Comparison of the effects of bimatoprost and a fixed combination of latanoprost and timolol on circadian intraocular pressure

OBJECTIVE: To compare the effect of bimatoprost and the fixed combination of latanoprost and timolol (LTFC) on 24-hour mean intraocular pressure (IOP) after patients are switched from a nonfixed combination of latanoprost and timolol. DESIGN: Randomized, double-masked, multicenter clinical trial. PARTICIPANTS: Two hundred patients with glaucoma or ocular hypertension. METHODS: Included were patients who were controlled (IOP < 21 mmHg) on the nonfixed combination of latanoprost and timolol for at least 3 months before the baseline visit or patients on monotherapy with either latanoprost or timolol who were eligible for dual therapy not being fully controlled on monotherapy. The latter group of patients underwent a 6-week wash-in phase with the nonfixed combination of latanoprost and timolol before baseline IOP determination and study inclusion. Supine and sitting position IOPs were recorded at 8 pm, midnight, 5 am, 8 am, noon, and 4 pm at baseline, week 6, and week 12 visits. MAIN OUTCOME MEASURE: An analysis of covariance model was used for a noninferiority test of the primary efficacy variable, with mean area under the 24-hour IOP curve after 12 weeks of treatment as response variable and treatment, center, and baseline IOP as factors. A secondary analysis was performed on the within-treatment change from baseline. RESULTS: Mean baseline IOPs were 16.3+/-3.3 mmHg and 15.5+/-2.9.mmHg in the bimatoprost and LTFC groups, respectively. At week 12, mean IOPs were 16.1+/-2.5 mmHg for the bimatoprost group and 16.3+/-3.7 mmHg for the LTFC group, and no significant difference between the 2 treatment groups could be found. As compared with baseline, mean IOP increased by 0.3+/-3.6 mmHg during the day and decreased by 0.8+/-3.8 mmHg during the night in the bimatoprost group, whereas there were increases of 1.43+/-2.6 mmHg and 0.14+/-3.2 mmHg in the LTFC group, respectively. CONCLUSIONS: Bimatoprost is not inferior to the LTFC in maintaining IOP at a controlled level during a 24-hour period in patients switched from the nonfixed combination of latanoprost and timolol.

Effects of an aging vascular model on healthy and diseased hearts

The vitamin D(3) and nicotine (VDN) model is a model of isolated systolic hypertension (ISH) due to arterial calcification raising arterial stiffness and vascular impedance similar to an aged and stiffened arterial tree. We therefore analyzed the impact of this aging model on normal and diseased hearts with myocardial infarction (MI). Wistar rats were treated with VDN (n = 9), subjected to MI by coronary ligation (n = 10), or subjected to a combination of both MI and VDN treatment (VDN/MI, n = 14). A sham-treated group served as control (Ctrl, n = 10). Transthoracic echocardiography was performed every 2 wk, whereas invasive indexes were obtained at week 8 before death. Calcium, collagen, and protein contents were measured in the heart and the aorta. Systolic blood pressure, pulse pressure, thoracic aortic calcium, and end-systolic elastance as an index of myocardial contractility were highest in the aging model group compared with MI and Ctrl groups (P(VDN) < 0.05, 2-way ANOVA). Left ventricular wall stress and brain natriuretic peptide (P(VDNxMI) = not significant) were highest, while ejection fraction, stroke volume, and cardiac output were lowest in the combined group versus all other groups (P(VDNxMI) < 0.05). The combination of ISH due to this aging model and MI demonstrates significant alterations in cardiac function. This model mimics several clinical phenomena of cardiovascular aging and may thus serve to further study novel therapies.

Gentamicin increases the efficacy of vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model

In experimental meningitis a single dose of gentamicin (10 mg/kg of body weight) led to gentamicin levels in around cerebrospinal fluid (CSF) of 4 mg/liter for 4 h, decreasing slowly to 2 mg/liter 4 h later. The CSF penetration of gentamicin ranged around 27%, calculated by comparison of areas under the curve (AUC in serum/AUC in CSF). Gentamicin monotherapy (-1.24 log(10) CFU/ml) was inferior to vancomycin monotherapy (-2.54 log(10) CFU/ml) over 8 h against penicillin-resistant pneumococci. However, the combination of vancomycin with gentamicin was significantly superior (-4.48 log(10) CFU/ml) compared to either monotherapy alone. The synergistic activity of vancomycin combined with gentamicin was also demonstrated in vitro in time-kill assays.

Grepafloxacin against penicillin-resistant pneumococci in the rabbit meningitis model

Grepafloxacin, a new fluoroquinolone, produced bactericidal activity comparable to that of vancomycin and ceftriaxone in the treatment in rabbits of meningitis caused by a pneumococcal strain highly resistant to penicillin (MIC 4 mg/L) (triangle uplog(10) cfu/mL*h for grepafloxacin, -0.32 +/- 0.15; dose, 15 mg/kg iv; triangle uplog(10) cfu/mL*h for vancomycin, -0.39 +/- 0.18; dose, 2 x 20 mg/kg iv; triangle uplog(10) cfu/mL*h for ceftriaxone, -0.32 +/- 0. 12; dose, 125 mg/kg iv). Higher doses of grepafloxacin (30 mg/kg and 2 x 50 mg/kg) did not improve the killing rates. The combination of grepafloxacin with vancomycin was not significantly superior to monotherapies (P > 0.05). In vitro, grepafloxacin was bactericidal at concentrations above the MIC. Using concentrations around the MIC, addition of vancomycin to grepafloxacin showed synergic activity.

Synergy between trovafloxacin and ceftriaxone against penicillin-resistant pneumococci in the rabbit meningitis model and in vitro

The bactericidal activities of monotherapy with trovafloxacin (-0.37 +/- 0.15 Delta log(10) CFU/ml. h), vancomycin (-0.32 +/- 0.12 Delta log(10) CFU/ml. h), and ceftriaxone (-0.36 +/- 0.19 Delta log(10) CFU/ml. h) for the treatment of experimental meningitis in rabbits due to a clinical penicillin-resistant pneumococcal strain (MIC, 4 mg/liter) were similar. The combination of ceftriaxone with trovafloxacin considerably improved the killing rates (-0.67 +/- 0.16 Delta log(10) CFU/ml. h) and was slightly superior to ceftriaxone with vancomycin (killing rate, -0.53 +/- 0. 22 Delta log(10) CFU/ml. h), the regimen most commonly used in clinical practice. In vitro, synergy was demonstrated between ceftriaxone and trovafloxacin by the checkerboard method (fractional inhibitory concentration index, 0.5) and by time-killing assays over 8 h.

Meropenem alone and in combination with vancomycin in experimental meningitis caused by a penicillin-resistant pneumococcal strain

In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 microg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (-0.48+/-0.14 deltalog10 cfu/ml h) and slightly superior to ceftriaxone (-0.34+/-0.23 deltalog10 cfu/ml x h) and vancomycin (-0.39+/-0.19 deltalog10 cfu/ml x h). Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (-0.55+/-0.19 deltalog10 cfu/ml x h), only an insignificant gain was observed by the addition of vancomycin to meropenem (-0.55+/-0.28 deltalog10 cfu/ml x h).

Comparative efficacies of antibiotics in a rat model of meningoencephalitis due to Listeria monocytogenes

The antibacterial activities of amoxicillin-gentamicin, trovafloxacin, trimethoprim-sulfamethoxazole (TMP-SMX) and the combination of trovafloxacin with TMP-SMX were compared in a model of meningoencephalitis due to Listeria monocytogenes in infant rats. At 22 h after intracisternal infection, the cerebrospinal fluid was cultured to document meningitis, and the treatment was started. Treatment was instituted for 48 h, and efficacy was evaluated 24 h after administration of the last dose. All tested treatment regimens exhibited significant activities in brain, liver, and blood compared to infected rats receiving saline (P < 0.001). In the brain, amoxicillin plus gentamicin was more active than all of the other regimens, and trovafloxacin was more active than TMP-SMX (bacterial titers of 4.1 +/- 0.5 log10 CFU/ml for amoxicillin-gentamicin, 5.0 +/- 0.4 log10 CFU/ml for trovafloxacin, and 5.8 +/- 0.5 log10 CFU/ml for TMP-SMX; P < 0.05). In liver, amoxicillin-gentamicin and trovafloxacin were similarly active (2.8 +/- 0.8 and 2.7 +/- 0.8 log10 CFU/ml, respectively) but more active than TMP-SMX (4.4 +/- 0. 6 log10 CFU/ml; P < 0.05). The combination of trovafloxacin with TMP-SMX did not alter the antibacterial effect in the brain, but it did reduce the effect of trovafloxacin in the liver. Amoxicillin-gentamicin was the most active therapy in this study, but the activity of trovafloxacin suggests that further studies with this drug for the treatment of Listeria infections may be warranted.

Inhibition of L-type amino acid transport with non-physiological amino acids in the Pahenu2 mouse model of phenylketonuria

Phenylketonuria, an autosomal recessive Mendelian disorder, is one of the most common inborn errors of metabolism. Although currently treated by diet, many suboptimal outcomes occur for patients. Neuropathological outcomes include cognitive loss, white matter abnormalities, and hypo- or demyelination, resulting from high concentrations and/or fluctuating levels of phenylalanine. High phenylalanine can also result in competitive exclusion of other large neutral amino acids from the brain, including tyrosine and tryptophan (essential precursors of dopamine and serotonin). This competition occurs at the blood brain barrier, where the L-type amino acid transporter, LAT1, selectively facilitates entry of large neutral amino acids. The hypothesis of these studies is that certain non-physiological amino acids (NPAA; DL-norleucine (NL), 2-aminonorbornane (NB; 2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid), α-aminoisobutyrate (AIB), and α-methyl-aminoisobutyrate (MAIB)) would competitively inhibit LAT1 transport of phenylalanine (Phe) at the blood-brain barrier interface. To test this hypothesis, Pah-/- mice (n=5, mixed gender; Pah+/-(n=5) as controls) were fed either 5% NL, 0.5% NB, 5% AIB or 3% MAIB (w/w 18% protein mouse chow) for 3 weeks. Outcome measurements included food intake, body weight, brain LNAAs, and brain monoamines measured via LCMS/MS or HPLC. Brain Phe values at sacrifice were significantly reduced for NL, NB, and MAIB, verifying the hypothesis that these NPAAs could inhibit Phe trafficking into the brain. However, concomitant reductions in tyrosine and methionine occurred at the concentrations employed. Blood Phe levels were not altered indicating no effect of NPAA competitors in the gut. Brain NL and NB levels, measured with HPLC, verified both uptake and transport of NPAAs. Although believed predominantly unmetabolized, NL feeding significantly increased blood urea nitrogen. Pah-/-disturbances of monoamine metabolism were exacerbated by NPAA intervention, primarily with NB (the prototypical LAT inhibitor). To achieve the overarching goal of using NPAAs to stabilize Phe transport levels into the brain, a specific Phe-reducing combination and concentration of NPAAs must be found. Our studies represent the first in vivo use of NL, NB and MAIB in Pah-/- mice, and provide proof-of-principle for further characterization of these LAT inhibitors. Our data is the first to document an effect of MAIB, a specific system A transport inhibitor, on large neutral amino acid transport.

Effects of EDP-420 on penicillin-resistant and quinolone- and penicillin-resistant pneumococci in the rabbit meningitis model

OBJECTIVES: To test the efficacy of EDP-420, a new ketolide, in experimental pneumococcal meningitis and to determine its penetration into the CSF. METHODS: The experimental rabbit model was used in this study and EDP-420 was tested against a penicillin-resistant and a penicillin- and quinolone-resistant mutant. EDP-420 was also tested against both strains in time-killing assays over 8 h in vitro. RESULTS: In experimental meningitis, EDP-420 produced a bactericidal activity comparable to the standard regimen based on a combination of vancomycin with ceftriaxone against a penicillin-resistant Streptococcus pneumoniae and a penicillin- and quinolone-resistant S. pneumoniae isolate. The penetration of EDP-420 into inflamed meninges was 38% after an i.v. injection of 10 mg/kg. The bactericidal activity of EDP-420 was also confirmed in in vitro time-killing assays. CONCLUSIONS: EDP-420 is an efficacious alternative treatment in pneumococcal meningitis, especially when resistant strains are suspected.

Prosthetically driven, computer-guided implant planning for the edentulous maxilla: a model study

OBJECTIVES: To analyze computer-assisted diagnostics and virtual implant planning and to evaluate the indication for template-guided flapless surgery and immediate loading in the rehabilitation of the edentulous maxilla. MATERIALS AND METHODS: Forty patients with an edentulous maxilla were selected for this study. The three-dimensional analysis and virtual implant planning was performed with the NobelGuide software program (Nobel Biocare, Göteborg, Sweden). Prior to the computer tomography aesthetics and functional aspects were checked clinically. Either a well-fitting denture or an optimized prosthetic setup was used and then converted to a radiographic template. This allowed for a computer-guided analysis of the jaw together with the prosthesis. Accordingly, the best implant position was determined in relation to the bone structure and prospective tooth position. For all jaws, the hypothetical indication for (1) four implants with a bar overdenture and (2) six implants with a simple fixed prosthesis were planned. The planning of the optimized implant position was then analyzed as follows: the number of implants was calculated that could be placed in sufficient quantity of bone. Additional surgical procedures (guided bone regeneration, sinus floor elevation) that would be necessary due the reduced bone quality and quantity were identified. The indication of template-guided, flapless surgery or an immediate loaded protocol was evaluated. RESULTS: Model (a) - bar overdentures: for 28 patients (70%), all four implants could be placed in sufficient bone (total 112 implants). Thus, a full, flapless procedure could be suggested. For six patients (15%), sufficient bone was not available for any of their planned implants. The remaining six patients had exhibited a combination of sufficient or insufficient bone. Model (b) - simple fixed prosthesis: for 12 patients (30%), all six implants could be placed in sufficient bone (total 72 implants). Thus, a full, flapless procedure could be suggested. For seven patients (17%), sufficient bone was not available for any of their planned implants. The remaining 21 patients had exhibited a combination of sufficient or insufficient bone. DISCUSSION: In the maxilla, advanced atrophy is often observed, and implant placement becomes difficult or impossible. Thus, flapless surgery or an immediate loading protocol can be performed just in a selected number of patients. Nevertheless, the use of a computer program for prosthetically driven implant planning is highly efficient and safe. The three-dimensional view of the maxilla allows the determination of the best implant position, the optimization of the implant axis, and the definition of the best surgical and prosthetic solution for the patient. Thus, a protocol that combines a computer-guided technique with conventional surgical procedures becomes a promising option, which needs to be further evaluated and improved.

Combination of daptomycin plus ceftriaxone is more active than vancomycin plus ceftriaxone in experimental meningitis after addition of dexamethasone

We examined the cerebrospinal fluid penetration of daptomycin after the addition of dexamethasone and its bactericidal efficacy with and without ceftriaxone in an experimental rabbit model of pneumococcal meningitis. The combination of daptomycin with ceftriaxone was the most efficacious regimen for pneumococcal meningitis. The previous addition of dexamethasone affected the antibacterial activity of daptomycin only marginally, either as monotherapy or combined with ceftriaxone, although the penetration of daptomycin into inflamed meninges was significantly reduced from 6 to 2%. Daptomycin with ceftriaxone might be a potential candidate for the empirical therapy of bacterial meningitis, although the activity of this regimen against Listeria monocytogenes remains to be demonstrated.

A real time simulation model of glucose-insulin metabolism for type 1 diabetes patients

In this paper, a simulation model of glucose-insulin metabolism for Type 1 diabetes patients is presented. The proposed system is based on the combination of Compartmental Models (CMs) and artificial Neural Networks (NNs). This model aims at the development of an accurate system, in order to assist Type 1 diabetes patients to handle their blood glucose profile and recognize dangerous metabolic states. Data from a Type 1 diabetes patient, stored in a database, have been used as input to the hybrid system. The data contain information about measured blood glucose levels, insulin intake, and description of food intake, along with the corresponding time. The data are passed to three separate CMs, which produce estimations about (i) the effect of Short Acting (SA) insulin intake on blood insulin concentration, (ii) the effect of Intermediate Acting (IA) insulin intake on blood insulin concentration, and (iii) the effect of carbohydrate intake on blood glucose absorption from the gut. The outputs of the three CMs are passed to a Recurrent NN (RNN) in order to predict subsequent blood glucose levels. The RNN is trained with the Real Time Recurrent Learning (RTRL) algorithm. The resulted blood glucose predictions are promising for the use of the proposed model for blood glucose level estimation for Type 1 diabetes patients.

Assessment of the Matrix Degenerative Effects of MMP-3, ADAMTS-4 and HTRA1 injected into a bovine Intervertebral Disc Organ Culture Model

Study Design. In vitro study to develop an intervertebral disc degeneration (IDD) organ culture model, using coccygeal bovine intervertebral discs (IVDs) and injection of proteolytic enzymes MMP-3, ADAMTS-4 and HTRA1.Objective. This study aimed to develop an in-vitro model of enzyme-mediated IDD to mimic the clinical outcome in humans for investigation of therapeutic treatment options.Summary of Background Data. Bovine IVDs are comparable to human IVDs in terms of cell composition and biomechanical behavior. Researchers injected papain and trypsin into them to create an IDD model with a degenerated nucleus pulposus (NP) area. They achieved macroscopic cavities as well as a loss of glycosaminoglycans (GAGs). However, none of these enzymes are clinically relevant.Methods. Bovine IVDs were harvested maintaining the endplates. Active forms of MMP-3, ADAMTS-4 and HTRA1 were injected at a dose of 10μg/ml each. Phosphate buffered saline (PBS) was injected as a control. Discs were cultured for 8 days and loaded diurnally (day 1 to day 4 with 0.4 MPa for 16 h) and left under free swelling condition from day 4 to day 8 to avoid expected artifacts due to dehydration of the NP. Outcome parameters included disc height, metabolic cell activity, DNA content, glycosaminoglycan (GAG) content, total collagen content, relative gene expression and histological investigation.Results. The mean metabolic cell activity was significantly lower in the NP area of discs injected with ADAMTS-4 compared to the day 0 control discs. Disc height was decreased following injection with HTRA1, and was significantly correlated with changes in GAG/DNA of the NP tissue. Total collagen content tended to be lower in groups injected with ADAMTS4 and MMP-3.Conclusion. MMP-3, ADAMTS-4 and HTRA1 neither provoked visible matrix degradation nor major shifts in gene expression. However, cell activity was significantly reduced and HTRA1 induced loss of disc height which positively correlated with changes in GAG/DNA content. The use of higher doses of these enzymes or a combination thereof may therefore be necessary to induce disc degeneration

The Incidence of AIDS-Defining Illnesses at a Current CD4 Count >=200 Cells/ L in the Post-Combination Antiretroviral Therapy Era

Background. Few studies consider the incidence of individual AIDS-defining illnesses (ADIs) at higher CD4 counts, relevant on a population level for monitoring and resource allocation. Methods. Individuals from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) aged ≥14 years with ≥1 CD4 count of ≥200 µL between 1998 and 2010 were included. Incidence rates (per 1000 person-years of follow-up [PYFU]) were calculated for each ADI within different CD4 strata; Poisson regression, using generalized estimating equations and robust standard errors, was used to model rates of ADIs with current CD4 ≥500/µL. Results. A total of 12 135 ADIs occurred at a CD4 count of ≥200 cells/µL among 207 539 persons with 1 154 803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0–21.1 per 1000 PYFU) with current CD4 200–349 cells/µL to 4.1 per 1000 PYFU (95% CI, 3.6–4.6 per 1000 PYFU) with current CD4 ≥ 1000 cells/µL. Persons with a current CD4 of 500–749 cells/µL had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10–1.32), whereas those with a current CD4 of ≥1000 cells/µL had a similar rate (aIRR, 0.92; 95% CI, .79–1.07), compared to a current CD4 of 750–999 cells/µL. Results were consistent in persons with high or low viral load. Findings were stronger for malignant ADIs (aIRR, 1.52; 95% CI, 1.25–1.86) than for nonmalignant ADIs (aIRR, 1.12; 95% CI, 1.01–1.25), comparing persons with a current CD4 of 500–749 cells/µL to 750–999 cells/µL. Discussion. The incidence of ADIs was higher in individuals with a current CD4 count of 500–749 cells/µL compared to those with a CD4 count of 750–999 cells/µL, but did not decrease further at higher CD4 counts. Results were similar in patients virologically suppressed on combination antiretroviral therapy, suggesting that immune reconstitution is not complete until the CD4 increases to >750 cells/µL.

Erythropoietin neuroprotection is enhanced by direct cortical application following subdural blood evacuation in a rat model of acute subdural hematoma

Recombinant human erythropoietin (EPO) has been successfully tested as neuroprotectant in brain injury models. The first large clinical trial with stroke patients, however, revealed negative results. Reasons are manifold and may include side-effects such as thrombotic complications or interactions with other medication, EPO concentration, penetration of the blood-brain-barrier and/or route of application. The latter is restricted to systemic application. Here we hypothesize that EPO is neuroprotective in a rat model of acute subdural hemorrhage (ASDH) and that direct cortical application is a feasible route of application in this injury type. The subdural hematoma was surgically evacuated and EPO was applied directly onto the surface of the brain. We injected NaCl, 200, 2000 or 20,000IU EPO per rat i.v. at 15min post-ASDH (400μl autologous venous blood) or NaCl, 0.02, 0.2 or 2IU per rat onto the cortical surface after removal of the subdurally infused blood t at 70min post-ASDH. Arterial blood pressure (MAP), blood chemistry, intracranial pressure (ICP), cerebral blood flow (CBF) and brain tissue oxygen (ptiO2) were assessed during the first hour and lesion volume at 2days after ASDH. EPO 20,000IU/rat (i.v.) elevated ICP significantly. EPO at 200 and 2000IU reduced lesion volume from 38.2±0.6mm(3) (NaCl-treated group) to 28.5±0.9 and 22.2±1.3mm(3) (all p<0.05 vs. NaCl). Cortical application of 0.02IU EPO after ASDH evacuation reduced injury from 36.0±5.2 to 11.2±2.1mm(3) (p=0.007), whereas 0.2IU had no effect (38.0±9.0mm(3)). The highest dose of both application routes (i.v. 20,000IU; cortical 2IU) enlarged the ASDH-induced damage significantly to 46.5±1.7 and 67.9±10.4mm(3) (all p<0.05 vs. NaCl). In order to test whether Tween-20, a solvent of EPO formulation 'NeoRecomon®' was responsible for adverse effects two groups were treated with NaCl or Tween-20 after the evacuation of ASDH, but no difference in lesion volume was detected. In conclusion, EPO is neuroprotective in a model of ASDH in rats and was most efficacious at a very low dose in combination with subdural blood removal. High systemic and topically applied concentrations caused adverse effects on lesion size which were partially due to increased ICP. Thus, patients with traumatic ASDH could be treated with cortically applied EPO but with caution concerning concentration.