International Journal of Clinical Pharmacology Research

This study evaluated the sputum penetration of cefpirome following slow intravenous infusion of 0.5 and 1.0 g using a comparative cross-over design to reduce variability. Five patients with chronic respiratory tract infections were randomized to receive either 0.5 g followed by 1.0 g, or by 1.0 g followed by 0.5 g cefpirome, by slow intravenous infusion over 1 h, with a 24-h wash-out period between each treatment. With the exception of one patient, sputum concentration correlated well with plasma concentration. Higher sputum levels of cefpirome were achieved following the higher dose.

D-003 is a mixture of high molecular weight aliphatic primary acids purified from sugar cane wax with antiplatelet and cholesterol-lowering effects. Previous studies showed that D-003 (10-20 mg/day) administered for a short time inhibits platelet aggregation, 14 days being the longest duration investigated. This study was conducted to investigate the effects of D-003 (5 and 10 mg/day) for 30 days on platelet aggregation in normocholesterolemic subjects. This report shows the effects of D-003 on platelet aggregation to arachidonic acid (AA) (1.5 mM), collagen (2 microg/ml) and adenosine 5'-diphosphate ADP (2 microM) assessed at baseline and at treatment completion. Fifty-four subjects were randomized to placebo or D-003 (5 or 10 mg/day) for 30 days. Platelet aggregation to AA, collagen and ADP were assessed. D-003 at the lowest dose (5 mg/day) significantly but modestly inhibited (p < 0.01) platelet aggregation to AA (5.0%) and (p < 0.01) to collagen (7.5%). D-003 at 10 mg/day inhibited (p < 0.001) platelet aggregation to AA and collagen (p < 0.01) by 20.3% and 14.7%, respectively. ADP-induced aggregation, however, was unchanged. D-003 at 10 mg/day, but not at 5 mg/day, lowered (p < 0.01) plasma fibrinogen. D-003 (5 and 10 mg/day) reduced low-density lipoprotein cholesterol (LDL-C) by 17.7% and 26.4%, respectively, and total cholesterol (TC) by 14.5% and 18.5%, while at 10 mg/day, but not at 5 mg/day, it increased high-density lipoprotein cholesterol (HDL-C) by 9.6%. Triglycerides, however, were unchanged with D-003. No disturbances in safety indicators were induced with D-003. One subject (D-003 5 mg/day) discontinued the study and four patients (three taking D-003 and one taking placebo) reported adverse effects (AE) (headache in two patients taking D-003 and one patient taking placebo, and polyphagia in one patient taking D-003). In conclusion, D-003 (5-10 mg/day) for 30 days inhibited platelet aggregation to AA and collagen but not to ADP Therefore, the antiplatelet effect was present with the longer treatment, even at a dose of 5 mg/day. The cholesterol-lowering effects of D-003 were consistent with those expected for such a short treatment. In addition, D-003 at 10 mg/day significantly lowered plasma fibrinogen. The treatment was well tolerated.

Biphosphonates, which are antiresorptive agents used to treat osteoporosis, inhibit the mevalonate pathway, preventing protein prenylation and inhibiting osteoclast activity. Statins decrease cholesterol biosynthesis by blocking the mevalonate pathway and have been reported to have beneficial effects on bone. D-003 is a mixture of high molecular weight acids purified from sugarcane wax that inhibits cholesterol biosynthesis before mevalonate production. D-003 prevents bone loss and resorption in rats with osteoporosis induced with ovariectomy or corticoids. Biochemical markers of bone turnover are used to monitor the short-term efficacy of antiosteoporotic therapy. This randomized, double-blind, placebo-controlled study was undertaken to investigate the short-term effects of D-003 (10 mg/day) on biochemical markers of bone turnover in postmenopausal women with low bone mineral density (BMD). After 4 weeks on a low-fat diet, 34 women were randomized to D-003 (10 mg/day) or placebo for 6 months. Pre- and post-treatment samples were analyzed for urinary excretion of deoxypyridinoline (DPD)/creatinine (Cr), a marker of bone resorption, and serum bone specific alkaline phosphatase (BSAP), a marker of bone formation. The effects on lipid profile and safety indicators, as well as adverse events (AE), were investigated. D-003 (10 mg/day) lowered urinary excretion of tDPD/Cr versus baseline (20.6%) (p < 0.001) and placebo (33.7%) (p < 0.01), but did not modify serum BSAP. D-003 decreased low-density lipoprotein-cholesterol (LDL-C) (32.8%), total cholesterol (TC) (16.4%) and the TC/high-density lipoprotein-cholesterol (HDL-C) ratio (34.7%), increased HDL-C (30.3%) (p < 0.001) and did not modify triglycerides. The effects on these variables were significant as early as 3 months after treatment initiation. D-003 was well tolerated. Three patients (one in the placebo group and two in the D-003 group) withdrew from the study. Two of these withdrawals were due to AE: abdominal pain (placebo) and heartburn (D-003). Five patients (four in the placebo group [22.2%] and one in the D-003 group [6.3%]) reported mild AE. In conclusion, D-003 (10 mg/day) reduced urinary excretion of tDPD/Cr, a bone resorption marker and did not change serum BSAP, a bone formation marker, while it lowered cholesterol in study patients. These preliminary results suggest that D-003 could be useful in treating postmenopausal women with low BMD. However, the potential value of D-003 in treating or preventing osteoporosis deserves further clinical investigation.

D-003 is a mixture of very high molecular weight aliphatic acids purified from sugar cane wax showing cholesterol-lowering and antiplatelet effects proven in experimental and clinical studies. Experimental evidence indicates that inhibition of platelet aggregation induced by D-003 is associated with a reduction of thromboxane B2 (TxB2) and an increase of prostacyclin (Pgl2) serum levels. This double-blinded, randomized, placebo-controlled study was undertaken to investigate whether D-003 (20 mg/day) modifies serum levels of TxB2 and Pgl2 and inhibits platelet aggregation in human healthy volunteers. Thirty-one subjects were randomized to placebo or D-003 at 20 mg/day for 14 days. Serum levels of TxB2 and Pgl2 and platelet aggregation to arachidonic acid (AA) (1.75 mM) and collagen (1 microg/ml) were assessed. D-003 (20 mg/day) significantly reduced (p < 0.001) TxB2by 36.4% and increased Pgl2 serum levels by 31% compared with baseline, and these changes were different from placebo. As expected, D-003 significantly inhibited (p < 0.001) platelet aggregation to AA (81.9-65.6%) and to collagen (75.3-62.3%). No subject withdrew from the study. No drug-related disturbances were observed. We conclude that D-003 at 20 mg/day for 14 days significantly inhibited platelet aggregation to AA and collagen and reduced TxB2 and increased Pgl2 serum levels. These results are consistent with those observed in experimental models, indicating that the antiplatelet effect of D-003 is associated with the observed changes on the levels of AA metabolites. Further studies, however, should explore the mechanism involved in this action in greater depth.

A major component of genetic susceptibility to rheumatoid arthritis (RA) appears to be explained by inheritance of HLA-DRB1 alleles. Multiple HLA-DRB1 alleles (DRB1*0401, *0404, *0405, *0408, *0101, *102, *1001 and *1402) encoding a shared epitope at amino acid positions 70-74 are associated with susceptibility to RA. There is ethnic variation in the clinical expression of RA and in both the frequency and type of HLA-DRB1 alleles carrying the shared epitope. We evaluated the prevalence of the alleles of HLA-DRB1 locus encoding for SE in 42 outpatients with RA attending the Rheumatology Center of the University of Genoa, Bruzzone Institute, and living in Liguria. A control group was composed of Italian marrow donors. DNA genotyping was performed using a low-resolution polymerase chain reaction technique for characterization of the families of HLA-DRB1 alleles for each of the 42 patients studied. Subsequently, subjects with *01 and *04 haplotype were tested with high-resolution HLA-DRB 1 typing to characterize the *01 and *04 alleles. No statistically significant differences were found in the prevalence of RA-associated single alleles *01 and *04 in the study group or in the control group. In contrast, the sum of susceptibility *04 alleles studied by resolution typing was strongly related to RA in the study group in comparison with the control group.

Twelve healthy male subjects participated in a double-blind, placebo-controlled, randomized, three-period, crossover study to investigate the safety, tolerability, biochemical activity and pharmacokinetics of ibuprofen, a cyclooxygenase inhibitor and MK-0591, a 5-lipoxygenase inhibitor, given as single entities and in combination. Each subject received for three consecutive 8-day periods, separated by 1 week washout, each of the following treatments: ibuprofen 600 mg three times a day with 125 mg MK-0591 twice a day, ibuprofen 600 mg three times a day with placebo for MK-0591 and MK-0591 125 mg twice a day with placebo for ibuprofen. Cyclooxygenase inhibition was measured by platelet thromboxane (TxB2) generation test, and 5-lipoxygenase inhibition was measured by urinary leukotriene E4 excretion and ex vivo LTB4 generation in calcium-ionophore-stimulated blood. TxB2 suppression on day 8 by ibuprofen was not affected by concomitant treatment with MK-0591. MK-0591 alone had no effect on TxB2 generation. Leukotriene biosynthesis was inhibited by more than 90% by MK-0591 alone and by combined treatment, while ibuprofen alone had no effect. Coadministration appears to affect the pharmacokinetics of MK-0591 (decrease of area under the plasma concentration-vs-time curve [AUC] and maximum plasma concentrations [Cmax]) and of ibuprofen (increase of AUC and half-lives of elimination (t1/2) of the (S)-enantiomer, increase of t1/2 the (R)-enantiomer). Combined treatment had no effect on creatinine clearance nor on the number and intensity of the reported adverse experiences.

Vitamin D deficiency may be one reason for the onset and development of osteoporosis. The aim of the present study was to determine the occurrence rates of hypovitaminosis D in an unselected group of individuals presenting with common medical conditions and hospitalized for long periods. Concentrations of 1,25-(OH)2 D3 were measured in 89 patients (38 males and 51 females). Mean age was 70 years. Thirty-eight patients were tested in the spring and the remaining 51 patients in the autumn. Vitamin D3 levels were significantly reduced in patients tested in the autumn (p < 0.001). The reason for this surprising observation may have been the small number of sunny days and the long hospital stays during the study period, differences in the composition of both groups and the fact that 1,25-(OH)2 D3 reflects the actual vitamin D3 levels rather than those of its reserve in the human body. The results obtained suggesting hypovitaminosis D in an unselected group of elderly patients hospitalized with common diseases, even after the summer season, suggest the need for general supplementation of this vitamin throughout the year, regardless of the risk factors.

Pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly subjects were compared with those in younger subjects. Fourteen healthy male volunteers (7 elderly subjects aged 68-79 years and 7 young subjects aged 20-32 years) were included in the study. In a parallel group design, a tablet containing 100 mg NS-105 was administered orally after breakfast. One young subject was excluded from the pharmacokinetic analyses owing to an insufficient urine collection. The maximum plasma concentration (Cmax) was higher in the elderly (3.06 +/- 0.69 vs. 2.13 +/- 0.34 micrograms/ml, the elderly vs. the young, mean +/- SD, p = 0.0117) and area under the plasma concentration curve (AUC) was also higher in the elderly (24.6 +/- 4.4 vs. 14.4 +/- 3.1 micrograms.hr/ml, p = 0.0006). There is a tendency that time to reach Cmax was longer in the elderly (2.1 +/- 1.1 vs. 1.3 +/- 0.5 hr, p = 0.1199), and a tendency of prolongation of elimination half-life. Urinary recovery of NS-105 was less in the elderly up to 8 h after administration, while total recovery of the dose was not different in the two groups. Total clearance was reduced in the elderly (0.076 +/- 0.013 vs. 0.121 +/- 0.025l/kg/hr, p = 0.0013) and the decrease seemed to be mainly due to a decrement in renal clearance of the drug in the elderly. A significant correlation was found between renal clearance of NS-105 and creatinine clearance of each subject (r = 0.583, p = 0.0364). These observations indicate that the plasma concentration of NS-105 will increase in elderly subjects mainly due to a decrement in renal clearance of the drug. Careful observation is needed when prescribing the drug to an elderly patient.

Chondroprotective agents represent a model for basic therapy of osteoarthritis (OA), thanks to their activity directed towards the protection and repair of articular cartilage. One of the most recent compounds capable of interfering with the pathogenic mechanisms of OA is galactosamino-glycuronoglycan-sulfate (GGGS), a highly depolymerized glycosaminoglycan with favourable chondroprotective and anti-inflammatory properties. The present paper describes the experience with GGGS given to a group of patients with symptomatic OA of the knee as compared to a parallel group treated with placebo. The drug (or placebo) was administered in two series of 25 intramuscular injections each over a period of 11 months, and four successive evaluations of treatment were made at various times during this period, and a fifth evaluation one month after the suspension of treatment to better evaluate the permanence of the therapeutic effect. The results obtained showed significant improvements on pain, algofunctional index and consumption of NSAIDs only in the group treated with GGGS. The drug was well tolerated and no reduction of dosage or drop-out from therapy were required. The favourable clinical effects and the patients' good compliance make GGGS a useful drug for successful chondroprotective treatment of OA.

An open, non-comparative study, with a new calcium antagonist-tiapamil, was undertaken in 22 patients with mild and moderate essential hypertension (stage I-II WHO). After a two-week placebo period, patients were treated with tiapamil, 300-600 mg twice daily during a period of six weeks (Dose-finding period). Thereafter patients were continued on tiapamil during a 54 week period (Long-term follow-up). In some patients it was necessary to add the diuretic hydrochlorothiazide to obtain adequate control of the arterial hypertension. Monotherapy with tiapamil normalized supine diastolic blood pressure after the first six weeks in 17 of the 21 evaluable patients, and reduced it by greater than or equal to 10 mmHg (1.3 kPa) from baseline without normalization in two patients. In the two remaining cases the decrease was less than 10 mmHg. The optimal dose administered at six weeks in those patients who responded to treatment (normalization or decrease by greater than or equal to 10 mmHg.) was 600 mg/day in 32% of the cases, 750-900 mg/day in 47% and more than 900 mg/day in 21%. After completion of the dose-finding part, 19 patients continued treatment for a further 54 weeks. In 16 out of 19 patients hydrochlorothiazide was added to enhance the antihypertensive effect. All three patients who received tiapamil monotherapy throughout the trial, had normalized supine diastolic blood pressure on completing the study. In the 16 patients with the combination therapy, the addition of hydrochlorothiazide led in two patients to no further decrease in supine diastolic blood pressure, to an additional decrease by less than 10 mmHg in ten patients and by greater than or equal to 10 mmHg in four in comparison with the values obtained before starting combination therapy. At the end of the study 11 of these 16 patients had normalized supine diastolic blood pressure. The mean daily dose was 900 +/- 45 mg of tiapamil and 39 +/- 4 mg of hydrochlorothiazide. Both monotherapy and the combination regimen were well tolerated, and no effects attributable to drug interactions were observed. It may be concluded that tiapamil in oral doses of 300-600 mg twice daily is an effective antihypertensive agent with an excellent tolerance when administered for a period of 54 weeks.

The therapeutical efficacy and the clinical and biological tolerance of a treatment with a new mucolytic agent, CO-1177 (Nesosteine), were assessed by evaluating clinical symptoms and functional respiratory parameters in 40 patients suffering from acute relapsing bronchitic syndrome. The therapy was performed for 15 days, at the dosage of one vial given intramuscularly twice daily for the first seven days and then of one tablet orally thrice daily for the remaining eight days. A marked mucolytic activity of the drug was clearly evident from the first days of treatment, with consequent loosening of secretions obstructing the bronchial tract, and prompt improvement both of clinical symptoms and of functional parameters in all the patients. In no case was clinical or biohumoral intolerance observed.

In a double-blind, parallel-group multicentre study, the efficacy and safety of a fixed low-dose combination of ramipril 2.5 mg and hydrochlorothiazide (HCT) 12.5 mg was compared with each of the component drugs when given as monotherapy. After a four-week placebo run-in, patients were randomized to receive either ramipril 2.5 mg (n = 218) or HCT 12.5 mg (n = 220), or the fixed-dose combination of ramipril 2.5 mg and HCT 12.5 mg (n = 222), for a period of eight weeks. At the end of the study, in which 624 patients had completed treatment, it was found that the decrease in supine diastolic blood pressure (the main efficacy parameter) was greater in the ramipril-HCT combination group than in either the ramipril or the HCT monotherapy groups, the difference being statistically significant when compared with the HCT group (-14.3, -13.1 and -12.4 mm Hg, respectively). Reductions in standing DBP and supine and standing systolic blood pressure (SBP) were also greatest in the combination group. The incidence of adverse events was lower in the combination group than in either of the monotherapy groups, and there were no serious clinically significant laboratory abnormalities in the combination group.

Sixteen patients with RA (3 males, 13 females), diagnosed according to RA revised criteria, were selected and entered the study. They underwent six intra-articular injections of 750 mcg of SST14 at 15-day intervals. The thickness of the synovial membrane (SM) was measured with a 5-MHz linear sound with longitudinal and transversal scanning carried out on the upper patellar cavity. The contralateral knee was also assessed together with the injected knee in order to ascertain any systemic effect of the drug. A significant reduction of SM thickness was observed already at the first control (T3) in 14 out of 16 patients. At the 5th and 6th injections (T5 and T6) the reduction was still significant but to a lower extent. In 8 out of 16 cases a reduction of SM thickness was observed in the contralateral knee. Analysis of these data clearly shows that the intra-articular injection of SST14 is able to reduce the thickness of SM in patients with RA, and indicates that SST14 may directly reduce synovitis. This particularity has been detected in our work with a non-invasive technique such as the joint ultra-sound (US). In conclusion, our work confirms the efficacy of SST14 in the control of RA synovial hypertrophy and the reliability of US technique in the measurement of SM thickness.

CDRI compound 81/470 (AH) is a new broad-spectrum anthelminthic agent under development for clinical and veterinary application. We herewith report the synthesis of 14C-labelled AH, and a study of the tissue distribution and excretion of radioactivity after administering a single 1 mg/kg p.o. or i.v. dose in young male rats. After oral administration of the dose, percent radioactivity recovered in 24-h urine, faeces and tissues were 17.9, 59.7 and 22.9 respectively. The levels were below detection limit in brain and gonads up to 24 h. In bile-duct-cannulated rats, the majority (37.8 +/- 2.8 and 43.8 +/- 6.4) of the radioactivity was excreted in the bile within 24 h of p.o. and i.v. administration, respectively. After an oral dose (1 mg/kg), the urinary excretion of radioactivity in rats was found to be approximately one-half (21 +/- 5.7, 18.3 +/- 2.1) of that obtained by i.v. administration of an equal dose (40.2 +/- 3.1 and 35 +/- 1.3), in bile-duct-intact and cannulated rats respectively.

In 18 patients with congestive heart failure, the 14C-aminopyrine demethylation rate was studied by the breath-test, 24 hours after the measurement of haemodynamic parameters. In the 12 patients with a cardiac index higher than 2.2 l/m2/min, the half life of 14CO2 specific activity in breath was found to be significantly correlated (p less than 0.001, r = 0,82) with the telediastolic pressure of the right ventricle. On the other hand, in the 6 patients with a cardiac index below 2.2 l/m2/min the 14C-aminopyrine half life was higher than the value predicted by this correlation. Congestive heart failure probably reduces hepatic demethylation of aminopyrine through altered hepatic microsomal function associated with congestion and possibly hypoxia.

We have previously reported the superiority of the epirubicin 180 mg/m2-cisplatin combination over single drug epirubicin 180 mg/m2 for advanced soft tissue sarcoma both in terms of response (54% vs. 29%, p = 0.025) and survival (p = 0.001). The aim of the present study was to establish whether decreasing the dosage of epirubicin to 150 mg/m2 would result in the same activity but with less hematological toxicity. One hundred fifty-nine patients with advanced soft tissue sarcoma were randomized for either epirubicin 150 mg/m2-cisplatin 120 mg/m2 (group A) or epirubicin 180 mg/m2-cisplatin 120 mg/m2 (group B). The results were as follows: group A: 79 patients were evaluated. Overall response rate was 24/79 (30%) (95% CI 21-41%). Median survival was 11 months and probability of survival at 1 year was 0.46. Grade IV granulocytopenia was present in 111/274 cycles and febrile neutropenia in 22/274. Group B: 73 patients were evaluated. The overall response rate was 39/73 (53%), (95% CI 42-64%). Median survival was 14 months and probability of survival at 1 year was 0.58. Grade IV granulocytopenia was present in 136/295 cycles and febrile neutropenia in 30/295. The differences were as follows: for overall response rate p = 0.004; power (for p = 0.05) 85%; for survival p = 0.09; for grade IV granulocytopenia p = 0.3; and for febrile neutropenia p = 0.61. A survival advantage (p = 0.043) was evident for patients randomized to group B and with performance status 0 or 1 compared with similar patients from group A. A plateau-like formation on the probability level of 0.26 on the survival curve started from month 26 onwards. In conclusion, both regimens share the same toxicity but epirubicin 180 mg/m2-cisplatin seems more active in soft tissue sarcoma, possibly indicating a breakthrough for activity between an epirubicin dosage of 150 mg/m2 and 180 mg/m2 in combination with cisplatin. The superiority of the epirubicin 180 mg/m2-cisplatin regimen appears evident both in terms of response and survival.

In recent years an antimitotic effect has been observed in animal studies for bromocryptine, an ergot-alkaloid derivative. In this paper a case of severe leucopenia in a hyperprolactinaemic woman on chronic bromocryptine treatment is reported. Furthermore, results are reported of an experimental study carried out in vitro on blood lymphocytes from healthy human donors. The suggested cytostatic activity of bromocryptine was studied by evaluating the effects of progressively increasing doses (1, 5, 20 micrograms) of the drug on methyl-[3H]-thymidine incorporation by lymphocytes. A significant reduction of thymidine incorporation was observed corresponding to the increase of the bromocryptine dose which had been added to the cultures. With only 20 micrograms of bromocryptine the viability of cells was reduced by 50%. These results, which demonstrate that bromocryptine has an inhibitory action on DNA synthesis of cultured lymphocytes, suggest that it is justified to employ bromocryptine for medical therapy of large prolactinomas, in order to favour the subsequent surgical approach to these tumours.

Flunoxaprofen S-(+)-2 [p-fluorophenyl]-alpha-methyl-5-benzoxazole acetic acid, a new propionic acid derivative, was studied to investigate its long-term effectiveness and tolerability in the management of osteoarthritis (OA). To the study were admitted 154 patients suffering from radiologically proven OA of the large joints; 37% of them were hospitalized. The patients received flunoxaprofen 100 mg twice daily for a period of 45-60 days. The variables investigated were: pain at rest, pain on passive motion and pain on active motion with or without load, quality of sleep, articular flexion. In addition, the usual clinical and laboratory controls were carried out (arterial blood pressure, hepatic and renal function tests, haematological examinations). The assessments were made before and at 15, 30, 45 and 60 days of treatment. The results obtained show significant improvements for all variables considered and a very good tolerability of the drug concerning either laboratory controls or adverse reactions.

An evaluation was made of the possibility of exerting a protective action by administering natural water with a very low saline content, equal to 22 mg/l (oligomineral water), during the course of prolonged treatment with 9-alpha-fluoro-16-beta-methylprednisolone. The study was carried out using guinea-pigs (66 animals in all, of both sexes, clinically healthy, and of standard weight), which were divided into four groups which received, respectively: 9-alpha-fluoro-16-beta-methylprednisolone and aqua fontis, 9-alpha-fluoro-16-beta-methylprednisolone and oligomineral water, aqua fontis by itself, and oligomineral water by itself. Examinations carried out after thirty-four days of experimentation showed that the histomorphological damage to the liver and the digestive apparatus caused by the cortisonic therapy appeared to be considerably reduced and possibly eliminated when this therapy was combined with adequate administration of oligomineral water, such as the one considered in the present experiment.

A series of experiments was conducted on guinea-pigs treated with 9-alpha-fluoro-16-beta-methylprednisolone in order to evaluate the histomorphological damage to the renal parenchyma. Animals that were subjected at the same time to hydropinic therapy based on a mineral water with a very low saline content (oligomineral waters) exhibited far less damage than the control group which received aqua fontis.

Comparative absorption kinetics in volunteers of a new antiinflammatory drug (Selezen), in the form of 750 mg tablets and suppositories, were studied. The two components of the drug, imidazole and salicylic acid were found in plasma. Pharmacokinetic parameters were calculated according to a first order absorption. Salicylic acid showed a maximum concentration 59.2 +/- 5 min and 75.4 +/- 7.6 min after the administration of the tablet and suppository respectively; and imidazole after 86.3 +/- 10.8 min and 75.2 +/- 5.4 min, respectively.

Between July 1983 and December 1987, 13,108 strains of enterobacteriaceae were isolated at Charles Nicolle Hospital in Tunis. This study reports the prevalence of different species isolated, their resistance and the evolution of bacterial resistance during that period. There appeared to be a great stability in the distribution of bacterial groups. Among the commonly sensitive species, Proteus mirabilis showed a high proportion of strains resistant to ampicillin (79.3%), carbenicillin (75.9%), cefalotin (73.8%) and gentamicin (46%). The proportions of resistant strains in P. mirabilis were much the same for each successive year from 1983 to 1987, and the percentages of resistant strains in the majority of the bacterial species were similarly stable. Amikacin and cefotaxime remained the most active antibiotics against enterobacteriaceae.

Pharmacokinetics and electroencephalographic [EEG; power spectral analysis] effects of the acute oral Ca-antagonist darodipine (50 mg MR, 100 mg MR, and 200 mg MR) were investigated in a cross-over, placebo-controlled study on healthy male volunteers (age 23-28 yrs). No effects on heart rate, blood pressure or behaviour were observed with these doses at average Cmax levels ranging between 4.74 and 33.53 ng/ml and with a Tmax ranging from 2 to 6 h depending on the dose. No significant differences in drug kinetics were observed between the 100-mg and the 200-mg dose. A significant increase of EEG total power and a decrease of relative power in the 14.5-32.0 Hz frequency interval were observed at the 100-mg and 200-mg doses. These effects were greater and more consistent across subjects at 100 mg than at 200 mg, and were correlated with darodipine plasma concentrations, with indications of an active concentration threshold at approximately 4-5 ng/ml. The 50-mg dose proved ineffective on the EEG signal.

The pharmacokinetics of ciprofloxacin were examined after five days of treatment with 500 mg orally and 200 mg intravenously twice a day, in six healthy volunteers in an open, randomized crossover study. The ciprofloxacin concentrations were determined in serum by high performance liquid chromatography. The mean serum peak concentrations were obtained in 1 to 1.5 h by the oral route and the values reached were similar after the oral and intravenous dose (2.56 +/- 0.62 micrograms/ml and 2.6 +/- 0.67 micrograms/ml respectively). The terminal elimination half-life was about 4.5 h for oral form and 5 h for intravenous form. The absolute bioavailability of the oral ciprofloxacin was about 83%.

A randomized, three-way crossover study by gastroscopic examination in 24 healthy male volunteers was performed to compare the gastric tolerance of a single dose of buffered or unbuffered acetylsalicylic acid. Gastroscopic assessment was made two hours after administration of the buffered (800 mg ASA) or unbuffered (500 mg ASA) tablets taken with 200 ml of water. Mucosal changes were rare and of a minor nature. Only two volunteers in the unbuffered ASA group presented minor changes (erythema and oedema). No pathological changes were observed after the buffered ASA. Subjective adverse reactions, e.g. epigastric complaints, were reported by four volunteers in the unbuffered group and by two in the buffered group. Based on the limited number and the minor extent of visible changes, statistical tests did not appear to be warranted. The results indicate that buffered ASA is better tolerated.

Kinetics of trans- and cis-resveratrol (3,4',5-trihydroxystilbene), a natural compound from grape products, have been evaluated in rats after oral administration of red wine. Resveratrol concentrations were measured in plasma, heart, liver and kidneys. Tissue concentrations showed a significant cardiac bioavailability and strong affinity for liver and kidneys.

The enzyme inductive effect of flumecinol (Zixoryn, RGH-3332), a new hepatic enzyme inducer, was studied in healthy volunteers. The dosages employed were as follows: 25, 50, 100, 200, 400, 600 and 800 mg single doses; and during a 7-day period single doses of 50 mg daily, and doses of 200, 300 and 400 mg three times daily. The intensity of enzyme induction was measured by the following parameters: antipyrine metabolic clearance, D-glucaric acid excretion, menthol loading, and total serum bilirubin. The minimal and optimal inductive doses of flumecinol were determined. A single dose of 600 mg of flumecinol is recommended at intervals of 7 days. This dosage also induces the first and the second phases of reactions. The induction effect becomes manifest after 24 hours. Its peak is reached between 48 and 96 hours, and the inductive activity ceases between 216 and 408 hours.

We investigated the efficacy and tolerability of short-term treatment with tropisetron, a selective, competitive 5-HT3-receptor antagonist in fibromyalgia. The trial was designed as a prospective, multicenter, double-blind, parallel-group, dose-finding study. We randomly assigned 418 patients suffering from primary fibromyalgia to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily for 10 days. Clinical response was measured by changes in pain score, visual analog scale, tender point count and ancillary symptoms. Responders were prospectively defined as patients showing a 35% or higher reduction in pain score. Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) than placebo (26.2%) (p < 0.05). In the visual analog scale, the group administered 5 mg tropisetron showed a significant improvement (p < 0.05) and the group administered 10 mg tropisetron showed a nonsignificant clinical benefit. The number of painful tender points was significantly reduced (p = 0.002) in the 5 mg tropisetron group. Regarding ancillary symptoms, the 5 mg tropisetron group showed a significant improvement (p < 0.05) in sleep and dizziness. The patients' overall assessment of efficacy was significantly higher for 5 mg (p = 0.016) and 10 mg (p = 0.002) tropisetron than for placebo. The safety and tolerability of tropisetron was good; gastrointestinal tract symptoms were the most frequently reported adverse events. Short-term treatment of fibromyalgia patients with 5 mg tropisetron for 10 days proved to be efficacious and well tolerated. In this study a bell-shaped dose-response curve was seen.

The effect of the beta-adrenoceptor blocking drug propranolol was investigated in patients with alcoholic liver disease and in those without liver disease before and after ten days treatment with 80 mg daily. Caffeine as a marker drug for the 3-methylcholanthrene-inducible subtype had a significantly enhanced clearance after propranolol in liver-diseased patients, while the clearance of antipyrine which represents the phenobarbital-inducible subtype was unchanged. D-glucaric acid excretion as an endogenous compound which serves as an indicator of induced state of drug-metabolizing capacity of the liver was slightly enhanced in liver patients, but significantly decreased in patients without liver disorders. Indocyanine green elimination as a test material for substances limiting liver blood flow was not significantly reduced by this propranolol dosage.

The recoveries were compared of acetylsalicylic acid (ASA) and indalpine (1) after buccal absorption in three trained human volunteers. Recovery of the poorly lipid soluble ASA was less than 1% at pH 5 or 8, while that of the lipid soluble I was 19% and 13% at pH 5 and 8 respectively. This difference in recovery may represent a difference in their storage within the buccal mucosa dependent on their different lipid solubilities.

In this study measurements were made of the minimal inhibitory concentrations of 6 cephalosporins (cefamandole, cefuroxime, cefadroxil, cefoxatin and cefotaxime in comparison with cefalothin) against 532 bacterial strains isolated at the Regional Hospital Centre, Nantes, France, between 15.12.1977 and 15.3.1978. There were 163 Gram-positive bacteria of 2 species and 369 Gram-negative bacilli of 11 species and different genera. The results have been produced in the form of cumulative curves, in percentage for the most numerous genera or species. Cefalothin remained the most active on S. aureus and Listeria. Cefamandole came second. The action of the four other cephalosporins was very closely related to that in relation to S. aureus. For all the Gram-negative bacilli, Cefotaxime was the most active. Its MIC's can be up to more than 100 times lower than those of the other cephalosporins. Of the others, cefamandole appeared the best. It was difficult to classify the last four, as the MIC's may vary from one bacterial species to another. The bacterial activity (MBC) in a liquid medium was found for 178 of the strains (10 genera or species) of which one was Gram-positive (S. aureus). The ratio MBC/MIC (the measurements were taken in a liquid medium in all cases) confirmed the fact that all the cephalosporins are clearly bactericidal (the ratio was most often equal to 1 and sometimes to 2) for all the Gram-negative bacilli. Cefalothin and cefotaxime appeared the most bactericidal and cefamandole the least.

The pharmacokinetics and tolerance of a single oral dose (150 mg) of a new 3-azinomethyl rifamycin (SPA-S-565, USAN rifametane) was compared with 150 mg of conventional rifampicin in six healthy volunteers. The mean maximum concentration (Cmax) of SPA-S-565 was 3.94 +/- 0.26 micrograms/ml, and resulted significantly higher as compared with the Cmax after rifampicin, which was 2.89 +/- 0.20 micrograms/ml. The mean maximum time (tmax) for SPA-S-565 was 2.1 +/- 0.3 h as compared with that of rifampicin, which was 1.6 +/- 0.3 h, the difference between these values not being statistically significant. The elimination half-life (t1/2) of SPA-S-565 was 17.5 +/- 2.6 h in contrast to the half-life of 2.8 +/- 0.26 h seen with rifampicin; the difference was found to be highly significant. The mean area under the serum concentration curve from 0 to the last detectable concentration (AUC0-t) and the mean area under the serum concentration-versus-time curve from 0 to infinity (AUC0-infinity) of SPA-S-565 were almost six times than those obtained with conventional rifampicin. The differences between the two compounds were highly significant. In all cases except one volunteer all the biochemical parameters remained within normal range following single oral dose administration of SPA-S-565. In one volunteer, although there was a slight rise in serum alkaline phosphatase above the normal range, the original value itself was at the very upper limit of the normal range (i.e., 80 IU/L). Although there was a significant increase in the levels of serum alkaline phosphatase, serum gamma-glutamyl transpeptidase (GGTP) and serum amylase levels, 24 h following the administration of SPA-S-565 these levels remained within the normal range.

The pharmacokinetics of benflumetol as a fixed combination, artemether-benflumetol (CGP 56697), following three regimens [regimen A: four tablets at 0, 8, 24 and 48 h (320 mg artemether, 1,920 mg benflumetol); regimen B: two tablets at 0, 8, 24 and 48 h (160 mg artemether, 960 mg benflumetol); regimen C: four tablets at 0, 8 and 24 h (240 mg artemether, 1,440 mg benflumetol)] were investigated in 39 patients with acute uncomplicated falciparum malaria. All patients showed a rapid initial response with a median parasite clearance time of 40, 41 and 39.5 h and a fever clearance time of 27.8, 32 and 24.5 h for regimens A, B and C, respectively. In nine patients (two, four and three patients in regimens A, B and C, respectively), however, parasitemia reappeared in the peripheral blood smear between days 9 and 23. The pharmacokinetics of benflumetol were highly variable, with coefficients of variation in pharmacokinetic parameters ranging from 14.9% to 144%. Absorption and elimination of benflumetol were relatively slow. Median Cmax per dose (first dose) was significantly higher in regimen B (6.29 ng/ml/mg dose) than in regimen A (2.6 ng/ml/mg dose) and regimen C (3.06 ng/ml/mg dose). Mean T1/2z in regimen C (2.65 h) was significantly shorter than in regimen A (4.5 h) and regimen B (3.89 h). In patients on regimens A and B who showed a sensitive response, plasma concentrations of benflumetol were significantly higher than in those with treatment failure.

The plasma pharmacokinetics and urinary excretion of CM 57755, an H2-receptor antagonist, were studied after administration of single oral doses in a range between a 100 and 700 mg in human volunteers. Pharmacokinetic parameters were calculated model-independent. Absorption of CM 57755 was bimodal and the maximum plasma concentration was reached between 2 and 4 h after dosing. The drug was widely distributed with an apparent volume of distribution between 140 and 200 l. The plasma clearance was between 56 and 69 L/h. The plasma concentrations declined following a monoexponential function with an elimination half-life of 2 h. No modification in the plasma clearance or other pharmacokinetic parameters with these doses was observed. Therefore, a linear pharmacokinetic profile of CM 57755 was proposed. About 40% of the parent drug was unchanged in urine excreted over the 24 h. The drug was compared with cimetidine and ranitidine, the three compounds seemed to exhibit a consistent pharmacokinetic profile.

Etodolac SR is the sustained-release formulation of etodolac, an effective anti-inflammatory drug used in the treatment of various rheumatic diseases. The efficacy and safety of etodolac SR were compared with those of tenoxicam in 120 elderly patients with radiographic and clinical evidence of active osteoarthritis (OA) of the knee and/or the hip. This was a double-blind, double-dummy, randomized, parallel-group, multicentre study conducted at 4 Italian rheumatic-disease units. Sixty patients received 600 mg of etodolac SR once daily (u.i.d.) for 8 weeks; the remaining 60 patients received 20 mg of tenoxicam u.i.d. Significant improvements in all 6 efficacy parameters (viso-analogic scale of the global pain, pain at active movements, night pain, joint tenderness, joint motility, and Lequesne's algofunctional index) were observed within each of the treatment groups even after the first 2 weeks of therapy. There were no significant differences in the therapeutic response between the two groups for any efficacy parameters. Adverse reactions, mostly regarding the G-I tract, were significantly more frequent in the tenoxicam group than in the etodolac group: 23.3% vs 8.3% respectively, albeit in the majority of the cases they were not considered to be so severe as to cause the interruption of the study. There were no clinically important changes from baseline in laboratory tests performed during the study. Endoscopy of the upper G-I tract was performed both at baseline and after 8 weeks of therapy in 30 patients per treatment group in order to obtain a reliable comparative evaluation of the G-I safety of the two drugs. Both drugs were found to be well tolerated; only 2 ulcers were observed after therapy in both groups, but minor lesions were more frequently detected in the mucosa of the stomach in the patients who received tenoxicam. The cumulative endoscopic index that reflected both the erosive and the haemorrhagic lesions found in the stomach taken as a whole was significantly (p < 0.03) higher after therapy in the tenoxicam group. These results indicate that 600 mg of etodolac SR u.i.d. for 8 weeks is as effective as 20 mg of tenoxicam u.i.d. in the treatment of OA of the knee and/or of the hip. Both the overall and the G-I specific safety profiles were found to be more favourable in patients treated with etodolac SR. Renal function was not substantially affected in either treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

L-697,639, a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in vitro, was administered to healthy male volunteers to investigate the pharmacokinetics and tolerability of single and multiple oral doses. Single doses ranging from 25 to 500 mg, and multiple doses of up to 100 mg every 12 h for ten days, produced no clinically important adverse events. Dose proportionality with respect to AUC was seen over the range of 25-100 mg administered as a single dose. Single doses of 200 mg and 500 mg resulted in an increase in AUC and Cmax that was less than proportional to the increase in dose. The mean Cmax after single doses of 25 and 500 mg were 0.9 and 5.8 microM respectively. Mean Tmax values ranged from 1.7-3 h. Mean AUCs (0-48 h) were from 6.05 to 50.3 microM h after doses from 25 to 500 mg respectively. After the 500-mg dose less than 0.7% appeared unchanged in the urine over 48 hours. During multiple doses, steady-state was reached on day 3 and slight accumulation occurred (approximately 1.5-fold). L-697,639 was well tolerated for up to ten days at doses that resulted in mean steady-state trough concentrations that exceed their in-vitro susceptibilities.

Some investigators have postulated that a constant low blood level might be the ideal mode of treatment, while others have seen no reason to divide up the daily dose. To our knowledge, this study is the first to include crossover of subjects to eradicate individual differences. Our aim was to compare the pharmacokinetic effects of administering etoposide three times a day vs. once a day as 25 mg capsules. Two groups of four patients each received 75 mg/day oral etoposide for 2 days either as 75 mg once daily, or as 25 mg three times daily for 2 days. On days 8 and 9, the treatments were switched between groups. On the one-dose schedule, Cpeek (peak plasma concentration) was greater than 2 micrograms/ml in five patients and greater than 3 micrograms/ml in three patients, while in none of the patients on the three-dose schedule did the peak exceed 2 micrograms/ml. No significant difference was found in terms of Cmean (calculated by dividing the area under the curve by the observed time) between the two treatments. Variability of blood concentrations of etoposide over a 24 h period was high on the one-dose schedule (median 95%, range 54-148%) but it was lower on the three-dose schedule (median 39%, range 28%-55%). No significant differences were found between the two different dosing schedules in terms of the median duration of etoposide blood levels above 0.5 microgram/ml and above 1.0 microgram/ml. These results suggest that detailed clinical toxicity and efficacy data are needed to clarify the possible benefits of the fractionated administration of oral etoposide.

The mechanism capable of transforming episodic migraine into chronic migraine is attributed by the authors to hyperalgesia and related neuroplastic changes, chiefly long-term potentiation, due to the action of excitatory amino acids, chiefly the ones acting at N-methyl D-aspartate (NMDA) receptor. A preeminent role has been attributed to 'third hyperalgesia', a newly observed type of hyperalgesia which is inheritable and can act as a ground for the above-mentioned mechanism of 'chronicization' of migraine. The role of primary and secondary hyperalgesia in giving redundance to neuraxial abnormalities is also discussed. The fact that NMDA noncompetitive antagonist ketamine and gabapentin, inhibitor of the neuronal synthesis of L-glutamate, can cure chronic migraine, so far considered refractory to prophylactic therapies, gives indirect but evident support to the mechanism suggested above. The antinociceptive role of the above-mentioned negative modulators of excitatory amino acids and the possible interplay between ionotropic and metabotropic receptors are also taken into consideration.

The chorioallantoic membrane (CAM) assay is a bioassay used widely for testing angiogenic activities of compounds. In the present study, we used this assay to explore the gross and micropathological effects of 2-piperadino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo[3,4-d] pyrimidine maleate (MS-818) in combination with basic fibroblast growth factor (bFGF). Light microscopy revealed that application of 1, 10 and 100 ng/ml bFGF to the CAM induced a concentration-dependent increase in the number of new blood vessels, whereas application of 0.01, 0.1 and 1.0 mM MS-818 did not increase angiogenesis significantly. The combinations of 10 ng/ml bFGF with 0.1, 0.1 and 1.0 mM MS-818 showed significantly greater angiogenic effects than 10 ng/ml bFGF alone. However, 1 and 100 ng/ml bFGF in combination with these concentrations of MS-818 showed no additive effects. Histologically, numerous mononuclear cells became present in the mesodermal stroma, especially around the capillaries, when MS-818 alone and with bFGF was applied to the CAM. The new vessels formed in response to MS-818 plus bFGF were smaller than those formed with bFGF alone. These results suggest that, in the CAM assay system, MS-818 promoted angiogenesis effectively when the concentration or activity of the angiogenic factor (bFGF) was potentiated by MS-818 at a real optimal level.

Digoxin and Verapamil may often be used in association in heart diseases; we tested whether this coadministration increases digitalis activity. Ten patients with failing heart were given 0.10 mg of beta-methyldigoxin, twice a day, for nine days; then they received in addition 80 mg of Verapamil, four times a day, for seven days. Digoxin activity was measured on the eighth, ninth and 16th days of treatment by 86Rubidium uptake in erythrocytes. The steady-state concentration was 0.91 +/- 0.13 ng/ml; during the coadministration the concentration rose to 1.23 +/- 0.16 ng/ml (an increase of 35.12%). The change was significant (p less than 0.001). The mechanism of this increase is unknown: it is important that there exists an increase in digitalis activity and not only a haematic elevation.

The cardiovascular effects of a new antihypertensive agent, prizidilol hydrochloride (SK&F 92657), have been evaluated in a group of 13 patients with mild to moderate essential hypertension, both at rest and during mental stress and isometric or dynamic exercise. After 6 weeks of therapy (200-300 mg of prizidilol b.i.d.) both systolic and diastolic blood pressure values at rest were significantly lower than those recorded before treatment and during placebo (with an average decrease of about 22/11 mm Hg in the supine position). Heart rate at rest was slightly reduced. Cardiovascular responses to dynamic exercise and mental stress were not prevented by prizidilol, but blood pressure and heart rate levels around which variation occurred were lowered to a significant extent. During isometric exercise prizidilol did not protect against a rise in diastolic blood pressure. Blood pressure and heart rate reduction both at rest and during stimulation were not related to plasma drug concentrations. Side-effects were very rare. It is concluded that prizidilol significantly reduces blood pressure both at rest and during mental stress and physical activity with only sight effects on heart rate, and with a very simple therapeutic scheme.

Three different doses (50, 100 and 200 mg) of prizidilol hydrochloride (SK&F 92657), a novel antihypertensive agent with vasodilating and beta-adrenoreceptor blocking properties, were given to three (n = 5) groups of essential hypertensive patients in order to evaluate hypotensive dose-response relationship of the drug and its beta-adrenoreceptor blocking properties. Irrespective of the dose given, acute administration of prizidilol did not effectively decrease blood pressure; however after one-week of treatment prizidilol was effective in reducing blood pressure at both the 100 and the 200 mg b.i.d. schedules. At these doses the drug decreased resting heart rate and plasma renin activity for the first 4-6 h after both acute and steady-state dosing. Similarly postdynamic exercise tachycardia was reduced to a significant extent by the drug; after acute administration this effect lasted 2 h with the lowest dose and 4 h with the highest one. After chronic administration this effect lasted up to 10 h for both the 100 and 200 mg doses. These data indicate that: chronic prizidilol treatment can achieve a satisfactory control of blood pressure in patients with mild-moderate essential hypertension; when prizidilol is administered chronically in hypertensive patients, an equally effective control of blood pressure can be obtained with either a 200 mg b.i.d. or a 100 mg b.i.d. schedule; prizidilol possesses beta-adrenoceptor blocking properties in man which can contribute to its pharmacodynamic activity.

The pharmacokinetics of oxmetidine (SK&F 92994) were investigated in nine cirrhotic patients and compared with ten control subjects with gastroduodenal ulcers, but without any symptoms of hepatic pathology. On two separate occasions each patient received 200 mg oxmetidine as a single oral dose and 100 mg as a single intravenous dose. In the cirrhotics, the bioavailability of the oral dose and the plasma elimination half-life after both oral and intravenous administration were significantly higher than in the controls. Moreover, a positive correlation was found between the plasma elimination half-lives and the biochemical parameters of cholestasis. Such findings indicate that in severe liver disease and in cholestasis the accumulation of oxmetidine in the circulation may limit the use of this drug.

The effects of a single-dose oral administration of a thromboxane A2 receptor antagonist, vapiprost (SN-309), on pharmacokinetic profile and inhibition of platelet aggregation were investigated in six healthy elderly volunteers (age: 65-72 years) and the influence of age on these parameters was studied by comparison with the results obtained in phase-I data involving healthy young participants. Although direct comparison of pharmacokinetic parameters was inappropriate because of different models, high Cmax and AUC values were obtained on comparison with the young. The inhibition of platelet aggregation in platelet rich plasma induced by U-46619 or collagen was rapidly established and remained suppressed for more than 8 h, although the effect was short-acting compared with the inhibition period in the young. This suggests that dose adjustment in the elderly is unnecessary In addition to a routine pharmacokinetic approach to determine the time-profile of vapiprost, population pharmacokinetics were studied using data from 51 volunteers in five clinical trials including the two above-mentioned studies. By fitting 812 plasma-monitoring points into the two-compartment model, the effects of several factors including age on parameters were investigated, based on the nonlinear mixed effect model. Clearance in the elderly attenuated 82.2% of that in the young, the distribution volume varied with platelet counts and delayed absorption was observed in volunteers with, rather than without, food intake. Closer bridging studies with other countries have resulted in the current local situation of abbreviating phase-III studies. Consequently to clarify the pharmacokinetic profile of the elderly in Japan and other countries, the population pharmacokinetics approach based on the data in the various phase I-II trials is useful.

Pathophysiological aspects of acute myocardial infarction include altered hemostatic and fibrinolytic systems as well as platelet activation. Treatment with thrombolytics and GP IIb/IIIa antagonists has been described as having an additional influence on these systems. We investigated the effects of a new thrombolytic regimen with half-dose double-bolus reteplase (2 x 5 IU, 20 patients) combined with abciximab versus full dose reteplase (2 x 10 IU, 18 patients) on platelet-granulocyte complexes and on thrombin-antithrombin III complexes in patients with acute ST-segment elevation myocardial infarction. In vivo, the thrombolytic regimen with half-dose reteplase in combination with abciximab caused fewer platelet-granulocyte aggregates (measured as percentage of CD41-positive granulocytes) and a lower paradoxical activation of the coagulation system (measured as thrombin-antithrombin III complex) compared with the reteplase regimen. The combination regimen could therefore have benefical effects on platelet-induced leukocyte activation and leukocyte-mediated proinflammatory/cytotoxic effects as well as on granulocyte-induced effects on endothelium, tissue damage and coagulation. This could be, at least in part, a possible explanation for the significantly lower rates of reinfarction, recurrent ischaemia and percutaneous coronary interventions observed during the early phase after an acute myocardial infarction in the combination group in the GUSTO-V trial.

Seventy patients admitted for abdominal surgery requiring short-term perioperative prophylaxis were randomized to receive minocycline + gentamicin or metronidazole + gentamicin. Thirty patients were considered to be infected at the time of surgery and were treated with the same regimen. In the prophylactic cohort, one patient from each group developed postoperative fever. One patient receiving minocycline developed a wound infection. The overall infection rate was 2.6%. In the treatment cohort, it appeared that the patients receiving metronidazole had more severe underlying diseases than those receiving minocycline. Consequently, more postoperative non-infectious complications were observed in the former. Minocycline + gentamicin appeared at least as effective than metronidazole + gentamicin in preventing postoperative infectious complications associated with abdominal surgery or in treating intra-abdominal infections.

The immune responses against isolated microorganisms in patients with intraabdominal infections treated with meropenem or imipenem/cilastatin were investigated. Fifty-nine patients received meropenem 500 mg t.i.d. intravenously for 3-21 days (mean 5.4 days) and 50 patients imipenem/cilastatin 500 mg/500 mg t.i.d. intravenously for 3-17 days (mean 5.1 days). Three serum samples were taken from each patient, the first sample at admission, the second sample between three and seven days after start of antibiotic treatment, and the third sample between 14 and 28 days later. Ninety-eight per cent of the patients in the meropenem group and 95% of the patients in the imipenem/cilastatin group were cured. There was no difference in the clinical outcome between the two treatment groups. Escherichia coli, Bacteroides fragilis group, anaerobic cocci, Staphylococcus epidermidis, and Klebsiella spp. predominated among the isolated microorganisms. Thirty-nine patients in the meropenem group had significant immune responses against one or more of the isolated microorganisms while 31 patients in the imipenem/group had significant responses. E. coli and B. fragilis gave rise in antibody titres in most patients indicating that these species are the most important pathogens in intraabdominal infections.

Cefotetan has been compared with two regimens of combination antibiotic therapy in the treatment of peritonitis and serious intra-abdominal sepsis. One hundred predominantly elderly patients (median age 66 years) were entered into a prospective randomized surgical trial. Sixty-two per cent had peritonitis. There were seven non-septic deaths. Side-effects were similar in each group and generally of a minor, self limiting nature. Haematological and biochemical factors were closely monitored, and though there were increases in the prothrombin time, there was no statistical difference between cefotetan and comparators. Cefotetan is as effective as combination therapy in the treatment of surgical patients with serious intra-abdominal sepsis.

To investigate the influence of liver cirrhosis on the capacity of methylation, the urinary excretion of the methylated forms of arsenic was measured by atomic absorption spectrometry after the administration of a small dose of inorganic arsenic. The study was carried out in 13 normal controls, 18 patients with various clinical conditions, but without evidence of parenchymal liver disease, and 38 with cirrhosis of varied aetiology and severity. In normal controls, the percentage of arsenic excreted as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) averaged 12.3 +/- 2.8% and 23.3 +/- 6.4%, respectively, and was not significantly different from that obtained in disease controls. The presence of liver cirrhosis did not affect the percentage of the injected dose excreted within 24 h. However, cirrhotic patients excreted significantly less MMA (4.7 +/- 3.3, p less than 0.001) and more DMA (40.4 +/- 16.6%, p less than 0.001). The amount of MMA correlated with the 14C aminopyrine breath test (r = 0.43) and was invariably lower than the normal range in patients with severe liver disease. These findings indicate that liver cirrhosis is associated with profound abnormalities of the methylation pathway, which might have potential consequences in the metabolism of endogenous amines and xenobiotics.

Hyperalgesia is known to depend on neuroplastic changes chiefly represented by long-term potentiation. These phenomena are proved to depend on excitatory amino acids (EAAs) action at the level of NMDA receptors. This action is known to be related to nitric oxide (NO) release. We found a visceral/vascular hyperalgesia state in migraine (M) sufferers as well as an inheritable systemic hyperalgesia in healthy subjects who are first-degree consanguineous with M sufferers; this type was labelled 'third hyperalgesia'. We discovered that a hyper-increase of plasma L-citrulline, equimolar co-product in the synthesis of NO, characterizes both M sufferers and their first-degree relatives who are exempt from primary headache. A similar pattern never occurred in healthy subjects having both a personal and family history negative for primary headache. We conclude that both 'third hyperalgesia' and a pattern of NO synthase (NOS) hyperactivity seems to be inheritable and can constitute, at least in part, a ground for developing headache. Morphine, proved to be unable to relieve M attack, was given in low doses that caused pain and side-effects in M sufferers only. This outcome seemingly indicates that M sufferers are characterized by a set-up of opioid receptor subtypes different from that of healthy headache-exempts. Following a period of morphine addiction and a withdrawal period, 65.07% of a group of 63 opiate addicts developed M syndrome. All these subjects were first-degree consanguineous relatives of primary headache sufferers. Discussion topics concern the activity of morphine in NO release and the role of NO in sensory transmission of both controls and hyperalgesia sufferers. It is suggested that the inheritable couple consisting of hyperalgesia and NOS hyperactivity can play some role in setting off the pain occurring following morphine in M sufferers.