure (tamponnade péricardique, arythmie potentiellement mortelle, accident vasculaire cérébral ou décès). Conclusion Dans une population de patients ayant subi une BEM-VG par la voie transradiale, le taux de succès de l’intervention a été élevé et présentait un excellent profil d’innocuité. Des études ultérieures portant sur la comparaison des voies transradiale et transfémorale pourraient être utiles pour contribuer à populariser le recours à la voie transradiale dans les BEM-VG.

The advent of recombinant DNA technology has had a huge impact on bioprocessing, as any chapter in this handbook would attest. The same holds true for vaccines, even though the reputation of vaccine manufacturing outside the industry is that of an ancient art. Many of the commonly used anchor vaccines—pediatric vaccines for diphtheria, tetanus, and pertussis and the annual influenza shot—originated well before the advent of rDNA technology. However, manufacturing processes for modern vaccines have evolved alongside those for rDNA human therapeutics. From variolation, to Edward Jenner, the father of modern vaccinology, to Louis Pasteur, the pioneer of the germ theory of disease, to John Enders, who established virus growth in cell culture, and finally to recombinant and conjugate vaccines, the evolution of vaccines is a rich story of the triumphs of medicine. Early vaccines were often reactogenic, largely due to use of whole pathogens and impurities in the preparations, leading to newer vaccines that are characterized by a higher purity and a better safety profile. The evolution in vaccines reflects advancements in vaccine immunology, micro- and molecular biology, molecular etiology, process and formulation development and analytical characterization, and has been extensively documented Plotkin et al. [1]. This chapter attempts to outline contemporary production practices in the vaccine industry. Although not exhaustive, we include those strategies that have been employed in licensed vaccines, and those that are in development. Vaccines have had a major impact on human health, and have been an incredibly cost efficient instrument in the healthcare system, elevating in relevance in an era where we see an increased focus on the cost of health care.