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Arsenic is found in groundwater above regulatory limits in many countries and its origin is often from natural sources, making the definition of Natural Background Levels (NBLs) crucial. NBL is commonly assessed based on either dedicated small-scale monitoring campaigns or large-scale national/regional groundwater monitoring networks that may not grab local-scale heterogeneities. An alternative method is represented by site-specific monitoring networks in contaminated/polluted sites under remediation. As a main drawback, groundwater quality at these sites is affected by human activities. This paper explores the potential for groundwater data from an assemblage of site-specific datasets of contaminated/polluted sites to define NBLs of arsenic (As) at the meso-scale (order of 1000 km2). Common procedures for the assessment of human influence cannot be applied to this type of dataset due to limited data homogeneity. Thus, an “unorthodox” method is applied involving the definition of a consistent working dataset followed by a statistical identification and critical analysis of the outliers. The study was conducted in a highly anthropized area (Ferrara, N Italy), where As concentrations often exceed national threshold limits in a shallow aquifer. The results show that site-specific datasets, if properly pre-treated, are an effective alternative for the derivation of NBLs when regional monitoring networks fail to catch local-scale variability.

Groundwater quality in the Ferrara region (eastern Po Plain, northern Italy) is severely impacted by different types of contamination, two of which are of main human health concern: 1) Arsenic contamination from natural sources, in concentrations between 0.05 and 600 μg/L, is widespread in the shallowest local aquifer; 2) Vinyl Chloride contamination, in concentrations up to 18 mg/L, occurs in the same aquifer from degradation of higher chlorinated compounds of industrial origin. Although the two contaminants are of different nature and likely have different origins, in both cases contaminant occurrence in groundwater is strongly related to shallow peat-rich, swamp deposits. In the case of Arsenic, data from more than 40 sites were treated statistically to verify the natural origin of the compound, investigate its spatial distribution and hypothesize the mechanism of mobilization into groundwater. Good correlations between Arsenic, Iron and Manganese concentrations and the Redox potential suggest that organic-rich sediments allowed a reductive dissolution mobilization that considers Manganese and Iron oxides as Arsenic carriers (sources), and degraded organic matter as the redox driver of the release. Also, the organic matter could be a direct source of Arsenic in addition to its role of redox driver, as suggested by the strong spatial correlation between high Arsenic concentration in sediments and occurrence of the organic-rich deposits. Concerning Vinyl Chloride, previous studies in the same region based on hydrochemical and isotopic evidences pointed out the role of peat-rich deposits as “reactors” for reductive dechlorination of higher chlorinated compounds (mainly PCE and TCE), spilled or improperly stored in several sites of the region until few decades ago. In this study, we analyzed the evolution of contaminant composition over time in 12 sites contaminated by chlorinated ethenes and ethanes. Increase in VC concentration over time and decrease in higher chlorinated contaminants was observed in most sites, thus supporting the effectiveness of the peat-driven reductive dechlorination of parent compounds that led to the accumulation of Vinyl Chloride. At the regional scale, the highest concentrations of Arsenic and Vinyl Chloride showed good spatial correlation with the occurrence of shallow swamp deposits, thus supporting the key-role of organic-rich sediments in the deterioration of groundwater quality.

Peroxisome proliferator-activated receptor (PPAR)? is a potential pharmacological target for disease-modification in Parkinson's disease (PD), mainly acting by modulating the neuroinflammatory response. However, currently available agonists thiazolidinediones (TZDs) present limitations due to safety concerns. We evaluated a novel thiobarbituric-like compound MDG548, which acts as a functional PPAR? agonist displaying higher and selective binding affinity as compared to TZDs. Neuroprotection by MDG548 was tested in vitro and in a mouse MPTP model of PD, and neuroinflammation was investigated as a putative underlying mechanism. Viability assay on rat cortical neurons showed lack of cytotoxic effect in the dose-range of 100nM-10?M, which was therefore used for testing in vitro protection against H2O2 and MPP+ neurotoxicity. MDG548 dose-dependently increased cell viability of rat cortical neurons co-treated with H2O2 or pre-exposed to MDG548 prior to H2O2. Moreover, MDG548 induced neuroprotection in MPP+-treated PC12 cells. NF-kB activation was investigated to assess anti-inflammatory activity. MDG548 dose-dependently decreased NF-kB activation induced by LPS (100ng/100ml) in HEK-Blue-hTLR4 cells. Given the supposed cancer risk of other PPAR? agonists, Ames test for genotoxicity was performed in Salmonella typhimurium TA100 and TA98 strains, showing that MDG548 was not genotoxic. In vivo, BL/6J mice were treated with MPTP (20mg/kg i.p. once/day for 4days) in association with saline or MDG548 (2, 5, 10mg/kg i.p.). Stereological counting showed that MDG548 prevented the MPTP-induced reduction in TH-positive cells in the substantia nigra compacta (SNc) at all doses tested. Moreover, MDG548 reduced reactive microglia and iNOS induction in the SNc. MDG548, being a non-TZD compound with high PPAR? affinity, void of genotoxicity, and with in vitro as well as in vivo neuroprotective properties, provides a promising alternative in the search for safer PPAR? agonists to be tested as potential disease-modifying drugs in PD.

Journal of Applied Botany and Food Quality; 87; 108-116, Six Amazonian petitgrain samples from C. nobilis Lour., C. auran-tium L., C. limon L. and mixture of Citrus spp. (Rutaceae), named CN, CA, CL1, CL2, C1 and C2, were chemically characterized by GC-MS and 13C NMR and evaluated for antioxidant acitivity (DPPH and b-carotene bleaching tests), for antimicrobial properties (disk diffusion method) and for antifungal capacity (agar vapour assay). CN, C1, C2 samples evidenced the most interesting results: CN (g-terpinene/linalool chemotype: 14.3 %/41.6 %, with a considerable amount of thymol: 9.0 %), and C1 (linalool, 18.3 %; sabinene, 11.6 %; thymol, 5.5 %), showed relevant antioxidant activity with both DPPH (IC50 = 3.52 and 5.48 mg/ml, respectively) and b-carotene (IC50 = 0.387 and 0.491 mg/ml, respectively). Antibacterial properties of CN and C1 against P. mirabilis (MIC = 0.61 mg/ml for both) and B. subtilis (MIC = 0.61 and 0.44 mg/ml, respectively) were most probably due to thymol. C2 (geranial: 34.7 %, neral: 33.1 %) evidenced a valuable bioactivity against C. albicans (MIC = 0.44 mg/ml). The 50 % growth inhibition (IC50) of the dermatophytes T. mentagrophytes and N. cajetani was reached with amounts of C1, C2 and CN less than 4 ml/plate. Bioactivity of Amazonian Citrus spp. CN, C1 and C2 essential oils suggests their potential use as food preservatives or additives in cosmeceuticals as preventive against dermatophytic fungal infections.

Over the last twenty years polyurethane elastomers, and particularly their microcellular versions of mostly linear polymers, have proven to represent a very versatile and effective group of materials for the manufacturing of footwear soling. Two basic families of products established their presence in the marketplace: the polyether polyol and the polyester polyol-based systems. The differences in chemical composition, handling procedures, processing and mainly in polymer performance between these two classes of materials created an additional option for the manufacturers and the stylists, enlarging even more the wide range of the application latitude of polyurethanes and allowing a much more targeted selection of the materials to be used

The aim of our work is to describe the way in which physical figures of merit such as contrast-to-noise ratio (CNR) behave when varying acquisition parameters such as emission scan duration (ESD) or activity at the start of acquisition (A(acq)) that in clinical practice can be selected by the user, or object properties such as target dimensions or target-to-background (T/B) ratio, which depend uniquely on the intrinsic characteristics of the object being imaged. Figures of merit, used to characterize image quality and quantitative accuracy for a 3D-LSO based PET/CT scanner, were studied as a function of ESD and A(acq) for different target sizes and T/B ratios using a multivariate approach in a wide range of conditions approaching the ones that can be encountered in clinical practice. An annular ring of water bags of 3 cm thickness was fitted over an IEC phantom in order to obtain counting rates similar to those found in average patients. The average scatter fraction (SF) of the modified IEC phantom was similar to the mean SF measured on patients with a similar scanner. A supplemental set of micro-hollow spheres was positioned inside the phantom. The NEMA NU 2-2001 scatter phantom was positioned at the end of the IEC phantom to approximate the clinical situation of having activity that extends beyond the scanner. The phantoms were filled with a solution of water and 18F (12 kBq/mL) and the spheres with various T/B ratios of 22.5, 10.3, and 3.6. Sequential imaging was performed to acquire PET images with varying background activity concentrations of about 12, 9, 6.4, 5.3, and 3.1 kBq/mL, positioned on the linear portion of the phantom's NECR curve, well below peak NECR of 61.2 kcps that is reached at 31.8 kBq/mL. The ESD was set to 1, 2, 3, and 4 min/bed. With T/B ratios of 3.6, 10.3, and 22.5, the 13.0, 8.1, and 6.5 mm spheres were detectable for the whole ranges of background activity concentration and ESD, respectively. The ESD resulted as the most significant predictor of CNR variance, followed by T/B ratio and the cross sectional area of the given sphere. Only last comes A(acq) with a weight more than halved with respect to ESD. Thus, raising ESD seems to be much more effective than raising A(acq) in order to obtain higher CNR, which is the physical figure of merit closely related with target detectability, at least in the simple task of the signal known exactly background known exactly model.

1. This study investigated the effect of acute (2 days) and chronic (14 days) treatment with a selective inhibitor of noradrenaline uptake, reboxetine (10 mg kg(-1) day(-1)) by osmotic pumps, on extracellular noradrenaline and the sensitivity of alpha(2)-adrenoceptors in the prefrontal cortex of rats. 2. The effect of continuous infusion of reboxetine for 14 days on cortical extracellular noradrenaline was significantly higher (599% of vehicle levels) than after 2 days (263% of vehicle levels). 3. Brain concentrations of reboxetine after 2 and 14 days of infusion were 37.9+/-17.8 and 37.1+/-7.7 ng g(-1), respectively. 4. Reboxetine infused for 2 and 14 days significantly increased extracellular dopamine in the prefrontal cortex, to a similar extent (257 and 342% of vehicle levels, respectively), whereas extracellular 5-HT was not modified by either treatment. 5. Clonidine (10 and 30 microg kg(-1) i.p.) reduced cortical extracellular noradrenaline similarly in animals treated with reboxetine or vehicle for 2 days whereas the effects in rats infused with reboxetine for 14 days were markedly less than in vehicle-treated animals. 6. Clonidine (0.05 and 0.2 microM), infused through the dialysis probe into the prefrontal cortex, reduced cortical extracellular noradrenaline much less in rats treated with reboxetine for 14 days than in vehicle-treated animals. 7. Reboxetine's effect on extracellular noradrenaline in the prefrontal cortex was greater after chronic treatment and could be associated with desensitization of terminal alpha(2)-adrenoceptors that normally serve to inhibit noradrenaline release.

The purpose of this study was to evaluate the feasibility of a shorter method of performing platelet kinetic studies with respect to the conventional 8-9-day approach.We studied 41 patients (28 women, 13 men; mean age 52 yr) with primary idiopathic thombocytopenic purpura (ITP) (n = 20), secondary ITP (n = 9), HCV associated thrombocytopenia (n = 9), splenectomy (n = 1) and hairy-cell leukemia (n = 1). The patients were in a steady-state of platelet turnover. Initial platelet counts ranged from 19 to 302 x 10(9)/liter (mean value = 83). Platelet survival times (PST) were measured from the blood radioactivity disappearance curve of 111In-oxine-labeled autologus platelets following the recommendations of the International Committee for Standardization in Haematology: blood samples were taken at 30 min and 2 and 4 hr and thereafter daily for 7 days. PST was calculated by the weighted mean method and ranged from 18 to 219 hr (mean value = 98). PST was also calculated using only the data collected at 2, 48 and 96 hr. If the radioactivity in the blood at 96 hr exceeded 10% of the 2-hr value, the additional point at 168 hr was used.By using this reduced dataset, we obtained a correlation of r = 0.97 with the PST obtained from the whole dataset. In 24 patients, the difference was between +/- 10 hr and exceeded 1 day in only 4.About 94% of the data may be recovered with only three or four blood samples and the duration may be shortened to 4 days in a significant proportion of patients (48% of ITP patients). This approach offers the advantages of increased patient throughput, compliance and reduced examination costs.

Two strains of the dermatophyte Epidermophyton floccosum were treated with seven new synthetic azole derivatives to determine their possible antifungal activity. Among these, two diazopyrazoles (1-phenyl-3-methyl-4-diazo-5-methanesulphonamid and 1,3-dimethyl-4-diazo-5-methanesulphonamid) and the triazole (4-methyl-6-t-butylpyrazolo[3,4-d] [1,2,3]triazole) were inactive at the highest dose tested (100 micrograms/ml). The 4-methyl-6-phenyl-pyrazolo[3,4-d] [1,2,3]triazole produced only a partial inhibition of growth, whereas the most active compounds were the two thiadiazines (6H-3-phenyl-5-methyl-7-(3,4-dichlorophenyl)pyrazolo[3,4-c] [1,2,5]thiadiazine-2,2-dioxide and 7-methyl-2-phenyl-4H-pyrazolo[1,5-c] [1,3,5]thiadiazine-4-one), and an aminoisoxazole (3-methyl-5-aminoisoxazole-4-thiocyanate), which induced a remarkable and sometimes complete reduction in the growth rate of the fungus. The structure-activity relationships are discussed.

The AA examine the new Tables for occupational diseases in industry and agriculture, which have recently approved with the Presidential Decree n.336, april 13, 1994. The main innovations are analysed, like the elimination of some too generic terms, which had often allowed contrasting interpretations and a non univocal jurisprudence. Other innovative aspects regard the new acquisitions of occupational medicine and strengthen, in the new formulation, the principles of the presumption of law in establishing a relation of cause and effect.

The effect of amineptine (1.25-20 mg/kg i.p.), an antidepressant inhibiting dopamine uptake, on extracellular concentrations of dopamine was studied in the rat striatum and nucleus accumbens by using the microdialysis technique and two Ca++ concentrations (1.26 and 3.4 mM) in the perfusion medium. In one experiment the effect of amineptine was studied on extracellular concentrations of dopamine and noradrenaline in the frontal cortex perfused with a medium containing 1.26 mM Ca++. Basal extracellular concentrations of dopamine in the striatum and nucleus accumbens were significantly higher at 3.4 mM Ca++. At 5 to 20 mg/kg, amineptine dose-dependently increased extracellular dopamine in the striatum and nucleus accumbens. No differences were found in the effect of amineptine in the two brain regions at the two calcium concentrations. When extracellular dopamine was expressed as a percentage of basal values, amineptine (20 mg/kg) caused greater increases in rats perfused with 1.26 mM Ca++ than in rats perfused with 3.4 mM Ca++ in both brain regions. A similar effect was found when 10 microM amineptine was infused through the dialysis fiber. The effect of 10 mg/kg i.p. of amineptine on dopamine output in the two brain regions was prevented by infusing 1 microM tetrodotoxin in the dialysis fiber. In the frontal cortex, 10 and 20 mg/kg of amineptine significantly raised dopamine and noradrenaline concentrations, whereas 5 mg/kg only increased noradrenaline output significantly. At 10 mg/kg i.p., amineptine also increased extracellular noradrenaline in the dorsal hippocampus. Amineptine had no consistent effects on the concentrations of dihydroxyphenylacetic acid and homovanillic acid in the various brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related reduction in the steady-state levels of messenger RNA for D2415 and D2444, the alternatively spliced form of dopamine D2 receptors, was observed in different rat brain areas using the sensitive reserve transcription (RT)-polymerase chain reaction (PCR) technique. In both Sprague-Dawley and Wistar aged rats, the decrease was more pronounced in the D2434 isoform mRNA thus leading to a changed ratio in striatum as well as in the hyppocampus.

The serum level measurement of CA 15-3 antigen was evaluated in association with CEA and TPA, during the follow-up in mastectomized patients previously affected by breast cancer: 94 patients with metastases and 319 without apparent disease evolution. In the group of patients with metastases, the CA 15-3 antigen showed high sensitivity (70.2%). The CA 15-3 and TPA association increased the sensitivity (87.2%), while the CEA and CA 15-3 association did not increase this parameter. All markers showed good correlation with therapeutic response. Thirteen patients among 19 without apparent disease evolution, developed metastases, during the follow-up. The CA 15-3 and/or TPA increase allowed to predict disease progression in 13/13 cases, 2-10 months before clinical evidence. Our experience shows that CA 15-3 measurement associated with TPA, during the follow-up of patients affected by breast cancer, may be helpful for increasing the predictivity with respect to those patients most likely to develop recurrent disease.

A double-blind, placebo-controlled parallel-group study was carried out in 100 patients with postoperative pain. The analgesic activity of indoprofen given in a single dose as an i.v. bolus followed by a 2-h infusion, at total doses of 100, 200, and 400 mg was investigated. The highest dose of 400 mg was given additionally as an i.v. bolus alone. Intensity of pain was assessed before, and 30 min, 1, 2, 4, 6 and 8 h after treatment on a 0-4 point scale. An overall assessment was made at the end of treatment by the investigator and the patient using a 0-4 point scale and a visual analogue scale. Statistical analyses according to a multiple regression model on rating scale scores at fixed times and on overall assessments showed: (i) indoprofen was always more active than placebo in providing pain relief; (ii) there was a significant dose--response relationship; and (iii) there was no difference between the two schedules of administration of the largest dose.

The results of an open exploratory trial with different regimens of indoprofen in patients with acute gouty arthritis are described. Two main daily regimens were assessed: (a) indoprofen 200 mg as an intravenous bolus, followed by slow infusion of 100 mg/hour for about 4 hours (24 attacks treated in twenty-three patients); and (b) indoprofen 400 mg as an intravenous bolus (13 attacks treated in twelve patients). In both regimens intravenous indoprofen was supplemented with 400–600 mg daily of indoprofen by mouth. The patient's response, as judged by pain, tenderness, local heat, redness, range of motion and joint circumference, was dramatic in both series, with no significant difference between them at any time of observation. Substantial improvement was apparent for subjective variables already within 2 hours after the beginning of treatment, and a complete resolution was obtained in 35 of 37 attacks within 48 hours. A mild adverse reaction was recorded in one patient for each group (dizziness and gastric pain, respectively). Intravenous indoprofen appears to afford an extremely rapid relief of acute gout; of the two regimens assessed, the second should be preferred in that it seems to be at least equally effective but less troublesome for the patients.

Twenty in-patients with rheumatoid arthritis took part in a double-blind, crossover clinical trial to compare the effectiveness and tolerance of 400 mg indoprofen with 1000 mg aspirin each given 3-times a day for 1 week, with an interval of 2 days during which patients received an indistinguishable placebo. At the start and at the end of each treatment period several subjective and objective indices were measured. Both indoprofen and aspirin to remable improvement in patient conditions, with no significant differences between drugs in overall pain, number of swollen joints, grip strength and functional index. Indoprofen, however, was significantly superior to aspirin with regard to the number of painful joints (p < 0.01), duration of morning stiffness (p < 0.05) and articular index (p < 0.05). Moreover, both patients' and investigators' opinion of overall response favoured indoprofen. Small but significant decreases were recorded in ertythrocyte sedimentation rate and seromucoid levels in both treatment periods. Adverse reactions, mainly as gastric pyrosis and/or gastralgia, occurred in 6 patients while on aspirin, in 2 while on indoprofen, and in a further 2 while on both drugs. No statistically significant changes were observed in safety laboratory tests.

A controlled study of the clinical pharmacology of the biliary tract has been made. The rate of gallbladder emptying induced by a fatty meal was taken as a parameter for assessment of the inhibitory effect of indoprofen, a new analgesic-anti-inflammatory drug, pentazocine and morphine. The compounds were administered as single doses by iv (indoprofen and pentazocine) or im (morphine) injection. Indoprofen up to 400 mg had no effect, whereas morphine and pentazocine exerted a significant inhibitory effect on emptying of the gallbladder. Adverse reactions of clinical significance were associated with morphine and pentazocine, but were negligible with indoprofen.

Up to date 6 patients with initial presenile idiopathic cognitive decline (PICD) and 5 suffering from a presenile Alzheimer-type dementia (PAD) with a mean age of 59.5 were admitted to the trial. The 6 PICD patients were assigned to a double-blind nicergoline/placebo 6-month course with an oral dose of 30 mg twice a day. PAD patients were treated in an open design (nicergoline oral dose 30 mg twice a day) for at least 6 months. Until now only 4 PICD and 3 PAD patients have been treated regularly for 6 months. Two of 4 PICD patients showed a progressive enhancement of contingent negative variation (CNV), shorter reaction time (RT) and an improvement of clinical status. The other 2 PICD patients, on the contrary, showed a progressive mild worsening of CNV-RT and clinical patterns. The double-blind trial is not yet completed. CNV activity, RTs and clinical patterns progressively improved also in 2 PAD patients while in the 3rd they remained nearly unchanged or minimally worse during the 6-month treatment. The positive nicergoline effect on CNV-RT and clinical status noted in our patients appeared similar to that observed by other authors with DHEMT in patients with senile dementia of Alzheimer type. No adverse drug-related reactions were seen.

A controlled double-blind multiclinic trial comparing the activity and tolerability of tolciclate and clotrimazole on skin candidiasis was carried out in twenty-seven dermatological departments throughout Italy. Two hundred and seventy-eight patients were admitted to the trial. Tolciclate and clotrimazole 1% cream and lotion were applied twice a day for a mean time of about 3 weeks. Efficacy was evaluated weekly during the treatment both by clinical and mycological (culture) examinations. Culture baseline findings were positive for Candida sp in about 72% of cases; C. albicans was the most frequent species (41·5%) but also C. krusei and C. stellatoidea were isolated in a high percentage of cases. Tolciclate induced clinical cure or improvement in 89·7% of cases, mycological conversion in 73·6% with an overall efficacy (clinical + mycological) in 72·2%. Clotrimazole gave comparable results with, respectively, 95·7% of clinical cure or improvement, 75·3% of culture conversion and 77·6% of overall efficacy. The differences were small and statistically not significant. Tolerability was good and similar in both experimental groups.

1 Twenty-four patients suffering from severe pain due to chronic occlusive arterial disease of the legs were given oral doses of indoprofen (200 mg), ibuprofen (300 mg) and placebo. 2 Differences in pain intensity scored on a five-point scale were taken as measurement of pain relief. 3 This double-blind, cross-over trial showed that indoprofen had significantly greater analgesic effect than placebo and reference drug. 4 From a methodological point of view there are many arguments on favour of pathological ischaemic pain as a test for clinical assessment of analgesics.

Gallbladder emptying induced by a fatty meal (2 egg yolks) was studied by oral cholecystography in 402 subjects without gastrointestinal disorders.Roentgenograms were made at intervals up to the 6oth minute after the meal, and the radiopaque areas were measured planimetrically to provide a quantitative assessment of emptying.The pattern of emptying was compatible with an exponential function. The mean value for t½ was higher in the women; emptying tended to be slower in younger subjects.

Some morphological anomalies of the pelvis were radiologically evaluated in 25 mongoloid children within the first year of life, in comparison with 45 normal children, through the measurements of the acetabular and iliac angles. The results were statistically analyzed according to the model of discriminant functions, and the combination of the two measurements which gives the best discrimination between mongoloid and normal children was established; on this basis, a nomogram is presented, where-by a quantitative estimation of the morphological anomalies can be made, for diagnostic purposes, without numerical calculations and with a low error.

SummaryThe in vitro effect of the following substances on human platelet aggregation is studied: K 4423 (a ß-blocking drug), isoproterenol, phentolamine, papaverine, methamidoline (a myolytic agent).None of these substances causes aggregation. All inhibit aggregation induced by ADP or noradrenaline, except for phentolamine, which is active only on noradrenaline- induced aggregation.Hypothesis on the mechanism of action of the compounds tested are proposed.

Up to date 6 patients with initial presenile idiopathic cognitive decline (PICD) and 5 suffering from a presenile Alzheimer-type dementia (PAD) with a mean age of 59.5 were admitted to the trial. The 6 PICD patients were assigned to a double-blind nicergoline/placebo 6-month course with an oral dose of 30 mg twice a day. PAD patients were treated in an open design (nicergoline oral dose 30 mg twice a day) for at least 6 months. Until now only 4 PICD and 3 PAD patients have been treated regularly for 6 months. Two of 4 PICD patients showed a progressive enhancement of contingent negative variation (CNV), shorter reaction time (RT) and an improvement of clinical status. The other 2 PICD patients, on the contrary, showed a progressive mild worsening of CNV-RT and clinical patterns. The double-blind trial is not yet completed. CNV activity, RTs and clinical patterns progressively improved also in 2 PAD patients while in the 3rd they remained nearly unchanged or minimally worse during the 6-month treatment. The positive nicergoline effect on CNV-RT and clinical status noted in our patients appeared similar to that observed by other authors with DHEMT in patients with senile dementia of Alzheimer type. No adverse drug-related reactions were seen.

Single doses of indoprofen (400 mg, i.v.), morphine hydrochloride (10 mg, i.m.), and placebo were given to 12 women with moderate to severe tumor pain, mainly due to bone involvement, according to a Latin square design. Analgesic response, along with serum prolactin (PRL) and growth hormone (GH) levels, were measured after each treatment under double-blind conditions. Indoprofen and morphine were not significantly different as regards pain relief, but both were significantly more effective than placebo. Unlike morphine, however, indoprofen did not raise PRL. GH levels did not change following any treatment. In a second study indoprofen (400 mg, i.v., three times daily for 7 days) did not modify the PRL response to thyrotropin-releasing hormone nor serum GH levels. On the basis of the above findings it is suggested that indoprofen may be a safe alternative to opiates for relief of moderate to severe pain in women with breast tumors suspected of being prolactin-dependent.

The pharmacokinetics of indoprofen in healthy subjects after single oral and i.v. administrations is reviewed. During repeated administration of indoprofen to 6 normal subjects (200-mg tablet every 8 hours for 6 days) no variations in the disposition of the drug were found in comparison with single dose administration. In 6 inpatients, with rheumatoid arthritis, the pharmacokinetics of indoprofen was studied after single oral (tablet) and i.m. administration. As for oral doses, no difference in main kinetic parameters was detected between the patients and normal subjects except for a higher volume of distribution in the former population. The bioavailability of the drug given by i.m. injection was not significantly different from that observed after oral administration.

The influence of i.v. administration of indoprofen on template bleeding time and other haemostatic parameters was investigated in ten elderly subjects with osteoarthritis. The drug was given first as a single dose (400 mg bolus) and then, after an appropriate interval, as a short-term treatment (200 mg bolus t.i.d. for 7 days). Platelet count, prothrombin time and partial thromboplastin time were never affected, whereas a significant, though moderate, lengthening of bleeding time and a parallel reduction of platelet aggregation were observed in both trials. In the acute one these changes were seen at the first hour following administration and waned in all patients within 96 hours. In the subacute test the bleeding time was steadily prolonged throughout the week of treatment, being slightly still above the baseline value 7 days later, at which time no residual effects were noticeable in platelet aggregation.

Over the past decades, with the “progressive aging of the population”, increased attention has been given to the pathology associated with advancing age and characterized not so much or not only by vascular disorders but, more importantly, by the impairment of neuronal and metabolic functions [6, 24].

Acipimox is a new lipid-lowering agent with long-lasting antilipolytic activity chemically related to nicotinic acid (1,2). The aim o f the present trial was to study the effect of acipimox on plasma lipid levels and its tolerability during long-term treatment in diabetic patients with hyperlipoproteinemia. The trial included investigation of any influence of the drug on glucose tolerance.

Peripheral obliterative arterial disease (POAD) is a clinical condition characterized from a pathophysiological point of view by a reduction of nutritional blood flow due to atherosclerotic stenosis or occlusion of great or medium-sized arteries of the legs. In this condition, blood flow supply to the tissue can be insufficient to meet the metabolic needs and ischaemia can occur. The blood flow reduction usually develops slowly and a compensatory mechanism can be activated to antagonize ischaemia.

Periphere obliterierende arterielle Erkrankungen (im weiteren Text als POAD—peripheral obliterative disease —abgekurzt) sind pathophysiologisch durch eine Reduktion der nutritiven Durchblutung gekennzeichnet, die durch arteriosklerotische Stenosen oder Verschlusse der grosen oder mittleren Beinarterien hervorgerufen wird.

Postmarketing surveillance is becoming a relevant part of the medical evaluation of pharmaceutical products because there is a real need of an early warning on the adverse reactions which escape detection in premarketing clinical trials. Practical reasons limit the sensitivity of present methods to events with a frequency around 0.5–1 %. For rare and much delayed ADRs only spontaneous or pasive monitoring are the methods on which out of necessity we must rely at present The Authors review their experience in the methodology concerning validation of ADRs, planning of postmarketing surveillance trials and use of computers for analysing results. On the basis of such experience the Authors feel that postmarketing surveillance trials which can be carried out by a medical department of a pharmaceutical company should be planned also to supply information on how the drugs are actually employed by practising physicians so as to orient them on their proper clinical use. This approach could help in reducing the frequency of ADRs due to misuse of drugs which are the most commonly encountered and can be easily prevented. Postmarketing surveillance carried out by practising physicians with the technical aid of the pharmaceutical companies should be a running program meant to monitor also the efficacy of drugs and to identify new fields for their application.

Indoprofen, a non-steroidal anti-inflammatory agent, was investigated in a double-blind, randomized study in 44 osteoarthritic patients for its influence on haemostatic parameters and therapeutic effects. Twenty-two patients received indoprofen orally, 600 mg daily, and a similar group took acetylsalicylic acid 3 g daily for 21 days. Platelet count, partial thromboplastin time and prothrombin time showed no variations. Bleeding time wa prolonged and platelet aggregation reduced by both drugs. The effects of ASA, however, were significantly greater. Indoprofen, unlike ASA, showed almost no residual effect seven days after stopping medication. The therapeutic responses to indoprofen and ASA were comparable. However, adverse reactions (pyrosis and gastric pain) were much more frequent in the ASA group (15 patients) than in the indoprofen group (2 patients).

The pharmacokinetic and bioavailability properties of medroxyprogesterone acetate (MPA) after single PO and IM doses in man were used as a basis to predict, on a theoretical pharmacokinetic basis, the blood level profile of the drug during repeated dose administration with various dosage schedules. Because of the unusually long-lasting depot effect of IM MPA, a different build-up process of blood levels is expected during repeated IM or PO administration, and this should be taken into account when dose schedules for use in clinical oncology are selected. As regards the IM route, dose schedules based on 4 weeks' treatment with daily injections of 500-1,000 mg followed by a maintenance therapy with 1,000 mg/week are suggested, since they permit rapid achievement and maintenance of relatively high plasma levels. A similar plasma level profile can be obtained with oral MPA provided that daily doses twice as large as the IM doses are given during the first month of treatment and continued during the maintenance period. The serum levels observed in 25 patients with advanced breast cancer treated with MPA given IM or PO according to various dose schedules and recent literature data are very close to the serum level profiles predicted on a theoretical pharmacokinetic basis.

A double-blind, controlled clinical trial is described in which a total of forty hospital in-patients suffering from severe post-operative pain were randomly allocated to treatment with one of two non-steroidal anti-inflammatory drugs, namely, either indoprofen which has a short half-life (two hours) or naproxen which has a long half-life (thirteen hours). The drugs were administered orally on a single-dose-only basis. The doses used in this way were 300 mg of indoprofen or 250 mg of naproxen. Patients scored the severity of their pain on a five-point scale and these scores were recorded prior to and at fixed time intervals up to eight hours following administration of medication. No significant differences emerged between the two test drugs and the duration of the response was also found to be similar for the two compounds despite their very different plasma half-life values.