Effectiveness of Bach Nien Kien Health Supplement in the Treatment of Patients With Symptomatic Knee Osteoarthritis.

BACKGROUND/AIM: Knee osteoarthritis (KOA) is the most common disease in adults. We conducted a clinical study to evaluate the efficacy and safety of Bach Nien Kien (BNK) in supportive therapy for patients with symptomatic KOA. PATIENTS AND METHODS: An open interventional study was performed on 60 patients aged 38 to 70 with the diagnosis of symptomatic KOA. The patients were assigned to a study group (SG) with 30 subjects and a control group (CG) with 30 subjects using a matching method. The patients in SG were treated with electroacupuncture, glucosamine supplement, and BNK, while the patients in CG received the same treatment without BNK. RESULTS: At the end of the 30-day treatment (d30), the SG had a reduction in VAS score compared to a pre-treatment level of 3.03±0.96 points, which was more than the CG of 2.5±0.90 points. The excellent result in the SG was 10%, and the CG had no excellent result. The good result in the SG was 56.7%, and the CG group was only 26.7%. The moderate and poor results in the CG were high, 63.3%, and 10%, respectively; in the SG, only 26.7% and 6.7%. The difference in overall treatment results between the SG and CG was statistically significant (p<0.05). During the 30-day treatment period in both groups, no patient reported any undesirable effects. CONCLUSION: Bach Nien Kien health supplement is effective and safe for controlling KOA symptoms and improving joint motion and quality of life for patients with symptomatic KOA.

[Comparison of efficacy and safety of transurethral thulium laser vapoenucleation of prostate and transurethral thulium laser enucleation of prostate in the treatment of benign prostatic hyperplasia].

Objective: To compare early outcomes between transurethral thulium laser vapoenucleation of prostate and transurethral thulium laser enucleation of prostate for the treatment of benign prostatic hyperplasia (BPH). Methods: Retrospective analysis was conducted on the clinical data of 1 638 BPH patients admitted to the Department of Urology of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine from January 2018 to December 2021. There were 916 patients underwent transurethral thulium laser vapoenucleation of prostate (ThuVEP group) and 722 patients underwent transurethral thulium laser enucleation of prostate (ThuLEP group). The operation time, eliminated tissue weight, surgical complications, duration of post-operative catheter implantation were compared between the two groups. The improvement of International Prostate Symptom Score (IPSS), Quality of Life Index (QoL), maximum uroflow rate (Qmax) and post-void residual urine volume (PVR) at 1 month after operation was compared between the two groups. Results: There were no significant differences in age, preoperative and 1-month postoperative prostate volume, IPSS score, QoL score, Qmax, and PVR between the ThuVEP and ThuLEP group (all P>0.05). There were no significant differences in perioperative indicators such as operation time, cutting or enucleation time, tissue crushing time, tissue weight, hemoglobin change, catheter indwelling time, and postoperative hospital stay between ThuVEP group and ThuLEP group (all P>0.05). The incidence of minor gross hematuria after extubation in the ThuVEP group was 7.8% (56/916), which was lower than 9.4% (65/722) in the ThuLEP group (P=0.026); the incidence of temporary incontinence at 1 month after surgery was 5.2% (38/916) in ThuVEP group, lower than 11.9% (86/722) in ThuLEP group (P<0.001). A total of 3 patients (0.4%) in ThuLEP group required operative intervention for severe post-operation bleeding, but none of ThuVEP group suffered from this kind of surgical complications. Conclusions: ThuVEP has similar efficacy with ThuLEP for the treatment of BPH. ThuVEP can significantly reduce the incidence of post-operation temporary urine incontinence, and has much superiority in stanching bleeding.

A Prospective Study of AFree Oral Spray as an Adjuvant Therapy for Mild and Moderate COVID-19 in Community Health Stations: Clinical Progression and Viral Clearance Outcomes.

BACKGROUND/AIM: The aim of this study was to evaluate the safety and efficacy of AFree oral spray, in combination with Standard of Care, in treating mild to moderate COVID-19 patients. This was an open-label, single-blinded, and controlled randomized clinical trial. PATIENTS AND METHODS: The study involved 1,252 patients, who were randomly assigned to either the control or study group, with 626 patients in each group. Patients in the control group were treated with Standard of Care recommended by the Ministry of Health of Vietnam, while patients in the study group received AFree oral spray in addition to Standard of Care for a period of 10 days. The clinical progression and outcomes of both groups were compared. RESULTS: The results showed that the proportion of patients with clinical symptoms on the 5th, 7th and 10th days were significantly lower in the study group (45.05%, 3.19% and 0%, respectively) compared to the control group (86.10%, 67.73% and 22.84%, respectively). Additionally, the rate of Real-time PCR test positivity for COVID-19 was significantly lower in the study group compared to the control group on the 4th, 7th, and 10th days (82.75% vs. 98.72%, 9.27% vs. 92.97%, and 1.12% vs. 50.48%, respectively). Furthermore, no side effects or complications related to AFree oral spray were recorded in the study group. CONCLUSION: The use of AFree oral spray resulted in significant improvements in clinical symptoms, recovery time, and viral clearance in COVID-19 patients with mild to moderate symptoms. This therapy has been shown to be safe and can be used as an adjuvant treatment for COVID-19 as well as other respiratory viral infections.

Targeting Skeletal Muscle Dysfunction With L-Carnitine for the Treatment of Patients With Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a major medical problem and the world's third leading cause of death. COPD is a chronic disease with heterogeneous clinical symptoms, disease progression, and treatment responses. Besides pulmonary symptomatology, the common systemic clinical manifestations are cachexia, muscle weakness, and widespread comorbidities such as cardiovascular diseases, diabetes, osteoporosis, and infections. The adverse effects of pharmaceutical therapies contribute to the difficulty of health risk assessment and management of COPD patients. This review shows how skeletal muscle dysfunction and metabolic abnormalities contribute significantly to COPD patients' symptoms, functional activities, quality of life, and overall disease outcomes. Based on the clinical evidence of L-carnitine and derivatives as metabolic and muscle bioenergetic enhancers, we propose broader research and implementation of this nutraceutical agent as an effective, inexpensive, and safe adjuvant therapeutic for the long-term management of COPD patients. Moreover, we believe the management of COPD as a chronic disease should be shifted from symptomatic reactive pharmaceutical intervention to more constructive and non-toxic approaches using a single or combination of natural and nutritional agents with potential muscle metabolic enhancing and immunomodulating activities to achieve a better overall outcome for the patients in terms of morbidity, mortality, and medical cost-reduction.

Successful Phytotherapy for Acute Refractory Radiation Cystitis in a Cervical Cancer Patient: A Case Report.

BACKGROUND/AIM: Radiation cystitis is a frequent complication that can occur after therapeutic irradiation of pelvic cancers. The current treatment for this condition is complex and often ineffective. CASE REPORT: We present a clinical case of a 54-year-old patient diagnosed with small cell cervical cancer FIGO stage IIIC who developed grade 2-3 radiation cystitis following post-operational chemoradiation therapy. The patient exhibited increased urinary urgency and frequency, dysuria, and low abdominal pain, which failed to respond to acupuncture and corticosteroid treatments. A course of Ich Nieu Khang phytotherapy tablets, resulted in significant improvement of symptoms within 24 hours of initiation. The symptoms resolved completely within 10 days, and ultrasonography documented a marked decrease in bladder wall thickening and improved bladder evacuation function. The phytotherapy was well-tolerated, and no side-effects were observed during the 60-day treatment period. CONCLUSION: These findings suggest that phytotherapy may be viable for managing radiation cystitis. However, further controlled clinical trials are needed to confirm the efficacy of Ich Nieu Khang and promote its broader clinical applications.

Nowarta110 Topical Versus Placebo for the Treatment of Plantar Warts: A Phase I/II Randomized Controlled Clinical Trial.

BACKGROUND/AIM: Plantar warts are cutaneous lesions on the plantar aspect of the foot caused by the infection of keratinocytes with the human papillomavirus (HPV). The severity and magnitude of warts can vary, but they cause pain and discomfort for all age groups. The treatment for plantar warts remains a continuing challenge. The purpose of this research was to compare the efficacy and safety of naturally derived Nowarta110 topical formula versus a matching placebo in treating plantar warts. PATIENTS AND METHODS: The study is a randomized, double-blind, parallel assignment control interventional phase I/II clinical trial. This study included 54 patients with plantar warts. Patients were randomized to two groups: the placebo group, which included 26 patients treated with a matching placebo and the Nowarta110 group, which included 28 patients who received topical Nowarta110. The diagnosis of plantar warts was made by clinical examination. The treatment's efficacy and safety were assessed every week and after 6 weeks from the initiation of the intervention. RESULTS: In the Nowata110 group, 18 patients (64.3%) were completely cleared of their warts, and 10 patients (35.7%) partially responded to the therapy with a 20% to 80% decrease in warts dimensions. In the placebo group, only 2 patients (7.7%) were completely cleared of their warts, and 3 patients (11.5%) partially responded to the intervention with a 10% to 35% decrease in warts dimensions. The difference was highly significant between the two groups. There was 1 event with minor pain as a side effect in the Nowarta110 group and 9 events of non-serious local side effects in the placebo group, which included 2 patients who dropped out. CONCLUSION: Topical Nowarta110 is a safe, well-tolerated, and highly effective therapeutic modality in treating refractory and recurrent plantar warts. The breakthrough findings of the study encourage further extensive clinical trials to fully explore the prospect of Nowarta110 in managing all types of warts and HPV-related diseases.

Inhibitory effects of herbal decoction Ojeoksan on proliferation and migration in vascular smooth muscle cells.

The proliferation of vascular smooth muscle cells plays a crucial role in pathogenesis of cardiovascular disease. The principal objective of this study was to determine the effects of Ojeoksan (OJS) on human aortic smooth muscle cell (HASMC) proliferation induced by tumor necrosis factor α (TNF-aα). Thymidine incorporation after TNF-α treatment was increased and this effect was inhibited significantly by OJS treatment. HASMC proliferation and migration by kinetic live cell imaging were also reduced by treatment with OJS. TNF-α induced the expression of cyclins/cyclin-dependent kinases (CDKs) and reduced the expression of p21waf1/cip1/p27kip1. However, OJS also attenuated the expression of TNF-α-induced cell-cycle regulatory proteins. The results of Western blot analysis demonstrated that the TNF-α treated HASMC secreted gelatinases, probably including MMP-2/-9, which may be involved in the invasion and migration of HASMC. Additionally, OJS suppressed the mRNA expression levels of matrix metalloproteinase-2/-9 (MMP-2/-9) in a dose-dependent manner. OJS inhibited the production of TNF-α-induced hydrogen peroxide (H2O2) and the formation of DCF-sensitive intracellular reactive oxygen species (ROS). Further, OJS suppressed the nuclear translocation and phosphorylation of inhibitor of kappa B-α (IκB-α) of nuclear factor κB (NF-κB) under TNF-α conditions. Our results demonstrate that OJS exerts inhibitory effects on TNF-α-induced HASMC proliferation and migration, suggesting the involvement of the inhibition of both MMP-2 and MMP-9 expressions, and the downregulation of ROS/NF-κB signaling. Thus, herbal decoction OJS may be a possible therapeutic approach to the inhibition of cardiovascular disease including atherosclerosis.

Effects of metabolic abnormalities, hyperandrogenemia and clomiphene on liver function parameters among Chinese women with polycystic ovary syndrome: results from a randomized controlled trial.

PURPOSE: To investigate the effects of metabolic abnormalities, hyperandrogenemia and ovulation induction by clomiphene/acupuncture on liver function parameters among women with polycystic ovary syndrome (PCOS). METHODS: This is a secondary analysis of a randomized controlled trial. All 1000 subjects were diagnosed as PCOS by modified Rotterdam criteria. Liver function parameters, metabolic panel and hormone profile were measured at baseline and after treatment. The relationship between liver parameters with metabolic, hormonal parameters and ovulation induction was examined. RESULTS: PCOS women with metabolic syndrome had higher liver enzyme levels but lower bilirubin and bile acid levels than without. PCOS women with hyperandrogenemia had higher liver enzyme, bilirubin levels than without. Correlation analyses showed that worsening of metabolic parameters was associated with higher liver enzyme levels but lower bilirubin and bile acid levels, while increased androgen levels were associated with higher liver enzyme, bilirubin and bile acid levels. Ovulation induction with clomiphene citrate could decrease bilirubin and bile acid levels, while acupuncture had no obvious effect on liver function. CONCLUSIONS: Among PCOS women, metabolic abnormalities and hyperandrogenemia impaired different liver function parameters. Clomiphene could decrease the bilirubin and bile acid levels while acupuncture had no obvious effect on liver function.

[Evolution of the Origin of Jixuecao].

Jixuecao was first recorded in the Shennong bencaojing. The variety of plant referred to is undefined because of a lack of detailed description in the medical books of the Han and Tang dynasties. From the Song dynasty to the Republican period Jixuecao refers to Glechoma longituba (Nakai) Kupr. The name was also recorded as Jinqiancao instead of Jixuecao in the Bencao gangmu shiyi from the Qing dynasty to the Republican period, though it refers to the same plant. In recent times, Jixuecao has evolved to refer to Centella asiatica (L.) Urb, Jinqiancao now refers to Lysimachia christinae Hance, while G. longituba (Nakai) Kupr. is now called Lianqiancao. It is thus determined that G. longituba (Nakai) Kupr. alone is unequivocally the original plant referred to as Jixuecao, and has the longest medicinal history.

[Development of the harvest processing and application of Mulberry leaves].

Mulberry leaf was first recorded in the Shennong Bencao Jing(The Classic of Herbal Medicine)《》 on the list of drugs affixed, and first separate recorded in the Bencao Shiyi(Supplement to Materia Medica)《》. By checking Chinese herbs' literature of the harvest processing and application of mulberry leaves, we found that Mulberry leaves can be harvested in Summer and autumn before the Qing dynasty, but from Qing dynasty to present, those harvested in autumn and winter, which were called frost mulberry leaves or winter mulberry leaves, were seen as better. Before the Republic of China, mulberry leaves were dried in shade or on the fire, after that, they were dried in the sun. It can be found that the harvest processing of mulberry leaves was changing as time went on. The clinical application of mulberry leaves had multiplicity, depending on different picking time and different processing method. It is suggested that research of mulberry leaves on chemistry and pharmacology of picking time, processing method can result in new scientifically clinical application.

Study on the effects of blueberry treatment on histone acetylation modification of CCl4-induced liver disease in rats.

The objective of this study was to investigate the effects of blueberry treatment on histone acetylation modification of carbon tetrachloride (CCl4)-induced liver disease in rats. Laboratory rats were randomly divided into control, hepatic fibrosis, blueberry treatment, blueberry intervention, and natural recovery groups. Rats in the model groups were treated with CCl4 administered subcutaneously at 4- and 8-week intervals, and then executed. Both the 4- and 8-week treatment groups were treated with blueberry juice for 8 weeks, and then executed after 12 and 16 weeks, respectively. Following the experiment, four liver function and hepatic fibrosis indices were measured. Liver index was calculated, hematoxylin-eosin staining was conducted, and H3K9, H3K14, and H3K18 expressions were evaluated among the nuclear proteins of the liver tissues. No differences in alanine transaminase were noted between the control and intervention groups, but significant differences were detected among the model, treatment, and natural recovery groups (P < 0.01). Significant differences were also observed in aspartate transaminase, hyaluronic acid, and collagen IV among the model, treatment, intervention, and natural recovery groups (P < 0.01, P < 0.01, P < 0.01). Liver index, and H3K9 and H3K14 expression were significantly different among the model groups (P < 0.05 and P < 0.01), whereas H3K18 expression was dramatically different among model, treatment, intervention, and natural recovery groups (P < 0.01). Following blueberry treatment, rat liver function and hepatic fibrosis improved, potentially indicating that blueberry components could regulate histone acetylation and improve liver pathologic changes in rats with CCl4-induced disease.

Supplemental lipoic acid relieves post-weaning diarrhoea by decreasing intestinal permeability in rats.

Lipoic acid (LA) is a naturally existing substance which widely distributed in the cellular membranes and cytosol of animal cells. Its intracellular functions include quenching of free radicals and repairing oxidized proteins. The purpose of this study was to evaluate the effects of LA on post-weaning diarrhoea using a rat model. Sixty weaned rats were fed either a basal diet or a LA-supplemented diet, or a zinc oxide (ZnO)-supplemented diet as a positive control. Rats in the LA and ZnO groups had better performance and reduced incidence of diarrhoea (p < 0.05). Both LA and ZnO treatments enhanced intestinal homeostatic and architecture, significantly decreased urinary lactulose to mannitol ratios (p < 0.05) and increased the expression of the intestinal mucosal tight junction proteins occludin (OCLN) and zonula occludens protein-1 (ZO-1) (p < 0.05). LA significantly increased the activities of antioxidant enzymes, and reduced glutathione while decreasing the levels of oxidative glutathione and malondialdehyde in the intestinal mucosa (p < 0.05). Furthermore, an in vitro study indicated that supplementation with LA in IEC-6 intestinal epithelial cells significantly enhanced the expression of OCLN and ZO-1 under hydrogen peroxide-induced oxidative stress. Collectively, these results suggest that LA relieves post-weaning diarrhoea by reducing intestinal permeability and improving antioxidant indices.

[Evolution of the Origin of Herba Schizonepetae].

Herba Schizonepetae was firstly recorded in the Sheng nong ben caojing (Shennong's Materia Medica) with the title Jiasu. It could be sure that the original plant of Jiasu is Ocimumbasilicum L. ofLabiatae based on the record of Jiasu's name, morphology, edible property before the Song Dynasty. Beginning from the Ben cao tu jing (Illustrated Classic of Materia Medica) in the Song Dynasty, the source of this drug evolved as SchizonepetatenuisfoliaBriq. ofLabiatae, and it has been in use until now. Hence, the sources of Jiasu should be both O. basilicum L. and the co-existence of S. tenuisfolia Briq in the Qing Dynasty. It is claimed that the hometowns of those herb writers who considered the source ofOcimumbasilicum L. to be the producing areas of cultivation of the edible Ocimumbasilicum L. It was found that the source of Jiasu recorded in the Sheng nong ben cao jing should be O. basilicum L. , hence, it is suggested the title Jiasu should be recorded for the source of O. basilicum L, and the original plant of Herba Schizonepetae was Schizonepetatenuisfolia Briq. of Labiatae, and this medicine should be separately recorded. In fact, Jiasu and Herba Schizonepetae were two different kinds of medicines.

Trypanosoma brucei DHFR-TS Revisited: Characterisation of a Bifunctional and Highly Unstable Recombinant Dihydrofolate Reductase-Thymidylate Synthase.

Bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a chemically and genetically validated target in African trypanosomes, causative agents of sleeping sickness in humans and nagana in cattle. Here we report the kinetic properties and sensitivity of recombinant enzyme to a range of lipophilic and classical antifolate drugs. The purified recombinant enzyme, expressed as a fusion protein with elongation factor Ts (Tsf) in ThyA- Escherichia coli, retains DHFR activity, but lacks any TS activity. TS activity was found to be extremely unstable (half-life of 28 s) following desalting of clarified bacterial lysates to remove small molecules. Stability could be improved 700-fold by inclusion of dUMP, but not by other pyrimidine or purine (deoxy)-nucleosides or nucleotides. Inclusion of dUMP during purification proved insufficient to prevent inactivation during the purification procedure. Methotrexate and trimetrexate were the most potent inhibitors of DHFR (Ki 0.1 and 0.6 nM, respectively) and FdUMP and nolatrexed of TS (Ki 14 and 39 nM, respectively). All inhibitors showed a marked drop-off in potency of 100- to 1,000-fold against trypanosomes grown in low folate medium lacking thymidine. The most potent inhibitors possessed a terminal glutamate moiety suggesting that transport or subsequent retention by polyglutamylation was important for biological activity. Supplementation of culture medium with folate markedly antagonised the potency of these folate-like inhibitors, as did thymidine in the case of the TS inhibitors raltitrexed and pemetrexed.

Hydrogen sulfide in posthemorrhagic shock mesenteric lymph drainage alleviates kidney injury in rats

Posthemorrhagic shock mesenteric lymph (PHSML) is a key factor in multiple organ injury following hemorrhagic shock. We investigated the role of hydrogen sulfide (H2S) in PHSML drainage in alleviating acute kidney injury (AKI) by administering D,L-propargylglycine (PPG) and sodium hydrosulfide hydrate (NaHS) to 12 specific pathogen-free male Wistar rats with PHSML drainage. A hemorrhagic shock model was established in 4 experimental groups: shock, shock+drainage, shock+drainage+PPG (45 mg/kg, 0.5 h prehemorrhage), and shock+drainage+NaHS (28 µmol/kg, 0.5 h prehemorrhage). Fluid resuscitation was performed after 1 h of hypotension, and PHMSL was drained in the last three groups for 3 h after resuscitation. Renal function and histomorphology were assessed along with levels of H2S, cystathionine-γ-lyase (CSE), Toll-like receptor 4 (TLR4), interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-α in renal tissue. Hemorrhagic shock induced AKI with increased urea and creatinine levels in plasma and higher H2S, CSE, TLR4, IL-10, IL-12, and TNF-α levels in renal tissue. PHSML drainage significantly reduced urea, creatinine, H2S, CSE, and TNF-α but not TLR4, IL-10, or IL-12. PPG decreased creatinine, H2S, IL-10, and TNF-α levels, but this effect was reversed by NaHS administration. In conclusion, PHSML drainage alleviated AKI following hemorrhagic shock by preventing increases in H2S and H2S-mediated inflammation.

Hydrogen sulfide in posthemorrhagic shock mesenteric lymph drainage alleviates kidney injury in rats.

Posthemorrhagic shock mesenteric lymph (PHSML) is a key factor in multiple organ injury following hemorrhagic shock. We investigated the role of hydrogen sulfide (H2S) in PHSML drainage in alleviating acute kidney injury (AKI) by administering D,L-propargylglycine (PPG) and sodium hydrosulfide hydrate (NaHS) to 12 specific pathogen-free male Wistar rats with PHSML drainage. A hemorrhagic shock model was established in 4 experimental groups: shock, shock+drainage, shock+drainage+PPG (45 mg/kg, 0.5 h prehemorrhage), and shock+drainage+NaHS (28 µmol/kg, 0.5 h prehemorrhage). Fluid resuscitation was performed after 1 h of hypotension, and PHMSL was drained in the last three groups for 3 h after resuscitation. Renal function and histomorphology were assessed along with levels of H2S, cystathionine-γ-lyase (CSE), Toll-like receptor 4 (TLR4), interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-α in renal tissue. Hemorrhagic shock induced AKI with increased urea and creatinine levels in plasma and higher H2S, CSE, TLR4, IL-10, IL-12, and TNF-α levels in renal tissue. PHSML drainage significantly reduced urea, creatinine, H2S, CSE, and TNF-α but not TLR4, IL-10, or IL-12. PPG decreased creatinine, H2S, IL-10, and TNF-α levels, but this effect was reversed by NaHS administration. In conclusion, PHSML drainage alleviated AKI following hemorrhagic shock by preventing increases in H2S and H2S-mediated inflammation.

Trypanosoma brucei (UMP synthase null mutants) are avirulent in mice, but recover virulence upon prolonged culture in vitro while retaining pyrimidine auxotrophy.

African trypanosomes are capable of both de novo synthesis and salvage of pyrimidines. The last two steps in de novo synthesis are catalysed by UMP synthase (UMPS) - a bifunctional enzyme comprising orotate phosphoribosyl transferase (OPRT) and orotidine monophosphate decarboxylase (OMPDC). To investigate the essentiality of pyrimidine biosynthesis in Trypanosoma brucei, we generated a umps double knockout (DKO) line by gene replacement. The DKO was unable to grow in pyrimidine-depleted medium in vitro, unless supplemented with uracil, uridine, deoxyuridine or UMP. DKO parasites were completely resistant to 5-fluoroorotate and hypersensitive to 5-fluorouracil, consistent with loss of UMPS, but remained sensitive to pyrazofurin indicating that, unlike mammalian cells, the primary target of pyrazofurin is not OMPDC. The null mutant was unable to infect mice indicating that salvage of host pyrimidines is insufficient to support growth. However, following prolonged culture in vitro, parasites regained virulence in mice despite retaining pyrimidine auxotrophy. Unlike the wild-type, both pyrimidine auxotrophs secreted substantial quantities of orotate, significantly higher in the virulent DKO line. We propose that this may be responsible for the recovery of virulence in mice, due to host metabolism converting orotate to uridine, thereby bypassing the loss of UMPS in the parasite.

TU-E-BRB-07: An EPID Based Dosimetric Verification Tool for SBRT with High Dose Rate FFF Beams.

PURPOSE: The increasing use of unflattened high dose rate and/or small sized fields in stereotactic body radiosurgery (SBRT) presents a significant challenge and calls for new tools for dosimetric measurements and quality assurance (QA). The purpose of this work is to investigate a high spatial resolution (0.2mm) and high frame rate (50Hz) amorphous silicon flat-panel electronic portal imaging device (EPID) from Perkin Elmer for SBRT. METHODS: A Monte Carlo N-Particle eXtended (MCNPX) simulation and convolution based calibration procedure has been developed to derive a voxel-based response function specific to the EPID construct and beam characteristics. Both standard photon beams and flattening filter free (FFF) beams of all energies from Varian TrueBeam STX were studied and the linearity and dose rate dependence were tested. EPID with detailed materials composition was simulated using the MCNPX to generate a scatter kernel composed of dose deposition in the EPID phosphor, and optical photon spreading and to deconvolve the EPID images to high spatial resolution photon fluence map. The fluence map was convolved with MCNPX generated kernels to the 3D dose distribution in the phantom and compared with pinpoint ion chamber and film measurements. RESULTS: EPID response showed excellent linearity (R2>0.9998) and dose rate dependence less than 1.8% for up to 2400MU/min. Output factors for field sizes ranging from 1×1 to 20×20cm2 were measured and used to fit the optical photon glare kernel. Fluence profiles deconvolved using MCNPX scattering kernel agrees with the measurements to within 2%. Results of typical pre-treatment QA test exhibit excellent spatial resolution required for SBRT. CONCLUSIONS: The high spatial resolution and high frame rate EPID proved to be an accurate and efficient tool for SBRT QA. Through convolution with MCNPX scattering core and comprehensive EPID calibration, accurate 3D dose maps can be generated for independent dosimetric verification of SBRT treatments.

Design, synthesis and biological evaluation of novel inhibitors of Trypanosoma brucei pteridine reductase 1.

Genetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for the survival of the protozoan parasite Trypanosoma brucei. Herein, we describe the development and optimisation of a novel series of PTR1 inhibitors, based on benzo[d]imidazol-2-amine derivatives. Data are reported on 33 compounds. This series was initially discovered by a virtual screening campaign (J. Med. Chem., 2009, 52, 4454). The inhibitors adopted an alternative binding mode to those of the natural ligands, biopterin and dihydrobiopterin, and classical inhibitors, such as methotrexate. Using both rational medicinal chemistry and structure-based approaches, we were able to derive compounds with potent activity against T. brucei PTR1 (K(i)(app)=7 nM), which had high selectivity over both human and T. brucei dihydrofolate reductase. Unfortunately, these compounds displayed weak activity against the parasites. Kinetic studies and analysis indicate that the main reason for the lack of cell potency is due to the compounds having insufficient potency against the enzyme, which can be seen from the low K(m) to K(i) ratio (K(m)=25 nM and K(i)=2.3 nM, respectively).