Cannabinoids for Cancer-related Pain Management: An Update on Therapeutic Applications and Future Perspectives.

Pain is a debilitating phenomenon that dramatically impairs the quality of life of patients. Many chronic conditions, including cancer, are associated with chronic pain. Despite pharmacological efforts that have been conducted, many patients suffering from cancer pain remain without treatment. To date, opioids are considered the preferred therapeutic choice for cancer-related pain management. Unfortunately, opioid treatment causes side effects and inefficiently relieves patients from pain, therefore alternative therapies have been considered, including Cannabis Sativa and cannabinoids. Accumulating evidence has highlighted that an increasing number of patients are choosing to use cannabis and cannabinoids for the management of their soothing and non-palliative cancer pain and other cancer-related symptoms. However, their clinical application must be supported by convincing and reproducible clinical trials. In this review, we provide an update on cannabinoid use for cancer pain management. Moreover, we tried to turn a light on the potential use of cannabis as a possible therapeutic option for cancer-related pain relief.

Medicinal Cannabis: Extended Stability of Cannabis Extracts Produced Using a New Ethanol-based Extraction Method.

Cannabis as a therapeutic agent is increasing in popularity all around the globe, particularly in Western countries, and its potential is now well assessed. On the other hand, each country has its own regulation for the preparation of cannabis macerated oils; in Italy, there are only a few preparation methods allowed. With this work, we aim to perform a stability study of cannabis oils produced with a novel method for the extraction of cannabinoids from cannabis inflorescence. Three different varieties of cannabis were used, with and without the adding of tocopherol acetate as an antioxidant. Cannabinoids were extracted using ethanol at room temperature; then, the solvent was evaporated under reduced pressure and the preparations reconstituted with olive oil. In this work, we assessed the stability of both cannabinoids and terpenes in these formulas over 8 months. Cannabinoid stability was assessed by monitoring the concentrations of THC and CBD, while terpene stability was assessed by monitoring ß-Caryophyllene and α-Humulene concentrations. Stability of the extracts was not influenced by the presence of tocopherol acetate, though refrigeration seems to be detrimental for a long storage of products, especially regarding THC concentrations. The improvements offered by this method reside in the flexibility in controlling the concentration of the extract and the ability to produce highly concentrated oils, alongside the possibility to produce standardized oils despite the variability of the starting plant material.

Wireless Peripheral Nerve Stimulation for The Upper Limb: A Case Report.

Peripheral neuro-stimulation (PNS) has been proved to be effective for the treatment of neuropathic pain as well as other painful conditions. We discuss two approaches to PNS placement in the upper extremity. The first case describes a neuropathic syndrome after the traumatic amputation of the distal phalanx of the fifth digit secondary to a work accident with lack of responsiveness to a triple conservative therapy. An upper arm region approach for the PNS was chosen. The procedure had a favorable outcome; in fact, after one month the pain symptoms were absent (VAS 0) and the pharmacological therapy was suspended. The second case presented a patient affected by progressive CRPS type II in the sensory regions of the ulnar and median nerve in the hand, unresponsive to drug therapy. For this procedure, the PNS device was implanted in the forearm. Unfortunately, in this second case the migration of the catheter affected the effectiveness of the treatment. After examining the two cases in this paper, we changed our practice and suggest the implantation of PNS for radial, median and/or ulnar nerve stimulation in the upper arm region, which has significant advantages over the forearm region.

Phytocannabinoids in Triple Negative Breast Cancer Treatment: Current Knowledge and Future Insights.

Triple negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, which is deficient in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Thus, TNBC cells are unable to respond to the conventional hormonal therapies, making chemotherapy the only therapeutic choice. Patients with TNBC develop metastasis and recurrence over time and have reduced survival compared to patients with other subtypes of breast cancer. Therefore, there is a need for innovative therapies. Data emerged from pre-clinical studies, highlighted various antitumor activities of plant-derived Cannabis sativa and synthetic cannabinoids (CBs), including delta-9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD). On the contrary, some studies indicated that CBs might also promote tumor progression. At present, clinical studies on the effects of CBs from Cannabis sativa in cancer patients are few. In the present study, we reviewed known and possible interactions between cannabinoids and TNBC therapies.

THE "NEAPOLITAN SCHOOL OF ELECTROTHERAPY" BETWEEN THE LATE NINETEENTH AND THE FIRST DECADES OF THE TWENTIETH CENTURY

Electrotherapy is the use of electrical energy as a medical treatment. In the nineteenth century, the "golden age" of electrotherapy, the development of this discipline was part of a historical-scientific context characterized by the affirmation of neurology as an autonomous branch and, finally, detached from psychiatry. After a period of limited scientific interest and development, in the second half of the 20th century, electrotherapy underwent a revival. Nowadays, the use of electrotherapy has been researched and accepted in various fields of medicine, including but not limited to rehabilitation, neurology, pain management, and oncology. From its first applications, electrotherapy joined neurology which used it for both diagnostic and therapeutic purposes. In Italy, several scientists carried out experiments on the subject, and an important contribution to the development of the discipline was provided by the "Neapolitan school of electrotherapy". This improvement was made above all by Francesco Vizioli (1834- 1899) and his pupil Francesco Paolo Sgobbo (1860-1936). Despite these premises, however, the decline of electrotherapy as an autonomous science soon came. Meanwhile, radiology, associated initially with electrotherapy, developed rapidly. When Mario Bertolotti (1876- 1957), former professor of Radiology at the University of Turin and one of the founders of Italian radiology, succeeded Sgobbo in 1935, the name (and the discipline) "electrotherapy" was deleted from the diction of the new chair, and from that of the department, which was indicated only as "Radiology". Radiodiagnostic devices, supplies, and roentgen therapy equipment replaced the numerous devices used for electrotherapy. This manuscript is focused on the Neapolitan school of electrotherapy from the late nineteenth century to the beginning of the twentieth. The work of the leading figures who have given the greatest impetus to the study and application of electrotherapy is described. Finally, the electrotherapy devices used are briefly illustrated.

An Overview on the Potential Roles of EGCG in the Treatment of COVID-19 Infection.

Coronavirus disease-19 (COVID-19) pandemic is currently ongoing worldwide and causes a lot of deaths in many countries. Although different vaccines for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been developed and are now available, there are no effective antiviral drugs to treat the disease, except for Remdesivir authorized by the US FDA to counteract the emergency. Thus, it can be useful to find alternative therapies based on the employment of natural compounds, with antiviral features, to circumvent SARS-CoV-2 infection. Pre-clinical studies highlighted the antiviral activities of epigallocatechin-3-gallate (EGCG), a catechin primarily found in green tea, against various viruses, including SARS-CoV-2. In this review, we summarize this experimental evidence and highlight the potential use of EGCG as an alternative therapeutic choice for the treatment of SARS-CoV-2 infection.

Potential Antiviral Drugs for SARS-Cov-2 Treatment: Preclinical Findings and Ongoing Clinical Research.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), initially termed 2019-new CoV (2019-nCoV), is a novel coronavirus responsible for the severe respiratory illness currently ongoing worldwide from the beginning of December 2019. This beta gene virus, very close to bat coronaviruses (bat-CoV-RaTG13) and bat-SL-CoVZC45, causes a severe disease, similar to those caused by Middle East respiratory syndrome (MERS)-CoV and SARS-CoV viruses, featured by low to moderate mortality rate. Unfortunately, the antiviral drugs commonly used in clinical practice to treat viral infections, are not applicable to SARS-Cov-2 and no vaccine is available. Thus, it is extremely necessary to identify new drugs suitable for the treatment of the 2019-nCoV outbreak. Different preclinical studies conducted on other coronaviruses suggested that promising clinical outcomes for 2019-nCoV should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs. Moreover, clinical trials with these suitable drugs should be performed on patients affected by SARS-Cov-2 to prove their efficacy and safety. Finally, a very promising therapeutic drug, tocilizumab, is discussed; it is currently used to treat patients presenting COVID-19 pneumonia. Herein, we recapitulate these experimental studies to highlight the use of antiviral drugs for the treatment of SARS-Cov-2 disease.

Physician Attitudes and Perceptions of Complementary and Alternative Medicine (CAM): A Multicentre Italian Study.

Purpose: Complementary and Alternative Medicine (CAM) interventions are widely used by patients with chronic disorders, including cancer, and may interact with cancer treatment. Physicians are often unaware of this, probably due to poor patient-physician communication on CAM. The purpose of this study was to evaluate physicians' knowledge, attitudes and practice patterns regarding CAM in a survey conducted in Italy. Methods: A questionnaire was administered to 438 physicians (11 Italian hospitals) who predominantly treat patients with chronic disease, to collect personal and professional data and information on attitudes toward CAM and its possible role in Conventional Medicine (CM). Results: Of the 438 participants, most were specialists in oncology (18%), internal medicine (17%), surgery (15%), and radiotherapy (11%). Most worked at university (44%) or research hospitals (31%). Forty-two percent of participants believed that CAM could have an integrative role within CM. Oncologists were the physicians who were best informed on CAM (58%). Physicians working at research institutes or university hospitals had a greater knowledge of CAM than those employed at general hospitals (p < 0.0001), and those who were also involved in research activity had a greater knowledge of CAM than those who were not (p < 0.003). Length of work experience was significantly related to CAM knowledge. Moreover, 55% of participants suggest CAM interventions to their patients and 44% discuss CAM with them. The best-known interventions were acupuncture, Aloe vera and high-dose vitamin C. Conclusion: CAM use by patients with chronic disease and/or cancer has become a topical issue for the scientific community and for physicians. Knowing the reasons that prompt these patients to use CAM and guiding them in their decisions would improve treatment and outcomes and also benefit healthcare systems. Our findings contribute to a greater understanding of CAM knowledge, attitudes, and practice among Italian physicians. Further research is needed to identify the more effective CAM treatments and to work toward an integrated healthcare model.

Dissecting the roles of thymoquinone on the prevention and the treatment of hepatocellular carcinoma: an overview on the current state of knowledge.

Thymoquinone (TQ) is the principal active monomer isolated from the seed of the medicinal plant Nigella sativa. This compound has antitumor effects against various types of cancer including hepatocellular carcinoma (HCC), mainly due to its anti-inflammatory and anti-oxidant properties. Several pre-clinical studies showed that TQ, through the modulation of different molecular pathways, is able to induce anti-apoptotic and anti-proliferative effects in HCC, without signs of toxicity. Moreover, it has been suggested that TQ has hepatoprotective effects by enhancing the tolerability and effectivity of neoadjuvant therapy prior to liver surgery, although the underlying mechanisms are not completely understood. Based on these findings, is assumable that TQ could represent a valuable therapeutic option for patients suffering from HCC. In this review, we summarize the potential roles of TQ in the prevention and treatment of HCC, by revising the preclinical studies and by highlighting the potential applications of TQ as a therapeutic choice for HCC treatment into clinical practices.

Epigallocatechin-3-gallate in the prevention and treatment of hepatocellular carcinoma: experimental findings and translational perspectives.

Hepatocellular carcinoma (HCC), a primary liver malignancy, is one of the deadliest cancers worldwide. Despite orthotopic liver transplantation and hepatic resection representing the principal lines of treatment for this pathology, only a minority of patients can be resected owing to cirrhosis or late diagnosis. Keeping in mind the end goal of conquering these challenges, new alternative approaches have been proposed. Accumulating evidence has demonstrated that epigallocatechin-3-gallate (EGCG), the principal catechin of green tea with multiple biological properties, is able to modulate different molecular mechanisms underlying HCC, mainly through its antioxidant activity. In this article, we revise these findings reported in the literature, in order to highlight the potential roles of EGCG in the treatment of HCC. The CAMARADES criteria were applied for quality assessment of animal studies, and a narrative synthesis performed. New bits of information available for translational perspectives into clinical practice are addressed.

The roles of epigallocatechin-3-gallate in the treatment of neuropathic pain: an update on preclinical in vivo studies and future perspectives.

Neuropathic pain (NP) is a complex and chronic disease caused by lesions or defects of the somatosensory nervous system. The treatments normally used for managing NP usually lack efficacy. Several animal models of NP have been engineered in order to understand the molecular mechanisms underlying NP and to find alternative molecules to use as new therapeutic agents. Preclinical in vivo studies identified the epigallocatechin-3-gallate (EGCG), a main active component of green tea (Camellia sinensis), as a possible therapeutic molecule for NP treatment due to its anti-inflammatory and antioxidant properties. Interestingly, it has been shown that EGCG reduced bone cancer pain. The purpose of this article is to discuss the potential use of EGCG for control and treatment of NP, by reviewing the preclinical studies reported in the literature and by shedding light on the potential schemes based on EGCG's application in clinical practices.

An overview of pre-clinical studies on the effects of (-)-epigallocatechin-3-gallate, a catechin found in green tea, in treatment of pancreatic cancer

Human pancreatic cancer is one of the leading causes of mortality and morbidity worldwide. Despite surgical resection remains the only curative therapeutic treatment for this disease, only the minority of patients can be resected due to late diagnosis. Recently, new chemotherapy schemes with the combination of different drugs have been shown to improve disease-free survival, although best results were obtained mostly as neoadjuvant chemotherapy in the minority of patients with resectable tumor. Consequently, there is stimulated interest in new chemotherapeutic approaches and alternative medicines. Several studies showed that the use of natural compounds, such as phytochemicals, represents a promising strategy for pancreatic cancer treatment. One popular phytochemical with great anticancer properties, is the (-)-epigallocate-chin3-O-gallate (EGCG), the most abundant catechin found in green tea. Accumulating evidences demonstrated that EGCG induces apoptosis and inhibits tumor progression by modulating different signaling pathways in pancreatic cancer. For these encouraging results, this catechin is currently used in clinical trials for treatment of various type of cancer and other diseases, although its poor bioavailability and poor stability represent severe limitations. Therefore, many researchers tried to develop a new strategy based of the use of nanotechnology which increases EGCG stability and bioavailability and simultaneously targets cancer cells in order to improve its anti-tumor effects. The aim of this article is to dissect the use of EGCG for management of pancreatic cancer, by reviewing the pre-clinical studies reported in literature.

The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer's disease: an overview of pre-clinical studies and translational perspectives in clinical practice.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia characterized by cognitive and memory impairment. One of the mechanism involved in the pathogenesis of AD, is the oxidative stress being involved in AD's development and progression. In addition, several studies proved that chronic viral infections, mainly induced by Human herpesvirus 1 (HHV-1), Cytomegalovirus (CMV), Human herpesvirus 2 (HHV-2), and Hepatitis C virus (HCV) could be responsible for AD's neuropathology. Despite the large amount of data regarding the pathogenesis of Alzheimer's disease (AD), a very limited number of therapeutic drugs and/or pharmacological approaches, have been developed so far. It is important to underline that, in recent years, natural compounds, due their antioxidants and anti-inflammatory properties have been largely studied and identified as promising agents for the prevention and treatment of neurodegenerative diseases, including AD. The ester of epigallocatechin and gallic acid, (-)-Epigallocatechin-3-Gallate (EGCG), is the main and most significantly bioactive polyphenol found in solid green tea extract. Several studies showed that this compound has important anti-inflammatory and antiatherogenic properties as well as protective effects against neuronal damage and brain edema. To date, many studies regarding the potential effects of EGCG in AD's treatment have been reported in literature. The purpose of this review is to summarize the in vitro and in vivo pre-clinical studies on the use of EGCG in the prevention and the treatment of AD as well as to offer new insights for translational perspectives into clinical practice.

Role of Nigella sativa and Its Constituent Thymoquinone on Chemotherapy-Induced Nephrotoxicity: Evidences from Experimental Animal Studies.

BACKGROUND: Most chemotherapeutic drugs are known to cause nephrotoxicity. Therefore, new strategies have been considered to prevent chemotherapy-induced nephrotoxicity. It is of note that Nigella sativa (NS), or its isolated compound Thymoquinone (TQ), has a potential role in combating chemotherapy-induced nephrotoxicity. AIM: To analyze and report the outcome of experimental animal studies on the protective effects of NS/TQ on chemotherapy-associated kidney complications. DESIGN: Standard systematic review and narrative synthesis. DATA SOURCES: MEDLINE, EMBASE databases were searched for relevant articles published up to March 2017. Additionally, a manual search was performed. Criteria for a study's inclusion were: conducted in animals, systematic reviews and meta-analysis, containing data on nephroprotective effects of NS/TQ compared to a placebo or other substance. All strains and genders were included. RESULTS: The database search yielded 71 studies, of which 12 (cisplatin-induced nephrotoxicity 8; methotrexate-induced nephrotoxicity 1; doxorubicin-induced nephrotoxicity 2; ifosfamide-induced nephrotoxicity 1) were included in this review. CONCLUSIONS: Experimental animal studies showed the protective effect of NS, or TQ, on chemotherapy-induced nephrotoxicity. These effects are caused by decreasing lipid peroxidation and increasing activity of antioxidant enzymes in renal tissue of chemotherapy-treated animals.

Potential application of the Kampo medicine goshajinkigan for prevention of chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and severe adverse effects related to cancer treatment. Unfortunately, although several agents and protocols have been proposed, no prophylactic strategies have yet to be proven useful. Therefore, new alternative therapies have been considered for CIPN prevention. Herbal medicine in Japan, called Kampo medicine, is derived from traditional Chinese medicine. Goshajinkigan (GJG) is a Kampo medicine, that is comprised of ten herbs. The aim of this work is to analyse the results of pre-clinical and clinical studies on the potential applications of GJG in CIPN prevention.

Features and Role of Minimally Invasive Palliative Procedures for Pain Management in Malignant Pelvic Diseases: A Review.

Pain is a common and debilitating symptom in pelvic cancer diseases. Failure in controlling this pain through pharmacological approaches calls for employing multimodal management and invasive techniques. Various strategies are commonly used for this purpose, including palliative radiotherapy, epidural medications and intrathecal administration of analgesic and local anesthetic drugs with pumps, and neural or plexus blockade. This review focuses on the features of minimally invasive palliative procedures (MIPPs), such as radiofrequency ablation, laser-induced thermotherapy, cryoablation, irreversible electroporation, electrochemotherapy, microwave ablation, and cementoplasty as well as their role in palliation of cancer pelvic pain. Despite the evidence of effectiveness and safety of these interventions, there are still many barriers to accessing MIPPs, including the availability of trained staff, the lack of precise criteria of indication, and the high costs.

Multidisciplinary approach and anesthetic management of a surgical cancer patient with methylene tetrahydrofolate reductase deficiency: a case report and review of the literature.

INTRODUCTION: Hyperhomocysteinemia is a known risk factor for myocardial infarction, stroke, peripheral vascular disease, and thrombosis. Elevated plasma homocysteine levels have been demonstrated in patients with recurrent episodes or a single episode of thrombosis. Here we describe the development of cardiovascular disease as a complication of a surgical intervention in a patient with colorectal cancer and hyperhomocysteinemia. CASE PRESENTATION: A 65-year-old Caucasian man complained of pain and constipation, attributed to previously diagnosed adenocarcinoma (stage IIB) of the hepatic flexure. An anamnestic investigation showed that he had undergone two surgical interventions. During both, he suffered thrombotic postoperative complications, a deep vein thrombosis of the upper extremity after the first operation and retinal vein occlusion after the second. He was diagnosed with hyperhomocysteinemia associated with a homozygous C677T mutation of the gene encoding the enzyme methylenetetrahydrofolate reductase. Our patient was initially treated with folic acid and high-dose B vitamins. On day 7 he underwent a right hemicolectomy. Anesthesia was performed with sevoflurane in 40% O2 and without the use of nitrous oxide. Postoperatively, our patient remained on folic acid and B vitamins and was without immediate or subsequent complications. CONCLUSIONS: Neoplastic disease and related surgery followed by the administration of chemotherapeutic drugs alter the hemostatic balance in cancer patients. Those suspected of also having a thrombophilic disease require a thorough laboratory diagnostic workup, including a molecular analysis aimed at identifying the genetic mutation responsible for the hyperhomocysteinemia, as indicated. The case described in this report highlights the importance of a multidisciplinary approach that includes expertise in peri-operative anesthesia, surgery, oncology, and hematology.

The Experiments on Electrical Anesthesia in Italy in the Second Half of the Nineteenth Century. A Dispute Between a Fearless Surgeon Patriot and a Positivist Researcher.

Electric anesthesia is the anesthesia, usually general anesthesia, produced by the application of an electrical current. This fascinating issue of the anesthesia history was made possible thanks to the pioneering experiments on electrotherapy and electrophysiology performed by two researchers: the neurologist Guillaume Duchenne (1806-1875) and the biologist Stéphane Leduc (1853-1939). The aim of this study is the review of the dispute between two Italian scientists on the effectiveness of electric anesthesia in the second half of the 19th century. One of the two contenders was Rodolfo Rodolfi (1827-1896), an Italian surgeon and patriot who took part in the First Italian War of Independence of 1848, whereas the other protagonist of the dispute was the positivist Plinio Schivardi (1833-1908), a pupil of Duchenne who brought to Italy his knowledge of electrotherapy, collecting these experiences in the Theoretical Practical Manual of Electrotherapy, the first book on the subject written in Italian.