Outcomes of minimally invasive surgery for pulmonary metastasis: who benefits the most?

Introduction: Metastatic disease is one of the main causes of death and factors affecting overall survival. It is known that selected patients with pulmonary oligometastases whose primary tumor is under control and who have adequate respiratory capacity may benefit from metastasectomy by resecting all detected lesions. Aim: To report our findings on the use of video-assisted thoracoscopic surgery (VATS) for pulmonary metastasectomy, with a focus on identifying suitable candidates. Material and methods: Between August 2010 and 2023 a total of 532 pulmonary metastasectomy procedures were performed in our institution. Metastasectomy was performed with VATS for 281 of those patients. Results: VATS metastasectomy was performed in 131 patients with a single lesion on preoperative imaging, while 110 patients underwent metastasectomy for multiple lesions. The rate was significantly (p < 0.05) lower in the group with multiple lesions removed during surgery (38 months) than in the group with only one lesion removed during surgery (60 months). The predicted survival time in the group with other tumor histology (79 months) was significantly (p < 0.05) higher than in the groups with tumor histology carcinoma (41.4 months) and sarcoma (55.5 months). Conclusions: The best prognosis after metastasectomy is provided in cases with a single nodule. Grade is also an important prognostic factor affecting survival, particularly for grade 1 tumor. The histopathological type of the primary tumor is also a significant prognostic factor affecting survival after pulmonary metastasectomy in secondary pulmonary neoplasms, particularly for sarcoma and carcinoma.

Synthesis and investigation of the cholinesterase inhibitory and antioxidant capacities of some novel N'-(quinolin-4-ylmethylene)propanehydrazides against Alzheimer's disease.

One of the worst long-term health issues of the past few decades is Alzheimer's disease (AD). Unfortunately, there are currently insufficient choices for treating and caring for AD, which makes it a popular subject for drug development research. Studies on the development of drugs for AD have primarily concentrated on the use of multitarget directed ligands. Following this strategy, we designed new ChE inhibitors with additional antioxidant and metal chelator effects. In this research, eight novel N'-(quinolin-4-ylmethylene)propanehydrazide derivatives were synthesized and characterized. We then evaluated the inhibition potency of all the final compounds for cholinesterase enzymes. Among them, 4e (IC50 acetylcholinesterase [AChE] = 0.69 µM and butyrylcholinesterase [BChE]= 26.00 µM) and 4h (IC50's AChE= 7.04 µM and BChE= 16.06 µM) were found to be the most potent AChE and BChE inhibitors, respectively.

Post bar removal results of pectus deformity patients who underwent minimally invasive correction.

Introduction: The most common chest wall deformities are pectus excavatum and pectus carinatum. Surgical repair of these deformities via minimally invasive technique using pectus bars is commonly preferred by numerous thoracic surgeons. Despite this common choice for treatment, the duration of the bar stay, the bar removal process, the possible complications and ways to prevent them have been debated over the years and still there is no single decision. Aim: To determine the decision making, surgical outcomes and negative factors in the bar removal process. Material and methods: There were 1032 patients underwent bar removal between 2006-2020 and their data was recorded prospectively. We analyzed patients' demographics, family history, Haller index, bar count, body mass index, stabilizer and wire usage, length of hospital stay, time until bar removal, incision side and complications retrospectively. Results: There was no significant correlation between BMI and surgery time (p = 0.748). There was no statistically significant correlation between the age groups and the number of pectus bars removed. The other factors showed no significant difference. The surgery time was found to be significantly longer in those with callus tissue (p = 0.002). Conclusions: These findings suggest that pectus bars can be left in place for a shorter time than the standard 3-year interval without any additional recurrence risk and without compromising quality of life. As a result, patients with persistent pain after pectus repair should be well evaluated for the possibility of life-threatening complications during bar removal.

Can postoperative complications be reduced by the application of ERAS protocols in operated non-small cell lung cancer patients?

Background: In our study, we aimed to evaluate the length of hospital stay and complication rate of patients before and after application o f t he E nhanced R ecovery A fter S urgery ( ERAS) protocols. Methods: Between January 2001 and January 2021, a total of 845 patients (687 males, 158 females; mean age: 55±11 years; range, 19 to 89 years) who were operated with the diagnosis of non-small cell lung carcinoma were retrospectively analyzed. The patients were divided into three groups as follows: patients between 2001 and 2010 were evaluated as pre-ERAS (Group 1, n=285), patients between 2011 and 2015 as preparation for ERAS period (Group 2, n=269), and patients who had resection between 2016 and 2021 as the ERAS period (Group 3, n=291). Results: All three groups were similar in terms of clinical, surgical and demographic characteristics. Smoking history was statistically significantly less in Group 3 (p=0.005). The forced expiratory volume in 1 sec/forced vital capacity and albumin levels were statistically significantly higher in Group 3 (p<0.001 and p=0.019, respectively). The leukocyte count and tumor maximum standardized uptake value were statistically significantly higher in Group 1 (p=0.018 and p=0.014, respectively). Postoperative hospitalization day, complication rate, and intensive care hospitalization rates were statistically significantly lower in Group 3 (p<0.001). The rate of additional disease was statistically significantly higher in Group 1 (p=0.030). Albumin level (<2.8 g/dL), lymphocyte/monocyte ratio (<1.35), and hemoglobin level (<8.3 g/dL) were found to be significant predictors of complication development. Conclusion: With the application of ERAS protocols, length of postoperative hospital stay, complication rate, and the need for intensive care hospitalization decrease. Preoperative hemoglobin level, albumin level, and lymphocyte/monocyte ratio are the predictors of complication development. Increasing hemoglobin and albumin levels before operation may reduce postoperative complications.

Synthesis and evaluation of multitarget new 2-aminothiazole derivatives as potential anti-Alzheimer's agents.

In this study, two diverse series of 2-aminothiazole-based multitarget compounds, one propenamide and the other propanamide derivatives, were designed and synthesized. Subsequently, their anticholinesterease and antioxidant (ORAC) activities were tested. Among them, compound 3e was the most potent acetylcholinesterase (AChE) inhibitor (AChE IC50 = 0.5 µM, butyrylcholinesterase [BChE] IC50 = 14.7 µM) and compound 9e was the most potent BChE inhibitor (AChE IC50 = 3.13 µM, BChE IC50 = 0.9 µM). Kinetic experiments showed that both compounds were mixed-type inhibitors. According to the anticholinesterease activity results, five compounds (3e, 4e, 5e, 9d, and 9e) were selected for further activity studies, all of which are dual cholinesterase inhibitors. Then, selected compounds were investigated in terms of their metal chelation activity. Moreover, their neuroprotective effects against H2 O2 -induced damage in the PC12 cell line were evaluated at 10 µM and the results showed that the neuroprotective effect of 3e was 53% compared with the reference ferulic acid (77%). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results of selected compounds revealed that the compounds were noncytotoxic. Additionally, 3e was more effective in reducing lipopolysaccharides-induced interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO) production in the human monocyte derived from patient with acute monocytic leukemia cell line compared with other selected compounds. Finally, a molecular docking study was also performed.

Program development for leaders in the post-truth era: Arts-based creative leadership communication program.

Developments in media and communication technologies welcomed a new era, defined as post-truth, implying a general distancing from truth, where fake or speculative messages can be instantly shared by a vast audience. In this era, we need leaders with strong emotional and social skills to create a positive and ethical impact in society. In this study, due to the requirements of the Post-Truth Era which necessitates a new approach to leadership development, an arts-based learning intervention entitled Arts-Based Creative Leadership Communication Program is designed for leaders with three main objectives to increase, firstly, their creative communication skills; secondly, healing effect of arts for their resilience; and, thirdly, their social sensitivity through arts. After the design and implementation of this program, its targeted effects on the participants were analyzed. Results indicated that all of the expected outcomes were achieved successfully. The highest development was seen in the healing effect, while change in social sensitivity appeared as the lowest. Emotional skills as non-verbal communication element was developed more than social skills. Meanwhile, the emergence of the pandemic with its digital transformation process increased the effects of the program. To sum up, the program was found successful for the leaders in the Post-Truth Era.

New thiourea and benzamide derivatives of 2-aminothiazole as multi-target agents against Alzheimer's disease: Design, synthesis, and biological evaluation.

In this study, two series of compounds were designed and synthesized, bearing thiourea and benzamide derivatives at position 2 of 4-subtituted-2-aminothiazole, respectively. Then, the inhibition potency of all final compounds for cholinesterase enzymes were evaluated. Among the thiourea derivatives, 3c (IC50 = 0.33 µM) was identified as the most potent and selective butyrylcholinesterase inhibitor. Additionally, benzamide derivative 10e (AChE IC50 = 1.47 and BChE IC50 = 11.40 µM) was found as a dual cholinesterase inhibitor. The type of inhibition for both compounds was determined by kinetic studies and the results showed that the compounds were mixed type inhibitors. Moreover, all title compounds were investigated in terms of their antioxidant (DPHH, ORAC) and metal chelator activities. In addition, the neuroprotective effects of selected compounds (3c, 3e, 6c, 6e and 10e) against H2O2-induced damage in the PC12 cell line were tested. The experimental findings demonstrated that thiourea-derived 6e (40.4 %) and benzamide-derived 10e (37.8 %) have a neuroprotective effect of about half as ferulic acid at 10 µM. Subsequently, the cytotoxicity of selected compounds was examined by the MTT assay, and the compounds were found not to have cytotoxic effect on the PC12 cell line in 24 h. Additionally, compounds 6e and 10e were also found to be more effective in inhibiting the release of IL-1ß, IL-6, TNF-α and NO compared to other selected compounds in this study.

What is the impact of intellectual property rules on access to medicines? A systematic review.

BACKGROUND: It is widely accepted that intellectual property legal requirements such as patents and data exclusivity can affect access to medicines, but to date there has not been a comprehensive review of the empirical evidence on this topic. The World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) requires Member States to implement minimum standards of intellectual property protection including patents for pharmaceutical products, but also contains 'flexibilities' designed to address barriers to access to medicines. National intellectual property laws can also include TRIPS-plus rules that go beyond what is required by TRIPS. We aimed to systematically review literature that measures the impact of intellectual property rules on access to medicines, whether implemented as a result of TRIPS, TRIPS-plus provisions in other trade agreements, or unilateral policy decisions. METHODS: We searched Proquest, SCOPUS, Web of Science, PubMed, JSTOR, Westlaw and Lexis Nexis. Peer reviewed articles, government reports and other grey literature were included. Articles were eligible for inclusion if they were quantitative, in English, included a measure of cost, price, availability of or access to medicines, were about intellectual property or data exclusivity rules and published between January 1995 and October 2020. Ninety-one studies met our inclusion criteria. We systematically reviewed the studies' findings and evaluated their quality using a modified quality assessment template. RESULTS AND CONCLUSION: Five broad overarching themes and 11 subthemes were identified based on the articles' foci. They were: trade agreements (divided into EU FTAs and those that include the USA); use of TRIPS flexibilities (divided into compulsory licencing and parallel importation); patent expiry/generic entry/generic pathway (divided into comparative studies and single country studies); patent policies (also divided into comparative studies and single country studies) and TRIPS-plus rules (divided into data exclusivity, patent term extensions and secondary patenting). Most studies focused not on specific trade agreements, but on TRIPS-plus provisions, which can also be found within some trade agreements. The main finding of this review is that the stronger pharmaceutical monopolies created by TRIPs-plus intellectual property rules are generally associated with increased drug prices, delayed availability and increased costs to consumers and governments. There is evidence that TRIPS flexibilities can facilitate access to medicines although their use is limited to date. There were few studies that included resource poor settings, signalling a need for greater research in such settings where the impact on access to medicines is likely to be more damaging.

Thoracic splenosis mimicking pleural tumor after firearm injury: A case report with long-term follow-up.

Splenosis describe a clinical entity of autotransplantation after removal of the spleen secon-dary to a traumatic rupture or surgery. A 39-year-old female was referred to thoracic surgery department with complaints of severe chest pain. She had left thoracic and abdominal gun-shot injury that occurred 19 years earlier. Thorax computed tomograhy and thorax magnetic resonance imaging revealed pleural lesions. A video thoracoscopic biopsy disclosed splenosis in the patient. Splenic implants did not change in 6 years. The patient has mild thoracic pain. Thoracic splenosis can occur in patients who underwent abdominothoracic gunshot injury. The implants did not seem to change in long-term follow-up. Thoracic splenosis may occur, persist for years and it mimics pleural tumor after abdominal gun-shot injury and does not seem to necessitate any surgical intervention including diaphragmatic repair.

Design, synthesis and biological evaluation of new benzoxazolone/benzothiazolone derivatives as multi-target agents against Alzheimer's disease.

In this study, four series of compounds with benzoxazolone and benzothiazolone cores were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). Additionally, in order to shed light on the effect of the carbonyl groups of benzoxazolone/benzothiazolone, benzoxazole/benzothiazole-containing analogues were also synthesized and evaluated. Inhibition potency of all final compounds towards cholinesterase enzymes and their antioxidant activity were tested. Subsequently, the anti-inflammatory activity, cytotoxicity, apoptosis, and Aß aggregation inhibition tests were also performed for selected compounds. The results indicated that compounds 11c, a pentanamide derivative with benzothiazolone core, and 14b, a keton derivative with benzothiazolone core, were considered as promising multi-functional agents for further investigation against AD. The reversibility, kinetic and molecular docking studies were also performed for the compounds with the highest AChE 14b (eeAChE IC50 = 0.34 µM, huAChE IC50 = 0.46 µM) and BChE 11c (eqBChE IC50 = 2.98 µM, huBChE IC50 = 2.56 µM) inhibitory activities.

The effect of minimally invasive pectus excavatum repair on thoracic scoliosis.

OBJECTIVES: The Nuss technique comprises the placement of an intrathoracic bar behind the sternum. However, besides improving the body posture through the correction of the pectus excavatum (PE), this procedure may cause or worsen thoracic scoliosis as a result of the considerable stress loaded on the chest wall and the thorax. Our goal was to investigate the impact of the Nuss procedure on the thoracic spinal curvature in patients with PE. METHODS: A total of 100 patients with PE who underwent the Nuss procedure were included in the study and evaluated retrospectively. The Haller index (HI), asymmetry index and sternal torsion angle were calculated from thoracic computed tomography images before the operation. To evaluate the scoliosis in the T2-T8 thoracic vertebrae, Cobb angles were calculated on a plain chest X-ray before the Nuss operation and after the removal of the bar. Cobb angles were classified as normal (5°), scoliotic posture (5°-10°) and scoliosis (>10°). All angles before and after the Nuss operation were compared. The patients were followed up for a mean of 41 months. Substernal bars were removed after a mean of 33 months. RESULTS: The mean age of the patients was 19.6 ± 6.7 years. The Cobb angle was statistically significantly increased in all patients (P = 0.01), male patients (P = 0.01) and children (P = 0.046) but not in adults (P = 0.11) and female patients (P = 0.54). The Cobb angle was increased in patients with severe (HI ≥ 3.5) but not in patients with moderate (3.2 < HI < 3.5) or mild (2.0 < HI < 3.2) PE deformity. CONCLUSIONS: The present study shows that the Cobb angle indicates that the severity of thoracic scoliosis increases following the Nuss procedure, particularly in male patients, in patients with mild and moderate sternal torsion angle and in those with a high preoperative HI. This alteration might be due to correctional forces and torque applied by the bar. Patients undergoing the Nuss procedure for the correction of PE should be followed up strictly for timely diagnosis and management of the scoliosis.

Design, Synthesis and Investigation of New Diphenyl Substituted Pyridazinone Derivatives as Both Cholinesterase and Aß-Aggregation Inhibitors.

BACKGROUND: With respect to the increase in the average life expectancy, Alzheimer Disease (AD), the most common form of age-related dementia, has become a major threat to the population over the age of 65 during the past several decades. The majority of AD treatments are focused on cholinergic and amyloid hypotheses. OBJECTIVE: In this study, three series of diphenyl-2-(2-(4-substitutedpiperazin-1-yl)ethyl)pyridazin- 3(2H)-one derivatives were designed, synthesized and investigated for their ability to inhibit both cholinesterase enzymes and amyloid-ß aggregation. METHOD: The inhibitory activities of the synthesized compounds on AChE (from electric eel) and BChE (from equine serum) were determined by the modified Ellman's method. The reported thioflavin T-based fluorometric assay was performed to investigate the effect of the selected compounds on the aggregation of Aß1-42. The cytotoxic effect of the compounds (4g, 11g and 18g) was monitored in 3T3 cell lines to gain insight into therapeutic potential of the compounds by using MTT assay. The crystal structures of the AChE (1EVE) and BChE (1P0I) enzymes were retrieved from the RCSB Protein Data Bank and Molecular Operating Environment (MOE) software was used for molecular docking of the ligands. RESULTS: Among the tested compounds, 5,6-diphenyl derivative 18g was identified as the most potent and selective AChE inhibitor (IC50 = 1.75 µM, Selectivity Index for AChE > 22.857). 4,6- Diphenyl derivative 11g showed the highest and the most selectivity for BChE (IC50= 4.97 µM, SI for AChE < 0.124). Interestingly, 4,5-diphenyl derivative 4g presented dual cholinesterase inhibition (AChE IC50= 5.11 µM; BChE IC50= 14.16 µM, SI for AChE = 2.771). CONCLUSION: Based on biological activity results and low toxicity of the compounds, it can be said that diphenyl substituted pyridazinone core is a valuable scaffold. Especially, dual inhibitory potencies of 4,5-diphenylpyridazin-3(2H)-one core for the cholinesterase enzymes and Aß- aggregation makes this core a promising disease-modifying agent.

Thoracoscopic removal of ectopic mediastinal parathyroid adenoma causing hyperparathyroidism: a rare entity.

Ectopic mediastinal parathyroid adenomas are uncommon. Here, we report the successful thoracoscopic removal of a mediastinal parathyroid adenoma from a patient with hypercalcemia. A 58-year-old female patient was referred to our department with persistent hypercalcemia. Serum calcium and phosphorus levels were 13.2 mg/dl and 2.5 mg/dl respectively, while the intact parathormone level was 798.9 pg/ml. Parathyroid computed tomography revealed a solid and well-defined mass at the anterior mediastinum close to the distal aorta. Once the contrast was enhanced, our pre-diagnosis was ectopic parathyroid adenoma. The mass was detected at the anterior mediastinum, dissected free from the surrounding tissue and excised. The capsulated mass, which had a diameter of 3 × 1.5 × 0.7 cm, was confirmed as parathyroid adenoma histopathologically. Postoperative calcium and parathormone levels decreased dramatically to normal levels. Anterior mediastinal localization of an ectopic parathyroid adenoma is a rare entity. The transsternal approach is the most preferred method, but video-thoracoscopy can be used safely and effectively.

Comparative study of video-assisted thoracoscopic surgery versus open thymectomy for thymoma and myasthenia gravis.

INTRODUCTION: Thymectomy is the preferred standard treatment in younger non-thymoma patients with myasthenia gravis as well as in patients with early stage thymoma. Total thymectomy by median sternotomy has been the surgical approach since resection of the thymus with video-assisted thoracoscopic surgery (VATS). AIM: To compare the clinical outcomes of VATS thymectomy with conventional open thymectomy for neoplastic and non-neoplastic thymic diseases. MATERIAL AND METHODS: Forty patients underwent thymectomy between October 2012 and January 2016. Fifteen patients were male and 25 patients were female. The mean age was 40.3 ±17.7 years. Seventeen (55%) patients underwent VATS thymectomy and 23 (45%) patients underwent an open procedure. We retrospectively reviewed the data of the patients and compared these two techniques. RESULTS: The mean tumor size was 5.17 ±3.2 cm in the thymoma group (VATS 2.5 ±2.4 cm vs. open access 4.7 ±3.7 cm). None of the patients experienced a myasthenic crisis. Conversion to thoracotomy was required in 1 patient in the VATS group due to bleeding from the right internal mammary artery; therefore, the conversion rate was 2.5% among all the patients. No mortality occurred in either group. No significant difference was found in the perioperative blood loss, operative time or pain visual analogue scale scores. On the other hand, regarding postoperative drainage, duration of chest tube drainage and length of hospital stay, VATS thymectomy yielded better results and the differences were significant. CONCLUSIONS: Video-assisted thoracoscopic surgery thymectomy can be performed for both neoplastic and non-neoplastic thymic diseases with minimal morbidity and mortality.

Minimally invasive injection laryngoplasty in the management of unilateral vocal cord paralysis after video-assisted mediastinal lymph adenectomy.

INTRODUCTION: Video-assisted mediastinal lymphadenectomy (VAMLA) is a valuable tool for invasive staging of the mediastinum. Unilateral vocal cord paralysis (UVCP) may occur in patients following VAMLA and may result in secretion retention within the lungs, atelectasis and associated infectious situations such as pneumonia. Minimally invasive injection laryngoplasty (ILP) is the treatment of choice in UVCP. AIM: To evaluate the efficacy and success of acute minimally invasive injection laryngoplasty for patients with UVCP following VAMLA. MATERIAL AND METHODS: Patients with the symptom of dysphonia following VAMLA were reviewed. All of the patients had UVCP according to the video laryngoscopy examination and had symptoms of aspiration and ineffective coughing. The Voice Handicap Index (VHI) questionnaire and maximum phonation time (MPT) were measured. Minimally invasive ILP was performed under general anesthesia with 1 cm of hyaluronic acid. RESULTS: There were 525 consecutive non-small cell lung cancer (NSCLC) patients who underwent VAMLA. Five (0.95%) of the patients had UVCP and were suffering from aspiration during oral intake and ineffective coughing reflex. Maximum phonation time (MFT) was measured before and after ILP, and the results were 7.1 ±1.6 and 11.1 ±2.3 s, respectively (p < 001). The Voice Handicap Index-10 (VHI-10) score was 30.4 ±4.7 and 13.4 ±3.5 (p < 0.01), respectively. Patients underwent surgical lung resection. There was no morbidity or mortality. CONCLUSIONS: Unilateral vocal cord paralysis may occur as a complication of VAMLA. ILP may be an active tool for treating UVCP before anatomical lung resection to avoid potential morbidities. Successful management of this complication with multidisciplinary team work may encourage the use of VAMLA more frequently.

Uniportal versus multiport video-assisted thoracoscopic surgery for anatomical lung resections: a glance at a dilemma.

INTRODUCTION: As the number of operations performed by videothoracoscopy is increasing, there is also a tendency to decrease the number of port incisions. Apart from the reduced number of surgical incisions, there are a few reports and systematic reviews that demonstrate some potential advantages of the uniportal video-assisted thoracoscopic surgery, but the impact of the reduced incisions in the clinical setting still remains uncertain. AIM: To compare uniportal video-assisted thoracoscopic surgery to multiport video-assisted thoracoscopic surgery for anatomical lung resections in patients with malignant and benign lung diseases. MATERIAL AND METHODS: From August 2010 to April 2016, a total of 102 patients with malignant and benign lung diseases underwent videothoracoscopic lobar and sublobar lung resections in our department. Comorbidities, tumor stage, tumor localization, mortality, operative time, pain visual analogue scale, length of hospital stay, perioperative blood loss, duration and amount of postoperative drainage and air leak, number of harvested lymph nodes and complication rates were analyzed. RESULTS: No significant difference was found in the duration of chest tube drainage, pain visual analogue scale score, length of hospital stay, perioperative blood loss, amount of postoperative drainage, number of harvested lymph nodes or complication rate. There was no surgical mortality in either of the two groups. However, operative time was shorter (189 min vs. 256 min, p < 0.005) in the multiport group than in the uniportal group. CONCLUSIONS: Compared with the uniportal approach, the multiport approach is associated with a significantly shorter operative time in our study.

The Trans Pacific Partnership Agreement, intellectual property and medicines: Differential outcomes for developed and developing countries.

The final text of the Trans Pacific Partnership Agreement (TPP), agreed between the 12 negotiating countries in 2016, included a suite of intellectual property provisions intended to expand and extend pharmaceutical company exclusivities on medicines. It drew wide criticism for including such provisions in an agreement that involved developing countries (Vietnam, Peru, Malaysia, Mexico, Chile and Brunei Darussalam) because of the effect on delaying the introduction of low-cost generics. While developing nations negotiated transition periods for implementing some obligations, all parties would have eventually been expected to meet the same standards had the TPP come into force. While the TPP has stalled following US withdrawal, there are moves by some of the remaining countries to reinvigorate the agreement without the United States. The proponents may seek to retain as much as possible of the original text in the hope that the United States will re-join the accord in future. This article presents a comparative analysis of the impact the final 2016 TPP intellectual property chapter could be expected to have (if implemented in its current form) on the intellectual property laws and regulatory regimes for medicines in the TPP countries. Drawing on the published literature, it traces the likely impact on access to medicines. It focuses particularly on the differential impact on regulatory frameworks for developed and developing nations (in terms of whether or not legislative action would have been required to implement the agreement). The article also explores the political and economic dynamics that contributed to these differential outcomes.

Design and synthesis of some new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring and the investigation of their inhibitory potential on in-vitro acetylcholinesterase and butyrylcholinesterase.

A series of new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring were designed, synthesized and evaluated for their ability to inhibit both cholinesterase enzymes. In addition, a series of carboxamide and propanamide derivatives bearing biphenyl instead of phenylpyridazine were also synthesized to examine the inhibitory effect of pyridazine moiety on both cholinesterase enzymes. The inhibitory activity results revealed that compounds 5b, 5f, 5h, 5j, 5l pyridazine-3-carboxamide derivative, exhibited selective acetylcholinesterase (AChE) inhibition with IC50 values ranging from 0.11 to 2.69 µM. Among them, compound 5h was the most active one (IC50 = 0.11 µM) without cytotoxic effect at its effective concentration against AChE. Additionally, pyridazine-3-carboxamide derivative 5d (IC50 for AChE = 0.16 µM and IC50 for BChE = 9.80 µM) and biphenyl-4-carboxamide derivative 6d (IC50 for AChE = 0.59 µM and IC50 for BChE = 1.48 µM) displayed dual cholinesterase inhibitory activity. Besides, active compounds were also tested for their ability to inhibit Aß aggregation. Theoretical physicochemical properties of the compounds were calculated by using Molinspiration Program as well. The Lineweaver-Burk plot and docking study showed that compound 5 h targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.