Occurrence Of Severe Side Effects Research Articles

Integrated computational analysis, in vitro, in vivo investigation on Myristica fragrans Houtt. essential oils for potential anti rheumatic activities

Rheumatoid arthritis (RA) is an inflammation associated autoimmune disorder that is prevalent worldwide. Occurrence of severe side effects with current therapeutic regimens is major concern these days. We investigated Myristica fragrans mace and seed for management of inflammation and RA. Oils were extracted and analyzed using ATR-FTIR conforming occurrence of the aromatic amine, phenolic, and carboxylic acid groups mostly found in terpenoids. Most of tested compounds exhibited compliance with drug likeness, bioavailability and ADMET set parameters of safety. Molecular docking analysis showed interaction (-0.6 ΔG (kJ mol-1) of Myristicin with 4F5S. A significant antioxidant activity with DPPH, H2O2 and FRAP assays was observed in case of essential oil. Essential oil part also presented a significant protective effect during heat induced hemolysis (66 ± 1.0 %), BSA denaturation assay (61 ± 1.4 %) and higher levels of proteinase inhibition (70 ± 1.4 %). Acute antiflammatory model in rat presented a significant decrease in inflammation with essential oil. It was concluded that Myrictica fragrans essential oil possess significant (p < 0.005) anti-inflammatory potential that can play a key role in management of RA.

Novel half Salphen cobalt(III) complexes: synthesis, DNA binding and anticancer studies.

While platinum(II)-based drugs continue to be employed in cancer treatments, the escalating occurrence of severe side effects has spurred researchers to explore novel sources for potential therapeutic agents. Notably, cobalt(III) has emerged as a subject of considerable interest due to its ubiquitous role in human physiology. Several studies investigating the anticancer effects of Salphen complexes derived from cobalt(III) have unveiled intriguing antiproliferative properties. In a bid to enhance our understanding of this class of compounds, we synthesized and characterized two novel half Salphen cobalt(III) complexes. Both compounds exhibited notable stability, even in the presence of physiologically relevant concentrations of glutathione. The application of spectroscopic and computational methodologies unravelled their interactions with duplex and G4-DNAs, suggesting an external binding affinity for these structures, with preliminary indications of selectivity trends. Importantly, antiproliferative assays conducted on 3D cultured SW-1353 cancer cells unveiled a compelling anticancer activity at low micromolar concentrations, underscoring the potential therapeutic efficacy of this novel class of cobalt(III) complexes.

A Phase 2 Study of Docetaxel, Ramucirumab, and Pembrolizumab for Patients With Metastatic or Recurrent Non–Small-Cell Lung Cancer (NSCLC) who Progressed on Platinum-Doublet and PD-1/PD-L1 Blockade

BackgroundThere is an urgent and unmet need for more effective treatment options for patients with metastatic and recurrent non–small-cell lung cancer (NSCLC) who progressed on platinum-based therapy, immune checkpoint inhibitors (ICI), and targeted therapies. Currently, the combination of docetaxel (D) and ramucirumab (R) is the next best salvage therapy with a modest historical progression free survival (PFS) of 4.5 months and 6-month PFS rate of 37% predating the era of ICI use. Anecdotal reports in patients who progressed on ICI suggest a higher response rate to docetaxel compared to historical experience. Furthermore, tumor related angiogenesis promotes tumor growth and may contribute to immune escape in patients treated with ICI. Therapeutic combination with anti-angiogenic, ICI, and chemotherapy have independently demonstrated clinical efficacy without additive toxicities in NSCLC patients. Patients and methodsThis multicenter, single arm, open label, phase 2 study will evaluate the safety and preliminary efficacy of the combination of docetaxel 75 mg/m2, ramucirumab 10 mg/kg, and pembrolizumab 200 mg in up to 41 patients with metastatic or recurrent NSCLC after progression on concomitant or sequential platinum-based chemotherapy and ICI. This treatment will be given intravenously on the same day every 3 weeks until disease progression, occurrence of severe side effects, or no clinical benefit. The primary endpoint is 6-month PFS rate. ConclusionsThis is the first study to evaluate the safety and efficacy of ICI combined with docetaxel and ramucirumab. The findings could provide valuable information for developing new treatment strategies for NSCLC patients.

Phosphodiesterase‑4 inhibitors: a review of current developments (2013–2021)

ABSTRACT Introduction Cyclic nucleotide phosphodiesterase 4 (PDE4) is responsible for the hydrolysis of cAMP, which has become an attractive therapeutic target for lung, skin, and severe neurological diseases. Here, we review the current status of development of PDE4 inhibitors since 2013 and discuss the applicability of novel medicinal-chemistry strategies for identifying more efficient and safer inhibitors. Areas covered This review summarizes the clinical development of PDE4 inhibitors from 2013 to 2021, focused on their pharmacophores, the strategies to reduce the side effects of PDE4 inhibitors and the development of subfamily selective PDE4 inhibitors. Expert opinion To date, great efforts have been made in the development of PDE4 inhibitors, and researchers have established a comprehensive preclinical database and collected some promising data from clinical trials. Although four small-molecule PDE4 inhibitors have been approved by FDA for the treatment of human diseases up to now, further development of other reported PDE4 inhibitors with strong potency has been hampered due to the occurrence of severe side effects. There are currently three main strategies for overcoming the dose limitation and systemic side effects, which provide new opportunities for the clinical development of new PDE4 inhibitors.

Development of highly stable and de-immunized versions of recombinant alpha interferon: Promising candidates for the treatment of chronic and emerging viral diseases

Human interferon alpha (hIFN-α) administration constitutes the current FDA approved therapy for chronic Hepatitis B and C virus infections. Additionally, hIFN-α treatment efficacy was recently demonstrated in patients with COVID-19. Thus, hIFN-α constitutes a therapeutic alternative for those countries where vaccination is inaccessible and for people who did not respond effectively to vaccination. However, hIFN-α2b exhibits a short plasma half-life resulting in the occurrence of severe side effects. To optimize the cytokine's pharmacokinetic profile, we developed a hyperglycosylated IFN, referred to as GMOP-IFN.Given the significant number of reports showing neutralizing antibodies (NAb) formation after hIFN-α administration, here we applied the DeFT (De-immunization of Functional Therapeutics) approach to develop functional, de-immunized versions of GMOP-IFN. Two GMOP-IFN variants exhibited significantly reduced ex vivo immunogenicity and null antiproliferative activity, while preserving antiviral function. The results obtained in this work indicate that the new de-immunized GMOP-IFN variants constitute promising candidates for antiviral therapy.

Current Perspectives on Taxanes: Focus on Their Bioactivity, Delivery and Combination Therapy.

Taxanes, mainly paclitaxel and docetaxel, the microtubule stabilizers, have been well known for being the first-line therapy for breast cancer for more than the last thirty years. Moreover, they have been also used for the treatment of ovarian, hormone-refractory prostate, head and neck, and non-small cell lung carcinomas. Even though paclitaxel and docetaxel significantly enhance the overall survival rate of cancer patients, there are some limitations of their use, such as very poor water solubility and the occurrence of severe side effects. However, this is what pushes the research on these microtubule-stabilizing agents further and yields novel taxane derivatives with significantly improved properties. Therefore, this review article brings recent advances reported in taxane research mainly in the last two years. We focused especially on recent methods of taxane isolation, their mechanism of action, development of their novel derivatives, formulations, and improved tumor-targeted drug delivery. Since cancer cell chemoresistance can be an unsurpassable hurdle in taxane administration, a significant part of this review article has been also devoted to combination therapy of taxanes in cancer treatment. Last but not least, we summarize ongoing clinical trials on these compounds and bring a perspective of advancements in this field.

A review on potential drug delivery system as a treatment of intercellular bacterial infection

Introduction: Intracellular bacterial pathogens are hard to treat because of the inability of conventional antimicrobial agents belonging to widely used classes, like aminoglycosides and β-lactams, fluoroquinolones, or macrolides to penetrate, accumulate, or be retained in the mammalian cells. The increasing problem of antibiotic resistance complicates more the treatment of the diseases caused by these agents.&#x0D; Objectives: The purpose of this chapter is to present the limitations of each class of antibiotics in targeting intracellular pathogens and the main research directions for the development of drug delivery systems for the intracellular release of antibiotics.&#x0D; Methods: Different improved drug carriers have been developed for treating intracellular pathogens, including antibiotics loaded into liposomes, microspheres, polymeric carriers, and nanoplexes.&#x0D; Results: In many cases, the increase in therapeutic doses and treatment duration is accompanied by the occurrence of severe side effects. Taking into account the huge financial investment associated with bringing a new antibiotic to the market and the limited lifetime of antibiotics, the design of drug delivery systems to enable the targeting of antibiotics inside the cells, to improve their activity in different intracellular niches at different pH and oxygen concentrations, and to achieve a reduced dosage and frequency of administration could represent a prudent choice. An ideal drug delivery system should possess several properties, such as antimicrobial activity, biodegradability, and biocompatibility, making it suitable for use in biomedical and pharmaceutical formulations. Conclusions: This approach allow reviving old antibiotics rendered useless by resistance or toxicity, rescuing the last line therapy antibiotics by increasing the therapeutic index, widening the antimicrobial spectrum of antibiotics scaffolds that failed due to membrane permeability problems, and thus reducing the gap between increasingly drug-resistant pathogens and the development of new antibiotics.

Caffeine increases whole-body fat oxidation during 1h of cycling at Fatmax.

The ergogenic effect of caffeine on exercise of maximum intensity has been well established. However, there is controversy regarding the effect of caffeine on shifting substrate oxidation at submaximal exercise. The aim of this study was to investigate the effect of acute caffeine ingestion on whole-body substrate oxidation during 1h of cycling at the intensity that elicits maximal fat oxidation (Fatmax). In a double-blind, randomized, and counterbalanced experiment, 12 healthy participants (VO2max = 50.7 ± 12.1mL/kg/min) performed two acute experimental trials after ingesting either caffeine (3mg/kg) or a placebo (cellulose). The trials consisted of 1h of continuous cycling at Fatmax. Energy expenditure, fat oxidation rate, and carbohydrate oxidation rate were continuously measured by indirect calorimetry. In comparison to the placebo, caffeine increased the amount of fat oxidized during the trial (19.4 ± 7.7 vs 24.7 ± 9.6g, respectively; P = 0.04) and decreased the amount of carbohydrate oxidized (94.6 ± 30.9 vs 73.8 ± 32.4g; P = 0.01) and the mean self-perception of fatigue (Borg scale = 11 ± 2 vs 10 ± 2 arbitrary units; P = 0.05). In contrast, caffeine did not modify total energy expenditure (placebo = 543 ± 175; caffeine = 559 ± 170kcal; P = 0.60) or mean heart rate (125 ± 13 and 127 ± 9 beats/min; P = 0.30) during exercise. Before exercise, caffeine increased systolic and diastolic blood pressure whilst it increased the feelings of nervousness and vigour after exercise (P < 0.05). These results suggest that a moderate dose of caffeine (3mg/kg) increases the amount of fat oxidized during 1h of cycling at Fatmax. Thus, caffeine might be used as an effective strategy to enhance body fat utilization during submaximal exercise. The occurrence of several side effects should be taken into account when using caffeine to reduce body fat in populations with hypertension or high sensitivity to caffeine.

Green tea (Camellia sinensis) for the prevention of cancer.

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2009, Issue 3).Tea is one of the most commonly consumed beverages worldwide. Teas from the plant Camellia sinensis can be grouped into green, black and oolong tea, and drinking habits vary cross-culturally. C sinensis contains polyphenols, one subgroup being catechins. Catechins are powerful antioxidants, and laboratory studies have suggested that these compounds may inhibit cancer cell proliferation. Some experimental and nonexperimental epidemiological studies have suggested that green tea may have cancer-preventative effects. To assess possible associations between green tea consumption and the risk of cancer incidence and mortality as primary outcomes, and safety data and quality of life as secondary outcomes. We searched eligible studies up to January 2019 in CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and reference lists of previous reviews and included studies. We included all epidemiological studies, experimental (i.e. randomised controlled trials (RCTs)) and nonexperimental (non-randomised studies, i.e. observational studies with both cohort and case-control design) that investigated the association of green tea consumption with cancer risk or quality of life, or both. Two or more review authors independently applied the study criteria, extracted data and assessed methodological quality of studies. We summarised the results according to diagnosis of cancer type. In this review update, we included in total 142 completed studies (11 experimental and 131 nonexperimental) and two ongoing studies. This is an additional 10 experimental and 85 nonexperimental studies from those included in the previous version of the review. Eleven experimental studies allocated a total of 1795 participants to either green tea extract or placebo, all demonstrating an overall high methodological quality based on 'Risk of bias' assessment. For incident prostate cancer, the summary risk ratio (RR) in the green tea-supplemented participants was 0.50 (95% confidence interval (CI) 0.18 to 1.36), based on three studies and involving 201 participants (low-certainty evidence). The summary RR for gynaecological cancer was 1.50 (95% CI 0.41 to 5.48; 2 studies, 1157 participants; low-certainty evidence). No evidence of effect of non-melanoma skin cancer emerged (summary RR 1.00, 95% CI 0.06 to 15.92; 1 study, 1075 participants; low-certainty evidence). In addition, adverse effects of green tea extract intake were reported, including gastrointestinal disorders, elevation of liver enzymes, and, more rarely, insomnia, raised blood pressure and skin/subcutaneous reactions. Consumption of green tea extracts induced a slight improvement in quality of life, compared with placebo, based on three experimental studies. In nonexperimental studies, we included over 1,100,000 participants from 46 cohort studies and 85 case-control studies, which were on average of intermediate to high methodological quality based on Newcastle-Ottawa Scale 'Risk of bias' assessment. When comparing the highest intake of green tea with the lowest, we found a lower overall cancer incidence (summary RR 0.83, 95% CI 0.65 to 1.07), based on three studies, involving 52,479 participants (low-certainty evidence). Conversely, we found no association between green tea consumption and cancer-related mortality (summary RR 0.99, 95% CI 0.91 to 1.07), based on eight studies and 504,366 participants (low-certainty evidence). For most of the site-specific cancers we observed a decreased RR in the highest category of green tea consumption compared with the lowest one. After stratifying the analysis according to study design, we found strongly conflicting results for some cancer sites: oesophageal, prostate and urinary tract cancer, and leukaemia showed an increased RR in cohort studies and a decreased RR or no difference in case-control studies. Overall, findings from experimental and nonexperimental epidemiological studies yielded inconsistent results, thus providing limited evidence for the beneficial effect of green tea consumption on the overall risk of cancer or on specific cancer sites. Some evidence of a beneficial effect of green tea at some cancer sites emerged from the RCTs and from case-control studies, but their methodological limitations, such as the low number and size of the studies, and the inconsistencies with the results of cohort studies, limit the interpretability of the RR estimates. The studies also indicated the occurrence of several side effects associated with high intakes of green tea. In addition, the majority of included studies were carried out in Asian populations characterised by a high intake of green tea, thus limiting the generalisability of the findings to other populations. Well conducted and adequately powered RCTs would be needed to draw conclusions on the possible beneficial effects of green tea consumption on cancer risk.

Enhanced and Prolonged Antitumor Effect of Salinomycin-Loaded Gelatinase-Responsive Nanoparticles via Targeted Drug Delivery and Inhibition of Cervical Cancer Stem Cells.

Background Cervical cancer stem cells (CCSCs) represent a subpopulation of tumor cells that possess self-renewal capacity and numerous intrinsic mechanisms of resistance to conventional chemotherapy and radiotherapy. These cells play a crucial role in relapse and metastasis of cervical cancer. Therefore, eradication of CCSCs is the primary objective in cervical cancer therapy. Salinomycin (Sal) is an agent used for the elimination of cancer stem cells (CSCs); however, the occurrence of several side effects hinders its application. Nanoscale drug-delivery systems offer great promise for the diagnosis and treatment of tumors. These systems can be used to reduce the side effects of Sal and improve clinical benefit.MethodsSal-loaded polyethylene glycol-peptide-polycaprolactone nanoparticles (Sal NPs) were fabricated under mild and non-toxic conditions. The real-time biodistribution of Sal NPs was investigated through non-invasive near-infrared fluorescent imaging. The efficacy of tumor growth inhibition by Sal NPs was evaluated using tumor xenografts in nude mice. Flow cytometry, immunohistochemistry, and Western blotting were used to detect the apoptosis of CSCs after treatment with Sal NPs. Immunohistochemistry and Western blotting were used to examine epithelial–mesenchymal transition (epithelial interstitial transformation) signal-related molecules.ResultsSal NPs exhibited antitumor efficacy against cervical cancers by inducing apoptosis of CCSCs and inhibiting the epithelial–mesenchymal transition pathway. Besides, tumor pieces resected from Sal NP-treated mice showed decreased reseeding ability and growth speed, further demonstrating the significant inhibitory ability of Sal NPs against CSCs. Moreover, owing to targeted delivery based on the gelatinase-responsive strategy, Sal NPs was more effective and tolerable than free Sal.ConclusionTo the best of our knowledge, this is the first study to show that CCSC-targeted Sal NPs provide a potential approach to selectively target and efficiently eradicate CCSCs. This renders them a promising strategy to improve the therapeutic effect against cervical cancer.

Activity profile of the cisplatin analogue PN149 in different tumor cell lines

The efficacy of the anticancer drug cisplatin is restricted by tumor cell resistance and occurrence of severe side effects. One strategy to overcome these limitations is the development of new, improved platinum drugs. Previous investigations showed that platinum(IV)-nitroxyl complexes are able to circumvent cisplatin resistance in bladder cancer cells. In the present study the mode of action of the platinum(IV)-nitroxyl complex PN149 was investigated in the bladder cancer cell line RT112 and the renal cell carcinoma cell line A498 on the molecular and cellular level. Gene expression analysis showed that PN149 induced genes related to DNA damage response (RRM2B, GADD45A), cell cycle regulation (CDKN1A, PLK3, PPM1D) as well as those coding for the pro-apoptotic factors PUMA and Noxa. These findings on the transcriptional level were confirmed on the functional level revealing that PN149 treatment increased levels of p53 and resulted in cell cycle arrest and drug-induced cytotoxicity via induction of apoptosis. Regarding the expression of oxidative-stress sensitive genes, PN149 induced FTH1, GCLC, HMOX1 and TXNRD1 but relevant effects were restricted to RT112 cells treated with 50 µM. The pro-inflammatory IL-8 was induced by PN149 in RT112 but not A498 cells indicating a cell-type specific activation. Taken together, PN149 possessed promising activity in different tumor cell lines rendering it an interesting alternative to cisplatin in chemotherapy.

Factors associated with poor satisfaction with treatment and trial discontinuation in chronic schizophrenia.

Using data from 1,136 trial participants with schizophrenia or schizoaffective disorder, we explored associations between predictor variables with (1) dropout due to WOC and ITE and (2) satisfaction with treatment among patients and investigators by means of hierarchic multiple regression analyses. ITE was associated with poor clinical improvement, poor investigator satisfaction with treatment, and poor patient insight into their own disease, whereas WOC only showed a meaningful association with poor patient satisfaction with treatment. Investigator satisfaction with treatment appeared most strongly associated with Positive and Negative Syndrome Scale (PANSS) positive factor endpoint scores, whereas patient satisfaction with treatment was best predicted by the endpoint score on the PANSS emotional distress factor. The occurrence of severe side effects showed no meaningful association to satisfaction with treatment among investigators and patients, and neither did a patient's experienced psychopathology, nor their self-rating of functional impairment. Whereas trial discontinuation due to ITE is associated with poor treatment effectiveness, a patient's decision to withdraw from an antipsychotic trial remains unpredictable and may occur even when the investigator observes a global clinical improvement and is satisfied with the treatment.

Smart Drug-Delivery Systems for Cancer Nanotherapy.

Despite all the advances achieved in the field of tumor-biology research, in most cases conventional therapies including chemotherapy are still the leading choices. The main disadvantage of these treatments, in addition to the low solubility of many antitumor drugs, is their lack of specificity, which leads to the occurrence of severe side effects due to nonspecific drug uptake by healthy cells. The purpose of this manuscript is to review and analyze the recent progress made in cancer nanotherapy. Progress in nanotechnology and its application in medicine have provided new opportunities and different smart systems. Such systems can improve the intracellular delivery of the drugs due to their multifunctionality and targeting potential. First, we provide a global overview of cancer and different smart nanoparticles currently used in oncology. Then, we analyze in detail the development of drug-delivery strategies in cancer therapy, focusing mainly on the intravenously administered smart nanoparticles. Finally, we discuss the challenges, clinical trials, marketed nanomedicines and future directions of the nanotherapy applied to cancer treatment. In this review, we have evidenced the tremendous potential that smart drug-delivery systems have to enhance the therapeutic effect of current standard treatment modalities, including chemotherapies and radiotherapies.

Radiolabeled prostate-specific membrane antigen small-molecule inhibitors.

Prostate cancer (PC) is one of the most common malignancies worldwide. Prostate-specific membrane antigen (PSMA) has been found to be expressed in most PCs and represents an ideal target for diagnostic and therapeutic purposes. Numerous PSMA tracers have been recently developed. This review aims to provide an overview on the clinical influence of PSMA tracers in primary staging, biochemical recurrence (BCR) of PC and advanced, metastatic PC. Additionally, the use of PSMA tracers in systemic radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC), as well as non-prostatic specific uptake of PSMA tracers and the use of PSMA imaging to manage therapy have been described. A computerized search of the literature (PubMed) was conducted in order to find evidence on the role of PSMA tracers in the diagnosis and therapy of PC. PSMA positron-emission tomography/computed tomography (PET/CT) outperforms conventional imaging in the settings of primary PC, BCR and advanced PC. Especially in BCR of PC, PSMA PET/CT shows clinical value with significantly higher detection rates than standard modalities. The use of PSMA PET/CT resulted in a change of the therapeutic management in up to half of the cases. Regarding RLT, smaller studies were able to show positive clinical effects of 177Lu-labeled PSMA tracers without the occurrence of severe side effects. The currently available data clearly shows that PSMA targeting has a clinical impact on the diagnosis of PC, and that RLT using radiolabeled PSMA tracers has high potentiality in the settings of resistance to conventional therapeutic approaches.

Treatment of axillary bromhidrosis through a mini-incision with subdermal vascular preservation: a retrospective study in 396 patients.

Axillary bromhidrosis is a condition presenting as malodor caused by an interaction between the discharge of apocrine glands and bacteria. Topical agents, liposuction, and elective surgery are currently the main therapeutic modalities. However, the efficiency of these treatments and incidences of side effects are various and frequent, and depend on patient characteristics, surgical technique, and other unknown factors. We report a retrospective study of outcomes in 396 patients treated by mini-incision with subdermal vascular preservation. At 2 years postoperatively, 87.1% of patients had achieved very satisfactory results. Short-term side effects included hematomas, epidermal erosions, infections, necrosis, incision dehiscence, and skin ripples. Long-term side effects comprised comedones, epidermoid cysts, relapsing cyst infections, skin gauffers, scars, keloids, and persistent malodor. Some patients reported unsatisfactory cosmetic results, including skin gauffers, scars, or epidermoid cyst formations. Two discrete aspects of the procedure that must be considered are the extent of apocrine gland clearance, which must be thorough in order to achieve the resolution of malodor, and the maintenance of an intact subdermal vascular plexus to support the regrowth of skin flaps after surgery and to avoid the occurrence of severe side effects.

Synthesis and Anti-onchocercal Activity of Isonicotinoylhydrazones and their Copper(II) and Zinc(II) Complexes

Background: Onchocerciasis is one of the neglected tropical diseases with over 37 million persons affected and a risk population of over 120 million. Ivermectin, the only available drug for the treatment of onchocerciasis is microfilaricidal and there is no current drug effective against macrofilariae. The long duration of treatment of this parasite coupled with the emergence of resistance and the occurrence of severe side effects especially in cases of co-infection with Loa loa, necessitate the search for safe and more effective drug leads. Methods: Six isoniazid-derived Schiff bases were synthesized by condensation of isoniazid and various aromatic aldehydes in methanol. The complexes were synthesized in the metal to ligand molar ratio of 1:2. The ligands and the Zn(II) and Cu(II) complexes were characterized by 1H- and 13C-NMR, as well as infrared spectroscopy. Results: From the spectroscopic data, the ligands were found to coordinate to the central metal ions through the carbonyl oxygen atom as well as the azomethine nitrogen atom. The Zn(II) complexes were octahedral while the Cu(II) complexes were tetrahedral. The ligands and their Zn(II) complexes were inactive against microfilaria while the Cu(II) complexes showed significant activity against both micro- and macrofilaria with IC50 values of 5 µg/mL and 10 μg/mL respectively. Conclusion: The Cu(II) complexes are potential targets for the development of more effective anti-onchocercal agents. This is the first report of the anti-onchocercal activity of these isoniazid-derived Schiff bases and their complexes. Keywords: Anti-onchocercal, coordination, ligand, metal complexes, Onchocerca ochengi, Schiff base.

D01* - MITO (Multicentre Italian Trials in Ovarian cancer) - CERV 2 trial: a randomized phase II study of carboplatin and paclitaxel +/- cetuximab, in advanced and/or recurrent cervical cancer

Background: Carboplatin (C) plus paclitaxel (P) is among standard options for treatment of advanced or recurrent cervical cancer (ARCC) patients (pts). Cervical cancer cells often express Epidermal Growth Factor receptor (EGFR). Cetuximab (CET), an anti-EGFR monoclonal antibody, can be safely combined with CP. MITO-CERV 2 is a comparative randomized phase 2 study, testing the addition of CET to CP. Methods: ARCC pts, <2 previous chemotherapy, ECOG PS = 1, were randomized to CP (C AUC5 + P 175 mg/m2, d1q21) for 6 cycles +/- CET (400 mg/m2 one week before starting CP, then 250 mg/m2 weekly) until disease progression or unacceptable toxicity. Primary endpoint was event-free survival (EFS), i.e. time from randomization to progression, death, definitive discontinuation of the whole treatment or loss to follow-up, whichever occurred first. With a 4.5 mos expected median EFS and a 6.4 mos auspicated EFS (HR 0.70), 0.20 one-tailed a and 80% power, 89 events were required for the final intent-to-treat analysis. Results: 108 pts were randomly assigned to CP (n = 53) or to CP-CET (n = 55). Median age was 50, 69% were PS0, 76% had recurrent disease, 91% had distant metastasis and 57% had received previous chemotherapy. A median number of 6 CP cycles was given in both arms. After a median follow-up of 23 mos (95% CI:20-26), 102 pts had an event, 97 progressed and 61 died. Median EFS was 4.7 and 6.0 mos (one-tail p = 0.43), median PFS was 5.2 and 7.6 mos (one-tail p = 0.20) and median OS was 17.7 and 17 mos (one-tail p = 0.27), with CP and CP-CET, respectively. One patient died for a stroke during standard treatment. There was no difference in the occurrence of severe side-effects, except grade 3-4 skin toxicity reported only with CP-CET (8 cases, 6 with acneiform rash, p = 0.004). Out of 86 patients eligible for RECIST, objective response rate was 43% and 38% with CP and CP-CET respectively (p = 0.63). Conclusion: The addition of CET to CP is not worthy of further investigation in unselected ARCC pts. Efforts are ongoing to retrospectively collect tumor samples for an exploratory biomarker analysis. ClinicalTrials.gov NCT00997009. Partially supported by Merck Serono.

FDA Policy and Cardiovascular Medicine.

The US Food and Drug Administration (FDA) is among the oldest agencies in the federal government. Its origins can be traced back to 1862, when President Abraham Lincoln appointed a chemist, Charles M. Wetherill, to serve in the Department of Agriculture.1 One of the key early pieces of legislation that initiated the evolution of the FDA into its modern form was the 1906 Pure Food and Drug Act, which prohibited interstate commerce in misbranded drugs, thereby giving the FDA its first regulatory oversight over medical product labeling.2 The transformation of the FDA took another major step forward in 1938 with passage of the Food, Drug and Cosmetic Act, which gave the FDA authority to require evidence of safety before new drugs could be marketed.3 Finally, in the 1962 Kefauver-Harris Amendments, the FDA’s drug regulatory authority was expanded to require the FDA to certify drug efficacy and safety before marketing.4 The Medical Device Amendments in 1976 gave the FDA similar authority to certify the effectiveness and safety of high-risk medical devices before their approval.5 Each of these points in the FDA’s early history represented a broadening of its authority and occurred in the context of public health crises related to widely promoted unsafe or ineffective drugs or medical devices, justifying the need for greater government oversight. For example, the Kefauver-Harris Amendments were designed to address the proliferation of medications with poorly documented efficacy and the occurrence of severe side effects caused by some drugs, the most noteworthy example of which was the sedative-antinauseant thalidomide.6,7 The 1976 legislation was passed after >100 deaths of young women from a widely promoted, but largely untested, implantable intrauterine contraceptive device.8 Currently, the FDA describes its responsibilities as ensuring the safety, efficacy and security of the medical …

Photoactivatable Prodrugs of Antimelanoma Agent Vemurafenib.

In this study, we report on novel photoactivatable caged prodrugs of vemurafenib. This kinase inhibitor was the first approved drug for the personalized treatment of BRAF-mutated melanoma and showed impressive results in clinical studies. However, the occurrence of severe side effects and drug resistance illustrates the urgent need for innovative therapeutic approaches. To conquer these limitations, we implemented photoremovable protecting groups into vemurafenib. In general, this caging concept provides spatial and temporal control over the activation of molecules triggered by ultraviolet light. Thus, higher inhibitor concentrations in tumor tissues might be reached with less systemic effects. Our study describes the first development of caged vemurafenib prodrugs useful as pharmacological tools. We investigated their photochemical characteristics and photoactivation. In vitro evaluation proved the intended loss-of-function and the light-dependent recovery of efficacy in kinase and cellular assays. The reported vemurafenib photo prodrugs represent a powerful biological tool for novel pharmacological approaches in cancer research.

Adoptive Cell Therapy with Tumor Infiltrating Lymphocytes and Intermediate Dose Interleukin-2 for Metastatic Melanoma

ABSTRACT Aim: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TILs) achieved impressive clinical results in several single institution phase I/II clinical trials performed outside Europe, and holds the promise to enter the mainstream of standard melanoma care in the near future. However, although transient, the toxicities associated with high-dose interleukin-2 (IL-2) classically administered together with TILs are severe and recent results have questioned its use. To further scrutinize IL-2 dosing, we have carried out a phase II trial using TILs after classical lymphodepletion but followed by an attenuated regimen of IL-2. Methods: A total of 25 patients with progressive metastatic melanoma, PS ≤1, age Results: The trial is fully recruited. Data indicate that the lower dose of IL-2 considerably decreased the toxicity of the treatment, and imaging evaluations of the first 20 patients evaluated showed two complete responses (29 + , 15+ months) and seven partial responses (28 + , 12, 19 + , 12 and 11 + , 8, 5+ months) with most responses still ongoing. Clinical responses were associated with high numbers of tumor reactive T-cells infused. Importantly, in most responding patients we observed induction and durable persistence of anti-melanoma T-cell responses in the peripheral blood. Updated results will be presented at the 2014 ESMO conference. Conclusions: As the first European institution we show that TIL-based ACT is reliable, logistically feasible to administer and clinically effective in metastatic melanoma. Importantly, a high response rate including long-lasting complete responses can be induced after treatment with TILs followed by an attenuated regimen of IL-2, which considerably reduced the occurrence of severe side effects. Effective TIL treatment is associated with induction and long-term persistence in the blood of T cells producing in vitro anticancer responses. Disclosure: All authors have declared no conflicts of interest.