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Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy has emerged as a promising treatment option due to its favorable toxicity profile. However, selecting the most appropriate immunotherapeutic agent for neoadjuvant use—aimed at curative intent in early-stage NSCLC—based on efficacy and safety remains a critical question. This review aims to compare the efficacy and safety profiles of nivolumab and pembrolizumab when used as neoadjuvant treatments in NSCLC. A systematic review was conducted across PubMed, Scopus, Wiley Online Library, ProQuest Dissertations and Theses Global, and Google Scholar, utilizing the search terms "Nivolumab OR Pembrolizumab AND Neoadjuvant Immunotherapy AND non-small cell lung cancer." Out of 1444 retrieved studies, 4 retrospective studies met the inclusion criteria by providing comparative data on nivolumab and pembrolizumab within the same study cohorts. Despite the critical risk of bias and the evidence quality ranging from moderate to very low across these studies, both nivolumab and pembrolizumab demonstrated efficacy rates exceeding 30% and maintained favorable safety profiles. There is no observed superiority between nivolumab and pembrolizumab in terms of efficacy and safety for the neoadjuvant treatment of early-stage NSCLC. [ABSTRACT FROM AUTHOR]

Copyright of Eurasian Journal of Ecology is the property of Al-Farabi Kazakh National University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BackgroundChloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have recently emerged as potential antiviral and immunomodulatory options for the treatment of 2019 coronavirus disease (COVID-19). To examine the safety profiles of these medications, we systematically evaluated the adverse events (AEs) of these medications from published randomized controlled trials (RCTs).MethodsWe systematically searched MEDLINE, the Cochrane library, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov for all the RCTs comparing CQ or HCQ with placebo or other active agents, published before June 20, 2020. The random-effects or fixed-effects models were used to pool the risk estimates relative ratio (RR) with 95% confidence interval (CI) for the outcomes.ResultsThe literature search yielded 23 and 19 studies for CQ and HCQ, respectively, that satisfied our inclusion criteria. Of these studies, we performed meta-analysis on 6 studies for CQ and 18 studies for HCQ. We did not limit our analysis to published records involving viral treatment alone; data also included the usage of either CQ or HCQ for the treatment of other diseases. The trials for the CQ consisted of a total of 2,137 participants (n = 1,077 CQ, n = 1,060 placebo), while the trials for HCQ involved 2,675 participants (n = 1,345 HCQ and n = 1,330 control). The overall mild and total AEs were significantly higher in CQ-treated non-COVID-19 patients, HCQ-treated non-COVID-19 patients, and HCQ-treated COVID-19 patients. The AEs were further categorized into four groups and analyses revealed that neurologic, gastrointestinal (GI), dermatologic, and sensory AEs were higher in participants taking CQ compared to placebo, while GI, dermatologic, sensory, and cardiovascular AEs were higher in HCQ-treated COVID-19 patients compared to control patients. Moreover, subgroup analysis suggested higher AEs with respect to dosage and duration in HCQ group. Data were acquired from studies with perceived low risk of bias, so plausible bias is unlikely to seriously affect the main findings of the current study.ConclusionsTaken together, we found that participants taking either CQ or HCQ exhibited more AEs than participants taking placebo or control. Precautionary measures should be taken when using these drugs to treat COVID-19. The meta-analysis was registered on OSF (https://osf.io/jm3d9).RegistrationThe meta-analysis was registered on OSF (https://osf.io/jm3d9).

Approval of apalutamide, enzalutamide and darolutamide has transformed the treatment landscape and guideline recommendations for patients with nonmetastatic castration-resistant prostate cancer but now raises the issue of decision-making regarding treatment selection. In this perspective, we discuss the efficacy and safety of these second-generation androgen receptor inhibitors and propose that for patients with nonmetastatic castration-resistant prostate cancer, safety considerations for these treatments are especially important. We examine these considerations in the context of patient and caregiver preferences as well as patient clinical characteristics. We further posit that consideration of treatments' safety profiles should include not only the initial direct impacts from potential treatment-emergent adverse events and drug–drug interaction events, but also the full cascade of potentially avoidable healthcare complications. Prostate cancer is one of the most common cancers in men. Because male hormones fuel the growth of prostate cancer cells, initial treatments generally focus on reducing these hormones to very low levels. Although these treatments are usually effective in controlling the cancer in the short term, over time, patients often stop responding to them. These patients need more advanced treatments to control their prostate cancer. For patients whose cancer has not spread to other body parts ('nonmetastatic castration-resistant prostate cancer'), more advanced treatment options were unavailable until recently, but during 2018–2019, three novel therapies became available. These new therapies have raised the question of how to choose a particular therapy when deciding on a patient's treatment regimen. Here we contend that patient safety is critical when deciding among these treatments, which are all similarly effective in terms of helping patients to live longer. We review the key differences of each drug's safety profile among these treatments. We assert that treatment selection should consider patients' preferences and clinical characteristics, as the latter can influence the potential for serious harm when treatment-related complications arise. Finally, treatment selection should consider the multiple after-effects that can occur following a treatment-related safety event. Key safety differences exist among second-generation androgen receptor inhibitors for nonmetastatic castration-resistant prostate cancer. We discuss these differences and their potential for patient harm for patient treatment selection. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a chronic and progressive condition with a significant global burden. Currently, available treatments primarily provide symptomatic relief and retard disease progression, yet they do not offer a cure and are frequently associated with adverse effects. Therefore, the discovery of new targets and therapeutic drugs for IBD is crucial. Phosphodiesterase 4 (PDE4) inhibitors have emerged as promising candidates in the search for effective IBD treatments, although dose-dependent side effects hamper their clinical utility. In this study, building upon heterocyclic biaryl derivatives (TPA16), we designed and synthesized a series of N 2-substituted indazole-based PDE4D inhibitors, emphasizing improving safety profiles. An enzyme activity screening discovered an optimized compound, LZ-14 (Z21115), which exhibited high PDE4D7 (IC 50 = 10.5 nM) inhibitory activity and good selectivity. More interestingly, LZ-14 has demonstrated promising effects in treating IBD in mouse models by improving the inflammatory response and colon injury. Furthermore, LZ-14 displayed low emetogenic potential in ketamine/xylazine anesthesia mice alternative models. [Display omitted] • Thirty-six novel N 2-indazole derivatives were designed and synthesized. • LZ-14 displayed satisfactory inhibitory activities against PDE4D. • LZ-14, with a high safety profile, showed low emetic potential. • LZ-14 was a potential novel agent for treating Inflammatory Bowel Diseases. [ABSTRACT FROM AUTHOR]

Background: Several recent phase 3 trials have reported manageable safety profiles and promising antitumor activities of molecular-targeted drugs (MTDs; sorafenib, lenvatinib), immune checkpoint inhibitors (ICIs; nivolumab, pembrolizumab, atezolizumab), hepatic arterial infusion chemotherapy (HAIC) and their combinations in advanced hepatocellular carcinoma (AHCC); however, head-to-head comparisons among these regimens are lacking. Methods: We aimed to comprehensively review and compare the efficacy and safety of different MTDs, ICIs, HAIC and their combinations in AHCC. Adverse events (AEs), disease control rates (DCRs), objective response rates (ORRs), overall survival (OS) and progression-free survival (PFS) were assessed. Results: The pooled incidence rates of grade 1–5/3–5 AEs were 98.0%/48.6%, 98.3%/57.4%, 91.4%/22.0%, 96.4%/54.6%, 98.2%/61.1%, 86.3%/34.1%, 88.9%/9.4%, and 95.2%/53.2% for sorafenib, lenvatinib, nivolumab, pembrolizumab, atezolizumab plus bevacizumab, HAIC-cisplatin plus sorafenib, HAIC-oxaliplatin, and HAIC-oxaliplatin plus sorafenib, respectively, which suggested that nivolumab exhibited optimal safety regarding grade 1–5 AEs, whereas HAIC-oxaliplatin monotherapy ranked lowest regarding grade 3–5 AEs. According to RECIST1.1, lenvatinib (72.8%), atezolizumab plus bevacizumab (73.6%), HAIC-oxaliplatin (78.8%) and HAIC-oxaliplatin plus sorafenib (75.2%) showed higher DCRs than sorafenib (57.3%), nivolumab (33.9%), and pembrolizumab (62.3%), whereas only HAIC-oxaliplatin-based treatments demonstrated a higher ORR than the others. Pooled OS and PFS analysis favored the combination regimens other than sorafenib along. Conclusions: Here, we present preliminary evidence for the comparative safety and efficacy of existing MTDs, ICIs, HAIC and their combinations in AHCC, which indicated that HAIC-oxaliplatin monotherapy has acceptable toxicity and efficacy and could be the cornerstone for future combination of systemic treatments in AHCC. Our findings might provide insight into the future design of multidisciplinary treatments in AHCC.

Animal medicine (AM), as a kind of traditional Chinese medicine (TCM), has been used for thousands of years. However, sometimes AM can cause a variety of side effects similar to those caused by biogenic amines (BAs). So far, there has been no information about the type and content of BAs in AMs. Thus, an HPLC method with precolumn derivatization was developed for the characterization of ten kinds of BAs in seven commonly used AMs to provide referential data for the safety profile of AMs. The described method has good repeatability and reproducibility for the quantification of BAs in seven kinds of AMs. Among the ten selected BAs, histamine in Scolopendra was found to be 96 ± 4 mg/kg, exceeding the limit regulated by the US Food and Drug Administration. Although the levels of BAs in Scorpio, Hirudo, Bombyx Batryticatus, Gecko, Pheretima, and Eupolyphaga Steleophaga are below the amine toxicity level currently regulated and are safe to use individually, AMs are often used in combination with other TCMs containing BAs. This would lead to the overdose of toxic BAs. Therefore, it is necessary to propose limit standards for BAs in AMs and their polypharmacy to ensure their safety profiles and improve the quality standards. [ABSTRACT FROM AUTHOR]

Abstract Recent phase 1–2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1–5/3–5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1–5 AEs whereas camrelizumab and nivolumab regarding grade 3–5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1–positive and PD-L1–negative patients, respectively (P = 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC.

BackgroundChloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have recently emerged as potential antiviral and immunomodulatory options for the treatment of 2019 coronavirus disease (COVID-19). To examine the safety profiles of these medications, we systematically evaluated the adverse events (AEs) of these medications from published randomized controlled trials (RCTs).MethodsWe systematically searched MEDLINE, the Cochrane library, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov for all the RCTs comparing CQ or HCQ with placebo or other active agents, published before June 20, 2020. The random-effects or fixed-effects models were used to pool the risk estimates relative ratio (RR) with 95% confidence interval (CI) for the outcomes.ResultsThe literature search yielded 23 and 19 studies for CQ and HCQ, respectively, that satisfied our inclusion criteria. Of these studies, we performed meta-analysis on 6 studies for CQ and 18 studies for HCQ. We did not limit our analysis to published records involving viral treatment alone; data also included the usage of either CQ or HCQ for the treatment of other diseases. The trials for the CQ consisted of a total of 2,137 participants (n = 1,077 CQ, n = 1,060 placebo), while the trials for HCQ involved 2,675 participants (n = 1,345 HCQ and n = 1,330 control). The overall mild and total AEs were significantly higher in CQ-treated non–COVID-19 patients, HCQ-treated non–COVID-19 patients, and HCQ-treated COVID-19 patients. The AEs were further categorized into four groups and analyses revealed that neurologic, gastrointestinal (GI), dermatologic, and sensory AEs were higher in participants taking CQ compared to placebo, while GI, dermatologic, sensory, and cardiovascular AEs were higher in HCQ-treated COVID-19 patients compared to control patients. Moreover, subgroup analysis suggested higher AEs with respect to dosage and duration in HCQ group. Data were acquired from studies with perceived low risk of bias, so plausible bias is unlikely to seriously affect the main findings of the current study.ConclusionsTaken together, we found that participants taking either CQ or HCQ exhibited more AEs than participants taking placebo or control. Precautionary measures should be taken when using these drugs to treat COVID-19. The meta-analysis was registered on OSF (https://osf.io/jm3d9).RegistrationThe meta-analysis was registered on OSF (https://osf.io/jm3d9).

Introduction: The cardiovascular efficacy of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM) are well documented; however, the differences in cardiovascular efficacy among subpopulations remain unknown. This systematic review and meta-analysis aimed to explore the differences in cardiovascular efficacy of long-acting GLP-1RAs among subpopulations of patients with T2DM and to assess the drug safety. Methods: Relevant studies up to March 31, 2020 were searched for in six electronic databases, namely PubMed, Cochrane Library, Embase, Clinical Trials, Science Direct, and Web of Science. The primary outcome was three-point major adverse cardiovascular events (including cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke). Subpopulations were defined using ten selected influential factors, and the differences in cardiovascular efficacy in subpopulations stratified by different influential factors were accessed by synthesizing studies with random-effects models one by one. Results: A total of six cardiovascular outcome trials of long-acting GLP-1RAs, comprising 49,936 participants, were included. Among stratified subpopulations, no significant differences in the cardiovascular efficacy of long-acting GLP-1RAs were observed across the ten characteristics of subjects (all P for interaction > 0.05). Favorable trends were observed in the subpopulation with established cardiovascular disease (CVD) compared to that without (P = 0.171). With regards to safety, long-acting GLP-1RAs did not significantly increase the risk of retinopathy (OR 1.09; 95% CI 0.92–1.29; P = 0.316), but increase the risk of serious gastrointestinal events (OR 1.37; 95% CI 1.02–1.83; P = 0.037). Long-acting GLP-1RAs did not significantly increase the risk of serious adverse events (OR 0.92; 95% CI 0.85–1.00; P = 0.039). Conclusions: Our analysis suggested no subpopulation differences in the cardiovascular efficacy of long-acting GLP-1RAs among stratified subpopulations, and favorable trends were only observed in the subpopulation with established CVD. These findings may have implications for the management of long-acting GLP-1RAs across subpopulations of patients with T2DM. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Taibah University Medical Sciences is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: In spite of the development and availability of newer contrast media with reduced and enhanced safety profiles, certain patients remain at risk for serious adverse reactions. Creatinine clearance is widely used to assess at-risk patients. This is an acceptable practice for estimating the glomerular filtration rate. Aim: The aim of the study was to find out whether creatinine clearance is determined before administration of intravenous iodinated contrast medium (IICM) in some selected contrast-usage hospitals in Ghana. Method: The research was a descriptive survey. The participants were selected through purposive sampling. Fifty-nine (59) questionnaires were sent to radiographers, radiologists and physicians from the respective imaging and urology departments of the selected hospitals. Fifty (n=50) completed questionnaires were received. Descriptive statistics was used to generate the results. Results: The study achieved a response rate of 85%. Most of the respondents (n=41; 82%); did not enquire or determine creatinine clearance of their patients before referring or performing procedures that involved the use of IICM. Reasons given for not doing so were as follows: cost involved (n=16; 32%), delay in booking (n=15; 30%), and booking disruptions (n=4; 8%). The test was considered to be cumbersome by eight (16%) of the respondents, whereas ten (20%) indicated they did not determine it because they relied on other staff (radiographers/radiologists relied on referring physicians and vice versa). Conclusion: Determination of creatinine clearance before IICM examinations by referring clinicians appeared lacking in the selected hospitals in Accra. The imaging departments also do not check their patients' creatinine clearance or levels before performing procedures. It is appropriate that the creatinine status is checked to avoid serious adverse reactions to at-risk patients. However, there are challenges in checking patients' creatinine status, such as delays in booking patients, booking disruptions, high cost, the cumbersome nature of the test and communication gap. [ABSTRACT FROM AUTHOR]

This study evaluated the effectiveness and safety of Labisia pumila var alata ( L. pumila) water extract for improving quality of life, cardiovascular and hormonal balance. A randomized, double-blind, placebo-controlled, parallel group, 16-week study in healthy pre- and postmenopausal women aged 40-60 years was conducted in Kelantan, Malaysia. The subjects were randomized to 400 mg propriety extract of L. pumila or placebo. A Women's Health Questionnaire was used to assess quality of life. Repeated-measures analysis of variance was used to evaluate the data. A total of 197 subjects ( L. pumila: n=102 and placebo: n=95) were analyzed. Subjects in the herbal group showed improved memory/concentration, vasomotor symptoms, menstrual symptoms, and sleep problems by 8.3%, 15.9%, 11.8%, and 31.0%, respectively. The greatest improvement was observed for the question: 'I get frightened or panic feelings for apparently no reason at all' with a 53% decrease as compared with placebo. Improvements were also seen in the cardiovascular parameters, and the safety profiles were normal. Postmenopausal women supplemented with L. pumila showed no changes in gynecological relevant hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), and 17 β-Estradiol. Water extract of L. pumila was shown to be safe and effective for improving several parameters of quality of life and cardiovascular risks factors (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C]). [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study was to investigate the effect of Tualang honey on the safety profiles among post- menopausal women. Designs: A preliminary trial to investigate the effect of Tualang honey involving postmenopausal women aged 45-60 years old. Materials and Methodology: Forty healthy postmenopausal Malay women were given 20 g/day of Tualang honey and followed up for 4 months. The primary outcome was changes from baseline on the safety profiles. Paired t-test was performed to evaluate the difference between the baseline and the 4 month values of the renal, liver, haematological and lipid profiles. Results: 40 women were given Tualang honey. There was no significant change in biochemical parameters such as liver enzymes and haematological profile. There was a significant increase in the total cholesterol, LDL-C and fasting blood sugar level at four months of study. Conclusion: Daily intake of Tualang honey at 20 g/day for four months was found to be safe in terms of the renal, liver and haematological profile. However, the levels of the cholesterol and fasting blood sugar was increased at four months of the study. [ABSTRACT FROM AUTHOR]

Background: Amongst the most important issues in women's health are the risks and benefits of estrogen replacement therapy. However, continual uncertainty and lack of consensus of standard estrogen replacement therapy has driven many women to seek alternative sources of estrogen, including herbal remedies. To date, there has been no clinical study to look at the effects of Labisia pumila var. alata (Kacip Fatimah) on post- menopausal women. In view of the initial evidence from animal studies that the plant contains phytoestrogens and exert androgenic and estrogenic activities, it is postulated that Labisia pumila may be beneficial to these women. BioLabisia™ is a water extract of Labisia pumila var. alata, produced using a patented technology developed by a group of Malaysian scientists. The objectives of this study were to determine the effects of varying doses of BioLabisia™ a standardized sprayed-dried water extract of Labisia pumila var. alata on the safety profiles such as haematological indices, liver and renal function and the cardiovascular effects from body mass index, waist hip ratio, the effects on blood pressure, chest x-ray and ECG changes. Methodology: This is a randomized, double-blind, placebo-controlled study comparing the effects of BioLabisia™, at 140, 280 or 560 mg/day, given for 6 months, in a group of post-menopausal, but otherwise healthy, Malay women aged 48-55 years old. Ethical approval from participating hospitals were obtained prior to the study. 70 eligible participants were divided into four groups. Group 1 received 140 mg/day BioLabisia™, Group 2 received 280 mg/day BioLabisia™, Group 3 received 560 mg/day BioLabisia™ and group 4 received placebo (maltodextrine). Pre study screening and assessment was done and if the subject was eligible, informed consent was taken and baseline investigations including hematological, liver and renal function tests, chest x-ray and electrocardiography (ECG) were performed. Those respondents with normal baseline investigations were invited to participate in this study. The study duration was six months and all participants were required to come to the clinic for clinical examination two monthly. During each visit the participants were asked regarding any side effects of medication. The participants were also required to come for a supply of medication each month and the investigator team had to ensure that all participants complied with the medication and scheduled visits. On visit 4, all blood investigations, blood pressure, chest x-ray and ECG were repeated again. Results: There was no significant difference seen in demographic profile between the four groups of post-menopausal women. No significant changes were seen in the measurement of body mass index and the waist hip ratio at the end of study period. In terms of haematological indices, liver and renal function, no significant changes were seen in each of the four groups. Other investigations such as blood pressure, chest x-ray and ECG were all normal. Conclusion: In summary, based on the clinical and laboratory evidence, daily intake of BioLabisia™ up to 560 mg/day for 6 months, was found to be safe and has not been shown to cause any adverse effect to the body. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, debilitating disease affecting not only the skin, but also having a significant impact on a patient's quality of life. The treatment of severe psoriasis is quite challenging due to the chronic, relapsing nature of the disease and the difficulties inherent in treatment planning. Though the biologics are perhaps the most promising of available psoriasis treatments, the decision to institute a given therapy may be fraught with complexity for the clinician. Patients now hear of these promising new treatments for psoriasis via print, television and radio advertising; they frequently come to their physician asking if they are eligible for any of these agents and, if so, ‘which biologic is best?’. This paper attempts to determine the ideal biologic agent based upon several parameters: FDA‐ and EU‐approved indications, therapeutic efficacy, impact on quality of life, cost‐effectiveness, and safety profile. Certainly the physician is central to medical decision‐making, though ultimately patient preference may play the largest role in determining the ‘best’ biologic agent. There is no single ideal biologic for all patients and a physician's job is to educate patients on the relative advantages and disadvantages of each agent. Through informed discussion, the clinician can help each individual patient decide which biologic agent is ideal for them. [ABSTRACT FROM AUTHOR]

Vectors based on adeno-associated viruses (AAVs) show promise for the treatment of genetic diseases. This study evaluates the biology of AAV-mediated gene transfer to liver in nonhuman primates (NHPs) using vectors based on AAV serotypes 2, 7, and 8. Transgenes encoding self-proteins were selected to minimize the confounding development of transgene-specific immune responses. These included the β subunit of choriogonadotropic hormone (bCG) and erythropoietin (Epo), both derived from cDNAs from rhesus macaques. Experiments were performed with bCG in rhesus macaques and Epo in cynomolgus macaques. We demonstrated the previously untested hypothesis that preexisting immunity to a natural infection does substantially diminish the efficacy of gene transfer with a vector derived from an endogenous virus. Route of vector administration clearly has an impact on the development of immune responses to self-antigens. In general, efficiency of gene transfer to liver with AAV7 and 8 vectors was higher than what was achieved with AAV2, although a variety of host factors may influence this important parameter, such as preexisting immunity, gender, and transgene immunity.Molecular Therapy (2006) 13, 77–87; doi: 10.1016/j.ymthe.2005.08.017 [ABSTRACT FROM AUTHOR]

Polymer polyethylene glycol (PEG), or PEGylation of polypeptides improves protein drug stability by decreasing degradation and reducing renal clearance. To produce a pharmaceutical disintegrin derivative, the N-terminal PEGylation technique was used to modify the disintegrin derivative [KGDRR]trimucrin for favorable safety, pharmacokinetic profiles, and antithrombotic efficacy. We compared intact [KGDRR]trimucrin (RR) and PEGylated KGDRR (PEG-RR) by in vitro and in vivo systems for their antithrombotic activities. The activity of platelet aggregation inhibition and the bleeding tendency side effect were also investigated. PEG-RR exhibited optimal potency in inhibiting platelet aggregation of human/mouse platelet-rich plasma activated by collagen or ADP with a lower IC50 than the intact derivative RR. In the illumination-induced mesenteric venous thrombosis model, RR and PEG-RR efficaciously prevented occlusive thrombosis in a dose-dependent manner. In rotational thromboelastometry assay, PEG-RR did not induce hypocoagulation in human whole blood even given at a higher concentration (30 μg/mL), while RR slightly prolonged clotting time. However, RR and PEG-RR were not associated with severe thrombocytopenia or bleeding in FcγRIIa-transgenic mice at equally efficacious antithrombotic dosages. We also found the in vivo half-life of PEGylation was longer than RR (RR: 15.65 h vs. PEG-RR: 20.45 h). In conclusion, injectable PEG-RR with prolonged half-life and decreased bleeding risk is a safer anti-thrombotic agent for long-acting treatment of thrombus diseases. [ABSTRACT FROM AUTHOR]