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21.
Loxapine is a tricyclic antipsychotic drug of the dibenzoxapine class. An uncontrolled open trial of this compound has been performed by intramuscular route in 28 patients previously refractory to other neuroleptic drugs. These patients received 50 to 200 mg loxapine daily by intramuscular route. Clinical evaluation, BPRS, NOISE and biological evaluation were performed before and at the 8th day of the treatment. Global clinical evaluation and statistical analysis of BPRS showed the high efficacy of loxapine with a sedative effect during the initial phase and a disinhibiting and "hallucinolytic" character at a later stage. Tolerance to the preparation appeared good both locally and systematically with the possible exception of transient effects upon body temperature. 相似文献
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Katherine Lu John A. Benvenuto Gerald P. Bodey Jeffrey A. Gottlieb Michael G. Rosenblum Ti Li Loo 《Cancer chemotherapy and pharmacology》1982,8(1):119-123
Summary Resistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, -2-deoxythioguanosine (-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of -TGdR in patients with cancer after intravenous administration. [35S]--TGdR (5.4 mg/kg, 200 mg/m2, 200 Ci total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t1/2) of 14 min and a terminal t1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [35S]-6-TG (3.4 mg/kg, 125 mg/m2, 200 Ci total) the average initial t1/2 was 40 min while the terminal phase t1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6 thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that -TGdR is merely a latent form of TG.Deceased, to whose memory this paper is dedicated 相似文献
24.
Peritoneal dialysis favorably influences early graft function after renal transplantation compared to hemodialysis 总被引:5,自引:0,他引:5
BACKGROUND: Delayed graft function (DGF) and acute renal failure (ARF) after renal transplantation negatively influence short- and long-term graft outcome. Peritoneal dialysis as pretransplantation dialysis modality was reported to influence favorably the recovery of renal function immediately after kidney transplantation. It has been hypothesized that fluid status was the factor explaining this better outcome. This hypothesis was tested in this study by multivariate analysis, also including other factors related to DGF and ARF. METHODS: The records of peritoneal dialysis (PD; n=40) and hemodialysis (HD; n=79) patients receiving a first cadaveric kidney transplantation at the University Hospital Gent were analyzed. RESULTS: DGF and ARF were observed in 33 (27 HD and 6 PD, P=0.03) and 14 (14 HD and 0 PD, P=0.01) patients, respectively. The number of days needed to reach a serum creatinine 50% below that before transplantation (T1/2(SCr)), was correlated with cold ischemia time (CIT) (P<0.001) and body weight gain (BWG) (P<0.01) and was inversely correlated with urinary output in the first 24 hr (P<0.001), fluid load (P<0.001), and central venous pressure (P<0.001). A multivariate model with CIT (P<0.001), PD as pretransplantation dialysis mode (P=0.01), urinary output in the first 24 hr (P=0.001), BWG (P=0.05), and fluid load (P=0.01) resulted in an R2 of 0.32 (P<0.001). Using Cox regression analysis, the relative risk for a prolonged T1/2(SCr) increased with 4%/hr CIT (P=0.01) and with 1%/kg BWG (P=0.02). Fluid load decreased the relative risk with 5%/liter (P<0.001) and PD as pretransplantation modality favorably modified the relative risk by a factor of 1.6 (P=0.01). CONCLUSION: PD as pretransplantation dialysis modality can reduce the incidence and the severity of delayed recovery of renal function after renal transplantation. This protective effect was independent from CIT, and fluid status, two other major influencing factors. 相似文献
25.
Kimberly Loo Hannah L Kalvin Katherine S Panageas Vivian Park Michael A Postow 《The oncologist》2022,27(9):e755
BackgroundLittle is known about patient outcomes with advanced melanoma following inpatient initiation or continuation of immune checkpoint blockade (ICB).Methods and ResultsWe conducted a single institution retrospective case series of advanced melanoma patients who initiated ICB as an inpatient (initial inpatient cohort, n = 9), or continued ICB as an inpatient after previously starting as an outpatient (outpatient then inpatient cohort, n = 5). One patient had a partial response to ICB initiated as an inpatient, but ultimately died of melanoma after 13.5 months. Median overall survival for initial inpatient cohort was 1.0 month (95% CI: 0.2-11.2), and 1.4 months (95% CI: 0.4-58.0) for the outpatient then inpatient cohort. Three patients were alive >6 months after inpatient ICB administration.ConclusionDespite overall poor outcomes, some patients may benefit from inpatient ICB. This study provides additional information for clinicians to appropriately counsel patients on expectations following inpatient ICB. 相似文献
26.
Louis Nevejan Lize Cuypers Lies Laenen Liselotte Van Loo Franois Vermeulen Elke Wollants Ignace Van Hecke Stefanie Desmet Katrien Lagrou Piet Maes Emmanuel Andr 《Emerging infectious diseases》2022,28(8):1729
Illustrated by a clinical case supplemented by epidemiologic data, early reinfections with SARS-CoV-2 Omicron BA.1 after infection with Delta variant, and reinfection with Omicron BA.2 after Omicron BA.1 infection, can occur within 60 days, especially in young, unvaccinated persons. The case definition of reinfection, which influences retesting policies, should be reconsidered. 相似文献
27.
Nina Streefkerk Marianne J. Heins Jop C. Teepen Elizabeth A. M. Feijen Dorine Bresters Eline van Dulmen‐den Broeder Margriet van der Heiden‐van der Loo Marry M. van den Heuvel‐Eibrink Flora E. van Leeuwen Jacqueline J. Loonen Helena J. H. van der Pal Ccile M. Ronckers A. Birgitta Versluys Wim J. E. Tissing Joke C. Korevaar Leontien C. M. Kremer 《Pediatric blood & cancer》2019,66(8)
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29.
Ramsay Macdonald Brendan J. Mahoney Jess Soule Andrew K. Goring Jordan Ford Joseph A. Loo Duilio Cascio Robert T. Clubb 《Proceedings of the National Academy of Sciences of the United States of America》2023,120(5)
Streptococcus pyogenes (group A Streptococcus) is a clinically important microbial pathogen that requires iron in order to proliferate. During infections, S. pyogenes uses the surface displayed Shr receptor to capture human hemoglobin (Hb) and acquires its iron-laden heme molecules. Through a poorly understood mechanism, Shr engages Hb via two structurally unique N-terminal Hb-interacting domains (HID1 and HID2) which facilitate heme transfer to proximal NEAr Transporter (NEAT) domains. Based on the results of X-ray crystallography, small angle X-ray scattering, NMR spectroscopy, native mass spectrometry, and heme transfer experiments, we propose that Shr utilizes a “cap and release” mechanism to gather heme from Hb. In the mechanism, Shr uses the HID1 and HID2 modules to preferentially recognize only heme-loaded forms of Hb by contacting the edges of its protoporphyrin rings. Heme transfer is enabled by significant receptor dynamics within the Shr–Hb complex which function to transiently uncap HID1 from the heme bound to Hb’s β subunit, enabling the gated release of its relatively weakly bound heme molecule and subsequent capture by Shr’s NEAT domains. These dynamics may maximize the efficiency of heme scavenging by S. pyogenes, enabling it to preferentially recognize and remove heme from only heme-loaded forms of Hb that contain iron.To successfully mount infections bacterial pathogens must overcome host nutritional immunity mechanisms that limit access to iron, an essential metal nutrient required for microbial survival because it functions as a cofactor in enzymes that mediate cellular metabolism. Human hemoglobin (Hb) contains ~75 to 80% of the body’s total iron in the form of heme (iron–protoporphyrin IX) and is thus a prime nutrient source for invading microbes (1–9). Bacteria gain access to Hb’s iron-laden heme molecules when erythrocytes are ruptured by bacterial cytotoxins or when they spontaneously lyse. In gram-positive monoderm bacteria, extracellular Hb is captured by surface-displayed microbial receptors. Hb’s heme molecules are then released and transferred via microbial heme-binding chaperones across the expanse of the peptidoglycan to the membrane, where they are imported into the cell and degraded to release iron. The acquisition mechanisms that many pathogens use to bind to Hb and remove its tightly bound heme molecules are not well understood. Streptococcus pyogenes (group A Streptococcus) colonizes the skin and mucosal surfaces in humans and is estimated to cause more than 500,000 deaths annually (10–12). It causes a range of illnesses, ranging from acute pharyngitis to life-threatening diseases such as scarlet fever, bacteremia, pneumonia, necrotizing fasciitis, myonecrosis, and streptococcal toxic shock syndrome (13, 14). S. pyogenes employs the streptococcal hemoprotein receptor (Shr) to capture Hb and acquire its heme molecules, and it is an important virulence factor that when genetically deleted reduces the ability of the pathogen to grow in human blood and to cause infections in murine and zebrafish models (15–17). Strategies that interfere with the ability of S. pyogenes and other pathogenic bacteria to harvest heme from Hb could be useful in treating infections, as they would effectively starve pathogens of iron.The S. pyogenes Shr protein is a structurally unique multidomain Hb receptor that is also found in other streptococci and clostridia species (e.g., Clostridium novyi, Streptococcus iniae, Streptococcus equi, and Streptococcus dysgalactiae) (Fig. 1A). Its N-terminal region (NTR, residues 26 to 364) binds to Hb using two Hb interacting domains (HIDs), called HID1 and HID2 (formally known as DUF1533 domains) (18, 19). The HIDs are structurally novel binding modules and are joined via a structured linker domain (L) to a C-terminal region (CTR, residues 365 to 1,275) which contains two heme-binding NEAr iron Transporter domains (NEAT domains N1 and N2) that are separated by a series of leucine-rich repeats (LRR). The NTR and N1 domain within Shr (called NTR-N1) preferentially bind to holo-Hb and remove its heme (18). In vitro, heme bound by the N1 domain is then readily transferred to either the C-terminal N2 domain, or to Shp, a cell wall-associated protein that relays heme to the membrane-associated HtsABC/SiaABC transporter that pumps heme into the cytoplasm (20–22). The N2 domain in Shr may act as a storage unit, since it binds to heme with much higher affinity than N1 and does not directly transfer heme to Shp (23). Shr also interacts via its N2 domain with the human extracellular matrix (ECM) proteins fibronectin and laminin (15, 16, 18), and its exposure on the cell surface may make it a useful epitope in S. pyogenes vaccines (24, 25). However, it remains poorly understood how Shr acquires heme from Hb. Here we show using a combination of biophysical and structural methods that Shr uses its HIDs to selectively bind to the heme-loaded form of Hb, slowing the rate of heme release by directly contacting the edges of its protoporphyrin rings. However, receptor dynamics within the Shr–Hb complex act to transiently uncap the HIDs from Hb’s β subunit, enabling heme’s gated release and subsequent capture by the receptor. This “cap and release” mechanism exploits the β subunit’s inherent weaker affinity for heme (26), allowing S. pyogenes to preferentially capture only heme-saturated forms of Hb that contain iron.Open in a separate windowFig. 1.Structure of the Hb–ShrH2 complex. (A) Domain schematic of the Shr receptor. The polypeptide constructs used in this study are shown below. (B) Crystal structure of the Hb–ShrH2 complex. The asymmetric unit of the crystal contains two tetramers of Hb that are bound by three molecules of ShrH2. (C and D) HID2 binds over the heme pockets in both the α and β chains of Hb. These capping interactions directly contact both the heme and globin chain, burying an average of ~153 Å2 and ~408 Å2 of solvent-accessible surface area, respectively. Hb contacts originate from three surface loops in HID2: β2-α1, β4-β5, and β5-β6. (E) Expanded view of the Hb-receptor interface showing interactions with the heme molecule bound to the α subunit. The heme molecules are shown in stick format with oxygen and nitrogen atoms colored red and blue, respectively. Side chains in the receptor that interact with Hb are shown in stick format. (F) Identical to panel (E), except that receptor contacts to the β subunit in Hb are shown. Hb is in its ferric form. Color scheme: α subunit (salmon), β subunit (green), and HID2 (blue). 相似文献
30.
Hui Xing Lau Sarah El-Heis Qai Ven Yap Yiong Huak Chan Cheryl Pei Ting Tan Neerja Karnani Karen Mei Ling Tan Elizabeth Huiwen Tham Anne Eng Neo Goh Oon Hoe Teoh Kok Hian Tan Johan Gunnar Eriksson Yap Seng Chong Mary Foong-Fong Chong Hugo Van Bever Bee Wah Lee Lynette P. Shek Keith M. Godfrey Evelyn Xiu Ling Loo 《Clinical and experimental allergy》2021,51(10):1346-1360