Clinical effectiveness of cefiderocol for the treatment of bloodstream infections due to carbapenem-resistant Acinetobacter baumannii during the COVID-19 era: a single center, observational study.

BACKGROUND: We assessed the clinical effectiveness of cefiderocol (CFDC) in comparison with colistin (COL) for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections (BSI). MATERIALS/METHODS: Retrospective cohort study including adults with CRAB-BSI. Outcomes were mortality, clinical cure and adverse events during therapy. The average treatment effect of CFDC compared to COL was weighted with the inverse-probability treatment weight (IPTW). RESULTS: Overall, 104 patients were included (50 CFDC, 54 COL), median age 66.5 years, median Charlson Comorbidity Index 5, septic shock in 33.6% of patients. Primary BSI accounted for 43.3% of cases, followed by ventilator-associated pneumonia (VAP) (26%), catheter-related BSI (20.2%) and hospital-acquired pneumonia (HAP) (9.6%). Although not significantly, mortality at all time points was lower for CFDC than COL, while clinical cure was higher in CFDC than COL (66% vs. 44.4%, p = 0.027). Adverse events were more frequent in COL than CFDC-group (38.8% vs. 10%, p < 0.0001), primarily attributed to acute kidney injury (AKI) in the COL group. Patients with bacteremic HAP/VAP treated with CFDC had a significant lower 30-d mortality and higher clinical cure than COL (p = 0.008 and p = 0.0008, respectively). Increment of CCI (p = 0.005), ICU (p = 0.025), SARS-CoV2 (p = 0.006) and ECMO (p < 0.0001) were independently associated with 30-d mortality, while receiving CFDC was not associated with survival. CONCLUSIONS: CFDC could represent an effective and safe treatment option for CRAB BSI, especially in patients with bacteremic HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided.

Ultrasound-guided collagen injections in the treatment of supraspinatus tendinopathy: a case series pilot study.

Aim of the present pilot study was to verify, for the first time ever, the effects of collagen injections in patients with chronic supraspinatus tendinopathy. Eighteen patients with chronic supraspinatus tendinopathy were treated with a series of 4 type I porcine collagen ultrasound-guided injections, at weekly intervals. The effects were verified at 2-week, 1-month and 3-month follow-up by means of shoulder scoring systems and sonography. A very strong evidence (p<0.001) of a statistically significant main effect amongst the multiple clinical observation was found. Ultrasound imaging highlighted improvement in the structural integrity of the tendon. Compared to other injection therapies, collagen injections proved to be at least equally effective, faster acting and safer.

Calibration and functional analysis of three genetically encoded Cl(-)/pH sensors.

Monitoring of the intracellular concentrations of Cl(-) and H(+) requires sensitive probes that allow reliable quantitative measurements without perturbation of cell functioning. For these purposes the most promising are genetically encoded fluorescent biosensors, which have become powerful tools for non-invasive intracellular monitoring of ions, molecules, and enzymatic activity. A ratiometric CFP/YFP-based construct with a relatively good sensitivity to Cl(-) has been developed (Markova et al., 2008; Waseem et al., 2010). Recently, a combined Cl(-)/pH sensor (ClopHensor) opened the way for simultaneous ratiometric measurement of these two ions (Arosio et al., 2010). ClopHensor was obtained by fusion of a red-fluorescent protein (DsRed-monomer) to the E(2)GFP variant that contains a specific Cl(-)-binding site. This construct possesses pK a = 6.8 for H(+) and K d in the 40-50 mM range for Cl(-) at physiological pH (~7.3). As in the majority of cell types the intracellular Cl(-) concentration ([Cl(-)] i ) is about 10 mM, the development of sensors with higher sensitivity is highly desirable. Here, we report the intracellular calibration and functional characterization of ClopHensor and its two derivatives: the membrane targeting PalmPalm-ClopHensor and the H148G/V224L mutant with improved Cl(-) affinity, reduced pH dependence, and pK a shifted to more alkaline values. For functional analysis, constructs were expressed in CHO cells and [Cl(-)] i was changed by using pipettes with different Cl(-) concentrations during whole-cell recordings. K d values for Cl(-) measured at 33°C and pH ~7.3 were, respectively, 39, 47, and 21 mM for ClopHensor, PalmPalm-ClopHensor, and the H148G/V224L mutant. PalmPalm-ClopHensor resolved responses to activation of Cl(-)-selective glycine receptor (GlyR) channels better than did ClopHensor. Our observations indicate that these different ClopHensor constructs are promising tools for non-invasive measurement of [Cl(-)] i in various living cells.

Arthroscopic patellar reinsertion of the MPFL in acute patellar dislocations.

PURPOSE: The objective of this study was to evaluate the mid-term results of a new technique for the arthroscopic repair of MPFL after an acute patellar dislocation (APD). MATERIALS: The series included 17 patients (11 men and 6 women) with a first episode of acute patellar dislocation; treated over a period of 6 years. Re-dislocation, subjective symptoms and functional limitations were evaluated at an average follow-up of 2.2 years (1-5.5). The patients were evaluated with the Lysholm and the Kujala scoring systems. RESULTS: At follow-up, no re-dislocation was reported. Only one patient referred an episode of patellar instability, without a distinct dislocation. The postoperative median Lysholm score was 90 (72-100). The median Kujala score was 92 (75-100). Fourteen out of 17 patients were able to return to sports at the same level as before. CONCLUSION: When the MPFL is avulsed from the patella, the proposed technique has the advantage of restoring tension of the ligament through reattachment at the patellar border with two trans-patellar sutures. The full-arthroscopic approach has the advantage of being less invasive and having a shorter recovery time.

Crystallization of the membrane protein hVDAC1 produced in cell-free system.

Structural studies of membrane proteins are in constant evolution with the development of new improvements for their expression, purification, stabilization and crystallization. However, none of these methods still provides a universal approach to solve the structure of membrane proteins. Here we describe the crystallization of the human voltage-dependent anion channel-1 produced by a bacterial cell-free expression system. While VDAC structures have been recently solved, we propose an alternative strategy for producing the recombinant protein, which can be applied to other membrane proteins reluctant to expression, purification and crystallization by classical approaches. Despite a lot of efforts to crystallize a cell-free expressed membrane protein, this study is to our knowledge one of the first reports of a successful crystallization. Focusing on expression in a soluble and functional state, in a detergent environment, is the key to get crystals. Although the diffraction of VDAC crystals is limited, the simplicity and the rapidity to set-up and optimize this technology are drastic advantages in comparison to other methods.

Various protein kinases regulate human sperm acrosome reaction and the associated phosphorylation of Tyr residues and of the Thr-Glu-Tyr motif.

Acrosome reaction (AR) is an exocytotic process of fundamental importance for the spermatozoon to fertilize the oocyte. The mechanisms mediating this process are only partially defined. The aim of the present study was to investigate the role of various kinases and the extracellular signal-regulated kinase (ERK) pathway in the induction of the AR and associated phosphorylation of tyrosine (Tyr) residues and of the threonine-glutamic acid-tyrosine (Thr-Glu-Tyr) motif that occurs in 80 and 105 kDa proteins (p80/p105). Human spermatozoa were capacitated and AR was induced with lysophosphatidylcholine in the presence of inhibitors of various kinases and of the ERK pathway. Phosphorylation of Tyr and of Thr-Glu-Tyr peaked 15 min after the induction of the AR. Both phosphorylations were prevented by inhibitors of protein kinase C, MEK, phosphoinositide 3-kinase and Akt but not by protein kinase A inhibitors. Phosphorylation of Thr-Glu-Tyr, but not Tyr, was decreased by inhibitors of protein tyrosine kinase and Grb2-SH2. All the inhibitors prevented lysophosphatidylcholine-induced AR, indicating the involvement of PKC, PKA, PTK, PI3K, Akt and the ERK pathway. These results show that phosphorylation of Tyr and Thr-Glu-Tyr are associated with the AR and are differently regulated by the various kinases emphasing the complexity of this process.

Effects of diadenosine polyphosphates and seminal fluid vesicles on rabbit sperm cells.

Membrane vesicles were isolated from rabbit seminal plasma. Electron microscopy analyses showed the presence of numerous small, round vesicles with a diameter of about 70 nm. Determination of enzyme activities was carried out by high performance liquid chromatography and showed that the vesicles can degrade the diadenosine polyphosphates (ApnA), Ap3A and Ap4A and ATP and ADP, but not AMP. Studies of the degradation of diadenosine compounds by the vesicles present in seminal fluid showed an increasing production of AMP as the by-product and a time-dependent generation of dephosphorylated products consistent with the presence of ecto-ATP diphosphophosphatase (ecto-apyrase). In the presence of rabbit spermatozoa, AMP did not accumulate because 5'nucleotidase and adenosine deaminase, present at the surface of sperm cells, transformed AMP into adenosine and inosine. The effects of seminal fluid vesicles and diadenosine compounds on the acquisition of fertilizing capacity by rabbit spermatozoa were evaluated by Pisum sativum agglutinin fluorescein isothiocyanate conjugated staining. The results obtained with uncapacitated spermatozoa showed that the capacitating effector BSA could be substituted efficiently by the addition of diadenosine compounds and vesicles previously incubated for 2 h to the capacitative medium. Under these experimental conditions, the spontaneous acrosome reaction rate was not increased. Capacitated rabbit spermatozoa did not undergo acrosome reaction when l-alpha-lysophosphatidylcholine was substituted by diadenosine compounds previously incubated with vesicles. In conclusion, this study has shown that rabbit seminal fluid vesicles can degrade diadenosine compounds to AMP and that the addition of the vesicles and diadenosine compounds to uncapacitated rabbit spermatozoa favours the acquisition of the fertilizing capacity.

Effects of the purified IGF-I complex on the capacitation and acrosome reaction of rabbit spermatozoa.

A protein complex containing IGF-I, purified from rabbit seminal plasma, was used to investigate its effects on the capacitation and acrosome reaction of rabbit spermatozoa. Uncapacitated sperm (Pattern F), capacitated sperm (Pattern B), and acrosome-reacted sperm (Pattern AR) were determined by CTC staining, and the results were validated by PSA-staining. The addition of the IGF-I complex to the capacitative medium directed the spermatozoa to spontaneous acrosome reaction. On the other hand, IGF-I complex, added to capacitated spermatozoa, acted as inducer of the acrosome reaction. Results of IVF experiments showed high rates of fertilization with capacitated spermatozoa, acrosome-reacted by either A23187 or IGF I complex, whereas significantly lower rates were obtained with spermatozoa capacitated in the presence of IGF-I complex.

Stimulation by n6-cyclopentyladenosine of A1 adenosine receptors, coupled to galphai2 protein subunit, has a capacitative effect on human spermatozoa.

The effects of selective A(1) receptor agonist on human spermatozoa were examined to verify physiological responses and to investigate the signal transduction pathway. N6-Cyclopentyladenosine on uncapacitated spermatozoa did not induce spontaneous acrosome reaction after 5 h capacitation, whereas the number of capacitated spermatozoa, assessed by lysophosphatidylcholine-induced acrosome reaction with Pisum sativum agglutinin staining, was significantly increased. N6-Cyclopentyladenosine was also added to capacitated human spermatozoa to find out whether the agonist could induce the acrosome reaction. Results, although statistically significant, could not be considered biologically significant. A1-Mediated capacitation was followed by the increase of tyrosine phosphorylation of a protein subset ranging between M(r) = 200 000 and 30 000. Stimulation of A1 receptor with the selective agonist elicited an agonist-induced inositol phospholipid hydrolysis leading to a transient rise of inositol triphosphate (IP3). This increase was not induced by A(1) receptor antagonist and was blocked by phospholipase C inhibitor. Coimmunoprecipitation experiments showed that the A(1) receptor is coupled to Galphai2 subunit suggesting that the activation of phospholipase C is mediated by betagamma subunits. In conclusion, the A(1) adenosine receptor in human spermatozoa is coupled to Galphai2, signals via IP3, and affects the capacitative status of ejaculated spermatozoa.

[Therapy with nitro derivatives and the development of tolerance: a comparative study with stress ECG and dipyridamole ECG]. / Terapia con nitroderivati e sviluppo di tolleranza: studio comparativo con ECG da sforzo ed ECG-dipiridamolo.

The ECG stress test represents the most commonly-used technique to evaluate the occurrence of nitroglycerin tolerance. It acts by increasing cardiac O2 demand with resulting insufficient blood flow through a stenotic coronary artery and development of cardiac ischemia. However, other tests are also potentially suitable, such as the ECG-dipyridamole test. The aim of the present study was to evaluate the acute response of ECG-dipyridamole and ECG-stress tests to nitroglycerin. In particular, the development of nitroglycerin tolerance during chronic therapy was evaluated with both tests in patients with stable angina. Eleven patients (8 men and 3 women) with CAD proven by a previous coronarography, a known history of stable angina within at least six months and a positive response to both the tests were studied. At the end of a seven-day wash-out period, all patients were positive to initial ECG-stress and ECG-dipyridamole tests; after 3 days a new evaluation was carried out (Effort 0 and Dip 0) and this confirmed the previous results. We performed a randomized trial in two phases: acute and chronic therapy. In the acute phase, all patients underwent ECG-stress and ECG-dipyridamole tests (Effort 1 and Dip 1) in a randomized fashion one day apart, four hours after administration of a 10 mg/24 h nitroglycerin patch. The chronic phase consisted of 25 days of continuous treatment with a nitroglycerin patch. The two tests (Effort 2 and Dip 2) were always repeated after four hours of the morning therapy. Nitroglycerin does not modify the hemodynamic response to dipirydamole in either acute or chronic treatment. Lastly, our data confirm the efficacy of nitroglycerin on stress and dipyridamole tests after acute administration. Nitroglycerin tolerance is confirmed by both tests although with different patterns. ECG stress test showed nitroglycerin tolerance because time to ischemia and max ST deteriorated during chronic therapy. Moreover, the ECG-dipyridamole test showed nitroglycerin tolerance because five patients with a negative acute test (Dip 1) became positive during chronic therapy (Dip 2).

Left ventricular systolic and diastolic function in severe obesity: a radionuclide study.

To verify the impact of sever obesity (defined as body mass index > 31 kg/m2) on left ventricular (LV) function, 32 asymptomatic obese but otherwise healthy subjects (16 men; age 38 +/- 11 years) voluntarily underwent first-pass and equilibrium 99mTc radionuclide angiography at rest and, in 22 of them, during bicycle supine exercise. Data were compared to those obtained from 10 normal volunteers (age 48 +/- 13; p < 0.05, vs. obeses). End-diastolic and stroke volumes did not differ between the two groups, whereas end-systolic volume was significantly higher in obese subjects (67 +/- 20 vs. 49 +/- 20 ml; p < 0.05), and, as a consequence, LV ejection fraction at rest was decreased in obese subjects (59 +/- 7%) compared to normals (65 +/- 6%; p < 0.05). Due to the higher heart rate in obese subjects (81 +/- 13 vs. 69 +/- 10 pbm, respectively; p < 0.05) cardiac output was significantly greater compared to normals (7.1 +/- 0.8 vs. 6.2 +/- 0.2 liters/min, respectively; p < 0.01). During exercise, ejection fraction normally increased in normals (70 +/- 7%; p < 0.001, vs. baseline) but not in obese subjects (60 +/- 9%; p = nonsignificant vs. baseline). In addition, systolic blood pressure/end-systolic volume ratio was significantly decreased in obese subjects (23 +/- 1.3) compared to normals (2.8 +/- 1.6; p < 0.05). Peak filling rate, normalized to end-diastolic counts per second, was significantly lower in obese subjects (2.2 +/- 1.3) compared to normals (2.8 +/- 1.6; P < 0.05). This difference was also true when peak filling rate was computed in stroke counts per second (3.8 +/- 0.8 in obeses vs. 4.4 +/- 0.4 in normals; p < 0.05). Repeat analysis in a subgroup of 10 young obese subjects (age < or = 30 years) confirmed decreased ejection fraction at rest (60 +/- 4%; p < 0.05) and peak filling rate (2.4 +/- 0.4 end-diastolic counts/s; p < 0.05), as well as the lack of ejection fraction increase during exercise (59 +/- 9%). Thus, these data indicate a subclinical impairement of LV systolic and diastolic function at rest and during exercise in asymptomatic severely obese but otherwise healthy subjects.

[ECG-dipyridamole and ECG-exercise test in the assessment of ischemic cardiopathy: effects of the acute administration of nitroglycerin]. / ECG-dipiridamolo ed ECG da sforzo nella valutazione della cardiopatia ischemica: effetti della somministrazione acuta di nitroglicerina.

It is known that intravenous administration of dipyridamole can induce chest pain and ECG signs of ischemia in patients with coronary artery disease. In the present study we evaluated ECG and hemodynamic changes in response to dipyridamole (0.56 mg/kg in 10 min) under basal conditions and 3 hours after administration of nitroglycerin (10 mg/24 h patch) in 14 patients with coronary artery disease. The effects of nitroglycerin were also compared to those induced by the same drug on a bicycle stress test in the same patients. Exercise stress test induced specific ST changes in all patients when performed off-drug. Nitroglycerin administration completely prevented exercise-induced ischemia in 2 patients, and significantly prolonged exercise time in the remaining patients (p < 0.01). This effect was accompanied by a significant increase in heart rate (HR) and rate-pressure product at the threshold of ischemia (HRBP, p < 0.01); furthermore we observed a significant increase in HR at the maximal work load (p < 0.05). In the absence of treatment, dipyridamole infusion induced ST segment changes and/or typical chest pain in 12/14 patients. Moreover we observed a significant increase (p < 0.05) in HR, BP and HRBP during the test with respect to basal conditions. Following nitroglycerin administration, dipyridamole infusion failed to induce ischemia in 4 patients, and the time to ST depression in the remaining 8 patients (459 +/- 69 vs 610 +/- 127 s; p < 0.05) was significantly prolonged.(ABSTRACT TRUNCATED AT 250 WORDS)

[The laparoscopic treatment of common bile duct lithiasis]. / Trattamento laparoscopico della litiasi della via biliare principale.

Nowadays the laparoscopic cholecystectomy has become the main surgical therapy in the treatment of cholecysto-lithiasis. At the beginning the treatment of cholecysto-choledochal lithiasis was the sequential endoscopic-laparoscopic therapy. In fact, the endoscopic sphincterotomy allows transpapillary ablation of Common Bile Duct (CBD) stones, and the laparoscopic cholecystectomy completes the therapy. Recently we have brought the full-laparoscopic of CBD lithiasis. This has become possible on account of an improved intraoperative laparoscopic diagnostics and a better technical experience of the laparoscopic surgeon. Intraoperative examination of CBD requires suitable instruments: cholangiography is still a basic examination and now is easily performed in laparoscopy without a considerable increase of the surgical time; choledochoscopy allows an intraluminal inspection of completes the examination, supplying further detailed information. Afterwards the laparoscopic approach allows the transcystic ablation of stones, using a Dormia probe or through a choledochotomy, but is previously required for the surgeon a high-level operative and technical ability about laparoscopic surgery, in order to perform an excellent preparation of the CBD and precise stitches, making knots with extra corporeal or intra-abdominal technique. Clinical results in patients until now fully-laparoscopic treated are quite good and encourage the CBD lithiasis therapy by a mini-invasive approach, which has the advantage that's not requested the sacrifice of a sound papilla.

Clinical evaluation of a new rapid assay for serum lipase determination.

We evaluated a new continuous colorimetric method for serum lipase determination based on the use of a 1,2-diglyceride as substrate and a specific 2-monoglyceride lipase. This test was compared with a turbidimetric assay and also with serum alpha-amylase and pancreatic isoamylase determinations. We studied 32 patients with acute pancreatitis, 27 with chronic pancreatitis in acute painful relapse, 19 with pancreatic cancer, 44 with other digestive diseases, 53 with end-stage renal disease, and 102 healthy controls. The results of the new test were closely correlated with those of the turbidimetric method (r = 0.96). Sensitivity of the new method was elevated (100%): it was the same as that of the turbidimetric method, but slightly higher than that of alpha-amylase and pancreatic isoamylase determinations (93.7 and 96.9%, respectively). Specificity was 95.5%, i.e. higher than that observed using the other tests (86.4, 84.1 and 88.6% for lipase turbidimetric assay, amylase, and pancreatic isoamylase determinations, respectively). The results demonstrate that this new lipase assay is a sensitive, specific test for the diagnosis of acute pancreatitis.

[The usefulness of bioimpedance in patient monitoring in an intensive-therapy heart-surgery unit: a comparison with thermodilution]. / Utilità della bioimpedenza nel monitoraggio del paziente in unità di terapia intensiva di cardiochirurgia: comparazione con la termodiluizione.

Haemodynamic monitoring of intensive care unit (ICU) patients can be carried out by thermodilution system. This method is invasive, does not give a continuous monitoring and complications can occur. Thoracic electrical bioimpedance (TB), a non invasive, fast, easily repeatable method, is able to measure some important haemodynamic parameters: end diastolic volume (EDV), stroke volume, cardiac output (CO), ejection fraction (EF), some contractility indexes, systemic vascular resistances (SVR) and cardiac work. The aim of the present study is to compare CO and SVR obtained by thermodilution with the same indexes obtained by TB. Therefore, 20 ICU patients (12 males and 8 females, mean age 54 +/- 11 years) were studied. Out of them, 16 had been submitted to cardiac surgery in the previous 7 days and 4 were waiting for cardiac surgery. The patients were divided in 2 groups: Group A (N 4) included patients with valvular malfunction and/or cardiac arrhythmias and Group B (N 16) included patients with normal valvular function and sinus rhythm. CO obtained by TB was well related with the one obtained by invasive (INV; r = 0.878; p < 0.001). The mean value of difference of the 2 methods was 12.29 +/- 11.83 for the whole group of 20 patients but it was 26.07 +/- 14.16 in the Group A and 8.84 +/- 8.09 in the Group B confirming the less reliability of the method in patients with abnormal valvular function or in the presence of cardiac arrhythmias. As a consequence, SVR obtained by TB and INV resulted well related (r = 0.752; p < 0.001). The mean value of differences was 11.14 +/- 9.01 in the group of 20 patients and particularly 19.55 +/- 10.87 in the Group A and 9.04 +/- 7.07 in the Group B. In a subgroup of 9 patients, CO was measured at successive times (0, 30, 60, 90 min) by both TB and INV; when comparing the 2 CO values a significant correlation was observed. In conclusion, TB represents a valid method in haemodynamic monitoring of the ICU patients.

Iron protein succinylate in the treatment of iron deficiency: controlled, double-blind, multicenter clinical trial on over 1,000 patients.

A prospective, controlled, double-blind, double-dummy, multicenter clinical trial was made to assess the efficacy and tolerability of iron-protein-succinylate (ITF 282) in comparison with a well known iron preparation in the treatment of iron deficiency or iron deficient anemia. One thousand and ninety-five patients affected with iron deficiency or overt iron deficient anemia were randomized to receive either two ITF 282 tablets/day (60 mg iron each) or a commercially available ferrous sulphate controlled release tablet (one tablet containing 105 mg iron/day). Five hundred and forty-nine patients received ITF 282; 546 patients were treated with ferrous sulphate. Both treatments lasted 60 days. The treatment outcome was checked by evaluating special hematology, symptomatology, safety hematology and hematochemistry. After two months of treatment, the normalization of the main hematologic parameters in both groups was detected. Although in the first month the reference treatment appears to provide somewhat faster results, at the end of the observation, the values of hematocrit, hemoglobin and ferritin were greater in the ITF 282 group, indicating a more progressive and steady therapeutic effect. The overall clinical rating was significantly in favor of ITF 282, with 78.9% of favorable results vs 67.6%. By dividing the patient population according to pathological conditions (iron deficiency or overt anemia), or according to the etiopathogenesis of the iron deficiency (increased requirement, or increased loss in adults and in the elderly), separate analyses on the treatment outcome were made (and have been included). The general tolerability, although favorable with both treatments, was significantly more favorable with ITF 282. With this medication, 63 patients (11.5%) complained of 69 adverse reactions (25 heartburn, 19 constipation, 25 abdominal pain) vs 141 events reported by 127 patients (26.3%) with the reference medication (33 heartburn, 31 epigastric pain, 23 constipation, 32 abdominal pain, 8 skin rash, 14 nausea). These observations confirm that, although the most modern preparations of ferrous sulphate exhibit a relatively low frequency of adverse events of limited clinical concern, it is nevertheless possible to decrease both the prevalence and the duration of such events without prejudice for the clinical efficacy, with the use of more "physiological" preparations in which the iron is reversibly bound to a protein carrier, thus effectively removing one of the main obstacles to the correct compliance with treatments that must be administered for prolonged periods of time.

Double-blind, double-dummy, randomized, multi-centre clinical assessment of the efficacy, tolerability and dose-effect relationship of sulodexide in chronic venous insufficiency.

A multi-centre study was carried out in 476 patients with chronic venous insufficiency to compare the efficacy, tolerability and dose-effect relationship of sulodexide given orally as either capsules or as a new, enteric-coated tablet formulation. Three comparable groups of patients each with chronic venous insufficiency of thrombotic or varicose aetiology received during 60 consecutive days either sulodexide 250 LRU (= 25 mg) capsules twice daily, 50 mg sulodexide enteric-coated tablets twice daily or 100 mg sulodexide enteric-coated tablets once daily, according to a double-blind, double-dummy, randomized design. Doppler and echoduplex examinations, supine and standing peripheral venous pressure, specific symptoms and signs, peripheral haemodynamics and safety haematology and haematochemistry were monitored monthly. The results showed that peripheral venous pressure improved to a clinically relevant and statistically significant extent in all groups and symptoms and signs were rapidly and significantly relieved. These effects were dose-related, as in both cases the recovery was faster and greater with the 100 mg per day dose however administered. Both the thrombotic and varicose aetiologic sub-groups benefited from treatment to approximately the same extent. Mild to moderate gastro-intestinal adverse experiences occurred in 48 patients evenly split between groups but spontaneously disappeared within 72 hours, none leading to treatment withdrawal. No clinically relevant modifications of peripheral haemodynamics or of safety haematology and haematochemistry was observed. The haemocoagulation parameters failed to exhibit appreciable variations. While the known clinical usefulness of sulodexide 250 LRU (= 25 mg) capsules twice daily was confirmed in this trial, the enteric-coated tablets, 50 mg twice daily or 100 mg once daily, were shown to have greater efficacy and similar tolerability to the standard formulation and dose.