On the occurrence of radioactive fallout over Norway as a result of the Windscale accident, October 1957.

A fire at the Windscale plant at Cumbria in the UK between the 10th and the 11th of October 1957 resulted in the first publicised release of radioactivity to the wider environment. The cloud of contamination passed to the southeast of England before travelling northwards on the 14th of October as a result of weather fronts in Europe. Monitoring of radioactive fallout in Norway was at the time conducted by the Norwegian Defence Research Establishment (FFI) using a network of air and precipitation monitoring stations. This article presents results from these monitoring activities which were originally contained in laboratory journals and a series of internal reports produced by FFI. Although mainly classified during the 1950s and 1960s, recent years have seen the incremental declassification of these reports and as the 50th anniversary of the accident approaches, a distillation and reanalysis of this information has been conducted. Results indicate that radioactivity from Windscale was first detected at Bergen and Sola in the south west of Norway and a little later at Vaernes, significant amounts of radioactivity being deposited at these locations during the second and third weeks of that month. Results relating to concentrations of activity in air and precipitation and fallout levels are presented for the relevant period and discussed in relation to fallout levels in Norway during the period 1957-1960.

Kinetics of a sulfadiazine-trimethoprim combination.

The pharmacokinetics of a combination of sulfadiazine and trimethoprim has been studied in 16 patients with varying degrees of reduced renal function. In normal renal function, the serum half-life (t1/2) of active sulfadiazine, total sulfadiazine, and trimethoprim were quite close: 7.7, 9.6, and 12.1 hr, respectively. There was a gradual increase in serum t1/2 with reduction in renal function for both active and total sulfadiazine and for trimethoprim. With accurate determinations of endogenous renal clearance, t1/2 estimates may be made from regression curves presented. The relative distribution in the body was unrelated to renal function. It was similar for the two fractions of sulfonamide and higher for trimethoprim. The means were 0.371, 0.176, and 1.104 L/kg, respectively, for active and total sulfadiazine, and trimethoprim.

Pharmacokinetics of ciprofloxacin: intravenous and increasing oral doses.

The pharmacokinetics of ciprofloxacin, after administration of single oral doses of 100, 250, 500, and 1,000 mg, and an intravenous dose of 100 mg, were determined in 12 healthy volunteers (six women and six men). Serum concentrations were determined by high-pressure liquid chromatography, and urine samples were assayed microbiologically. The peak serum concentrations and the total areas under the serum concentration curves increased in proportion to the size of the oral dose. The pharmacokinetics of ciprofloxacin were described by a dose-independent linear relationship. The apparent oral bioavailability was 85 percent, based on comparison of the total areas under the serum concentration curves of the 100-mg dose. The serum concentrations during steady state were not significantly higher than after the first dose. The serum half-life ranged from 3.0 to 3.4 hours after the oral doses, and was 2.9 hours after the intravenous dose. The elimination-phase apparent distribution volume coefficient, delta d,area, was 2.76 liters/kg, and the total body clearance was 42.0 liters/hour. The 24-hour urinary excretion was 42.2 +/- 15.6 percent after the 100-mg intravenous dose and 42.5 +/- 17.6 percent after the 500-mg twice-daily oral dose during steady state.

Clinical pharmacokinetics of co-trimazine.

The clinical pharmacokinetics of co-trimazine (trimethoprim plus sulphadiazine) are reviewed and compared with those of co-trimoxazole (trimethoprim plus sulphamethoxazole). Both combination drugs have similar serum half-life values in persons with normal renal function (half-life of 8 to 12 hours), but the sulphamethoxazole metabolites are retained more than trimethoprim in reduced renal function. Sulphadiazine is less metabolised and the total sulphonamide load of therapeutic doses of co-trimazine is therefore less than for co-trimoxazole. Both co-trimazine and co-trimoxazole have high bioavailability. A suspension of co-trimazine gives serum concentrations comparable with those of tablets. The extravascular penetration of the co-trimazine components is reflected by the total area under the lymph concentration curve in comparison with serum. This measure shows a penetration into peripheral human lymph of 68% for sulphadiazine and 59% for trimethoprim. The proportions eliminated in urine are about 55% for sulphadiazine, 30% for its acetylated metabolite and 75% for trimethoprim. In comparison, for co-trimoxazole, the proportion of sulphamethoxazole eliminated in urine is 15%, that of the acetylated derivative 47%, and that of trimethoprim is also 75%. Urine concentrations of both combinations have similar bioactivity against urinary pathogens after 500 mg of co-trimazine and 960 mg of co-trimoxazole.

Quinolones in the elderly.

Aging results in a number of physiological changes that can affect drug disposition; these include reduced gastric acidity, decreased intestinal motility, lower lean body mass, and reduction in renal function. The age-related decline in renal function is the most important of these factors when administering quinolones to elderly patients. Elimination half-life (t1/2) values are prolonged in proportion to the degree to which the compound is normally eliminated by the renal route. Thus, age-related increases in t1/2 occur to a greater degree with ofloxacin (80 to 90% renal elimination) than with ciprofloxacin, which is also excreted by the gastro-intestinal route. Norfloxacin, pefloxacin, and sparfloxacin may also be eliminated to a substantial degree by the transintestinal route, as their excretion is not substantially affected by severe renal impairment. Prolonged drug elimination in the elderly can result in an increased incidence of adverse effects. Ofloxacin causes a higher frequency of drug-related events in the elderly, presumably reflecting the prolonged serum t1/2 and higher serum concentrations, and consequently higher tissue levels in this age group. Indeed, dosage reduction is recommended when treating elderly patients with ofloxacin, but does not appear necessary on the basis of advanced age for ciprofloxacin, norfloxacin and pefloxacin.

Pharmacokinetic properties of the cephalosporins.

Most cephalosporins can only be administered parenterally. Among agents that are absorbed from the gastrointestinal tract, those with bioavailabilities of 85 to 90% include cefroxadine, cefadroxil, cefsumide, cephalexin, cephradine, cephacetrile, and cefazaflur. Most cephalosporins are eliminated rapidly, with serum half-lives (t1/2s) of 1 to 2 hours. Exceptions are cefonicid with a t1/2 of 4.4 hours, cefpiramide with a t1/2 of 5.0 hours, and cefotetan with a t1/2 of 3.5 hours. The longest half-life is shown by ceftriaxone with a t1/2 of 8.5 hours. Cephalosporins are eliminated mostly by the kidneys, some with a substantial contribution from active tubular secretion, which is blocked by probenecid. The degree of metabolism varies. Only a few cephalosporins have a high biliary elimination. For example, with intravenously administered cefoperazone, about 70% appears in bile. High biliary elimination is also observed with cefmenoxime, ceftriaxone, cefbuperazone, and latamoxef (moxalactam). Because these are not appreciably absorbed from the gastrointestinal tract, the consequence is high intraintestinal concentrations of the drugs and a marked ensuing depression of the normal microflora with simultaneous emergence of resistant bacteria. The untoward ecological impact may even lead to Clostridium difficile-associated enterocolitis.

Temocillin penetration of peripheral lymph.

An intravenous dose of temocillin 1g was administered to 5 healthy human volunteers from whom peripheral lymph, serum and urine were monitored for 12 hours. The concentrations after 1 hour were 14.3 mg/L in lymph and 58.1 mg/L in serum. The mean peak concentration in lymph (appearing between 1.5 and 2 hours) was 30.6 mg/L, and the simultaneous serum level was 47.8 mg/L. The lymph concentrations were always below those in serum, and the elimination half-life was 4.4 hours from lymph compared with 4.9 hours from serum. The ratio between the total areas under the concentration curves in lymph and in serum was 0.56, which reflects the ability of temocillin to penetrate to lymph. Serum protein binding appeared to impede the rate of transport from serum to lymph, but when compared with the results of less highly bound penicillins the total penetration of temocillin was better than expected.

Pelvic inflammatory disease: etiologic studies with emphasis on chlamydial infection.

Chlamydia trachomatis is one of the main etiologic agents in pelvic inflammatory disease (PID) in Oslo. Up to two thirds of the 65 PID cases studied were associated with a chlamydial infection. The incidence of cervical gonorrhea was low (7.7%). Anaerobic bacteria were not isolated from the fallopian tubes or peritoneal fluid of any of the patients. Chlamydia-associated PID is characterized by a protracted course and vague symptoms. The laparoscopic findings indicate more severe inflammatory changes of the tubes than in patients in whom these agents were not found. The highest incidence of chlamydia-associated PID occurred in younger subjects, among whom the intrauterine contraceptive device was more frequently used. Perihepatitis was diagnosed in PID patients with and without chlamydial infection of the genital tract.

Extravascular penetration of ciprofloxacin. A review.

The pharmacokinetics of ciprofloxacin after oral and intravenous administration have been studied extensively, and the results have been published worldwide. This paper serves as a review of the pharmacokinetics of ciprofloxacin, with specific reference to its penetration into body fluids and tissues. Ciprofloxacin has a protein binding of approximately 30% and penetrates well into tissues. For instance, the total concentration (area under the serum concentration-time curve) in peripheral human lymph is 70% of the serum values, and the peak level in lymph appears with 1-2 hr. The corresponding value for suction skin blisters is 60% and for inflammatory blisters 120%. Ciprofloxacin is concentrated in white blood cells, lung, prostate, and kidney and reaches concentrations above serum in many other tissues as well. Urine concentrations are up to 100 times those in serum. The levels in bile are comparable or only slightly higher (less than or equal to x 10) than serum levels. The penetration into cerebrospinal fluid (CSF) is low; the CSF levels are 4-10% of the serum levels in noninflammatory CSF and 30-50% in CSF from patients with meningitis.

Transintestinal elimination of ciprofloxacin.

This study identified the routes of elimination of ciprofloxacin in two groups of five subjects each: one of healthy volunteers; the other of patients with severe renal failure having mean creatinine clearance of 12 ml/min (range, 8-16 ml/min). Each subject received one dose of 200 mg ciprofloxacin infused intravenously (IV) over 30 min. In an effort to recover the total drug administered, all urine and feces were collected for 7 days following dosing. Blood samples were drawn at set intervals. Serum, urine, and feces were assayed for ciprofloxacin and metabolites by high-pressure liquid chromatography. The ciprofloxacin elimination half-life was 3.9 +/- 0.4 hr in the healthy volunteers and 11.2 +/- 2.5 hr in the patients with severe renal failure. The total 7-day recovery of ciprofloxacin and its metabolites in urine and feces ranged from 74.0% to 114.7% of the dose (mean, 96.3 +/- 14.1%) in normal subjects and from 48.5% to 109.1% (mean, 88.1 +/- 20.9%) in patients. The dose of ciprofloxacin recovered in urine was 65.3 +/- 10.7% in healthy subjects and 19.0 +/- 15.9% in impaired patients (reduction factor, 3.4). In contrast, the dose recovered in feces was 11.4 +/- 2.6% in the group of normal subjects and 37.2 +/- 12.5% in the group of patients with impaired renal function in a 3.3-fold increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasmid profiles compared with serotyping and pyocin typing for epidemiological surveillance of Pseudomonas aeruginosa.

The plasmid profiles of 112 clinical isolates of Pseudomonas aeruginosa were determined by two reproducible, rapid, plasmid screening methods. Plasmid DNA was present in 15% of isolates examined. Plasmids varied in size from 1.2 X 10(6) to 60.2 X 10(6) mol. wt. The dominant serotypes encountered were O:11 and O:4, which comprised 38% and 12% of strains, respectively. Four pyocin types (1, 10, 3 and 5) dominated (respective frequencies: 56, 15, 12 and 6%). Reproducibility of pyocin typing was distinctly inferior to both plasmid profiling and serotyping. Strains of identical serotypes could be further differentiated by dissimilar plasmid profiles. Serologically untypable or polyagglutinable strains were successfully characterised by plasmid profile patterns. Thus, plasmid profiling was shown to be a useful adjunct to serotyping for the epidemiological typing of P. aeruginosa.

Chlorpromazine inhibition of enterotoxin-induced fluid secretion and cAMP production in rat ileum.

A heat-labile enterotoxin prepared from E. coli (EcLT) increased fluid secretion and cAMP production by segments of rat ileum in vivo and in vitro. The effect of this toxin was compared to that of cholera toxin (VcLT). The increase of cAMP occurred more rapidly after EcLT than after VcLT indicating a difference in the kinetics of uptake or action of the two toxins. Chlorpromazine (CPZ) 5 mg/kg given by intramuscular injection 1 h before application of the toxins inhibited the increase in cAMP levels and the increase in fluid secretion in vivo. CPZ 10(-4) M given together with the toxins to intestinal loops in vitro inhibited the increase in cAMP levels and fluid secretion by this preparation. Scanning electron microscopy revealed that CPZ caused extensive shedding of the fluid-producing mucosal cells.

Antibiotic usage in Nordic countries.

The consumption of antibacterials has remained relatively stable in Scandinavia and is low compared with most other countries. Measured as "Defined Daily Doses" (DDD), the highest consumption is found in Iceland and Finland, and the lowest in Denmark and Norway. The consumption in Iceland, Finland and Sweden is about twice that in Norway. The distribution of different classes of antimicrobials shows striking differences. Phenoxymethyl and benzylpenicillin make up about 55% of the DDDs in Sweden and 40% of the DDDs in Denmark and Norway, whereas the narrow-spectrum penicillins represent 20% of the DDDs in Iceland. Fluoroquinolones are little used except in Sweden where they account for about 10% of DDDs. The use of cephalosporins ranges from 1% (in Denmark) to 15% (in Finland) and between 3 and 5% in the other countries. The policy that narrow-spectrum penicillins may be used when necessary but broad-spectrum compounds should be avoided has the positive effect that there is greater susceptibility in the Nordic countries to these antibiotics than elsewhere.

Antibiotic resistance of pneumococci in Norway.

A collection of 178 pneumococcal isolates found in Norway during the period 1987-1994 were tested for their susceptibility to benzylpenicillin, macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, spiramycin), fluoroquinolones (ciprofloxacin, sparfloxacin), imipenem, chloramphenicol, and vancomycin by a standard agar dilution procedure. To benzylpenicillin, two strains (1%) showed resistance and 14 strains (8%) intermediate susceptibility. Towards erythromycin, eight strains (4%) showed resistance and four strains (2%) intermediate susceptibility. Cross-resistance was demonstrated among the macrolides. Among the fluoroquinolones, intermediate susceptibility occurred with 42% of the isolates for sparfioxacin and 90% for ciprofloxacin; to the latter 5.1% proved resistant. The sum of intermediate and highly resistant isolates was 53% for chloramphenicol. Both penicillin-resistant strains were isolated during the last 2 years of collection and came from patients of non-Norwegian ethnic background. Imported strains appeared over represented among the strains resistant to penicillin and macrolides. Only imipenem and vancomycin showed full susceptibility for all pneumococci tested. An over representation of serogroup 6 strains was apparent among the strains with intermediate susceptibility and high resistance to benzylpenicillin. It is apparent that high-level resistance has, not so far, become a difficult problem in Norway. Nevertheless, the situation requires monitoring of the resistance level, particularly in meningitis and septic patients, and certainly in patients who cntail a higher than usual possibility of acquiring pneumococci from pools of resistant strains outside Norway (visitors, immigrants and recent returness from abroad).

Vaginal disinfection with chlorhexidine during childbirth.

The purpose of this study was to determine whether chlorhexidine vaginal douching, applied by a squeeze bottle intra partum, reduced mother-to-child transmission of vaginal microorganisms including Streptococcus agalactiae (streptococcus serogroup B = GBS) and hence infectious morbidity in both mother and child. A prospective controlled study was conducted on pairs of mothers and their offspring. During the first 4 months (reference phase), the vaginal flora of women in labour was recorded and the newborns monitored. During the next 5 months (intervention phase), a trial of randomized, blinded placebo controlled douching with either 0.2% chlorhexidine or sterile saline was performed on 1130 women in vaginal labour. During childbirth, bacteria were isolated from 78% of the women. Vertical transmission of microbes occurred in 43% of the reference deliveries. In the double blind study, vaginal douching with chlorhexidine significantly reduced the vertical transmission rate from 35% (saline) to 18% (chlorhexidine), (P < 0.000 1, 95% confidence interval 0.12-0.22). The lower rate of bacteria isolated from the latter group was accompanied by a significantly reduced early infectious morbidity in the neonates (P < 0.05, 95% confidence interval 0.00-0.06). This finding was particularly pronounced in Str. agalactiae infections (P < 0.0 1). In the early postpartum period, fever in the mothers was significantly lower in the patients offered vaginal disinfection, a reduction from 7.2% in those douched using saline compared with 3.3% in those disinfected using chlorhexidine (P < 0.05, 95% confidence interval 0.01-0.06). A parallel lower occurrence of urinary tract infections was also observed, 6.2% in the saline group as compared with 3.4% in the chlorhexidine group (P < 0.01, 95% confidence p interval 0.00-0.05). This prospective controlled trial demonstrated that vaginal douching with 0.2% chlorhexidine during labour can significantly reduce both maternal and early neonatal infectious morbidity. The squeeze bottle procedure was simple, quick, and well tolerated. The beneficial effect may be ascribed both to mechanical cleansing by liquid flow and to the disinfective action of chlorhexidine.

Epidemiological markers for Pseudomonas aeruginosa. VII. Nosocomial occurrence in urological ward. Comparison of two phage typing sets, pyocine typing, and serogrouping.

A comparison of two pyocine typing methods with serogrouping, and two phage typing sets has been made. In one instance, a contaminated bladder irrigation fluid of 0.05% silver nitrate solution caused a series of urinary tract infections. By all systems, fewer of the presentstrains were typable than usual. Among the phage typing sets the one developed by LINDBERG et al. typed only 66% whereas that selected by BERGAN typed 83%, both less than observed previously. The set of LINDBERG et al. also rendered longer pattern codes, and yielded more variable results with related strains. A set of pyocine indicator strains, selected among the strains to be typed, was more suitable than one developed elsewhere. Comparison of five different methods of epidemiological typing of Ps. aeruginosa indicated that phage typing alone is not entirely satisfactory for this species and should therefore always be combined with serogrouping.

Initial slope technique for estimation of the apparent volume of distribution during constant-rate intravenous infusion.

A new technique is presented for estimating the apparent volume of distribution of drugs during constant-rate intravenous infusion. It is based on the initial slope of the plasma drug concentration versus time profile during the infusion. Equations are derived to provide estimates of the apparent volume of distribution for a one-compartment drug and for the central compartment of a two-compartment drug. The utility of the technique is illustrated by data obtained during constant-rate infusion of metronidazole in 11 healthy subjects. The average estimated value of the volume of the central compartment of metronidazole was 12% higher than the average value obtained by conventional pharmacokinetic analysis. The systematic error associated with this volume estimation procedure was assessed through the use of dimensionless concentration versus dimensionless time plots. The initial slope technique should prove useful in providing initial estimates of volume terms.

Renal biopsies in cystic fibrosis.

Pharmacokinetic studies on antibiotics as well as other studies on renal function indicate renal malfunction in cystic fibrosis. Renal biopsies from two children, and post mortem examination from one child, with this disorder were normal by light microscopy and close to normal by immunofluorescence examination and transmission and scanning electron microscopy, even in cases with advanced disease and marked renal malfunction. Renal biopsy interpretation thus seems to be of little value in the evaluation of renal malfunction in this disorder, and this suggests that the functional abnormalities are caused by metabolic/biochemical defects.

Pharmacokinetics of ciprofloxacin with reference to other fluorinated quinolones.

The third generation quinolones, ciprofloxacin, enoxacin, fleroxacin, norfloxacin, ofloxacin and pefloxacin are all quickly and quantitatively well (75-95% of an oral dose) absorbed upon oral administration. The maximum serum concentrations appear after 1-2 hours. The serum and urine concentrations after oral or intravenous ciprofloxacin are directly proportional with the doses and follow normal, dose-independent pharmacokinetics. Ciprofloxacin and norfloxacin reach the same serum levels after the same doses. Steady-state levels are indifferent from those after the first dose. In contrast, enoxacin, oflaxacin and pefloxacin do reach somewhat higher levels after chronic administration. Ciprofloxacin is eliminated by the kidneys (active tubular secretion which is blocked by probenecid) (60% after an intravenous administration), by metabolism and by the transintestinal route. Metabolism is minimal (ca. 15-20% for ciprofloxacin and norfloxacin). Transintestinal elimination implies that the drug is eliminated by transport across the intestinal wall without significant biliary elimination (which is less than 1%). Penetration into tissues occurs readily. Concentrations in prostate secretion are high for ciprofloxacin and norfloxacin. Ciprofloxacin reaches high intracellular concentrations; within human neutrophils the levels reach 6 times the concentrations in the surrounding fluid. Concentrations in bile and tissues are in general comparable to those in serum. Cerebrospinal fluid (CSF) concentrations are low when meningi are normal, but 40-90% of the serum levels when the meninges are inflamed. Because the transintestinal route of elimination compensates for loss of renal elimination, the serum half-life of ciprofloxacvin is raised only to 5-10 hours even in total renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic profile of brodimoprim: oral bioavailability and penetration into interstitial fluid.

The bioavailability of brodimoprim tablets given orally is 80-90%; their relative bioavailability compared to an aqueous solution is 100%. Penetration of brodimoprim to suction skin blisters is 73 +/- 8%. The elimination half-life is longer from blisters than from serum. The relative stability of extravascular concentrations suggests that, with adequate dose sizes, dosage may be once daily, and even only once every second day.