[Comparison of the efficacy of carelizumab combined with chemotherapy and chemotherapy alone in the induction therapy of locally advanced hypopharyngeal carcinoma].

Objective: To compare the efficacy and safety of carrelizumab combined with the modified TPF regimen (docetaxel, cisplatinand capecitabine) and TPF regimen alone in larynx preservation strategy for locally advanced resectable hypopharyngeal squamous cell carcinoma. Methods: A cohort study was conducted. Patients with locally advanced resectable hypopharyngeal carcinoma (cT3-4aN0-3bM0) who were treated at the Eye & ENT Hospital of Fudan University from January 2017 to April 2023 were enrolled in the study. One group was treated with a modified TPF regimen (TPF group) for 2-3 cycles (retrospective data), and the other group was a prospective phase Ⅱ trial with a modified TPF regimen combined with carrelizumab (TPFC group) for three cycles. The patients with complete or partial remission of the primary focus were treated with sequential radical radiotherapy and/or drug therapy. The patients in the TPFC group were treated with carrelizumab at the end of radiotherapy with a maximum of up to 18 doses. The patients with stable or progressive disease were given radical surgery, and those who refused the surgery were given radical chemoradiotherapy. Objective response rate (ORR), overall survival rate, progression-free survival (PFS) rate, larynx preservation rate (LPR), and adverse reactions were compared between the two groups. Results: There were 51 male patients in the TPFC group, with an median age of 57 (35, 69) years. Meanwhile, 44 patients were in the TPF group, among which 43 were male and one was female, with an median age of 62 (46, 70) years. The ORR of the TPFC group was higher than that of the TPF group [82.4% (42/51) vs 63.6% (28/44), P=0.039]. During a median follow-up of 24.4 (18.5, 31.4) months, the TPFC group showed a higher 2-year survival rate (84.8% vs 64.6%, P=0.013) and 2-year LPR (66.6% vs 48.6%, P=0.045) than those in the TPF group. In patients with poor effect of induction therapy for hypopharyngeal carcinoma, surgical combination therapy significantly prolonged the 2-year PFS rate (77.9% vs 18.2%, P<0.001) and 2-year survival rate (76.9% vs 45.5%, P=0.005)than those of non-surgical combination therapy. The incidences of nausea and/or vomiting, reactive cutaneous capillary endothelial proliferation, thyroid dysfunction, and rash were increased in the TPFC group (all P<0.05). There was no treatment-related death. Conclusion: Carrelizumab combined with a modified TPF regimen has good efficacy and safety and can improve the LPR of locally advanced hypopharyngeal carcinoma.

[Morphological changes of the central sulcus in children with complete growth hormone deficiency: a 3.0 T MRI study].

Objective: To analyze morphological changes in central sulcus of the cerebral cortex in children with complete growth hormone deficiency (CGHD). Methods: Patients attending the Shandong Provincial Hospital who were diagnosed with CGHD or idiopathic short stature were recruited from January 2015 to January 2019. Thirty children with CGHD (18 males and 12 females, 5 to 14 years old) and 30 children with idiopathic short stature (22 males and 8 females, 5 to 14 years old) were included. Measurements of the central sulcus, including the average width, maximum depth, average depth, top length, bottom length and depth position-based profiles (DPP), were obtained using Brain VISA software. The significant differences between groups were statistically analyzed. Results: The average width of bilateral central sulci in children with CGHD (left: (2.26±0.41) mm; right: (2.19±0.34) mm) were significantly higher than those in children with idiopathic short stature (left: (2.10±0.27) mm; right: (2.02±0.18) mm) (P<0.05) ; The maximum depth of the left central sulcus ((19.67±1.29) mm) and the average depth of the right central sulcus ((14.18±1.41) mm) were significantly lower than those in children with idiopathic short stature (left maximum depth: (20.69±1.43) mm; right average depth: (14.92±1.21) mm) (P<0.05) . Children with CGHD had significantly lower DPP at the middle part of the left central sulcus (sites: 46-54) and the inferior part of the right central sulcus(sites: 91-98). Conclusion: There are significant morphological changes of the central sulcus in children with CGHD, which may represent the structural basis of their relatively slower development in motor, cognitive and linguistic functional performance.

Intratumoral IL17-producing cells infiltration correlate with antitumor immune contexture and improved response to adjuvant chemotherapy in gastric cancer.

BACKGROUND: Tumor IL17-producing (IL17A+) cells infiltration has different prognostic values among various cancers. The objective of this study was to assess the effect of IL17A+ cells in gastric cancer. PATIENTS AND METHODS: The study included two patient cohorts, the Cancer Genome Atlas cohort (TCGA, n = 351) and the Zhongshan Hospital cohort (ZSHC, n = 458). The TCGA and ZSHC were used for mRNA-related and cells infiltration-related analyses, respectively. The roles of IL17A mRNA and IL17A+ cells in overall survival (OS), response to adjuvant chemotherapy (ACT), and immune contexture were evaluated. Another independent cohort was included to identify the correlation between mRNA of IL17A and IL17A+ cells infiltration (the preliminary Zhongshan Hospital cohort, PZSHC, n = 21). RESULTS: The infiltration of IL17A+ cells was positively correlated with the expression of IL17A mRNA (Spearman's ρ = 0.811; P < 0.001). High IL17A mRNA expression and intratumoral IL17A+ cells were correlated with improved OS and remained to be significant after adjusted for confounders. Patients with TNM II/III disease whose tumor present higher intratumoral IL17A+ cells or lower peritumoral IL17A+ cells can benefit more from ACT. Elevated IL17A mRNA expression and increased intratumoral IL17A+ cells infiltration was associated with more antitumor mast cells and nature killer cells infiltration and less pro-tumor M2 macrophages infiltration. High IL17A mRNA expression represented a Th17 cells signature and immune response process and was correlated with increased cytotoxic GZMA, GZMB, IFNG, PRF1, and TNFSF11 expression. CONCLUSIONS: IL17A mRNA expression and intratumoral IL17A+ cells infiltration were correlated with antitumor immune contexture. IL17A+ cells infiltration could be used as an independent prognostic biomarker for OS and predictive biomarker for superior response to ACT, and further prospective validation needs to be conducted.

Elevated levels of IL-24 in systemic lupus erythematosus patients.

OBJECTIVE: This study aimed to assess IL-24 levels and their association with clinical manifestations in patients with systemic lupus erythematosus (SLE). METHODS: There were 75 patients with SLE and 58 healthy controls recruited in this study. Serum levels of IL-24 were measured by enzyme-linked immunosorbent assays, and mRNA levels of IL-24 were tested by quantitative real-time polymerase chain reaction . The area under the curve of the receiver operating characteristic (ROC) curve was used for diagnostic ability of the inflammatory cytokine. RESULTS: Serum IL-24 levels were significantly higher in SLE patients than that in healthy controls. SLE patients with nephritis had higher IL-24 levels than those without nephritis. Active SLE patients showed higher expression of IL-24 as compared to less active disease patients. The mRNA levels of IL-24 were much higher in SLE patients. Correlation analysis showed significant correlation between serum IL-24 levels and SLE disease activity index. In addition, ROC analysis may suggest good ability of serum IL-24 in differentiating SLE. CONCLUSION: The inflammatory cytokine correlated with SLE disease activity, and may be involved in this disease pathogenesis.

[Study on the immunogenicity and safety of recombinant B-subunit/whole cell cholera vaccine infused with antacids in healthy population at ages of 2-6 years].

Objective: To assess the immunogenicity and safety of recombinant B-subunit/whole cell cholera vaccine (rBS/WC) oral cholera vaccine (Ora Vacs) infused with antacids in healthy population at ages of 2-6 years. Methods: Between December 2009 and January 2010, we recruited 900 volunteers aged 2-6 years od through giving out recruitment notice for the eligible children's parents from different vaccination clinics of Chongzuo city in Guangxi Zhuang Autonomous Region. This study was a randomized, double-blind, placebo-controlled trial, and subjects were randomly (2∶1) assigned to receive Cholera vaccine infused with antacids or placebo, and observed for safety. Serum samples of 300 subjects in immunogenicity subgroups (200 for vaccine groups, 100 for control groups) before the 1st dose and 49 d (±3 d) after immunization were collected, and determined for antibody levels against the cholera toxin (anti-CT) and cholera vibriocidal (anti-Vab) with Enzyme-linked immunosorbent assays (ELISA), based on which the GMT was calculated. There were 266 cases paired with the serum samples before and after immunization (177 for vaccine groups, 89 for control groups). The comparison of subjects' age at enrollment and the level of GMT before and after immunization between groups were analyzed by t test. The superiority test for the difference between seroconversion rates of vaccine groups and control groups were analyzed by χ(2) test. Results: Of 900 subjects enrolled, the number of males and females were 503 and 397 respectively (vaccine groups 335 vs. 265, control groups 168 vs. 132), the average ages of vaccine groups and control groups at enrollment were (4.8±1.2) years and (4.9±1.2) years respectively. There were no significant differences between groups in terms of gender and age (χ(2)=0.00, P=1.000; t=0.55, P=0.585). The 2 times increase rates of anti-CT and anti-Vab in vaccine groups after inoculation were 90.96% and 57.63% respectively, which were superiority to those of control groups (15.73% and 29.21%), and significant differences were observed between groups (χ(2)=15.89, χ(2)=3.85, P<0.001). There were significant differences between vaccine groups and control groups after inoculation in terms of GMTs of anti-CT (1∶647.56 vs. 1∶99.49) and anti-Vab antibodies (1∶16.19 vs. 1∶11.27) (t values were 15.82 and 3.43, respetively; both P values were<0.05), significant differences were observed in the growth rates when compared the GMTs of anti-CT (6.63 vs. 1.11) and anti-Vab antibodies (1.64 vs. 1.16) before inoculation between vaccine groups and control groups (t'=17.85 and 4.96, P<0.001). In terms of safety, the adverse reaction rates in vaccine groups and control groups were 37.67% (226/600) and 36.67% (110/300), respectively,the common adverse reaction including fever, nausea, vomiting, abdominal pain, diarrhea, headache, fatigue, allergies, rash, etc; and the severity degree were mainly for level 1. Conclusion: Ora Vacs infused with antacids could produce an positive effect on immune response and safety.

Liver fibrosis staging using T1 mapping on gadoxetic acid-enhanced MRI compared with DW imaging.

AIM: To evaluate the utility of T1 mapping on gadoxetic acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) for staging liver fibrosis. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and included 145 patients (mean age: 54 years old; 115 men and 30 women). Necro-inflammatory activity grade (G) and liver fibrosis stage (S) were histopathologically determined. T1 relaxation time and apparent diffusion coefficient (ADC) of the liver were measured and the reduction rate of the T1 relaxation time (Δ%) was calculated. T1 relaxation time measurements were compared with ADC values according to S/G scores. RESULTS: Unenhanced hepatobiliary phase (HBP) and Δ% of T1 relaxation times showed significant correlations with S/G scores (rho: 0.28, 0.51, -0.35 for the S score, 0.26, 0.39, -0.26 for the G score, respectively, p<0.05). ADC values showed significant correlation with the S score (rho: -0.17, p = 0.04) and did not correlate significantly with the G score (rho: -0.07, p = 0.39). The areas under receiver operator characteristics (AUC) curve of unenhanced HBP, Δ% T1 relaxation time, and the ADC value were 0.68, 0.82, 0.71, 0.61 for the identification of S ≥ 3, and 0.63, 0.68, 0.62, 0.52 for the identification of G ≥ 3, respectively. The HBP T1 relaxation time was better than that of ADC for identification of S ≥ 3 (p = 0.0005) and G ≥ 3 (p = 0.014). CONCLUSIONS: The HBP T1 relaxation time measurement on gadoxetic acid-enhanced MRI images might be a potential biomarker in the staging of hepatic fibrosis, and was more accurate than the ADC measurement.

Psoriasis is associated with decreased plasma adiponectin levels independently of cardiometabolic risk factors.

BACKGROUND: Psoriasis is an inflammatory skin disease that may be associated with an adverse cardiometabolic profile including modulated plasma adiponectin and leptin levels. Whether these levels are independent of cardiometabolic risk factors, which are also prevalent in psoriasis, is not known. METHODS: A consecutive sample of 122 participants with varying degrees of psoriasis severity, and a random sample of 134 participants without psoriasis, were recruited for this case-control study. Cardiometabolic risk factors including traditional cardiovascular risk factors, waist circumference, insulin resistance, and total plasma adiponectin and leptin were measured. Total plasma adiponectin and leptin levels were compared in unadjusted and adjusted analyses by psoriasis status. RESULTS: Participants with psoriasis had mostly mild disease and were mainly on topical therapies, but still had a more adverse cardiometabolic profile compared with those without psoriasis. Furthermore, plasma adiponectin levels were significantly lower in participants with psoriasis than those without {7.13 µg/mL [interquartile range (IQR) 4.9-11.3) vs. 14.5 µg/mL (IQR 8.4-24.1); P < 0.001]}. Plasma leptin (ng/mL) levels were higher in the psoriasis group but this did not reach statistical significance [11.3 (IQR 6.4-21.8) vs. 9.8 (IQR 4.9-20.5); P = 0.07]. In multivariable modelling, plasma adiponectin levels were still negatively associated with psoriasis status after adjusting for waist size (% difference = -41.2%, P < 0.001), insulin resistance (% difference = -39.5%, P < 0.001), and both waist size and insulin resistance (% difference = -38.5%, P < 0.001). CONCLUSIONS: Plasma levels of adiponectin were lower in psoriasis, and this relationship persisted after adjusting for cardiometabolic risk factors known to decrease adiponectin levels. These findings suggest that inflammation present in psoriasis may be associated with adipose tissue dysfunction; however, direct studies of adipose tissue are needed to confirm this.

A synopsis of current care of thalassaemia major patients in Hong Kong.

OBJECTIVE: To provide a synopsis of current thalassaemia major patient care in Hong Kong. DESIGN: Retrospective study. SETTING: All haematology units of the Hospital Authority in Hong Kong. PATIENTS: All patients with thalassaemia major with regular transfusion. RESULTS: To date, there were 363 thalassaemia major patients under the care of the Hospital Authority. Prenatal diagnosis has helped to reduce the number of indigenous new cases, but in recent years immigrant cases are appearing. The patients have a mean age of 23 (range, 1-52) years, and 78% of them are adults. In 2009, they received 18 782 units of blood. This accounted for 9.5% of all blood consumption from the Hong Kong Red Cross. In the past, cardiac iron overload was the major cause of death (65%) and few patients survived beyond the age of 45 years. The availability of cardiac iron assessment by magnetic resonance imaging (T2 MRI) to direct the use of oral deferiprone chelation has reduced the prevalence of heart failure and cardiac haemosiderosis, which should reduce mortality and improve life expectancy. CONCLUSION: The future for thalassaemia care in Hong Kong is bright. With better transfusion and chelation, it should be possible to avoid growth and endocrine deficiencies in younger patients.

An inter-subspecies cloned buffalo (Bubalus bubalis) obtained by transferring of cryopreserved embryos via somatic cell nuclear transfer.

The aim of this study was to explore the feasibility of cryopreservation of inter-subspecies cloned embryos in buffalo. In our experiment, river buffalo ear fibroblast nucleus was fused into swamp buffalo oocyte cytoplasm. The blastocyst formation rate for nuclear transfer of freshly thawed cells was not different from those of growing cells, confluent or serum-starved cells. A total of 122 cloned blastocysts derived from cryopreserved fibroblasts were cryopreserved and thawed, 37 were survived, the cryosurvival rate was 30.3%. The survived blastocysts were transferred into 15 recipient buffalos. Five of the recipients established pregnancy, but four of them aborted on day 53, 59, 145 and 179 of gestation respectively. One cross-bred buffalo (Murrah × Swamp buffalo (2n = 49) received three embryos delivered a 40.5 kg female calf by natural delivery on day 320 of gestation. Up to now (13-month old), the cloned calf has been growing well with no abnormity observed. These results demonstrated that cryopreservation of inter-subspecies cloned embryos is feasible to produce buffalo offspring.

Age distribution of human papillomavirus infection and neutralizing antibodies in healthy Chinese women aged 18-45 years enrolled in a clinical trial.

OBJECTIVES: Data from clinical trials of human papillomavirus (HPV) vaccines showed that women naïve (negative for both type-specific antibodies and DNA) to vaccine types would derive benefit from vaccination; therefore, an understanding of the proportion of naïve women in different age groups is important for developing HPV vaccination strategies. METHODS: From November 2012 to April 2013, a total of 7372 healthy women aged 18-45 years were recruited in five provinces in China. Cervical specimens and serum samples were collected for each woman at entry. Cervical specimens were first tested by the HPV DNA enzyme immunoassay method; if positive, the specimens were then tested by reverse hybridization line probe assay and HPV-16 and HPV-18 specific polymerase chain reactions. Neutralizing antibodies against HPV-16 or HPV-18 were tested with a pseudovirion-based neutralization assay. RESULTS: The overall prevalence of high-risk HPV DNA was 14.8% (1088/7367, 95% CI 14.0-15.6), and the seroprevalence of neutralizing antibodies against HPV-16 and HPV-18 was 12.6% (925/7367) and 4.9% (364/7367), respectively. In younger women (18-26 years) and middle-aged women (27-45 years), 83.8% (3116/3719) and 81.4% (2968/3648) were naïve to both HPV-16 and HPV-18 (both neutralizing antibodies and DNA were negative), respectively. In addition, 98.5% (3664/3719) and 98.0% (3575/3648) of the younger or middle-aged women were naïve to at least one HPV type (HPV-16 or HPV-18). DISCUSSION: This study revealed that the majority of Chinese women aged 18-26 years and 27-45 years were naïve to both HPV-16 and HPV-18 and would thus derive full benefit from bivalent HPV vaccination.

[Abuse of diphenoxylate and related factors of forced drug abstainer in Gansu province].

Objective: To investigate the prevalence of diphenoxylate abuse and related factors of forced drug abstainer in Gansu province. Methods: By using a self-designed questionnaire, an epidemiologic investigation was carried out among 2 108 forced drug abstainer selected from the compulsory isolation detoxification center of Gansu province. A case-control study was conducted to analyze the factors related with diphenoxylate abuse. Results: The diphenoxylate abuse rate among forced drug abstainer in Gansu was 19.8% (406/2 046), ranking first in medical drug abuse. Multiple logistic regression analysis showed that factors as relieving withdrawal symptoms (OR=2.08, 95%CI: 1.01- 4.32), ways to obtain diphenoxylate (other ways: OR=1.00; regular clinic: OR=27.67, 95%CI: 2.64-289.82; friend: OR=0.01, 95%CI: 0.01-0.03), degree of euphoria (high: OR=1.00; medium: OR =3.36, 95%CI: 1.18-9.55; low: OR=26.16, 95%CI: 10.30-66.42), years of drug abuse (<5 years: OR=1.00; 10-15 years: OR=2.48, 95%CI: 1.02-6.04), abuse at home or in friend's house (OR=3.04, 95%CI: 1.08-8.68), abuse in car (OR=0.05, 95%CI: 0.00-0.68) and detoxification for the first time (OR=0.61, 95%CI: 0.43-0.86) were the possible influencing factors for diphenoxylate abuse. Conclusions: The prevalence of diphenoxylate abuse in forced drug abstainer in Gansu was relatively high. Reasons of abusing, the way to obtain diphenoxylate, whether using drug together with friends, degree of euphoria, years of abuse, abuse place and times for detoxification were related factors influencing the abuse of diphenoxylate.

Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury.

The transcriptional factor Nrf2 has a unique role in various physiological stress conditions, but its contribution to ischemia/reperfusion injury has not been fully explored. Therefore, wildtype (WT) and Nrf2 knockout (Nrf2(-/-)) mice were subjected to 90-min occlusion of the middle cerebral artery (MCA) followed by 24-h reperfusion to elucidate Nrf2 contribution in protecting against ischemia/reperfusion injury. Infarct volume, represented as percent of hemispheric volume, was significantly (P<0.05) larger in Nrf2(-/-) mice than in WT mice (30.8+/-6.1 vs. 17.0+/-5.1%). Furthermore, neurological deficit was significantly greater in the Nrf2(-/-) mice. To examine whether neuronal protection was mediated by Nrf2, neurons were treated with various compounds to induce excitotoxic or oxidative stress. Translocation of Nrf2 into the nucleus was increased by the free-radical donor tert-butylhydroperoxide, but not by glutamate or N-methyl-D-aspartic acid (NMDA). In addition, a common Nrf2 inducer, tert-butylhydroquinone, significantly attenuated neuronal cell death induced by tert-butylhydroperoxide (83.6+/-1.6 vs. 62.0+/-7.7%) but not as substantially when excitotoxicity was induced by NMDA (91.9+/-1.6 vs. 79.3+/-3.3%) or glutamate (87.8+/-1.5 vs. 80.2+/-2.6%). The results suggest that Nrf2 reduces ischemic brain injury by protecting against oxidative stress.

[Prevalence of type-specific human papillomavirus infection among 18-45 year-old women from the general population in Liuzhou, Guangxi Zhuang Autonomous Region: a cross-sectional study].

Objective: To analyze the type-specific prevalence of human papillomavirus (HPV) among women aged 18-45 years from the general population in Liuzhou, Guangxi Zhuang Autonomous Region. Methods: Totally, 2 300 women aged 18-45 years old were enrolled in Liuzhou,from March to July, 2013. Cervical exfoliated cells were collected for liquid based cytological and HPV DNA tests. Women were referred to colposcopy exam, based on the clinical practice guideline. Results: Overall, the prevalence rates of any HPV or oncogenic HPV appeared as 22.7% (95% CI: 21.0%-24.4%) and 17.3% (95% CI: 16.0%-19.1%), respectively in this population under study. The high-risk HPV prevalence peaked at the age groups of 18-25 and 41-45, increasing along with the severity through cytological and histological tests. Statistically significant differences between the prevalence of CIN2+ (Cervical intraepithelial neoplasia 2+) in women older than 26 years (1.7%, 95% CI: 1.0%-2.4%) and 18-25 years (1.2%, 95% CI: 0.5%-1.9%) of age, were not observed. Among samples diagnosed as CIN2+, positivity of HPV bivalent (16/18) and nine-valent (6/11/16/18/31/33/45/52/58) vaccine, related high risks on the types of HPV types appeared as 44.1% and 97.1%. Conclusions: The age-specific HPV prevalence rates in the general women aged 18-45 in Liuzhou presented as having bimodal distribution, suggesting that the disease burden of cervical diseases in women aged 26-45 years should not be ignored. Nine-valent HPV vaccine might provide more effective prevention outcomes on cervical cancer in China.

Demonstration of selective protein kinase C-dependent activation of Src and Lck tyrosine kinases during ischemic preconditioning in conscious rabbits.

Src tyrosine kinases have been shown to mediate cellular responses to stress in noncardiac cells. However, the effect of myocardial ischemia on Src tyrosine kinases is unknown. Furthermore, the identity of the tyrosine kinase(s) involved in the genesis of ischemic preconditioning (PC) remains obscure. Here, we present the first evidence that ischemic PC (6 cycles of 4-minute coronary occlusion and 4-minute reperfusion) induces selective activation of 2 members of the Src family of tyrosine kinases, Src and Lck, in the heart of conscious rabbits. The activation of Src in the particulate fraction was not evident at 5 minutes after ischemic PC but became apparent at 30 minutes (+119% versus control), whereas the activation of Lck in the particulate fraction was apparent both at 5 minutes (+103% versus control) and at 30 minutes (+89%) after ischemic PC. The activity of the other 5 members of the Src tyrosine kinases expressed in the rabbit heart (Fyn, Fgr, Yes, Lyn, and Blk) was not affected by ischemic PC. Ischemic PC had no effect on the activity of epidermal growth factor receptor kinases, either at 5 or at 30 minutes. The activation of Src and Lck was completely abrogated by the tyrosine kinase inhibitor lavendustin A, given at doses that have previously been shown to block the protective effect of ischemic PC in this same conscious rabbit model, suggesting that Src and Lck kinases are essential for the development of ischemic PC. The activity of the epsilon isoform of protein kinase C (PKC) in the particulate fraction increased at 5 minutes (+72%) and at 30 minutes (+67%) after ischemic PC. Pretreatment with lavendustin A had no effect on the activation of PKCepsilon, whereas pretreatment with the PKC inhibitor chelerythrine (given at doses that have previously been shown to block ischemic PC) blocked not only the activation of PKCepsilon but also that of Src and Lck, indicating that Src and Lck are downstream of PKCepsilon in the signaling cascade of ischemic PC. This study identifies a new component of the signaling mechanism of ischemic PC. The results support the concept that, in conscious rabbits, 2 specific members of the Src family of tyrosine kinases, Src and Lck, play an important role in the genesis of late PC by serving as downstream elements of PKC-mediated signal transduction.

Achieving an optimal outcome in the treatment of infections. The role of clinical pharmacokinetics and pharmacodynamics of antimicrobials.

Over the past few decades, the importance of applying pharmacokinetic principles to the design of drug regimens has been increasingly recognised by clinicians. From the perspective of antimicrobial chemotherapy, an improvement in clinical outcome and/or a reduction in toxicity are of primary interest. Before application of these pharmacokinetic theories can be effective, the interrelationships between antimicrobial, pathogen and host factors must be clearly defined. Information regarding the pharmacokinetics of the antimicrobial and the quantification of pathogen susceptibility is required. Even though susceptibility end-points such as minimum inhibitory concentration (MIC) and minimum bactericidal concentration are widely employed, they do not provide any information on dynamic changes of bacterial densities. In this regard, time-kill studies can provide more basic knowledge of the complex bacterial responses to the antimicrobial. Better prediction of these responses can be afforded by the use of mathematical models. More recently, various surrogate end-points employing a combination of suitable pharmacokinetic parameters and susceptibility data, for example the ratio of peak concentration to MIC, the area under the concentration-time curve above the MIC (AUC > MIC), the time above the MIC, or the area under the inhibitory curve (AUIC), have been suggested for better prediction of the activity of different classes of antimicrobials. To allow more extensive investigations of the contribution of pharmacokinetics to the pharmacodynamics of antimicrobials, various in vitro kinetic models have been developed. However, certain limitations exist, and it is necessary to avoid over-interpretation of the data generated by these models. Two important microbial dynamic responses, postantibiotic effect and resistance selection, must be further explored before the full impact of pharmacokinetics on antimicrobial chemotherapy can be depicted. The present paper aims at discussing all the relevant factors and provides some pertinent information on the use of pharmacokinetic-pharmacodynamic principles in antimicrobial therapy.

Concentration-dependent protein binding of a novel oral thromboxane synthase inhibitor--FCE 22,178.

The protein binding of FCE 22,178 in humans was determined ex vivo by equilibrium dialysis using plasma samples obtained from a dose-ranging study in normal male volunteers. These data suggested that FCE 22,178 may exhibit concentration-dependent protein binding over an in vivo concentration range of .8 to 64 micrograms/mL. Increase in free fraction at higher plasma drug concentrations corresponded directly to the dose-dependent increase in renal drug clearance. Nonlinear parameter estimation showed that FCE 22,178 binds tightly to plasma proteins with an apparent equilibrium association constant of 1.44 x 10(5) mol/L. Predicted change in the free fraction is consistent with the observed changes in renal clearance.

A phase I dose-ranging safety and pharmacokinetics study of a novel oral thromboxane synthase inhibitor, FCE 22, 178.

A 100- to 3200-mg dose range of FCE 22,178 was studied in this phase I single-dose escalation safety/kinetics study. After oral administration, a rapid drug absorptive phase and a biexponential disposition profile were observed. Mean estimates of the terminal elimination half-life of FCE 22,178, over the doses studied, ranged from 7.6 to 14.4 hours. A disproportionate increase in both maximum peak plasma concentration (Cmax) and area under the curve (AUC0-infinity) was noticed for doses higher than 400 mg. Mean estimates of systemic clearance (CLs/F) over the 100- to 400-mg doses were 0.053 to 0.064 L/hour/kg, and were significantly higher for the three higher dose levels. This nonlinearity appears to be related to the changes in oral bioavailability. Estimates of distribution volume (Vd, lambda z/F) for FCE 22,178 increased from 0.75 L/kg at the 100-mg dose to 3.00 L/kg at the 3200-mg dose, and renal clearance (CLr) also increased with dose. Both observations may be related to an increase in free fraction of FCE 22,178 at higher doses. Urinary excretion of unchanged drug averaged < 10% for all dose levels. The urinary excretion of the glucuronide metabolite (M1) averaged 41 to 70% for doses up to 400 mg, but diminished to 13% at the 3200-mg dose. The disposition of M1 appeared to be formation-rate limited. In addition, the ratio of the formation to the disposition clearance for M1 was relatively stable and apparently dose independent. No drug-related adverse experiences were observed over the studied dose range after single doses at FCE 22,178.

New pharmacodynamic parameters for antimicrobial agents.

The application of pharmacodynamic theories to antimicrobial chemotherapy has greatly improved the prediction of the time course of activity expressed by antibiotics. Being a major component of the antibiotic-bacterium interaction system, pharmacodynamics, when properly integrated with the pharmacokinetics established for the antibiotic, allow better evaluation of the dosage regimen in conjunction with its clinical response. Before this approach becomes effective, detailed background information on the complex antibiotic-bacterium interactions have to be secured. To achieve this, proper characterization of a time-kill curve is a prerequisite. The use of susceptibility endpoints such as the MIC with respect to the antibiotic concentrations achievable in vivo represent the conventional approach to clinical dosing of antimicrobial agents, i.e. by maintaining concentrations above the MIC. Recently, a number of surrogate markers have been proposed by combining suitable pharmacokinetic parameters and susceptibility data, e.g. peak/MIC ratio, AUC>MIC, time above MIC, AUIC etc. to enhance the prediction of clinical outcomes. Attempts have been made to apply these pharmacokinetic/pharmacodynamic markers to antibiotics of the same class as well as to antibiotics from different classes. This review aims to discuss the various microbial dynamic responses in relation to antibiotic exposure and the development of different pharmacokinetic/pharmacodynamic markers for use in current antimicrobial chemotherapy.