Role of nitric oxide in the prevention of severe adverse events associated with blood products.

The reduction in vitro of nitric oxide binding to the globin portion of hemoglobin (SNOHb) in fresh and liquid preserved red blood cells has been reported to be responsible for the severe adverse events (SAEs) associated with red blood cell transfusion. No in vivo data were reported that the reduction in SNOHb in red blood cells following transfusion was irreversible. In addition, no clinical data were reported that the reduction in SNOHb in red blood cells produced severe adverse events (SAEs) in recipients.

Antiproliferative activity against human tumor cell lines and toxicity test on Mediterranean dietary plants.

Sixteen edible plants from Southern Italy were evaluated for their in vitro antiproliferative properties, using the sulforodamine B (SRB) assay, on four human cancer cell lines: breast cancer MCF-7, prostate cancer LNCaP, amelanotic melanoma C32 and renal adenocarcinoma ACHN. After 48 h of incubation the most antiproliferative plant extract was Cynara cardunculus ssp. cardunculus on C32 and ACHN cell lines with IC(50) of 21 and 18 microg/ml, respectively. Mentha aquatica showed a selective antiproliferative activity on breast cancer while significant activity was exerted by Cichorium intybus on melanoma. These species contained the highest amount of phenolics. The acute toxicity of the hydroalcohol extracts from all the plants were evaluated by using the Microtox acute toxicity test. This bacterial test measures the decrease in light emission from the marine luminescent Vibrio fischeri bacteria when exposed to organic extracts. This inhibition test was revealed to be highly sensitive, cost effective and easy to operate, requiring just 15 min to predict the sample toxicity. All the extracts analyzed resulted to give values very less than a limit of 20% value, demonstrating so an irrelevant toxicity for the human health. In contrast, Echium vulgare and Malva sylvestris showed bioluminescence inhibition values of 19.42% and 17.32%, respectively, just under the established limit.

Two cases of asbestosis and one case of rounded atelectasis due to non-occupational asbestos exposure.

Asbestos is a well-known cause of several neoplastic (malignant mesothelioma, lung cancer) and non-neoplastic (asbestosis, pleuropathies) occupational diseases. Lower-level exposure in the general environment may induce pleural plaques and thickenings, and is associated with an increased mesothelioma risk. We present two patients (a 68-year-old man and a 72-year-old woman) who developed asbestosis (in association with pleural plaques and calcifications), and a 78-year-old man who developed rounded atelectasis (with pleural plaques and benign effusion), after living for several decades in the proximity of large Italian asbestos-cement plant. None of them had been exposed to asbestos occupationally. Besides living in a contaminated area, the woman used to clean the work clothes of her brother, who was employed in the local asbestos factory. The three cases indicate that non-neoplastic, long-latency asbestos-related diseases which are usually observed as a consequence of occupational exposures, may rarely develop in subjects living in contaminated geographical sites and buildings. These unusual environmental diseases raise the diagnostic problem of differentiating them from other, more common respiratory illnesses, and impose the duties of patient notification, assessment and follow-up, to assess the possibility of progression of disease and increased neoplastic risk.

[Rhabdomyolysis in a worker exposed to paraffinic mineral oils. Unusual association with bronchiolitis obliterans and organizing pneumonia (BOOP)]. / Rabdomiolisi in operaio esposto ad olii minerali paraffinici. Insolita associazione con bronchiolite obliterante e polmonite organizzativa (BOOP).

We describe a 29-year-old worker; exposed to metal dust, sawdust and paraffinic mineral oils in a factory producing accessories for leather articles and clothing, who came to observation with fever (39 degrees C), chest pain and marked increase of muscular enzymes. Chest computed tomography showed two areas of lung consolidation, that subsequently appeared enlarged with central escavation. Lung biopsy lead to the diagnosis of BOOP. The case has been reported to the judicial and workers' compensation authorities as probable occupational toxic myopathy. Indeed, exposure to paraffinic mineral oils is a known, though unusual, cause of rhabdomyolysis. The association with BOOP has never been previously described.

Photostabilization of 1,4-dihydropyridine antihypertensives by incorporation into beta-cyclodextrin and liposomes.

Inclusion compounds of eleven dihydropyridine drugs were formed and investigated for protection against photo-induced drug degradation. Formulations of cyclodextrins and liposomes were prepared and their photoprotective ability for the encapsulated drug was monitored. Drug photodegradation was spectrophotometrically followed during exposure of the formulations to light of a Xenon lamp. ICH guidelines for photostability testing were applied. A comparison with common pharmaceutical formulations revealed optimal protection for both formulations. The use of the liposome and cyclodextrin inclusion complexes resulted in a mean drug recovery of 77 and more then 90% respectively, after a light exposure until to 30 minutes with an intensity of 21 kJ x min(-1) m(-2). Lercanidipine and Manidipine only did not show a satisfactory increase of photostabilization in the studied supramolecular complexes, due to their low inclusion in both the systems.

Accelerated photostability study of tretinoin and isotretinoin in liposome formulations.

The photodegradation of retinoic acids, tretinoin and isotretinoin, in ethanol and liposomes was studied. The light irradiation was performed according to the conditions suggested by the ICH Guideline for photostability testing by using a Xenon lamp within a wavelength range of 300-800 nm. The photodegradation process was monitored by UV spectrophotometry. In ethanol solution, tretinoin and isotretinoin undergo complete isomerization just within a few seconds of light exposure to give 13-cis and 9-cis isomers, respectively. The 13-cis isomer from tretinoin undergoes in turn a slow isomerization to the same 9-cis isomer. Both retinoic acids incorporated in liposome complexes showed an increased stability in comparison to the ethanol solutions. In particular for tretinoin, a residual concentration of 60% was still present after a light irradiance of 3470 kJ/m(2), by means of a 250 W/m(2) light power for 240 min, versus a residual value of just 8% measured at the same time in ethanol solution. Moreover, the isomerization rate in liposomes resulted reduced for isotretinoin and practically irrelevant for tretinoin. The degradation rate was found to be dependent on the drug concentration. The better stability of the tretinoin in liposome complex was supposed to be related to its higher incorporation value due to the linear structure of the molecule.

Effect of skin temperature on platelet function in patients undergoing extracorporeal bypass.

Thirty-seven patients undergoing cardiopulmonary bypass operations were studied to assess the effect of skin temperature on platelet function. Differences in skin temperature between the two arms were created during bypass, at the completion of bypass, and at 2 and 24 hours after the completion of bypass. In each of 37 patients the temperature of one arm was increased with a water-filled blanket set at 40 degrees C. In 11 of these patients the other arm was allowed to equilibrate with the environment, and in the other 26 patients the arm was cooled with ice. Except for the differences in local skin temperature between the two arms, all factors known to affect the patient's bleeding time were similar. Measurements were made of bleeding times and the levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha in shed blood obtained at the template bleeding time site. In the 33 patients not treated with aspirin, local hypothermia produced an increased bleeding time and a significant reduction in the thromboxane B2 level at the bleeding time site, but no reduction in 6-keto-prostaglandin F1 alpha level. Local rewarming produced a significant increase in the shed blood thromboxane B2 level. In the four patients treated with aspirin, local hypothermia produced no differences in bleeding times or shed blood levels of thromboxane B2 or 6-keto-prostaglandin F1 alpha. These data show the benefits of rewarming patients with hypothermia who have nonsurgical blood loss to restore to normal both core and peripheral temperatures before resorting to the transfusion of homologous blood products.

Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgical blood loss.

The hemostatic dysfunction induced by cardiopulmonary bypass is due, in part, to a platelet dysfunction evidenced by a postoperative extension of the bleeding time; it leads to increased postoperative blood loss and morbidity. This study, which was conducted in 85 patients undergoing cardiopulmonary bypass, was designed to characterize the hematologic changes during and after cardiopulmonary bypass and to elucidate the relationships between these changes, the extension of the bleeding time, and the magnitude of the postoperative nonsurgical blood loss. Variables were measured before, during, and 2, 24, 48, and 72 hours after cardiopulmonary bypass. Univariate and multivariate analyses were performed with either the 2-hour postbypass bleeding time or the 4-hour postbypass blood loss as the dependent variables. The reversal of the extension of the bleeding time in the postoperative period was accompanied by a significant increase in the mean platelet volume and by a significant increase in the level of thromboxane B2 measured in the blood shed from the site of the bleeding time determination. The postoperative bleeding time correlated with the postoperative blood loss, and both parameters were dependent on the duration of cardiopulmonary bypass. In addition, the postoperative bleeding time correlated with the skin temperature and the plasma level of D-dimer, while the postoperative blood loss also correlated with temperature and the plasma levels of C3. These data establish a direct relationship between the postoperative bleeding time, the postoperative blood loss, and temperature. They indicate that the reversal of the postoperative extension of the bleeding time is due in part to rewarming and to the release of larger platelets into the circulation, and they suggest that hyperfibrinolysis and complement activation may play an important role in the cardiopulmonary bypass-induced platelet dysfunction.

Safety and therapeutic effectiveness of reinfused shed blood after open heart surgery.

This prospective study was designed to determine whether use of nonwashed shed mediastinal blood exacerbated platelet and related hematologic dysfunctions after cardiopulmonary bypass, compared with the alternative use of autologous and homologous standard liquid preserved blood for volume support. Thirty-two patients undergoing cardiopulmonary bypass for open heart operations were randomized to receive either nonwashed shed mediastinal blood (group 1; n = 16) or liquid preserved packed red blood cells (group 2; n = 16) for transfusion therapy in the management of postoperative bleeding. Patient blood samples and bleeding times were obtained preoperatively, after cardiopulmonary bypass but before transfusions, 2 and 24 hours after transfusion, and on postoperative days 2, 3, and 7. Group 1 patients received an average of 710 +/- 90 mL (range, 300 to 1,700 mL) of nonwashed shed mediastinal blood containing significantly greater (p < 0.0001) amounts of fibrin degradation products and D-dimer protein. Of the hematologic, microaggregate, and plasma protein measurements performed, only the protein C level was significantly greater in group 1 (p < 0.05) after transfusion. Patient bleeding times were not significantly different between the groups at any of the time points, and the total postoperative blood loss was not different between the groups. There was a trend toward less need for homologous transfusion in group 1 (p < 0.1). This study documents the safety and ease of using nonwashed shed mediastinal blood as a primary blood volume support after an open heart operation.

Survival, function, and hemolysis of shed red blood cells processed as nonwashed blood and washed red blood cells.

BACKGROUND: Shed nonwashed blood and shed washed red blood cells (RBC) are being used as alternatives to allogeneic liquid-preserved RBC for patients during thoracic and cardiovascular surgical procedures. METHODS: Mongrel dogs were bled a volume of blood into the abdominal cavity and the shed blood was reinfused as nonwashed blood or washed RBC. The 51Cr RBC volumes were measured before, immediately after, and 24 hours after the exchange transfusion to assess the recovery of the shed RBC and the 24-hour posttransfusion survival. Compatible dogs were given allogeneic transfusions of 51Cr-labeled nonwashed blood and washed RBC, and 24-hour posttransfusion survival and half-life were measured. RESULTS: Immediately after the 100% exchange transfusion, the recovery value was 62% for the nonwashed shed blood and 82% for the washed RBC. Both the nonwashed blood and the washed RBC had 24-hour posttransfusion survival values of 90% and normal oxygen transport function after the exchange transfusion. Compatible allogeneic 51Cr-labeled nonwashed blood and washed RBC had normal 24-hour posttranfusion survival and 51Cr half-life values. CONCLUSIONS: The survival, function, and hemolysis of shed nonwashed blood and shed washed RBC were similar to fresh blood in the dog that underwent a 100% exchange transfusion.

Progesterone administration by nasal spray.

The bioavailability and the clinical usefulness of the P administered by nasal spray were investigated. Ten healthy menopausal women received an IN spray administration (4 doses of an oleic P solution 20 mg/mL, corresponding to nearly 11.2 mg of P) and the circulating P levels were calculated. Sixty minutes after administration, the maximum concentration (CMax, 3.75 +/- 0.214 ng/mL) was reached. High P levels (greater than 2 ng/mL) lasted until 360 minutes, and the AUC 0 to 720 was 1,481.6 +/- 343 ng.h/mL. Progesterone administration by spray formulation has proven to be effective in reaching therapeutic levels and to be acceptable to patients and, probably, clinically safe.

PIP: The bioavailability of progesterone administered by a nasal dose was investigated in 10 healthy menopausal women (average age. 56.4 years). Each woman received 2 spray doses per nostril, for a total progesterone dosage of 11.2 mg. Physiological circulating progesterone levels (greater than 2 ng/mL) were achieved within 2 minutes after intranasal spray administration, lasted an average of 6 hours, and returned to baseline values after 12 hours. The highest mean circulating level of progesterone was achieved at 60 minutes (3.750 + or - 0.214 ng/mL) and a secondary peak was recorded at 240 minutes (2.700 + or - 0.244 ng/mL). Variability in circulating levels of progesterone after spray administration did not exceed 34% in any patient until the final measurement point (720 minutes). There was no evidence of nasal irritation, but all subjects complained of the unpleasant taste of the spray. The effectiveness of intranasally administered progesterone appears due to progesterone's high solubility in the oleic carrier and the wide surface of the nasal mucosa covered by the nebulized solution. Considering the liver first-pass metabolic effect when progesterone is administered orally and the insufficient bioavailability of progesterone produced by rectal or vaginal administration, further investigation of the nasal spray approach is urged.

The effect of disinfection on viability and function of baboon red blood cells.

Methods that have been optimized for disinfection of red blood cells before transfusion must be evaluated for their effect on red blood cell viability and function in vitro and in vivo. This study evaluates (1) in vitro effects of Panavirocide treatment and benzoporphyrin (BPD) photosensitization on baboon and human red blood cell parameters and (2) in vivo effects of five disinfectant treatments on 24 h posttransfusion survival and cell lifetimes for baboon red blood cells. The in vitro studies showed that both disinfection methods resulted in a significant reduction in red blood cell potassium, suggesting that intracellular potassium is a sensitive measure of red cell injury during disinfection. The in vivo studies demonstrated significant reductions in the 24 h posttransfusion survival of baboon red blood cells and reductions in cell lifespan treated with a Panavirocide solution, BPD photosensitization and 15 mM nonactivated sodium chlorite. No effects were seen with 250 ppm formaldehyde, aluminum phthalocyanine photosensitization or activated sodium chlorite. These in vivo data showing effects of disinfection treatments support the use of baboons in studying disinfection procedures of autologous red blood cells before attempting studies in humans.

Nasally-administered progesterone: comparison of ointment and spray formulations.

The aim of the study was to compare the bioavailability and clinical usefulness of progesterone (P) administered nasally in spray or ointment form. Twenty healthy post-menopausal women were randomly allocated to treatment by either intranasal spray (4 doses of an oil-based P solution at a concentration of 2 mg/0.1 ml, corresponding to a total dose of approximately 11 mg of P) or an ointment (quantity 0.1 ml, P concentration 20 mg/0.1 ml). Circulating P levels were calculated at various time intervals following administration. The spray formulation yielded a mean maximum concentration (CMax) of 3.75 ng/ml after 60 min (TMax) and the area under the curve (AUC) 0-720 min was 1481.6 +/- 343 ng.h/ml. The ointment yielded a mean CMax of 1.19 ng/ml at TMax = 30 min, the AUC 0-720 value being 404.35 +/- 148 ng.h/ml. The study findings confirmed that the intranasal route is a potentially useful alternative for the administration of natural sex steroid hormones, making it possible to avoid first-pass liver metabolism. P administered by spray showed greater bioavailability than it did when administered in ointment form, while both formulations seemed to be acceptable to patients and were probably clinically safe.

Design and monitoring of photostability systems for amlodipine dosage forms.

Photostability of amlodipine (AML) has been monitored in several pharmaceutical inclusion systems characterized by plurimolecular aggregation of the drug and excipients with high molecular weight. Several formulations including cyclodextrins, liposomes and microspheres have been prepared and characterized. The photodegradation process has been monitored according to the conditions suggested by the ICH Guideline for photostability testing, by using a light cabinet equipped with a Xenon lamp and monitored by spectrophotometry. The formulations herein tested have been found to be able to considerably increase drug stability, when compared with usual pharmaceutical forms. The residual concentration detected in the inclusion complexes with cyclodextrins and liposomes was 90 and 77%, respectively, while a very good value of 97% was found for microspheres, after a radiant exposure of 11,340 kJm(-2).

Determination of p-aminosalicylic acid and m-aminophenol by derivative UV-spectrophotometry.

A direct method for the simultaneous determination of p-aminosalicylic acid (PAS) and its major decomposition product, m-aminophenol (MAP), is described. The analysis is based on the use of derivative UV-spectrophotometry and is a rapid procedure which gives accurate and precise results. A simple purity test which utilizes the third derivative spectrum is also reported and compared with the USP XX spectrophotometric method for the estimation of MAP in PAS formulations.

Propofol assay in biological fluids in pregnant women.

A rapid, accurate and sensitive UV derivative method was described for measuring the Propofol concentration in some biological fluids. Furthermore two alternative procedures, a gaschromatographic and a colorimetric, were also defined, and the results of the three methods, when applied on blood samples spiked with known amounts of analyte, were compared. The samples were preliminary purified by a solid phase extraction on octadecyl C18 cartridge. The UV derivative method was applied to a pharmacokinetic study on pregnant women undergoing cesarean sections. After an induction dose administration of 2.5 mg kg-1, the maternal and umbilical vein blood were found to have comparable concentrations of propofol, with a mean half like of about 3.5 min; on the contrary no detectable levels of the drug were found in amniotic fluid. The drug recoveries > 98% and the response was linear over the range 0.05-40 micrograms ml-1.

[Use of citicoline in high dosages in acute cerebrovascular disease]. / Uso della citicolina ad alti dosaggi nelle affezioni acute cerebro-vascolari.

The use of large doses (1 g) of citicoline was experimented in 30 patients with acute cerebrovascular disturbances. The treatment proved effective in resolving both mental disturbances and the focal condition.

A rapid evaluation of tetracycline and its dehydration products by UV derivative spectrophotometry.

This paper described a rapid ultraviolet spectrophotometric assay for simultaneous determination of tetracyclines (TC + ETC) and their anhydroderivatives (ATC + EATC), by using third- or fourth-derivative spectra recorded on samples in ethanol or dioxane. The analytical procedures are based on linear relationships between specific peak-trough values and the relative concentrations of tetracycline and of ATC-EATC, in mixtures containing TC, ATC and EATC. The toxic EATC can be estimated about half of the anhydrotetracyclines concentration values. The determination limit of anhydroderivatives is 0.05%. A simple purity test of the antibiotic is also reported. Accuracy, precision and linearity are discussed. The method is particularly applicable to routine analysis of products containing TC, in bulk and in some pharmaceutical formulations.

[Reliability of the Karasek scale in the assessment of perceived occupational stress and gender-related differences in scores. The SEMM study]. / Affidabilità della scala di Karasek per la valutazione dello stress lavorativo percepito e differenze dei punteggi tra sessi. Lo studio SEMM.

In recent years more attention has been paid to the relationship between work organization and job stress and chronic-degenerative diseases. Aims of this report are the assessment of the reliability and internal consistency of the Karasek's Job Content Questionnaire-JCQ and to assess age-specific distributions of core JCQ scores between the gender groups. The study has been carried out in a large group of employees (n. 7871 subjects, 5270 women and 2601 men) of the Municipality of Milano in the years between 1992 and 1996. Decision Latitude (DL), Psychological Job Demand (PJD) and Social Support at Work (SSW) scores were calculated. Reliability of the JCQ was satisfactory, with Cronback's alpha suitable values for DL and SSW and acceptable for PJD. From the distribution of gender- and age-specific mean scores, women show reduced probabilities of developing a favorable career and of perceiving satisfactorily the support from colleagues and supervisors than men when they get older. This results suggest that the Karasek's JCQ is an effective toll to describe perceived job stress conditions in this Italian work setting.