scholarly journals Evaluation of T-3811ME (BMS-284756), a New Des-F(6)-Quinolone, for Treatment of Meningitis Caused by Penicillin-Resistant Streptococcus pneumoniae in Rabbits

2002 ◽  
Vol 46 (6) ◽  
pp. 1760-1765 ◽  
Author(s):  
Masahiro Takahata ◽  
Hiroshi Yamada ◽  
Teiichi Morita ◽  
Shinichi Furubou ◽  
Shinzaburo Minami ◽  
...  

ABSTRACT T-3811ME (BMS-284756) is a new des-F(6)-quinolone with high levels of activity against gram-positive bacteria, including penicillin-resistant Streptococcus pneumoniae (PRSP) strains. T-3811, the free base of T-3811ME, exhibited potent activity against 28 clinical strains of PRSP isolated clinically (MIC at which 90% of the isolates tested are inhibited, 0.0625 μg/ml). After the intravenous dosing of T-3811ME (20 mg/kg of body weight as T-3811) in rabbits with meningitis caused by PRSP, the area under the concentration-time curve (AUC) of T-3811 in cerebrospinal fluid (CSF) was 5.79 μg · h/ml and was 4.5-fold higher than that of T-3811in the CSF of rabbits without meningitis. In addition, the AUC/MIC for T-3811ME (20 mg/kg as T-3811) in CSF was 185, which was 4.3-fold higher than that for ceftriaxone (administered intravenously at 100 mg/kg). After the administration of any dose of T-3811ME (5, 10, and 20 mg/kg as T-3811), the viable cell counts in CSF decreased in a dose-dependent manner. In particular, after dosing of 20 mg/kg (as T-3811), the viable cell counts in CSF were significantly less than those in the nontreated group (P < 0.01). By histopathological evaluation, 6 h after the administration of T-3811ME (20 mg/kg as T-3811), the thickening of the cerebral meninx and the infiltration of neutrophils into the cerebral meninx were less severe in the treated group than in the nontreated group. T-3811ME (BMS-284756) may be expected to be evaluated for the management of meningitis caused by highly penicillin-resistant pneumococci.

2010 ◽  
Vol 54 (10) ◽  
pp. 4300-4305 ◽  
Author(s):  
Tomoyuki Homma ◽  
Toshihiko Hori ◽  
Merime Ohshiro ◽  
Hideki Maki ◽  
Yoshinori Yamano ◽  
...  

ABSTRACT The pharmacokinetic (PK)/pharmacodynamic (PD) parameters and the antibacterial activity of S-013420, a novel bicyclolide, against Haemophilus influenzae and Streptococcus pneumoniae, including macrolide-resistant isolates, were investigated using an in vitro PD model. Various time-concentration curves were artificially constructed by modifying the PK data obtained in phase I studies. The activity against H. influenzae was evaluated using two parameters, that is, the area above the killing curve (AAC) and the viable cell reduction at 24 h. The relationships between the antibacterial activity of S-013420 and the three PK/PD parameters were investigated by fitting the data to the sigmoid maximum effective concentration model. The square of the correlation coefficient (R 2) values for AAC versus the area under the concentration-time curve from 0 to 24 h (AUC0-24)/MIC, the peak concentration (C max)/MIC, and the cumulative percentage of a 24-h period that the drug concentration exceeded the MIC under steady-state PK conditions (%T MIC) were 0.92, 0.87, and 0.49, respectively. The R 2 values for viable cell reduction at 24 h versus AUC0-24/MIC, C max/MIC, and %T MIC were 0.93, 0.61, and 0.56, respectively. These results demonstrated that AUC0-24/MIC is the most significant parameter for evaluation of the antibacterial activity of S-013420. The values of AUC0-24/MIC required for maximum and static efficacy were 10.8 and 9.63, respectively, for H. influenzae and 16.3 to 22.3 and 4.66 to 9.01, respectively, for S. pneumoniae. This analysis is considered useful for determining the AUC value at the infection site, which would be required for efficacy in clinical use.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Saimai Chatree ◽  
Chantacha Sitticharoon ◽  
Pailin Maikaew ◽  
Kitchaya Pongwattanapakin ◽  
Issarawan Keadkraichaiwat ◽  
...  

AbstractObesity is associated with the growth and expansion of adipocytes which could be decreased via several mechanisms. Cissus Quadrangularis (CQ) extract has been shown to reduce obesity in humans; however, its effect on human white adipocytes (hWA) has not been elucidated. This study aimed to investigate the effects of CQ on obesity, lipolysis, and browning of hWA. CQ treatment in obese humans significantly decreased waist circumference at week 4 and week 8 when compared with the baseline values (p < 0.05 all) and significantly decreased hip circumference at week 8 when compared with the baseline and week 4 values (p < 0.05 all). Serum leptin levels of the CQ-treated group were significantly higher at week 8 compared to baseline levels (p < 0.05). In hWA, glycerol release was reduced in the CQ-treated group when compared with the vehicle-treated group. In the browning experiment, pioglitazone, the PPAR-γ agonist, increased UCP1 mRNA when compared to vehicle (p < 0.01). Interestingly, 10, 100, and 1000 ng/ml CQ extract treatment on hWA significantly enhanced UCP1 expression in a dose-dependent manner when compared to pioglitazone treatment (p < 0.001 all). In conclusion, CQ decreased waist and hip circumferences in obese humans and enhanced UCP1 mRNA in hWA suggestive of its action via browning of hWA.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).


2010 ◽  
Vol 30 (7) ◽  
pp. 591-602 ◽  
Author(s):  
Abdul Basir ◽  
Ahrar Khan ◽  
Riaz Mustafa ◽  
Muhammad Zargham Khan ◽  
Farzana Rizvi ◽  
...  

The aim of this study was to investigate effects of lambda-cyhalothrin (LCT) on clinical, hematological, biochemical and pathological alterations in rabbits (Oryctolagus cuniculus). New Zealand white female rabbits (n = 24) of 4-5 months age having 997.92 ± 32.83 g weight were divided into four equal groups. Group A (control) received normal saline intraperitoneally (ip). Animals in groups B, C and D were treated with LCT 1.0, 4.0 and 8.0 mg/kg bw ip. Each group received seven consecutive doses at an interval of 48 hours. Blood and serum samples were collected at an interval of 96 hours. Blood analysis revealed a significant (p < 0.05) decrease in red blood cell and white blood cell counts, hemoglobin concentration and lymphocytes, while mean corpuscular hemoglobin concentration, mean corpuscular volume, neutrophils, monocytes and eosinophils were increased. Serum biochemical analysis revealed significant (p < 0.05) decrease in serum total proteins and serum albumin, while an increase was seen in serum alanine aminotransferase and aspartate aminotransferase activities compared with the control group. Serum globulin values varied non-significantly in all treatment groups as compared to control group. A dose-dependent increase in the incidence of micronucleated polychromatic erythrocyte was observed. All gross and histopathological lesions observed in LCT-treated rabbits were dose-dependent. Liver of the treated rabbits exhibited extensive perihepatitis, hyperplasia of bile duct, necrosis, hemorrhages and congestion. In lungs, there were hemorrhages, thickened alveolar walls, congestion, emphysema, collapsed alveoli and accumulation of extensive inflammatory cells. Kidneys were congested and hemorrhagic whereas renal parenchyma and stroma were normal. Microscopically, heart showed congestion of blood vessels and nuclear pyknosis, myodegeneration. It was concluded from the study that LCT produced toxicopathological alterations in rabbits in a dose-dependent manner. On the basis of the results, it can be suggested that overdosing of LCT be avoided while treating animals for ectoparasites.


2000 ◽  
Vol 44 (11) ◽  
pp. 2948-2953 ◽  
Author(s):  
F. B. Oleson ◽  
C. L. Berman ◽  
J. B. Kirkpatrick ◽  
K. S. Regan ◽  
J.-J. Lai ◽  
...  

ABSTRACT Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.


2009 ◽  
Vol 77 (9) ◽  
pp. 3826-3837 ◽  
Author(s):  
Anna Martner ◽  
Susann Skovbjerg ◽  
James C. Paton ◽  
Agnes E. Wold

ABSTRACT Streptococcus pneumoniae is a major pathogen in humans. The pathogenicity of this organism is related to its many virulence factors, the most important of which is the thick pneumococcal capsule that minimizes phagocytosis. Another virulence-associated trait is the tendency of this bacterium to undergo autolysis in stationary phase through activation of the cell wall-bound amidase LytA, which breaks down peptidoglycan. The exact function of autolysis in pneumococcal pathogenesis is, however, unclear. Here, we show the selective and specific inefficiency of wild-type S. pneumoniae for inducing production of phagocyte-activating cytokines in human peripheral blood mononuclear cells (PBMC). Indeed, clinical pneumococcal strains induced production of 30-fold less tumor necrosis factor (TNF), 15-fold less gamma interferon (IFN-γ), and only negligible amounts of interleukin-12 (IL-12) compared with other closely related Streptococcus species, whereas the levels of induction of IL-6, IL-8, and IL-10 production were similar. If pneumococcal LytA was inactivated by mutation or by culture in a medium containing excess choline, the pneumococci induced production of significantly more TNF, IFN-γ, and IL-12 in PBMC, whereas the production of IL-6, IL-8, and IL-10 was unaffected. Further, adding autolyzed pneumococci to intact bacteria inhibited production of TNF, IFN-γ, and IL-12 in a dose-dependent manner but did not inhibit production of IL-6, IL-8, and IL-10 in response to the intact bacteria. Fragments from autolyzed bacteria inhibited phagocytosis of intact bacteria and reduced the in vitro elimination of pneumococci from human blood. Our results suggest that fragments generated by autolysis of bacteria with reduced viability interfere with phagocyte-mediated elimination of live pneumococci.


2015 ◽  
Vol 59 (10) ◽  
pp. 6568-6574 ◽  
Author(s):  
Alexander J. Lepak ◽  
Ajit Parhi ◽  
Michaela Madison ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
...  

ABSTRACTAntibiotics with novel mechanisms of action are urgently needed. Processes of cellular division are attractive targets for new drug development. FtsZ, an integral protein involved in cell cytokinesis, is a representative example. In the present study, the pharmacodynamic (PD) activity of an FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, was evaluated in the neutropenic murine thigh infection model against 5Staphylococcus aureusisolates, including both methicillin-susceptible and methicillin-resistant isolates. The pharmacokinetics (PK) of the TXA-707 active metabolite were examined after oral administration of the TXA-709 prodrug at 10, 40, and 160 mg/kg of body weight. The half-life ranged from 3.2 to 4.4 h, and the area under the concentration-time curve (AUC) and maximum concentration of drug in serum (Cmax) were relatively linear over the doses studied. All organisms exhibited an MIC of 1 mg/liter. Dose fractionation demonstrated the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) to be the PD index most closely linked to efficacy (R2= 0.72). Dose-dependent activity was demonstrated against all 5 isolates, and the methicillin-resistance phenotype did not alter the pharmacokinetic/pharmacodynamic (PK/PD) targets. Net stasis was achieved against all isolates and a 1-log10kill level against 4 isolates. PD targets included total drug 24-h AUC/MIC values of 122 for net stasis and 243 for 1-log10killing. TXA-709 and TXA-707 are a promising novel antibacterial class and compound forS. aureusinfections. These results should prove useful for design of clinical dosing regimen trials.


2017 ◽  
Vol 117 (06) ◽  
pp. 1171-1181 ◽  
Author(s):  
Dorian L. Culmer ◽  
Misha L. Dunbar ◽  
Angela E. Hawley ◽  
Suman Sood ◽  
Robert E. Sigler ◽  
...  

SummarySelectins, such as E-selectin (CD62E), function in venous thrombosis by binding and activating immune cells to initiate the coagulation cascade. GMI-1271 is a small molecule antagonist that inhibits E-selectin activity. Here we determine whether inhibition of E-selectin is sufficient to decrease acute venous thrombosis and associated inflammatory events in both prophylactic and treatment protocols without significantly affecting haemostasis. Male C57BL/6 mice underwent surgery for experimental thrombosis induction and were harvested at peak thrombus formation in our animal model, two days post induction. Groups included non-thrombosed true controls, shams, controls, and prophylactic or treatment groups of GMI-1271 (10 mg/kg intraperitoneal BID (twice a day) and low-molecular-weight heparin (LMWH, Lovenox 6 mg/kg subcutaneously (SC), once a day (SID). Compared with control animals, prophylaxis or treatment with LMWH and GMI-1271 in a dose-dependent manner significantly decreased thrombosis. GMI-1271 significantly lowered tail bleeding times when compared to LMWH. GMI-1271 and LMWH prophylactically administered significantly decreased vein wall neutrophil cell extravasation. However, all treatment and prophylactic therapies significantly decreased vein wall monocyte extravasation versus controls. GMI-1271 prophylactic therapy significantly decreased intra-thrombus cell counts versus control animals and other treatment groups. Immunohistochemistry confirmed that both treatments with GMI-1271 and LMWH significantly decreased activated leukocyte migration. GMI-1271 therapy significantly decreased thrombus weight and resulted in significantly lower bleeding times than LMWH. GMI-1271 treated mice showed decreased local and systemic inflammatory effects while modulating neutrophil activation, suggesting that GMI-1271 is a viable therapeutic candidate for venous thrombosis prophylaxis and treatment.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3051-3051 ◽  
Author(s):  
Youssef Hijazi ◽  
Matthias Klinger ◽  
Andrea Schub ◽  
Benjamin Wu ◽  
Min Zhu ◽  
...  

3051 Background: Blinatumomab (AMG 103) is an investigational, bispecific, T cell engaging (BiTE) antibody targeting CD19-expressing B cells. We describe the exposure-pharmacodynamic (PD) response of blinatumomab in patients with NHL, using a quantitative pharmacology approach. Methods: In a phase 1 study, 76 patients with NHL received blinatumomab by continuous intravenous infusion (cIV) at doses of 0.5 to 90 μg/m2/d in 4- or 8-week cycles. Pharmacokinetics (PK) was determined. PD responses evaluated included lymphocytes and cytokines measured during treatment, and sum of the products of the greatest diameters of tumor size in lymph nodes (SPD) at the end of treatment. Blinatumomab concentration at steady state (Css) and the cumulative area under the concentration (AUCcum)–time curve over the period before the evaluation of SPD were used to evaluate the exposure-SPD relationship. Results: Blinatumomab showed linear PK. Early PD responses were characterized by B cell depletion, T cell redistribution, and transient cytokine release. Following cIV at doses from 0.5 to 90 μg/m2/d, B cells declined at a first-order rate with a dose-dependent rate constant, ranging from 0.16 to 1.0 h-1. Complete B cell depletion was achieved within 48 hours at doses ≥5 μg/m2/d. A dose-independent decrease in T cell counts was observed within 24 hours after dosing, and T cells returned to baseline within 2 weeks of treatment. Cytokine elevation occurred in some patients and was dose-dependent. Blinatumomab exposure-SPD relationship was best described by an inhibitory Emax model (E = E0-(Imax*C)/(IC50+C)). According to the model estimation, a 50% reduction in SPD would be achieved when Css is 2141 pg/mL and AUCcum is 1381 h*μg/L, equivalent to a blinatumomab dose of 54 µg/m2/d given over 27 days. Conclusions: B lymphocytes were completely depleted from the circulation at blinatumomab doses ≥5 μg/m2/d. Depletion was faster at higher doses. Higher blinatumomab Css and AUCcum were associated with better tumor reduction. Tissue accessibility may explain the higher dose requirement for SPD reduction versus peripheral B cell depletion. The PK/PD model has utility for the design of future studies of blinatumomab in NHL. Clinical trial information: NCT00274742.


Author(s):  
Shweta Kaur ◽  
Anurag Maurya

<p class="03-Address"><strong>Objective: </strong>The present study was aimed to evaluate the phototoxic effects of sunlight pre-irradiated/nonirradiated TiO<sub>2</sub>, TiSiO<sub>4</sub> nanoparticles and TiO<sub>2 </sub>bulk powder to Vigna radiata seedlings.</p><p class="03-Address"><strong>Methods</strong><strong>: </strong>Different concentrations (0.05, 0.2, 0.5 and 1.0 g/l) of nano/bulk particles were applied to the germinated seedlings for 24 h and various biochemical end points were assessed. The end points were superoxide dismutase activity, catalase activity, malondialdehyde (MDA) and proline content.</p><p class="03-Address"><strong>Results: </strong>The irradiated nano TiO<sub>2 </sub>was more phototoxic to the seedlings as compared to both the non-irradiated nano TiO<sub>2 </sub>as well as the irradiated/non-irradiated TiO<sub>2</sub> bulk powder, as revealed by the increased level of antioxidant enzymes activity in irradiated TiO<sub>2</sub> nanoparticles treated group. Toxicity in nano TiO<sub>2</sub> group was more confined to the lowest concentration (0.05 g/l). Proline, a well-recognized stress biomarker, was found to increase in all the irradiated as well as the non-irradiated groups in a dose dependent manner (0.20 to 1.0 g/l), offering a different mechanism of toxicity from that of antioxidative enzymes. TiSiO<sub>4</sub> nanoparticles were not found to be phototoxic significantly under either exposure conditions.</p><p class="03-Address"><strong>Conclusion: </strong>The seedlings of the three treatment groups responded variably to the stress biomarkers, indicating that the mode of action of the nanoparticles to the plant was different from that of the bulk particles in irradiated and non-irradiated conditions and was governed by more than a single factor.</p>


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