Background and objective : Current North American guidelines advocate the use of respiratory fluoroquinolones for the empirical management of community-acquired pneumonia (CAP). While community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a pathogen frequently encountered in skin and skin structure infections, it has also now been recognised as a causative pathogen in CAP. Since fluoroquinolones may be used empirically to treat unsuspected CA-MRSA pneumonia, the objective of this study was to evaluate the antibacterial properties of levofloxacin and moxifloxacin using human simulated drug exposures in epithelial lining fluid (ELF). Methods : An in vitro model was used to simulate the ELF concentrations, previously determined in older adults receiving multiple doses, of levofloxacin 500mg once daily and moxifloxacin 400mg once daily. Four CA-MRSA isolates were studied at a starting inoculum of 10 6 colony-forming units (CFU)/mL; selected isolates were also studied at 10 8 CFU/mL. Bacterial density and resistance were quantitatively assessed over 48 hours. Drug exposure (area under the concentration-time curve [AUC]) was confirmed using validated drug assays. Results : At a standard 10 6 starting inoculum, sustained bacterial kill (3.6–4.5 log) with both fluoroquinolones was noted for CA-MRSA isolates 27 and 44 (AUC/minimum inhibitory concentration [MIC] = 383–3923). Despite an MIC of 8 μg/ mL (AUC/MIC = 25) for isolate 3, levofloxacin displayed a 2.8 log kill, while moxifloxacin (MIC 1 μg/mL) sustained a 4.5 log kill (AUC/MIC = 207) over 48 hours. Against isolate 59, levofloxacin displayed no antibacterial effect (AUC/MIC = 3), while moxifloxacin with an MIC of 8 μg/mL (AUC/MIC = 31) killed 4.6 log. At a high inoculum (108), both fluoroquinolones showed 5.2–5.6 log kill for the susceptible isolate (44), while moxifloxacin showed no antibacterial activity against isolate 59. Drug exposure (AUC/MIC) appeared to correlate well (r 2 = 0.99) with the change in log CFU/mL. Maximal activity was observed for both drugs at an AUC/MIC of approximately 30. Conclusion : When evaluated at human simulated ELF concentrations, both levofloxacin and moxifloxacin appeared to demonstrate sustained antibacterial activity for CA-MRSA isolates with MICs ≤ 8 μg/mL at a starting inoculum of 10 6 . Use of a high inoculum (10 8 ) appeared to compromise the antimicrobial activity of the fluoroquinolones when the MIC was 8 μg/mL, but did not mitigate antibacterial kill for susceptible isolates.
Investments in systems biology approaches by the pharmaceutical industry have not yet yielded the payoffs envisaged by many. In most cases, a plethora of novel drug targets arising from genomics led to many more failed projects in the pipeline, suggesting that target-based drug discovery may not be an optimal strategy for the industry. Before high-throughput “-omics” technologies and computer analysis became commonplace, most drug candidates were laboriously screened in animal systems to identify compounds that produced useful responses. Interestingly, the targets of many of the compounds that became drugs are still uncertain to this day. It is likely that drugs act on multiple targets in concert over time, the identification of which will require not only system level cataloguing and measurements, but next generation multiscale systems modelling. The concept of a “differentiated drug response” — elucidating and integrating responses composed of a range of effects on different tissues and, importantly, different time scales — may eventually prove to be the dominant paradigm of systems biology research. In this article, we explore key relevant concepts and technologies that we believe are critical for the future of systems biology and its place in pharmaceutical research.
Objective: The aim of this study was to investigate the extent of variations in lamotrigine serum concentrations between two immediate-release tablet formulations. Data were compared with in vitro difference and similarity tests on dissolution profiles of the two formulations. Methods: Dissolution characteristics of formulations A (reference) and B (test) were evaluated at three points spanning the physiologic pH range (pH 1.2, pH 4.5, pH 6.8). A model-independent approach of difference (f1) and similarity (f2) tests were applied to dissolution data. A clinical study was performed with 16 patients who were divided into two groups — one group received formulation A (n=9) and the other received formulation B (n=7). Lamotrigine steady-state concentrations were determined by high-performance liquid chromatography on a reverse-phase column. Results: There were no statistically significant differences in lamotrigine serum concentrations between the two groups, although formulation B had slightly higher mean concentration values (formulation A: 3.97±4.1 μg/mL; formulation B: 5.78±2.7 μg/mL). Dissolution profiles of the two formulations were similar in the pH 1.2 dissolution medium; however, the dissolution profiles of formulation B were outside the dissolution limit (≥85% at 15 minutes) in the pH 4.5 and 6.8 dissolution media. Conclusions: No significant changes in the serum concentrations of lamotrigine were seen between the two investigated formulations. There is no evidence to suggest that the differences in dissolution profiles at pH 4.5 and pH 6.8 affect the therapeutic efficacy of the formulations. It is evident that the doses of test formulation given to the patients were higher as a consequence of common assumption that generic products have a lower absorption rate, which is proven unnecessary in this study. This investigation was a pilot study and thus further investigations with a larger sample size are necessary to determine if there is a connection between dissolution profiles and the therapeutic effect of investigated formulations.
Background: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14-4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a long-term special survey that we conducted as a post-marketing survey. Objective: The results of a prospective post-marketing survey that was conducted to assess the safety and efficacy of the b-adrenergic receptor antagonist (β-blocker) Artist® tablets 10 mg, 20mg (carvedilol) in patients with hypertension in Japan, were investigated in order to examine the safety and efficacy of the drug during long-term treatment (18 months). Patients: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. Methods: We performed this survey as a prospective cohort study (special survey) utilizing a centralized registration method over 3 years (starting from April 1994), for an observation period of 18 months of carvedilol treatment. Results: Sixty-one medical institutions across Japan collected 380 case report forms of patients who received long-term administration of carvedilol, with 363 and 341 cases evaluated for safety and efficacy, respectively. The discontinuation rate was 7.2% and the incidence of adverse drug reactions was 5.23% (19 of 363) in the safety population. There was no significant change in fasting plasma glucose levels from baseline (118.1 ± 46.5mg/dL) to after carvedilol treatment (114.6 ± 43.3 mg/dL) [n = 141; p = 0.310]. In 341 evaluable patients in the efficacy population, decreases in both blood pressure and pulse rate were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Similarly, in hypertensive patients with diabetes mellitus, decreases in blood pressure were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Conclusions: The results of this study show that carvedilol exerted stable antihypertensive effects leading to favorable blood pressure control throughout long-term treatment, without showing any safety concerns. It was concluded that there were no clinically significant issues in terms of safety or efficacy with the long-term treatment of carvedilol in patients with hypertension.
Background: Etamicastat is a novel, potent, and reversible peripheral dopamine-β-hydroxylase inhibitor that has been administered orally at doses up to 600mg once daily for 10 days to male healthy volunteers and appears to be well tolerated. Objective: The aim of this study was to investigate the effect of food on the pharmacokinetics of etamicastat. Material and Methods: A single-center, open-label, randomized, two-way crossover study in 12 healthy male subjects was performed. Subjects were administered a single dose of etamicastat 200mg following either a standard high-fat and high-calorie content meal (test) or 10 hours of fasting (reference). The statistical method for testing the effect of food on the pharmacokinetic parameters of interest was based upon the 90% confidence interval (CI) for the test/reference geometric mean ratio (GMR). The parameters of interest were maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUClast), and AUC from time zero to infinity (AUC∞). Bioequivalence was assumed when the 90% CI fell within the recommended acceptance interval (80, 125). Results: Etamicastat Cmax, AUClast, and AUC∞ were 229 ng/mL, 1856 • h/mL, and 2238 ng • h/mL, respectively, following etamicastat in the fasting, and 166 ng/mL, 1737 ng • h/mL, and 2119 ng • h/mL, respectively, following etamicastat in the fed condition. Etamicastat test/reference GMR was 72.27% (90% CI 64.98, 80.38) for Cmax, 93.59% (90% CI 89.28, 98.11) for AUClast, and 96.47% (90% CI 91.67, 101.53) for AUC∞. Time to Cmax was prolonged by the presence of food (p < 0.001). The Cmax, AUClast, and AUC∞ values of the inactive metabolite BIA 5-961 were 275 ng/mL, 1827 ng • h/mL, and 2009 ng • h/mL, respectively, in the fasting, and 172 ng/mL, 1450 ng • h/mL, and 1677 ng • h/mL, respectively, in the fed condition. BIA 5-961 test/reference GMR was 62.42% (90% CI 56.77, 68.63) for Cmax, 79.41% (90% CI 56.77, 68.63) for AUClast, and 83.47% (90% CI 76.62, 90.93) for AUC∞. A total of six mild to moderate unspecific adverse events were reported by four subjects. There was no clinically significant abnormality in laboratory assessments. Conclusion: Etamicastat was well tolerated. The Cmax of etamicastat decreased 28% following oral administration of etamicastat in the presence of food, while AUC remained within the pre-defined acceptance interval. The delay in absorption and decrease in peak exposure of etamicastat is not clinically significant, and therefore etamicastat could be administered without regard to meals.
Background and Objective: There are only a few publications on the effects of dexamethasone on the plasma levels of cell adhesion molecules (CAMs). The goal of this study was to investigate the effects of dexamethasone 4 mg on the perioperative plasma levels of CAMs (soluble intercellular adhesion molecules [sICAM-1] and soluble vascular cell adhesion molecules [sVCAM-1]) during laparoscopic cholecystectomy.Methods: Forty-two patients undergoing laparoscopic cholecystectomy under total intravenous anesthesia were enrolled and randomly divided into two groups: the first group received dexamethasone 4mg (DEX group, n = 21) and the second group were controls (C group, n = 21). Plasma levels of sICAM-1 and sVCAM-1 were assessed before anesthesia, after induction (before surgery), and at 2 and 24 hours after surgery, respectively. Comparisons were performed for area under the plasma concentration-time curve (AUC) and within-group values.Results: AUC comparison for sICAM-1 showed significantly increased levels in the C group (p = 0.036), while there was no significant difference for sVCAM-1 (p = 0.052). Within-group analysis showed increased levels for both sICAM- 1 and sVCAM-1 in the C group at 24 hours postoperatively (p = 0.35 and p = 0.025, respectively).Conclusions: In our study, dexamethasone 4mg given before laparoscopic cholecystectomy determined a significant decrease in plasma levels of sICAM-1. Both sICAM-1 and sVCAM-1 remained increased compared with baseline at 24 hours in the C group. This may partially explain the postoperative anti-inflammatory effects of dexamethasone. Further studies are needed.
Osteoarthritis (OA), also called degenerative joint disease, is the most frequently occurring chronic musculoskeletal disease, particularly affecting the aging population. The use of viscosupplementation, i.e. intra-articular (IA) hyaluronic acid (HA) drug therapy, to treat OA, is growing worldwide, due to important results obtained from several clinical trials, which reported IA HA-related improvements in functional activity and pain management. This review is an update of the IA use of this compound in the treatment of OA, with clinical evidence from the last few years being discussed and used to delineate new trends for the future.
Background: Hypertension is a common co-morbidity in patients with type 2 diabetes mellitus, and well tolerated, effective therapies are needed to achieve guideline-recommended blood pressure (BP) goals in these patients. Objective: The aim of this study was to present the results of a prespecified analysis of key secondary endpoints from a 12-week, open-label, single-arm study evaluating the efficacy and safety of olmesartan medoxomil plus hydrochlorothiazide (HCTZ) in patients with hypertension and type 2 diabetes. Study Design and Methods: After a placebo run-in period, 192 patients received olmesartan medoxomil 20mg/day for 3 weeks. If BP remained ≥120/70mmHg, patients were uptitrated at 3-week intervals to olmesartanmedoxomil 40mg/day, olmesartan medoxomil/HCTZ 40/12.5mg/day, and olmesartan medoxomil/HCTZ 40/25mg/day. Main Outcome Measure: Endpoints evaluated in this analysis were the change from baseline in mean seated cuff BP (SeBP), proportions of patients achieving SeBP goals, and distribution of SeBP reductions. Results: Mean SeBP was 158.1/90.0mmHg at baseline. The mean±standard error of BP reductions at 12 weeks for systolic and diastolic BP were 21.3±1.1mmHg and 9.8±0.6 mmHg, respectively (p<0.0001 for each). At the end of the study, the proportion of patients with diabetes achieving the recommended SeBP goal of <130/80 mmHg was 41.1%. Conclusions: An olmesartan medoxomil±HCTZ treatment regimen significantly reduced BP from baseline in patients with hypertension and type 2 diabetes. Clinical Trials Registration: ClinicalTrials.gov identifier: NCT00403481
Objective: The aim of this study was to investigate the effects of a potent CYP3A4 inducer, rifampicin (Study A), and a potent CYP3A4 inhibitor, itraconazole (Study B), on the pharmacokinetics of a single 300mg dose of vandetanib in healthy subjects. Study Design and Setting: Two phase I, randomized, open-label, two-way crossover, single-center studies. Participants and Intervention: Study A: 18 healthy male subjects aged 21–44 years were randomized to receive each of the following two regimens, separated by a ≥6-week washout period: (i) oral rifampicin 600mg/day on days 1–31 with a single oral dose of vandetanib 300mg on day 10; and (ii) a single oral dose of vandetanib 300mg on day 1. Study B: 16 healthy male subjects aged 20–44 years were randomized to receive each of the following two regimens, separated by a 3-month washout period: (i) oral itraconazole 200mg/day on days 1–24 with a single oral dose of vandetanib 300mg on day 4; and (ii) a single oral dose of vandetanib 300mg on day 1. Main Outcome Measure: Blood samples for measurement of vandetanib (both studies) concentrations and its metabolites, N-desmethylvandetanib and vandetanib N-oxide (Study A only), were collected before and at various timepoints after vandetanib administration for up to 28 days (Study A) and 37 days (Study B). Pharmacokinetic parameters were determined using noncompartmental methods. The area under the plasma concentration-time curve from time 0 to 504 hours (AUC504) and maximum plasma concentration (Cmax) of vandetanib were compared in the presence and absence of rifampicin, and in the presence and absence of itraconazole. Results: Study A: coadministration of vandetanib with rifampicin resulted in a statistically significant reduction in AUC504 (geometric least square [GLS]mean ratio [vandetanib + rifampicin/vandetanib alone] 0.60; 90% CI 0.58, 0.63). There was no significant difference in Cmax of vandetanib (GLSmean ratio 1.03; 90% CI 0.95, 1.11). AUC504 and Cmax of N-desmethylvandetanib increased by 266.0% and 414.3%, respectively, in the presence of rifampicin compared with vandetanib alone. Exposure to vandetanib N-oxide was very low compared with that of vandetanib, but was increased in the presence of rifampicin. Study B: coadministration of vandetanib with itraconazole resulted in a significant increase in AUC504 (GLSmean ratio [vandetanib + itraconazole/vandetanib alone] 1.09; 90% CI 1.01, 1.18) and no significant change in Cmax (GLSmean ratio 0.96; 90% CI 0.83, 1.11). Vandetanib was well tolerated in both studies. Conclusions: Exposure to vandetanib, as assessed byAUC504 in healthy subjects, was reduced by around 40% when a single dose was given in combination with the potent CYP3A4 inducer rifampicin. Because of this, it may be appropriate to avoid coadministration of potent CYP3A4 inducers with vandetanib. Vandetanib exposure was increased by about 9% when it was taken in combination with the CYP3A4 inhibitor itraconazole. It is unlikely that coadministration of vandetanib and potent CYP3A4 inhibitors will need to be contraindicated.
Objective: The aim of this study was to confirm the efficacy, safety, and expected palatability of amlodipine orally disintegrating tablets (ODT) [ RACTAB ® formulation (Towa, Osaka, Japan)]. We report the re-analyzed results of 1687 cases in clinical settings obtained through postmarketing surveillance in Japan. Method: Study subjects were patients receiving treatment for the first time with amlodipine ODT for hypertension under routine care. A multicenter central registration system was used for this prospective survey. The survey was conducted from October 2008 to October 2010. The observational period was 12 weeks, during which time surveys on outpatient blood pressure, adverse events, palatability, etc. were conducted. Results: Blood pressure stabilized following treatment, and both systolic and diastolic blood pressures were favorably controlled. Adverse events observed were not significantly different from those observed during drug use trials of amlodipine formulations reported in 2003. Moreover, palatability of amlodipine ODT showed a 99.6% (227 of 228 cases) favorable patient acceptance, which is consistent with the initial design concept of RACTAB ® formulation. Conclusions: The results of this postmarketing surveillance study indicated that the efficacy, safety, and palatability of amlodipine ODT met our expectations (dissolves quickly in the mouth, tastes good, and is not rough on the tongue). Accordingly, amlodipine ODT are believed to be an easy-to-use formulation for prescribing doctors, dispensing pharmacists, and patients receiving treatment.
Respiratory syncytial virus (RSV) is a highly contagious virus, and is the major cause of lower respiratory tract infections in infants and toddlers worldwide.RSV infection poses serious health risks to young children during the first 2 years of life. Several infant populations have been classified as high risk, and additional risk factors are known to increase the likelihood of severe RSV infection. Treatment for active RSV infection is limited to the symptoms of infection rather than the underlying cause; therefore, it is critical to reduce the transmission of RSV. As nurses, we highlight the importance of educating healthcare professionals, both in the hospital and community settings, aswell as parents and other caregivers about the risks and outcomes associated with RSV infection, and necessarymeasures to decrease the risk of infection. We also highlight the importance of the successful identification of those children who are at high risk of RSV infection. RSV prophylaxis (RSVP) with palivizumab has been shown to improve clinical outcome in infants who are considered high risk compared with those who have not received RSVP. The failure of healthcare staff and primary caregivers to protect children against an RSV infection can have lasting detrimental effects on the health and lives of affected children and their families.
Background: Opioid analgesics can be abused by crushing followed by solubilization and intravenous injection to attain rapid absorption. Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®, MS-sNT), indicated for management of chronic, moderate to severe pain, contain pellets of morphine sulfate with a sequestered naltrexone core. Should product tampering by crushing occur, the sequestered naltrexone is intended for release to reduce morphine-induced subjective effects. Objective: This study compared self-reports of high, euphoria, and drug-liking effects of intravenous morphine alone versus intravenous morphine combined with naltrexone in a clinical simulation of intravenous abuse of crushed MS-sNT. Methods: This single-center, randomized, double-blind, crossover study characterized subjective effects of naltrexone administered intravenously at the same ratio to morphine present in MS-sNT. Subjects were male and had used prescription opioids five or more times within the previous 12 months to get ‘high’ but were not physically dependent on opioids. The primary outcome was the response to the Drug Effects Questionnaire (DEQ) question #5, “How high are you now?” (100mm Visual Analog Scale [VAS]). The secondary outcome was the response to a Cole/Addiction Research Center Inventory (ARCI) Stimulation-Euphoria modified scale. Additional outcomes included resonse to VAS drug liking, the remaining DEQ questions, and pupillometry. Results: Administration of intravenous naltrexone following intravenous morphine diminished mean high (29.8 vs 85.2 mm), Cole/ARCI Stimulation-Euphoria (13.7 vs 27.8 mm), and drug-liking (38.9 vs 81.4 mm) scores (all p < 0.0001) compared with intravenous morphine alone. No serious adverse events occurred as a result of the tested ratio of naltrexone to morphine. Conclusions: Results in this study population suggest that naltrexone added to morphine in the 4% ratio within MS-sNT mitigates the high, euphoria, and drug liking of morphine alone, potentially reducing the attractiveness for product tampering. Assessment of the true clinical significance of these findings will require further study.
Objective: The aim of this study was to evaluate the pharmacokinetic profile of lesogaberan in healthy subjects after single oral and intravenous administration of 14C-labeled lesogaberan and non-14C-labeled lesogaberan. Study Design: This was an open-label, single-center, randomized, two-way crossover, phase I study. Participants: Ten healthy male subjects took part in the study. Intervention: Volunteers were randomized to receive a single dose of either orally dosed (100 mg) or intravenously infused (20 mg) non-14C-labeled lesogaberan, and then orally (100 mg) or intravenously (20 mg) administered 14C-labeled lesogaberan in a crossover design. Treatment periods were separated by a washout period of at least 7 days. Main Outcome Measures Analyses of the rate and route of excretion, dose recovery, area under the plasma concentration versus time curve (AUC), AUC to the last quantifiable concentration, maximal plasma concentration (Cmax), time to Cmax, the apparent elimination half-life, bioavailability, total clearance, renal clearance, fraction of the bioavailable dose excreted unchanged in the urine, cumulative amount of drug excreted unchanged in urine, and the apparent volume of distribution at steady state of lesogaberan. Results: Lesogaberan was rapidly and extensively absorbed from the gastrointestinal tract and Cmax was achieved within 1–2 hours of oral dosing. The terminal half-life of lesogaberan was between 11 and 13 hours. Renal clearance accounted for approximately 22% of total body clearance. Based on the recovery of administered radioactivity, approximately 84% of the dose was excreted into the urine either as the parent compound or as water-soluble metabolite(s). There were no safety concerns raised during the study. Conclusion: Orally administered lesogaberan is rapidly absorbed with high bioavailability and the majority of the dose is excreted by the kidneys either as the parent compound or as metabolites. The major elimination pathway for lesogaberan in man is metabolism.
Highly active antiretroviral therapy (HAART) has become the standard for treating HIV infection.[1] HIV protease inhibitors (PIs) have been used as a major component of the HAART regimens over the past 10 years, along with nucleoside and non-nucleoside reverse transcriptase inhibitors. The introduction of these regimens resulted in an appreciable decline in morbidity and mortality due to HIV infection.[2,3] Tipranavir (TPV) is a nonpeptidic PI, approved by the US FDA and the European Medicines Agency for the treatment of HIV infection. The structure of this molecule is a sulfonamide-substituted dihydropyrone. Similar to other PIs, TPV binds directly to HIV aspartyl protease, disrupting the catalytic site of the enzyme and preventing protease-dependent cleavage of HIV gag and gag-pol polyproteins into smaller functional proteins.[4–6] For this reason, the chance to develop resistance is not so easy. TPV is active against PI multidrug resistant viruses and it has been very difficult to corner HIV to mutate through subsequent in vitro passages.[7–9] TPV plus low-dose ritonavir (TPV/r) is used in combination with other antiretroviral (ARV) drugs. The advantages of this approach include raising trough drug concentrations, minimizing inter-patient variability, prolonging drug elimination half-life, and reducing pill burden.[10,11] Results in the efficacy of the selected dose of TPV/r (500/200 mg twice daily) were quite encouraging in extensively treated HIV-infected patients. TPV is generally well tolerated; the most frequent adverse events were in the gastrointestinal system and laboratory abnormalities, such as alteration of the lipid profile and liver function.[12] Darunavir (DRV) is another new-generation nonpeptidic HIV protease inhibitor approved by the FDA, used with low doses of ritonavir (600/100 mg twice daily) for pharmacologic enhancement (boosting). It has demonstrated potent activity against multidrug-resistant HIV in heavily treatment-experienced patients with HIV infection. Like TPV, DRV needs multiple mutations in the HIV protease for the virus to build a significant resistance to these drugs. For this reason, TPV and DRV exhibit a high genetic barrier to the emergence of novel resistant strains.[13,14] Boosted DRV is generally well tolerated, with a lower incidence of diarrhea and modification of the lipid profile.[15] The aim of the POTENT trial[16] was the head-to-head comparison of the safety and efficacy of TPV versus DRV plus a low dose of ritonavir, each with an optimized background regimen (OBR) in triple-class-experienced HIV-infected patients, being resistant to more than one PI. This study was designed in 2007 (20 September) to enroll and treat 800 HIV-1-positive patients, randomly assigned (1 : 1) to one of the two arms: TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily), with a treatment period of 50 weeks. Both drugs were administered in combination with another selected ARV, based on patient therapeutic history (and virtual phenotype screening results). The major shortcoming of the POTENT trial was the very low enrollment numbers: only 39 patients (5% of the planned number) were randomized and received drugs prior to early termination of the study (1 July 2008). The data from the trial, due to poor patient enrollment and premature termination, are insufficient to assess primary and secondary previously established endpoints. For this reason, statistical tests were not applied to this collected observational data. The demonstrations of effect of TPV/r have been more evident in treatment-experienced patients with HIV infection receiving an OBR including two fully active drugs. The use of enfuvirtide for the first time has been correlated with a higher rate of virologic success when combined with TPV/r.[12] TPV/r is generally well tolerated, nevertheless clinical hepatitis and hepatic decompensation have been associated with its use. Although initially reported, a recent case review from the FDA did not identify new safety concerns regarding intracranial hemorrhage. Hepatic evaluation is highly recommended in co-infected patients who are at risk for hepatic decompensation.[17,18] There is evidence that mutations conferring resistance to TPV are not related to resistance to DRV. This may be important for the potential sequencing of these two PI in multiple ARV-experienced patients. A substantial susceptibility to TPV and DRV of viral isolates derived from patients with a massive ARV drug experience has been reported.[19] In multiple ARV-experienced patients with resistance to one or more PI, TPV and DRV remain the most likely active PIs for constructing an effective drug regimen. Nowadays, mostly achievable goals of ARV are to further reduce HIV-related morbidity and mortality, improve quality of life, and restore and preserve immunologic function in HIV-infected individuals through a sustained suppression of HIV replication.[20,21] It is not so easy to design a trial such as POTENT where even after significant efforts to enroll patients, the number of individuals included in the study and time in the follow-up were insufficient to draw definitive conclusions. Furthermore, the POTENT trial included a comparison between two PIs; however what we really need are combination regimens including drugs with new mechanisms of action, new cellular targets and novel chemical structures (e.g. co-receptor or integrase inhibitors), together with an improved tolerability profile.[22]
Background and Aim: Neutropenia is a serious adverse event for patients who are treated with cetuximab, an inhibitor of endothelial growth factor receptor. However, there is no consistent result of the relationship between cetuximab and neutropenia in randomized controlled trials (RCTs). We did a systematic review and meta-analysis of published RCTs to assess the overall risk of neutropenia associated with cetuximab.Methods: PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and American Society of Clinical Oncology conferences were searched for relevant RCTs. Quantitative and qualitative analyses were carried out to evaluate the association between neutropenia and cetuximab. Both the fixed-effect model and random-effects model were used.Results: A total of 7186 patients with a variety of advanced cancers from 14 trials were included in our analysis. The overall incidence of neutropenia in patients receiving cetuximab was 33% (95% CI 26, 43). Patients treated with cetuximab had a significantly increased risk of neutropenia compared with patients treated with control medication, with a relative risk (RR) of 1.12 (95% CI 1.05, 1.19; fixed-effect model). Risk varied with tumor type. Higher risks were observed in patients with colorectal carcinoma (RR 1.17; 95% CI 1.04, 1.32; fixed-effect model) and non-small cell lung cancer (RR 1.07; 95% CI 0.99, 1.16; fixed-effect model).Conclusion: Cetuximab is associated with a significant risk of neutropenia in patients with advanced cancer receiving concurrent chemotherapy.
Background: The POTENT trial compared the safety and efficacy of tipranavir/ritonavir (TPV/r) to darunavir/ritonavir (DRV/r), each with an optimized background regimen (OBR) in triple-class experienced HIV-1-infected patients with resistance to more than one protease inhibitor (PI). Methodology/Principal Findings: POTENT was a prospective, open-label study of triple-class (PI, non-nucleoside reverse transcriptase inhibitors [NNRTI], nucleoside reverse transcriptase inhibitors [NRTI]), treatment-experienced, HIVpositive patients. Subjects were randomized to either TPV/r (500/200mg twice daily) or DRV/r (600/100mg twice daily) on a genotype-guided, investigatorselected OBR. CD4+ counts andHIV viral loads were assayed at key timepoints. The primary endpoint was time to virologic failure (viral load >-500 copies/mL). POTENT was prematurely terminated due to slow enrollment. Thirty-nine patients were treated with either TPV/r (n= 19) or DRV/r (n= 20); 82% were male, 77%White, with mean age of 43.6 years. Mean baselineHIV RNA was 3.9 log10 copies/mL.Median prior antiretrovirals was 11, with no prior raltegravir or maraviroc exposure. Raltegravir was the most common novel class agent in the OBRs (n = 14 TPV/r; n = 12DRV/r). In both groups, patients achieved mean viral load decreases >-2 log10 copies/mL by week 8, and by week 12 mean CD4+ counts rose by 40–50 cells/mm3. Total observation time was 32 weeks. Drug-related adverse events were reported in 21% (TPV/r) and 25% (DRV/r) of patients. Conclusions/Significance: TPV/r- and DRV/r-based regimens showed similar short-term safety and efficacy. These data support the use of next-generation PIs such as tipranavir or darunavir with novel class antiretroviral agents (integrase inhibitors, CCR5 antagonists, or fusion inhibitors). Trial Registration: Clinicaltrials.gov NCT00517192
Background: Intraoperative lidocaine is widely used in controlling discomfort during cataract surgery. However, recent studies have confirmed the toxic effect of lidocaine on ganglion cells. Ropivacaine is an anesthetic recently introduced in clinical practice that couples a long anesthetic effect with a mild vasoconstrictive action. Objective: The aim of this study was an in vitro evaluation of the efficacy of ropivacaine in reducing the degenerative effects usually observed during lidocaine treatment. Methods: Ropivacaine and lidocaine toxicity has been evaluated in murine fibroblasts 3T6 by measuring percentage of cell death, cell growth inhibition, and DNA degradation. The choice of this cellular line is motivated by the presence of a complete apoptotic system that can be assimilated to the endothelium precursor cells. Results: We observed that lidocaine 0.25% decreases cell viability and causes DNA degradation in murine fibroblasts 3T6, whereas ropivacaine 0.5% does not cause any cellular or molecular degenerative effect. Conclusions: Our in vitro studies confirm that ropivacaine is less toxic than lidocaine to these cells. Therefore, in vivo studies in the anterior chamber could be useful to evaluate the effects of ropivacaine versus lidocaine in intracameral anesthesia in cataract surgery.
Histone acetyltransferase and histone deacetylase are enzymes responsible for histone acetylation and deacetylation, respectively, in which the histones are acetylated and deacetylated on lysine residues in the N-terminal tail and on the surface of the nucleosome core. These processes are considered the most important epigenetic mechanisms for remodeling the chromatin structure and controlling the gene expression. Histone acetylation is associated with gene activation. Sodium phenylbutyrate is a histone deacetylase inhibitor that has been approved for treatement of urea cycle disorders and is under investigation in cancer, hemoglobinopathies, motor neuron diseases, and cystic fibrosis clinical trials. Due to its characteristics, not only of histone deacetylase inhibitor, but also of ammonia sink and chemical chaperone, the interest towards this molecule is growing worldwide. This review aims to update the current literature, involving the use of sodium phenylbutyrate in experimental studies and clinical trials.
