The application of Near-Infrared Spatially Resolved Spectroscopy in scope of achieving continuous real-time quality monitoring and control of tablets with challenging dimensions.

In scope of achieving real-time release of tablets, quality attributes need to be monitored and controlled through Process Analytical Technology tools such as near-infrared spectroscopy (NIRS). The authors evaluated the suitability of NIR-Spatially Resolved Spectroscopy (NIR-SRS) for continuous real-time monitoring and control of content uniformity, hardness and homogeneity of tablets with challenging dimensions. A novel user-friendly research and development inspection unit was used as standalone equipment for the analysis of small oblong tablets with deep-cut break lines. A total of 66 tablets varying in hardness and Active Pharmaceutical Ingredient (API) content were inspected, with each tablet being analysed five times and measurements repeated on three different days. Partial Least Squares (PLS) models were developed to assess content uniformity and hardness, of which the former showed higher accuracy. The authors attempted to visualize tablet homogeneity through NIR-SRS spectra by regressing all spectra obtained during a single measurement using a content uniformity PLS model. The NIR-SRS probe demonstrated its potential towards real-time release testing through its ability to quickly monitor content uniformity, hardness and visualize homogeneity, even for tablets with challenging dimensions.

TPLS as predictive platform for twin-screw wet granulation process and formulation development.

In recent years, the interest in continuous manufacturing techniques, such as twin-screw wet granulation, has increased. However, the understanding of the influence of the combination of raw material properties and process settings upon the granule quality attributes is still limited. In this study, a T-shaped partial least squares (TPLS) model was developed to link raw material properties, the ratios in which these raw materials were combined and the applied process parameters for the twin-screw wet granulation process with the granule quality attributes. In addition, the predictive ability of the TPLS model was used to find a suitable combination of formulation composition and twin-screw granulation process settings for a new API leading to desired granule quality attributes. Overall, this study helped to better understand the link between raw material properties, formulation composition and process settings on granule quality attributes. Moreover, as TPLS can provide a reasonable starting point for formulation and process development for new APIs, it can reduce the experimental development efforts and consequently the consumption of expensive (and often limited available) new API.

Comparing volume-clamp method and intra-arterial blood pressure measurements in patients with atrial fibrillation admitted to the intensive or medium care unit.

International guidelines highlight the importance of blood pressure (BP) in patients with atrial fibrillation (AF). However, BP measurement in AF is complicated by beat-to-beat fluctuation. Automated BP measurement devices are not validated for patients with AF and no consensus exists on how to measure BP in AF manually. Beat-to-beat BP measurement using the volume-clamp method (VCM) could represent a non-invasive method to accurately assess BP, but has not been validated in AF. 31 admitted patients with sustained AF and 10 control patients with sinus rhythm underwent simultaneous intra-arterial and non-invasive BP measurement using a VCM monitor (Nexfin®, BMEYE, Amsterdam, The Netherlands). Patients with compromised peripheral perfusion, high doses of vasopressor drugs or peripheral edema were excluded. Differences in systolic, diastolic and mean BP of 5 (standard deviation; SD 8) mmHg (accuracy and precision) between both methods were considered acceptable. Additionally, the magnitude of beat-to-beat fluctuations in systolic BP of both methods was compared. In AF, the differences between noninvasive and invasive BP were -4 (SD 12), +1 (SD 7) and 0 (SD 8) mmHg for systolic, diastolic and mean BP respectively. Absolute differences in beat-to-beat BP fluctuations were 1.5 (IQR 0.8-3.8) mmHg. Accuracy of VCM in AF was similar to sinus rhythm. In conclusion, in patients with AF, accurate and precise measurement of non-invasive beat-to-beat BP measurement using the VCM is possible, the one exception being the precision of systolic BP. Beat-to-beat variability can be accurately reproduced.

Hyperoxia does not directly affect vascular tone in isolated arteries from mice.

Hospitalized patients often receive oxygen supplementation, which can lead to a supraphysiological oxygen tension (hyperoxia). Hyperoxia can have hemodynamic effects, including an increase in systemic vascular resistance. This increase suggests hyperoxia-induced vasoconstriction, yet reported direct effects of hyperoxia on vessel tone have been inconsistent. Furthermore, hyperoxia-induced changes in vessel diameter have not been studied in mice, currently the most used mammal model of disease. In this study we set out to develop a pressure-myograph model using isolated vessels from mice for investigation of pathways involved in hyperoxic vasoconstriction. Isolated conduit and resistance arteries (femoral artery and gracilis arteriole, respectively) from C57BL/6 mice were exposed to normoxia (PO2 of 80 mmHg) and three levels of hyperoxia (PO2 of 215, 375 and 665 mmHg) in a no-flow pressure myograph setup. Under the different PO2 levels, dose-response agonist induced endothelium-dependent vasodilation (acetylcholine, arachidonic acid), endothelium-independent vasodilation (s-nitroprusside), as well as vasoconstriction (norepinephrine, prostaglandin F2α) were examined. The investigated arteries did not respond to oxygen by a change in vascular tone. In the dose-response studies, maximal responses and EC50 values to any of the aforementioned agonists were not affected by hyperoxia either. We conclude that arteries and arterioles from healthy mice are not intrinsically sensitive to hyperoxic conditions. The present ex-vivo model is therefore not suitable for further research into mechanisms of hyperoxic vasoconstriction.

[Carbapenem-resistant bacteria transferred to the Netherlands: patients colonised during hospitalisation in Romania]. / Carbapenemresistente bacteriën overgebracht naar Nederland.

Three patients were recently transferred to two Intensive Care Units (ICUs) in the Netherlands from two different ICUs in Bucharest, Romania. The patients appeared to be colonised with several, partly identical, carbapenemase-producing bacteria (CPB) after a short hospitalisation in Romania. In this article, we show that it is important to be aware of the possibility that patients are colonised with CPB after a short hospitalisation abroad. This has consequences for infection prevention measurements, but probably also for the discontinuation of selective bowel decontamination in the ICU.

Hyperoxia: At what level of SpO2 is a patient safe? A study in mechanically ventilated ICU patients.

BACKGROUND: Concerns have been expressed regarding a possible association between arterial hyperoxia and adverse outcomes in critically ill patients. Oxygen status is commonly monitored noninvasively by peripheral saturation monitoring (SpO2). However, the risk of hyperoxia above specific SpO2 levels in critically ill patients is unknown. The purpose of this study was to determine a threshold value of SpO2 above which the prevalence of arterial hyperoxia distinctly increases. METHODS: This is a cross-sectional study in adult mechanically ventilated intensive care patients in a tertiary referral center. In 100 patients, we collected 200 arterial blood gases (ABG) and simultaneously registered SpO2 levels, as well as hemodynamic and ventilation parameters and vasoactive medication. Patients under therapeutic hypothermia were excluded. RESULTS: The risk of arterial hyperoxia, defined as PaO2>100mmHg or >125mmHg, was negligible when SpO2 was ≤95% or ≤96%, respectively. The majority (89% and 54%, respectively for PaO2>100mmHg and 125mmHg) of ICU patients with SpO2 of 100% had arterial hyperoxia. The relation between SpO2 and PaO2 was not clearly affected by hemodynamic or other clinical variables (pH, pCO2, body temperature, recent blood transfusion). CONCLUSION: In critically ill patients, the prevalence of arterial hyperoxia increases when SpO2 is >95%. Above this saturation level, supplemental oxygen should be administered with caution in patients potentially susceptible to adverse effects of hyperoxia.

Cardiovascular effects of hyperoxia during and after cardiac surgery.

During and after cardiac surgery with cardiopulmonary bypass, high concentrations of oxygen are routinely administered, with the intention of preventing cellular hypoxia. We systematically reviewed the literature addressing the effects of arterial hyperoxia. Extensive evidence from pre-clinical experiments and clinical studies in other patient groups suggests predominant harm, caused by oxidative stress, vasoconstriction, perfusion heterogeneity and myocardial injury. Whether these alterations are temporary and benign, or actually affect clinical outcome, remains to be demonstrated. In nine clinical cardiac surgical studies in low-risk patients, higher oxygen targets tended to compromise cardiovascular function, but did not affect clinical outcome. No data about potential beneficial effects of hyperoxia, such as reduction of gas micro-emboli or post-cardiac surgery infections, were reported. Current evidence is insufficient to specify optimal oxygen targets. Nevertheless, the safety of supraphysiological oxygen suppletion is unproven. Randomised studies with a variety of oxygen targets and inclusion of high-risk patients are needed to identify optimal oxygen targets during and after cardiac surgery.

Treatment of hyperglycaemia in diabetic ketoacidosis: natura non facit saltus.

In the treatment of severe diabetic ketoacidosis the gradual correction of glucose, electrolyte and fluid derangements is of utmost importance. In this paper the authors provide practical recommendations for these corrections based on novel pathophysiological insights.

An unusual case of abdominal arterial thrombosis in a young woman using desmopressin.

We report an unusual case of severe abdominal arterial thrombosis in a young woman using oral desmopressin. Only a few cases with cerebrovascular accidents and coronary syndromes have been described so far, which could be attributed to intravenous administration of desmopressin. Because extensive diagnostic and laboratory investigations for (un)common coagulation disorders could not identify an alternative explanation associated with arterial thrombosis, we hypothesise that desmopressin in an oral dose of at least 200 ug once daily must have been sufficient to cause this dramatic vascular complication. Supportive of our hypothesis, we found remarkably high levels of factor VIII activity, Von Willebrand factor (vWF) antigen and vWF ristocetin cofactor activity (268%, 740%, 590% respectively). To the best of the authors' knowledge, this is the first report suggesting a relationship between oral desmopressin use and life-threatening abdominal arterial thrombosis.

Sino-nasal bony and cartilaginous destruction associated with cocaine abuse, S. aureus and antineutrophil cytoplasmic antibodies.

Three male patients aged 29, 30 and 34 years and a 36-year-old female are reported with nasal septum perforation and a history of cocaine abuse. Two of the patients also had a perforation of the hard palate. In all four, antineutrophil cytoplasmic antibodies (ANCA) were found. One had a cytoplasmic immunofluorescence-staining pattern (c-ANCA), the other three showed a perinuclear staining pattern (p-ANCA). Furthermore, all patients were found to be nasal carriers of S. aureus. We hypothesise that tissue damage to the nasal and palatal area in patients using cocaine may partly be mediated by the presence of ANCA antibodies. Furthermore, we speculate that S. aureus facilitates the development of these ANCA antibodies.

No effect of B vitamins on ADMA levels in patients at increased cardiovascular risk.

OBJECTIVE: Asymmetric dimethylarginine (ADMA) is a recently identified potent cardiovascular risk factor. ADMA levels are increased in hyperhomocysteinaemia and the metabolism of ADMA is linked with that of homocysteine in several ways. Treatment with B vitamins effectively reduces homocysteine levels, but studies investigating the effect on ADMA levels are scarce and show conflicting results. In this study we evaluated the effect of treatment with B vitamins on ADMA levels in two high cardiovascular risk populations. METHODS: In study I, 110 siblings of patients with clinical atherosclerotic disease and postmethionine hyperhomocysteinaemia were treated with 5 mg of folic acid and 250 mg of pyridoxine or placebo, and were analysed after 1 year. In study II, 41 patients with type 2 diabetes and mild hyperhomocysteinaemia were analysed after 6 months treatment with 5 mg of folic acid or placebo. RESULTS: A correlation between baseline homocysteine and ADMA levels was found, which was partly due to confounding by renal function. Homocysteine levels decreased by 43% in study I and by 28% in study II. In both studies, treatment with B vitamins had no effect at all on ADMA, arginine/ADMA ratio and SDMA levels. This result was confirmed in multiple linear regression analyses with adjustment for baseline values and gender. CONCLUSIONS: Our studies indicate that B vitamins, despite causing a substantial reduction in plasma homocysteine levels, have no beneficial effect on ADMA levels.

Aggressive antihypertensive strategies based on hydrochlorothiazide, candesartan or lisinopril decrease left ventricular mass and improve arterial compliance in patients with type II diabetes mellitus and hypertension.

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on left ventricular mass (LVM) index and arterial stiffness in hypertensive type II diabetic individuals. Seventy hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mm Hg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mm Hg. After titration, patients were treated for 12 months. Mean blood pressures were 157/93, 151/94 and 149/93 mm Hg at baseline in the hydrochlorothiazide (n = 24), candesartan (n = 24) and lisinopril (n = 22) groups, and 135/80, 135/82 and 131/80 mm Hg after titration. About 70% reached target blood pressures, with the median use of three antihypertensive drugs. Left ventricular mass index and all estimates of arterial stiffness showed significant improvement after 12 months: that is, LVM index (-11 g/m(2); -8%); carotid distensibility coefficient (DC; +2.8 x 10(-3) kPa(-1); +27%), compliance coefficient (CC; +0.13 mm2/kPa; +21%) and elastic modulus (-0.19 kPa; -16%); femoral DC (+1.6 x 10(-3) kPa(-1); +50%) and CC (+0.08 mm2/kPa; +26%); brachial DC (+2.1 x 10(-3) kPa(-1); +39%) and CC (+0.03 mm2/kPa; +27%) and total systemic arterial compliance (+0.29 ml/mm Hg; +16%). No differences in outcome variables between treatment groups were observed. Aggressive antihypertensive treatment, although difficult to achieve, resulted in substantial reductions of LVM index and arterial stiffness in relatively uncomplicated hypertensive type II diabetic individuals. Strategies based on renin-angiotensin system inhibitors were not clearly superior to conventional (i.e. diuretic-based) strategies.

Homocysteine levels are not associated with cardiovascular autonomic function in elderly Caucasian subjects without or with type 2 diabetes mellitus: the Hoorn Study.

OBJECTIVE: Homocysteine and cardiovascular autonomic function are both predictors of cardiovascular disease and death, particularly in patients with diabetes. The mechanism by which homocysteine causes disease is unknown. The objective of our study was to determine whether hyperhomocysteinaemia is associated with impaired cardiovascular autonomic function in an age-, sex-, and glucose tolerance-stratified sample of an elderly Caucasian population. METHODS: We studied 609 subjects, 252 with normal glucose metabolism, 173 with impaired glucose metabolism, and 184 with type 2 diabetes. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during (i) spontaneous breathing, (ii) six deep breaths over 1 min, and (iii) an active change in position from lying to standing. From these readings, 10 parameters of autonomic function were assessed (three Ewing tests, six heart rate variability tests and one test of baroreflex sensitivity). These 10 measurements were summarized in a single cardiovascular autonomic dysfunction score (CADS). RESULTS: Comparing values of autonomic function measures in the lowest versus the highest quartile of homocysteine revealed no significant association between homocysteine level and autonomic function in the whole study group, nor in the individual glucose tolerance groups. Multiple adjustment for age, sex, waist-to-hip ratio, serum creatinine, use of antihypertensives and fasting insulin, confirmed this result. We found no evidence of effect modification of glucose tolerance status on the association between homocysteine and autonomic dysfunction (P for interaction for CADS = 0.79). CONCLUSIONS: There is no evidence for an association between homocysteine levels and cardiovascular autonomic function in either diabetic or nondiabetic subjects. Cardiovascular autonomic dysfunction does not help explain why hyperhomocysteinaemia is related to cardiovascular mortality.

Aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril as initial choice in hypertensive type II diabetic individuals: effects on albumin excretion, endothelial function and inflammation in a double-blind, randomized clinical trial.

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals. A total of 70 hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mmHg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mmHg. After titration, patients were treated for 12 months. Mean blood pressures changed from 157/93, 151/94 and 149/93 at baseline to 135/80, 135/82 and 131/80 mmHg after titration in the hydrochlorothiazide (n=24), candesartan (n=24) and lisinopril (n=22) groups. About 70% reached target blood pressures. However, only 45% had blood pressures <130/85 mmHg. Urinary albumin excretion and levels of soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 decreased (GEE regression coefficients, -2.40 mg/24 h (P<0.001), -85 ng/ml (P=0.01) and -50 ng/ml (P=0.02)), but brachial artery endothelium-dependent and -independent vasodilation and levels of von Willebrand factor and C-reactive protein did not change (GEE regression coefficients, 0.21 mm (P=0.07), 0.04 mm (P=0.43), 0.04 IU/ml (P=0.33) and -1.15 mg/l (P=0.64)). No differences in outcome variables between treatment groups were observed. These data show that achievement of target blood pressures below 130/85 mmHg in hypertensive type II diabetes is difficult. Aggressive antihypertensive therapy can improve urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals, regardless of the type of antihypertensive therapy used.

No effect of folic acid on markers of endothelial dysfunction or inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia.

BACKGROUND: Mild hyperhomocysteinaemia is a cardiovascular risk factor in patients with type 2 diabetes mellitus. Homocysteine may exert its detrimental effects through induction of endothelial dysfunction and/or chronic inflammation. In this study, we examined the effects of homocysteine-lowering therapy with folic acid on biochemical markers of endothelial dysfunction and low-grade inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia (> or = 14 micromol/l). METHODS: In a randomised, double-blind, controlled trial, patients were treated with folic acid 5 mg or placebo for six months. At 0 and 6 months, albuminuria, von Willebrand factor, soluble cellular adhesion molecules, C-reactive protein, interleukin-6 and tumour necrosis factor-alpha were determined. RESULTS: Forty-one patients completed the study (folic acid 23, placebo 18). Baseline hyperhomocysteinaemia (median 17 micromol/l, range 14 to 30 micromol/l) was reduced by 29% in the folic-acid-treated group, and remained unchanged in patients receiving placebo. On average, folic acid treatment did not significantly affect any of the endothelial (e.g. von Willebrand factor: difference folic acid minus placebo +1%, confidence interval -3 to +16%) or inflammation (e.g. C-reactive protein: difference folic acid minus placebo +13%, confidence interval -42 to +52%) markers studied. Multiple regression analyses without and with adjustment for baseline differences in cardiovascular disease and ethnicity confirmed these results. An apparent beneficial effect of folic acid on albuminuria in crude analysis was attenuated by multiple adjustment (difference folic acid minus placebo -35%, confidence interval -178 to +32%, p=0.08, adjusted 0.26). CONCLUSION: The data indicate that, in this group of patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia, lowering homocysteine with folic acid for six months does not improve biochemical markers of endothelial dysfunction or low-grade inflammation.

Rapid progression of albumin excretion is an independent predictor of cardiovascular mortality in patients with type 2 diabetes and microalbuminuria.

OBJECTIVE: In patients with type 2 diabetes, microalbuminuria is associated with an increase in predominantly cardiovascular mortality. Considerable interindividual variability in the rate of progression of microalbuminuria exists. The prognostic significance of rate of progression of microalbuminuria with regard to cardiovascular and renal clinical end points is, however, unknown. The purpose of this study was to determine the prognostic significance of rate of progression of microalbuminuria for cardiovascular end points and renal function. RESEARCH DESIGN AND METHODS: In a previous prospective cohort study, progression of microalbuminuria (expressed as mean yearly change in albumin-to-creatinine ratio) was assessed in 58 patients with type 2 diabetes. During a median follow-up of 7 years after progression of microalbuminuria was determined, we registered all-cause mortality and coronary heart disease mortality as primary end points and coronary heart disease (fatal or nonfatal), peripheral vascular disease, ischemic stroke, retinopathy, macroalbuminuria, and change in serum creatinine as secondary end points. RESULTS: Seven subjects died during the study; five of these subjects died of coronary heart disease. Cox's regression analysis identified progression of microalbuminuria as a significant predictor of all-cause mortality (hazard ratio 1.46 per point increase in albumin-to-creatinine ratio per year, P < 0.001), coronary heart disease mortality (hazard ratio 2.32, P = 0.006), and macroalbuminuria (hazard ratio 1.79, P < 0.001). Adjustment for multiple cardiovascular risk factors did not affect these results. Identical analyses for baseline level of microalbuminuria instead of progression rate of microalbuminuria did not show significant hazard ratios. In addition, progression of microalbuminuria significantly predicted an increase in serum creatinine (r = 0.29, P = 0.04). CONCLUSIONS: In patients with type 2 diabetes and microalbuminuria, the rate of progression of albumin excretion seems to be a powerful independent predictor of mortality caused mainly by coronary heart disease.

Trimethoprim-sulphamethoxazole as primary Pneumocystis carinii prophylaxis does not increase serum homocysteine levels in HIV-positive subjects.

Background: We recently observed that a short course of trimethoprim 300 mg b.i.d. in healthy volunteers can cause a substantial increase in fasting plasma homocysteine levels, up to concentrations reportedly associated with atherothrombotic complications. The purpose of this study was to determine whether primary Pneumocystis carinii prophylaxis (PCP) with trimethoprim-sulphamethoxazole (TMP-SMX) adversely affects serum homocysteine levels in HIV-positive patients. Methods: We studied 34 subjects [29 male, 5 female, mean age 36.8+/-7.9 (S.D.) years] with no prior AIDS-defining disease who required primary PCP prophylaxis (CD4+ T-cell count <200/mm(3)). The common dose of TMP-SMX was 80/400 mg (80 mg trimethoprim and 400 mg sulphamethoxazole) once daily. Serum total homocysteine levels were determined in four samples: two collected prior to the start of TMP-SMX and two collected on average 2.6+/-2.2 and 5.3+/-3.5 months into the first year of prophylactic therapy. Results: Mean serum homocysteine was 13.9+/-3.7 &mgr;mol/l pre-treatment and 14.4+/-5.0 &mgr;mol/l during treatment with TMP-SMX, a non-significant increase of 0.5 &mgr;mol/l (95% CI: -0.5 to +1.4, P=0.34). Folate levels were equally unaffected by TMP-SMX (13.1+/-6.5 nmol/l versus 13.3+/-5.3 nmol/l, before and during therapy, respectively). Baseline folate levels did not predict the response of homocysteine to TMP-SMX, and neither did age, gender, or serum creatinine. Conclusion: Long-term therapy with 80/400 mg TMP-SMX does not adversely affect homocysteine levels.