[Long term prognosis of fulminant myocarditis and predictors related to impaired cardiac function post discharge].

Objective: To compare the long-term prognosis of fulminant myocarditis (FM) and non-fulminant myocarditis (NFM) patients who survived and discharged from hospital, and to explore the factors associated with the long-term prognosis and impaired cardiac function. Methods: This study was a retrospective study. Consecutive patients with acute myocarditis hospitalized in Tongji Hospital from January 2017 to December 2020 were enrolled and divided into FM group and NFM group according to the type of myocarditis. Then, patients in the FM group were further divided into normal cardiac function group and impaired cardiac function group according the left ventricular ejection fraction (LVEF). All patients with acute myocarditis were treated with antiviral, immunomodulatory, immunosuppressive medications and symptomatic and supportive treatment, while FM patients were treated with comprehensive treatment plan. Clinical data at admission of enrolled patients were collected through the electronic medical record system. Patients were clinically followed-up at 1, 3, 6 and 12 months, then once a year after discharge by clinical visit. The primary endpoints included major cardiovascular events, impaired cardiac function was defined by LVEF<55%. Kaplan-Meier survival curve was used to analyze the occurrence of LVEF<55% and left ventricular enlargement during the follow-up of patients in FM group and NFM group, and Log-rank test was used for comparison between groups. Cox regression model was used to analyze the risk factors of impaired cardiac function in patients with FM during follow-up. Results: A total of 125 patients with acute myocarditis were enrolled (66 in FM group and 59 in NFM group). Compared with NFM group, the proportion of FM patients with the lowest LVEF<55% during hospitalization was higher (P<0.01), and the recovery time of normal LVEF during hospitalization was longer (P<0.01). The proportion of LVEF<55% at discharge was similar between the two groups (P=0.071). During the follow-up of 12 (6, 24) months, 1 patient (1.5%) died due to cardiac reasons in FM group after discharge, 16 patients (24.2%) had sustained LVEF<55% after discharge, and 8 patients (12.1%) had left ventricular enlargement. In NFM group, 3 patients (5.1%) had sustained LVEF<55%, and 1 patient (1.7%) had left ventricular enlargement. Kaplan-Meier survival curve analysis showed that the incidence of sustained LVEF<55% in FM group was higher than that in NFM group (P=0.003), and the incidence of left ventricular enlargement was also higher than that in NFM group (P=0.024). Subgroup analysis of patients in the FM group showed that, compared with the normal cardiac function group, the time from onset to admission was shorter (P=0.011), the proportion of LVEF<55% at discharge was higher (P=0.039), the proportion of coronary angiography was higher (P=0.014), and the LVEF recovery time during hospitalization was longer (P=0.036) in FM patients with impaired cardiac function. Multivariate Cox regression analysis showed that longer LVEF recovery time during hospitalization was an independent risk factor for cardiac function impairment after discharge of FM patients (HR=1.199, 95%CI 1.023-1.406, P=0.025). Conclusions: The incidence of reduced LVEF is significantly higher in FM patients than that in NFM patients. Longer LVEF recovery time during hospitalization is an independent risk factor for cardiac function impairment in FM patients after discharge.

Adeno-associated virus-mediated expression of myostatin propeptide improves the growth of skeletal muscle and attenuates hyperglycemia in db/db mice.

Inhibition of myostatin, a negative growth modulator for muscle, can functionally enhance muscle mass and improve glucose and fat metabolism in myostatin propeptide (MPRO) transgenic mice. This study was to investigate whether myostatin inhibition by adeno-associated virus (AAV)-mediated gene delivery of MPRO could improve muscle mass and achieve therapeutic effects on glucose regulation and lipid metabolism in the db/db mice and the mechanisms involved in that process. Eight-week-old male db/db mice were administered saline, AAV-GFP and AAV-MPRO/Fc vectors and monitored random blood glucose levels and body weight for 36 weeks. Body weight gain was not different during follow-up among the groups, but AAV-MPRO/Fc vectors resulted high level of MPRO in the blood companied by an increase in skeletal muscle mass and muscle hypertrophy. In addition, AAV-MPRO/Fc-treated db/db mice showed significantly lower blood glucose and insulin levels and significantly increased glucose tolerance and insulin sensitivity compared with the control groups (P<0.05). Moreover, these mice exhibited lower triglyceride (TG) and free fatty acid (FFA) content in the skeletal muscle, although no difference was observed in fat pad weights and serum TG and FFA levels. Finally, AAV-MPRO/Fc-treated mice had enhanced insulin signaling in the skeletal muscle. These data suggest that AAV-mediated MPRO therapy may provide an important clue for potential clinical applications to prevent type II diabetes, and these studies confirm that MPRO is a therapeutic target for type II diabetes.

Active ingredients from natural botanicals in the treatment of obesity.

Obesity is considered as a chronic disease that can induce a series of comorbidities and complications. Chinese medicine has long clinical experiences in the treatment of obesity. This review summarizes the natural products from traditional Chinese medicine (TCM) that are reported to have anti-obesity effects in the past two decades. Botanic TCM comprises 90% of total Chinese crude drugs, and generally contains various active ingredients, in which the effective anti-obesity ingredients identified can be divided into saponins, polysaccharides, alkaloids, polyphenols and others. Astragaloside IV, glycyrrhizin, macrostemonoside A, berberine, betaine, capsaicin, matrine, methyl piperate, piperine, rutaecarpine, asimilobine, epigallocatechingallate, magnolol, resveratrol, soybean-isoflavone, α-linolenic acid, emodin, geniposide, phillyrin, salidroside and ursolic acid are specified in this review, and their sources, models, efficacy are described. It is concluded that the mechanisms of these components for the treatment of obesity include: (i) suppression of appetite, increase of satiety, reduction of energy intake; (ii) reduction in the digestion and absorption of exogenous lipid; (iii) attenuation of the synthesis of endogenous lipid; (iv) promotion of the oxidation and expenditure of lipid and (v) improvement of lipid metabolism disorder. Authors believe that the effective compounds from TCM will provide an alternative and hopeful way for the treatment of obesity.

Cell specificity and molecular mechanism of antibacterial and antitumor activities of carboxyl-terminal RWL-tagged antimicrobial peptides.

Antimicrobial peptides (AMPs) constitute a diverse class of naturally occurring or synthetic antimicrobial molecules that have potential for use in the treatment of drug-resistant infections. Several undesirable properties of AMPs, however, may ultimately hinder their development as antimicrobial agents. Thus, new synthetic strategies, including primarily the de novo design of AMPs, urgently need to be developed. In this study, a series of peptides, H-(RWL) n (n = 1, 2, 3, 4, or 5), were designed. H represents GLRPKYS from the C-terminal sequence of AvBD-4. Our results showed that these RWL-tagged peptides can kill not only bacteria but also human hepatocellular carcinoma HepG2 cells. However, the peptide tagged with two repeats of RWL (GW13) showed less affinity to human embryonic lung fibroblast MRC-5 cells or human red blood cells (hRBCs) than HepG2 cells. These results demonstrated that GW13, with high amphiphilicity, exerted great selectivity toward bacteria and cancer cells, sparing host mammalian cells. The mechanism of action against bacteria was elucidated through combined studies of scanning electron microscopy (SEM) and fluorescence assays, showing that the peptide possessed membrane-lytic activities against microbial cells. The fluorescence assays illustrated that GW13 induced apoptosis in HepG2 cells. The cell morphology of HepG2 cells, observed by SEM, further illustrated that GW13 causes cell death by damaging the cell membrane. Our results indicate that GW13 has considerable potential for future development as an antimicrobial and antitumor agent.

Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study.

BACKGROUND: Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. AIM: To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. METHODS: This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels. RESULTS: No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. CONCLUSIONS: Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

Chemical metabolism of medicinal compounds from natural botanicals.

Traditional Chinese medicine (TCM) and its natural products are complex mixtures containing hundreds of chemically different constituents but only a few components are responsible for the pharmacological effects and bioactivities. In order to clarify the functional mechanism of active compounds, the studies on metabolism are of great significance and necessity. Previously, research mainly focused on the aspect of pharmacokinetics, however in recent years, chemical metabolism of active compounds has drawn increasing attention. Researches on the chemical metabolism of single phytochemicals help to understand the transformation process in vivo and mechanism of action, also contribute to pharmacodynamics and toxicology studies and new drug development. In the present paper, the chemical metabolism of nine categories of phytochemicals was reviewed. This review focused on pharmacological action, metabolic characteristics, metabolic pathways, metabolites and assay method of alkaloids, flavonoids, saponins, terpenoids, stilbenes, phenols, quinones, lignans and esters. The parent drugs, perhaps the metabolites, or they together play a role in pharmacological effects. And different routes of administration may lead to different results of transformation pathways and metabolites. Moreover, high-tech assay methods, particularly the combined use of modern instrument analytical techniques, are beneficial to the research of drug metabolism.

Application of chromatography technology in the separation of active components from nature derived drugs.

Chromatography technology has been widely applied in various aspects of the pharmacy research on traditional Chinese medicine (TCM). This paper reviews literatures, published in the past decades, on the separation of active component from TCM using chromatography technology. Ultra-performance liquid chromatography (UPLC), high-speed counter-current chromatography (HSCCC), rapid resolution liquid chromatography (RRLC), supercritical fluid chromatography (SFC), affinity chromatography (AC), and bio-chromatography (BC) are introduced in detail. Compared to high performance of high-performance liquid chromatography (HPLC), analysis time and solvent loss are significantly reduced by UPLC with increase in resolution and sensitivity. Some ingredients from nature derived drugs can be separated more completely by HSCCC, which has remarkable characteristics such as low cost, simple operation and no pollution. Trace components from complex systems can be selectively and efficiently separated and purified by AC, This feature makes it effective in isolation and identification of active components of Chinese herbs. Interference of some impurities could be excluded by BC. Active ingredients that are difficult to be separated by normal method can be acquired by SFC. Currently, application of novel chromatography techniques in TCM is still in the exploratory stage and many problems, such as preparation of stationary phase and detection, need to be solved.

Knockdown of angiotensinogen by shRNA-mediated RNA interference inhibits human visceral preadipocytes differentiation.

OBJECTIVE: The immediate cause of obesity is the massive deposition of subcutaneous and visceral fat attributing to the continuous proliferation and differentiation of preadipocytes. The identification of the underlying molecular mechanisms of preadipocytes differentiation is urgent, and will have an important role in plastic and reconstructive surgical procedures. METHODS: Two small hairpin RNA (shRNA)-mediated RNA interference plasmids have been constructed on the basis of the activity of H1 promoter-driven expression vector psiRNA-hH1neo to suppress the expression of angiotensinogen (AGT) in human preadipocytes-visceral (HPA-v). Subsequently, glycerol-3-phosphate dehydrogenase (G3PDH) activity and intracytoplasmic lipids content were detected during the process of HPA-v differentiation. RESULTS: Small hairpin RNA-expressing vectors have been successfully constructed to suppress the expression of AGT significantly. Both intracytoplasmic lipids content and G3PDH activity decreased to a certain extent compared with that in the control group in the whole process of HPA-v differentiation. CONCLUSIONS: Two shRNA-mediated AGT-targeting plasmids inhibited the process of HPA-v differentiation to a certain extent. However, the accumulation of intracytoplasmic lipids was not exclusively determined by the expression of AGT, and it may also be regulated by other factors. In conclusion, this study provided a method to inhibit the process of preadipocytes differentiation, and it may have a role in obesity treatment and adipose tissue engineering application.

Effect of buccal dwell time on the pharmacokinetic profile of fentanyl buccal tablet.

BACKGROUND: The time fentanyl buccal tablet (FBT) takes to completely dissolve after placement on the buccal mucosa (i.e., 'dwell time') could exceed the time to onset of analgesia. OBJECTIVE: To examine the relationship between FBT dwell time and fentanyl pharmacokinetic parameters. RESEARCH DESIGN AND METHODS: This was a post hoc exploratory analysis of data from two randomized, open-label, crossover, pharmaco-kinetic studies that were designed to assess dose proportionality within the anticipated therapeutic dose range. Healthy adults received single FBT doses of 200-1080 microg in Study 1 (n = 28) and 270-1300 microg in Study 2 (n = 42). MAIN OUTCOME MEASURES: Assessments included buccal dwell time, defined as the duration of FBT presence in the oral cavity, and the following pharmacokinetic measures: maximum serum concentration (C(max)), time to C(max) (T(max)) and area under the concentration-time curve (AUC; exposure) from 0 minutes to median T(max) adjusted for the dose (T(max')) (AUC(0 T(max'))). Spontaneously reported adverse events were recorded. RESULTS: Mean buccal dwell time for FBT across the dose range varied from 14 to 25 minutes (range 3 - 62 minutes). There was no evidence of an association between FBT dwell time and values for T(max) (medians 45 - 60 minutes), dose-normalized C(max) (means 0.42-0.66 pg/ml/200 microg) or dose-normalized AUC(0 T(max')) (means 0.24-0.38 pg x h/ml/200 microg) over the range of FBT doses delivered. All adverse events reported were mild to moderate; none were unexpected or serious. CONCLUSION: The pharmacokinetic parameters of FBT did not appear to be related to its buccal dwell time.

Peroxisome proliferator-activated receptor gamma-mediated transcriptional up-regulation of the hepatocyte growth factor gene promoter via a novel composite cis-acting element.

Hepatocyte growth factor (HGF) is a pleotropic polypeptide that can function as a morphogen, motogen, mitogen, angiogen, carcinogen, and tumor suppressor, depending on the target cell and tissue. Previous studies from our laboratory using transgenic mice have shown that HGF gene expression is tightly regulated at the transcriptional level and that the upstream regulatory elements are crucial for the control of HGF gene transcription. In the present study, we have identified and characterized one of these elements as a peroxisome proliferator-activated receptor gamma (PPARgamma)-responsive element. This regulatory element was localized at -246 to -233 base pairs upstream from the transcription start site of the HGF gene promoter having the sequence GGGCCAGGTGACCT. Gel mobility shift and supershift assays demonstrated that this cis-acting element strongly binds to the PPARgamma isoforms as well as to chicken ovalbumin upstream promoter-transcription factor, a member of the orphan nuclear receptor subfamily. Mutational analysis and gel mobility band shift assays indicated that the binding site is an inverted repeat of the AGGTCA motif with two spacers (inverted repeat 2 configuration) and that the two spacers are important for PPARgamma binding. This binding site overlaps with functional binding sites for activating protein-2, nuclear factor 1, and upstream stimulatory factor, and together, they constitute a multifunctional composite binding site through which these different transcription factors exert their regulatory effects on HGF promoter activity. Functional assays revealed that PPARgamma, with its ligand, 15-deoxy-prostaglandin J2, strongly stimulates HGF promoter activity. On the other hand, nuclear factor 1, activating protein-2, and chicken ovalbumin upstream promoter-transcription factor transcription factors repress the stimulatory action of PPARgamma by competing with PPARgamma for their overlapping binding sites. Furthermore, for the first time, our studies demonstrate that the PPARgamma ligand, 15-deoxy-prostaglandin J2, induces endogenous HGF mRNA and protein expression in fibroblasts in culture.

Development of an ischemic stroke survival score.

BACKGROUND AND PURPOSE: There has been substantial interest in identifying predictors of survival for stroke patients. Current instruments used for measuring stroke severity are confined to either neurological, functional, or disability measures. The purpose of this study was to develop a stroke survival score that combines instruments from different domains to better predict long-term survival. METHODS: We took advantage of a particularly broad array of clinical and physiological variables collected during the Stroke Treatment with Ancrod Trial. Four hundred fifty-three patients completed a battery of instruments at day 7 after stroke and then were followed for 1 year. RESULTS: Of the 453 patients, 53% were male, 77% were aged 65 years or older, and 89% were white. One hundred nine patients (24%) died during the study period. Age was a highly significant predictor of mortality (P<0.001), but there were no statistically significant differences in 12-month survival with respect to sex, race, or educational level. The best model for predicting survival was the Ischemic Stroke Survival Score. This model included the Scandinavian Stroke Scale, Rapid Disability Rating Scale, age, and prior stroke. This model had substantially greater predictive power (R(2)=0.30, c statistic=0.86) than the Scandinavian Stroke Scale alone (R(2)=0.20, c statistic=0.78). CONCLUSIONS: This study demonstrates that combining day 7 poststroke information from multiple domains substantially improves the ability to predict 12-month survival of ischemic stroke patients compared with data from a single domain. The high mortality rate emphasizes the importance of preventive measures for a disease that has identifiable and modifiable risk factors.

Dose-response effect of combination hydrocodone with ibuprofen in patients with moderate to severe postoperative pain.

OBJECTIVE: The objective of this study was to demonstrate a dose-response effect with 1- and 2-tablet doses of combination hydrocodone 7.5 mg with ibuprofen 200 mg and placebo in patients with moderate to severe postoperative abdominal or gynecologic pain. BACKGROUND: Hydrocodone 7.5 mg with ibuprofen 200 mg is the only approved fixed-dose combination analgesic containing an opioid and ibuprofen. Previous studies with this combination have demonstrated that the components have an additive analgesic effect as well as efficacy compared with other fixed-dose combination analgesics. METHODS: This randomized, parallel-group, double-blind, single-dose, placebo-controlled study compared 1 tablet of hydrocodone 7.5 mg with ibuprofen 200 mg (n = 60), 2 tablets of hydrocodone 7.5 mg with ibuprofen 200 mg (n = 60), and placebo (n = 60) in patients with moderate or severe pain after abdominal or gynecologic surgery. Analgesia was evaluated over 8 hours. RESULTS: Mean pain relief (PR) scores were significantly greater for the 2-tablet dose than for the 1-tablet dose at 80 (P = 0.027) and 100 (P = 0.017) minutes and at 2 (P = 0.013), 2.5 (P = 0.012), 3 (P = 0.006), 4 (P = 0.029), 5 (P = 0.002), 6 (P = 0.032), 7 (P = 0.036), and 8 (P = 0.01) hours. Mean pain intensity difference scores were significantly greater for the 2-tablet dose than for the 1-tablet dose at 80 (P = 0.013) and 100 (P = 0.007) minutes and at 2 (P = 0.003), 2.5 (P = 0.002), 3 (P = 0.002), 4 (P = 0.009), 5 (P < 0.001), 6 (P = 0.004), 7 (P = 0.009), and 8 (P = 0.001) hours. Mean total PR scores were significantly greater for the 2-tablet dose than for the 1-tablet dose for all measured time intervals (0 to 3 hours, P = 0.01; 0 to 4 hours, P = 0.006; 0 to 6 hours, P = 0.003; 0 to 8 hours, P = 0.003). Mean sum of pain intensity differences was significantly greater for the 2-tablet dose than for the 1-tablet dose for all measured time intervals (0 to 3 hours, P = 0.004; 0 to 4 hours, P < 0.001; 0 to 6 hours, P < 0.001; 0 to 8 hours, P < 0.001). Mean peak PR score and median time-to-remedication were significantly greater for the 2-tablet dose than for the 1-tablet dose (P < 0.029 and P = 0.017, respectively). Both doses were superior to placebo. There were no significant differences in the number of patients experiencing adverse events between the 2-tablet dose (n = 6 [10.0%]), the 1-tablet dose (n = 4 [6.7%]), and placebo (n = 1 11.7%]). Adverse events were not serious, and none of the patients discontinued therapy because of side effects. CONCLUSIONS: This study demonstrated that a 2-tablet dose of hydrocodone with ibuprofen provided significantly more analgesia than a 1-tablet dose (a positive dose-response effect) and that both doses were superior to placebo.

Combination hydrocodone and ibuprofen versus combination codeine and acetaminophen for the treatment of chronic pain.

OBJECTIVE: The objective of this study was to compare the effectiveness of combination hydrocodone 7.5 mg and ibuprofen 200 mg with that of combination codeine 30 mg and acetaminophen 300 mg for the treatment of chronic pain. BACKGROUND: Hydrocodone 7.5 mg with ibuprofen 200 mg is the only approved fixed-dose combination analgesic containing an opioid and ibuprofen. METHODS: In this randomized, parallel-group, double-blind, repeated-dose, active-comparator, 4-week, multicenter study, 469 patients were randomly assigned to receive a 1-tablet (n = 156) or 2-tablet (n = 153) dose of combination hydrocodone 7.5 mg and ibuprofen 200 mg (HI1 and HI2, respectively) or a 2-tablet dose of combination codeine 30 mg and acetaminophen 300 mg (CA, n = 160), the active comparator, every 6 to 8 hours as needed for pain. Efficacy was measured through pain relief scores, number of daily doses of study medication, number of daily doses of supplemental analgesics, number of patients who discontinued therapy due to an unsatisfactory analgesic response, and global assessment scores. RESULTS: Of the 469 patients, 255 (54.4%) were female and 214 (45.6%) were male. The mean age was 51.1 years. Types of chronic pain included back (214; 45.6%), arthritic (145; 30.9%), other musculoskeletal (65; 13.9%), cancer (6; 1.3%), diabetic neuropathic (3; 0.6%), postherpetic neuralgic (5; 1.1%), other neurologic (21; 4.5%), and other unclassified chronic pain (10; 2.1%). During the 48 hours prior to the study, 351 (74.8%) patients had been treated with opioid or opioid-nonopioid combination analgesics. The overall mean daily pain relief score was significantly greater in the HI2 group (2.25+/-0.89) than in the HI1 group (1.98+/-0.87) (P = 0.003) or the CA group (1.85+/-0.96) (P < 0.001). The overall mean number of daily doses of study medication was significantly less in the HI2 group (2.94+/-0.99) than in the HI1 group (3.23+/-0.76) (P = 0.036) or the CA group (3.26+/-0.75) (P = 0.014). The overall mean number of daily doses of supplemental analgesics was significantly less in the HI2 group (0.24+/-0.49) than in the HI1 group (0.34+/-0.58) (P = 0.021) or CA group (0.49+/-0.85) (P = 0.010). The number of patients who discontinued treatment due to an unsatisfactory analgesic response was significantly less in the HI2 group (2; 1.3%) than in the CA group (12; 7.5%) (P = 0.008). HI2 was more effective than HI1 and CA as measured by pain relief scores for week 1 (P < 0.001 vs HI1 and CA), week 2 (P < 0.001 vs HI1 and CA), and week 3 (P = 0.008 vs HI1 and P < 0.001 vs CA); daily doses of study medication for week 1 (P = 0.019 vs HI1 and P = 0.011 vs CA); daily doses of supplemental analgesics for week 1 (P = 0.010 vs HI1 and CA); and global assessment scores for week 1 (P = 0.018 vs HI1 and P < 0.001 vs CA), week 2 (P = 0.005 vs HI1 and P < 0.001 vs CA), and week 4 (P = 0.013 vs HI1 and P = 0.023 vs CA). There were no significant differences between HI1 and CA in any efficacy variable. There were no significant differences in the number of patients experiencing adverse events in the HI2 (127; 83%), HI1 (124; 79.5%), and CA (129; 80.6%) groups. However, the mean number of patients who discontinued treatment due to adverse events was significantly greater in the HI2 group (40; 26.1%) than in the HI1 group (23; 14.7%) (P = 0.013). CONCLUSIONS: The results of this study suggest that 2-tablet doses of combination hydrocodone 7.5 mg and ibuprofen 200 mg may be more effective than either 1-tablet doses of this combination or 2-tablet doses of combination codeine 30 mg and acetaminophen 300 mg. Moreover, 1-tablet doses of combination hydrocodone 7.5 mg and ibuprofen 200 mg may be as effective as 2-tablet doses of combination codeine 30 mg and acetaminophen 300 mg.

Combination hydrocodone and ibuprofen versus combination oxycodone and acetaminophen in the treatment of postoperative obstetric or gynecologic pain.

OBJECTIVE: The objective of this study was to compare the effectiveness of combination hydrocodone and ibuprofen with that of combination oxycodone and acetaminophen in the treatment of moderate to severe postoperative obstetric or gynecologic pain. BACKGROUND: Hydrocodone 7.5 mg with ibuprofen 200 mg is the only approved fixed-dose combination analgesic containing an opioid and ibuprofen. METHODS: This randomized, double-blind, parallel-group, single-dose, active-comparator, placebo-controlled study compared the effects of a 2-tablet dose of hydrocodone 7.5 mg and ibuprofen 200 mg with those of a 2-tablet dose of oxycodone 5 mg and acetaminophen 325 mg and placebo. Analgesia was assessed over 8 hours. RESULTS: Mean pain relief (PR) scores were similar for the hydrocodone with ibuprofen and oxycodone with acetaminophen groups (n = 61 and 59, respectively) at 0.5, 1, 1.5, 2, 2.5, 3, 4, and 7 hours and significantly greater for the hydrocodone with ibuprofen group at 5, 6, and 8 hours (P < or = 0.05). Mean pain intensity difference (PID) scores were similar for hydrocodone with ibuprofen and oxycodone with acetaminophen at 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours and significantly greater for hydrocodone with ibuprofen at 5, 6, 7, and 8 hours (P < or = 0.05). Total PR scores were similar for hydrocodone with ibuprofen and oxycodone with acetaminophen for the 0- to 3- and 0- to 4-hour intervals and significantly greater for hydrocodone with ibuprofen for the 0- to 6- and 0- to 8-hour intervals (P < 0.05). The sum of the PID scores was similar for hydrocodone with ibuprofen and oxycodone with acetaminophen for the 0- to 3-, 0- to 4-, 0- to 6-, and 0- to 8-hour intervals. The median estimated time to onset of analgesia, mean peak PR score, median time to remedication, and mean global assessment score were similar for hydrocodone with ibuprofen and oxycodone with acetaminophen. Assay sensitivity was demonstrated by the presence of statistically significant differences between both active treatments and placebo (n = 60). The number of patients experiencing adverse events was similar for each of the 3 groups (11 [18.0%], hydrocodone with ibuprofen; 7 [11.9%], oxycodone with acetaminophen; and 6 [10.0%], placebo). CONCLUSIONS: In this study, a 2-tablet dose of combination hydrocodone 7.5 mg and ibuprofen 200 mg was as effective as a 2-tablet dose of combination oxycodone 5 mg and acetaminophen 325 mg in the treatment of moderate to severe postoperative obstetric or gynecologic pain. Both treatments were superior to placebo. The results of this study suggest that the combination of hydrocodone 7.5 mg and ibuprofen 200 mg may offer prescribers an additional option in combination pain therapy.

The repressive function of AP2 transcription factor on the hepatocyte growth factor gene promoter.

Hepatocyte growth factor is an important multifunctional growth factor whose gene expression is tightly regulated at the transcriptional level. Previous studies from our laboratory have shown that several cis-acting elements are present in the promoter and proximal promoter region of the HGF gene. In this study, we have uncovered that AP2 transcription factor specifically binds to a regulatory site located at -230 to -260 in the upstream region of the HGF gene promoter. Gelshift and supershift assays confirmed that AP2 has high binding affinity to this region. Functional studies which introduced a mutation in the AP2 core binding region as well as cotransfection experiments using an AP2 expression vector revealed that AP2 exerts a repressive role on the HGF gene promoter activity. The AP2 binding site overlaps with those of NF1 and USF/E-box binding sites which we have recently shown to constitute a composite multifunctional docking site for the members of the NF1 and USF transcription factor families. An inverse correlation was noted between AP2 binding activity to this composite site and HGF gene expression in different cell lines. Therefore, AP2-mediated repression of the HGF gene promoter may be part of the molecular mechanism responsible for regulating HGF expression.

The concerted regulatory functions of the transcription factors nuclear factor-1 and upstream stimulatory factor on a composite element in the promoter of the hepatocyte growth factor gene.

Hepatocyte growth factor (HGF) is an important multifunctional cytokine whose gene expression is regulated mainly at the transcriptional level. Previous studies using transgenic mice as well as in vitro analyses showed that a potential regulatory element(s) exists between -260 to -230 bp in the upstream region of the HGF gene promoter. In the present study, we have discovered that this region is a composite site through which members of the nuclear factor 1 (NF1) and upstream stimulatory factor (USF) families bind to and regulate HGF gene transcription. Gel mobility shift and supershift assays revealed that USF and NF1 have high binding affinity for this region and that the binding sites of the two different transcription factor families overlap. Functional studies showed that NF1 suppresses HGF gene promoter activity and that USF has an activating function. We found that the NF1/X and NF1/Red1 isoforms strongly suppressed HGF promoter activity while the NF1/L variant had no obvious effects. USF1, but not USF2, of the USF family stimulated HGF gene promoter activity. More interestingly, during liver regeneration after partial hepatectomy, a process which activates the HGF gene, we noted that the binding activity of USF to the HGF promoter element increased while that of NF1 decreased. These data provide insight into the molecular mechanisms that govern HGF gene transcription. Oncogene (2000).

Incidence and occurrence of total (first-ever and recurrent) stroke.

BACKGROUND AND PURPOSE: It has recently been hypothesized that the figure of approximately half a million strokes substantially underestimates the actual annual stroke burden for the United States. The majority of previously reported studies on the epidemiology of stroke used relatively small and homogeneous population-based stroke registries. This study was designed to estimate the occurrence, incidence, and characteristics of total (first-ever and recurrent) stroke by using a large administrative claims database representative of all 1995 US inpatient discharges. METHODS: We used the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, release 4, which contains approximately 20% of all 1995 US inpatient discharges. Because the accuracy of International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) coding is suboptimal, we performed a literature review of ICD-9-CM 430 to 438 validation studies. The pooled results from the literature review were used to make appropriate adjustments in the analysis to correct for some of the inaccuracies of the diagnostic codes. RESULTS: There were 682 000 occurrences of stroke with hospitalization (95% CI 660 000 to 704 000) and an estimated 68 000 occurrences of stroke without hospitalization. The overall incidence rate for occurrence of total stroke (first-ever and recurrent) was 259 per 100 000 population (age- and sex-adjusted to 1995 US population). Incidence rates increased exponentially with age and were consistently higher for males than for females. CONCLUSIONS: We conservatively estimate that there were 750 000 first-ever or recurrent strokes in the United States during 1995. This new figure emphasizes the importance of preventive measures for a disease that has identifiable and modifiable risk factors and for the development of new and improved treatment strategies and infrastructures that can reduce the consequences of stroke.

Analgesic efficacy of a combination of hydrocodone with ibuprofen in postoperative pain.

Two randomized, double-blind, parallel-group single-dose 2 x 2 factorial analgesic studies compared a single-dose or a 2-tablet dose of a combination of 7.5 mg hydrocodone bitartrate with 200 mg ibuprofen with each constituent alone and with a placebo in women with moderate or severe postoperative pain from abdominal or gynecologic surgery. A nurse-observer recorded patient reports of pain intensity and pain relief periodically for 8 hours. In both studies, the combination was significantly superior to placebo for sum of the pain intensity differences (SPID), total pain relief (TOTPAR), peak pain intensity difference (PID) and pain relief, global evaluation, and time to remedication. The combination was likewise significantly superior to both hydrocodone and ibuprofen for most of these summary measures of analgesia. In a factorial analysis, both the hydrocodone and ibuprofen effects were significant for most summary measures of analgesia, whereas results of the interaction contrast were consistent with the concept that the analgesic effect of the combination represents the additive analgesia of its 2 constituents.

The upstream regulatory regions of the hepatocyte growth factor gene promoter are essential for its expression in transgenic mice.

To understand the molecular mechanisms of hepatocyte growth factor (HGF) gene transcription in vivo, we report the generation and characterization of transgenic mice harboring various lengths of the mouse HGF promoter linked to the chloramphenicol acetyltransferase reporter gene. Analysis of different tissues of the transgenic mouse lines having the 2.7-kilobase (kb) promoter construct revealed a pattern of reporter gene expression in embryonic and adult tissues that paralleled that of endogenous HGF gene expression. A similar expression pattern was observed in the 0.7-kb transgenic lines. However, in contrast to in vitro data, no promoter activity was detected in four independent transgenic lines harboring the 0.1-kb construct. Akin to the activity of the endogenous HGF gene, which is induced in the liver, lung, and spleen in response to 70% partial hepatectomy, the reporter gene driven by the 2.7-kb promoter construct was strongly induced, whereas that driven by the 0.7-kb promoter construct was modestly induced in these organs after partial hepatectomy. Together, these data suggest that the region between -0.1 and -0.7 kb of the HGF gene promoter is essential to drive its expression in vivo and that additional upstream sequences located between -0.7 and -2.7 kb are also necessary for its maximum inducibility in response to cues that stimulate tissue growth and regeneration.