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Following iv bolus injection of 3.2 g Timentin (ticarcillin 3.0 g plus clavulanic acid 0.2 g) to 12 volunteers, the antibiotic concentrations were analysed by HPLC methods in serum, urine and fluids from subcutaneous threads, suction blisters and lymph during 8 h. Pharmacokinetic parameters, urine recovery, penetration and ticarcillin/clavulanic acid ratios were calculated.The antibiotic concentration in thread fluid closely followed the serum concentration. For ticarcillin the mean (±S.D.) elimination half-lives in serum and thread fluid were 1.0±0.1 and 1.2±0.1 h, respectively. For clavulanic acid the half-lives in these fluids were 0.9±0.1 and 1.0±0.1 h. The lymph and blister fluid concentration followed a similar pattern, but differed from those in serum, the mean (±S.D.) elimination half-lives for both compounds ranging from 1.1±0.2 to 3.2±0.3 h. The urine recovery of ticarcillin was 86% and of clavulanic acid 51% of the administered dose. The penetration of clavulanic acid into the different tissue fluids was superior to ticarcillin, ranging from 78 to 88% for clavulanic acid and 52–70% for ticarcillin. The concentration ratios of the two compounds, being 15 : 1 at the time of injection, varied widely in the different tissue fluids with time. This was also the case with AUC(0–∞) ratios. A relative decrease of clavulanic acid was observed, most pronounced in serum and thread fluid. However, the antibiotic concentrations achieved in serum, urine and extravascular fluid should be adequate in most infections caused by a wide range of clinically important pathogens. [ABSTRACT FROM PUBLISHER]

The elimination kinetics and penetration of ceftazidime into skin blister and lymphatic fluid were studied in nine healthy volunteers following a 1 g iv bolus injection. From the concentration time curve in plasma the following pharmacokinetic parameters (mean±S.D.) were calculated: elimination half-life 1.85±0.33 h; area under the curves 127±12 mg. h/l; apparent volume of distribution: 21.1±2.61; total plasma clearance: 133±13 ml/min and renal clearance: 109±7 ml/min. Urine recovery after 8 h was 82% of the administered dose. Nearly the same elimination rate constant, half-life and area under the curve were demonstrated for blister fluid and lymph.The penetration of ceftazidime into cerebrospinal fluid (n = 19), aqueous humour (n = 21) and pleural effusions (n = 5) were studied in patients after a 2 g iv bolus injection. In patients with normal meninges (n = 14) the penetration was poor: the concentrations were less than 1 mg/1. In patients with meningitis (n = 5) levels of 18, 17, 16, 1 and 0.8 mg/l were found. Aqueous humour penetration was satisfactory, and a mean concentration of 11±4 mg/l corresponding to a penetration ratio of 19% was found. The penetration of ceftazidime into large pleural effusions was also good with concentrations from 17±3 to 28±2 mg/l, corresponding to a mean penetration ratio of 38%. [ABSTRACT FROM PUBLISHER]

Eighty patients with suspected or diagnosed bacterial infections were treated with ceftazidime. Sixty-five patients with 88 sites of infections could be assessed clinically. A cure or improvement was achieved in 61 patients (94%) with a total of 83 infection sites (94%). Failures were seen in four critically ill patients with severe underlying diseases. Eighty-six pathogens, most frequently Enterobacteriaceae, were isolated from appropriate specimens. The infecting organisms were all eradicated during therapy. In two patients reinfection with a new strain occurred. Except for a severe anaphylactic reaction in one patient, ceftazidime was well tolerated. [ABSTRACT FROM PUBLISHER]

The serum pharmacokinetics of unchanged thio-TEPA and the active metabolite TEPA and the urinary excretion of thio-TEPA, TEPA and total alkylating activity were studied after a single i.v. bolus injection of thio-TEPA in six ovarian cancer patients. TEPA was present in serum as of 5 min after drug administration, and its concentration rapidly reached a plateau in the range of 50-100 ng/ml. After about 3 h the serum concentration of TEPA exceeded that of thio-TEPA, and in five of the six patients the metabolite persisted longer than the parent drug in serum. AUCs of thio-TEPA and TEPA were 822 +/- 83 and 1,084 +/- 234 ng h/ml, respectively. The great interindividual variation encountered in the serum pharmacokinetics of TEPA may be of clinical importance and represents a further indication that pharmacokinetically guided dosing of thio-TEPA could be valuable. Urinary recoveries of both thio-TEPA and TEPA were low, together constituting less than 2% of the delivered dose. A substantial gap existed between this and the total urinary alkylating activity, which averaged 13% of the dose in terms of thio-TEPA equivalents. This gap strongly indicates the presence of other unknown metabolites. [ABSTRACT FROM AUTHOR]

Triethylenethiophosphoramide (thio-TEPA) pharmacokinetics were studied in 15 patients being treated for epithelial ovarian carcinoma. Unchanged thio-TEPA was assayed in serum and urine by means of a gas chromatographic procedure. No accumulation or alteration of the pharmacokinetics occurred during therapy, which was continued for up to 7 months with biweekly administrations of 20 mg, after two initial loading courses with 20 mg daily for 3 consecutive days 2 weeks apart. No significant difference in the pharmacokinetics between i.m. and i.v. administration was demonstrated. However, three patients showed a reduced absorption ability from the i.m. injection site to the systemic circulation and an apparent increase in the elimination half-life (3.86 +/- 0.97 h), which could be of clinical relevance. A first-order elimination process with a short elimination half-life (approximately 1.5 h) was demonstrated for thio-TEPA in all patients after i.v. administration. The apparent volume of distribution averaged 50 1. The renal clearance was below 1% of the total-body clearance, which averaged 412 ml/min. The urinary excretion of unchanged thio-TEPA was complete within 8 h after administration, with an average urinary recovery of 0.14% of the dose. Calculation of the area under the serum concentration vs time curve revealed wide variation between patients (range 517-1480 ng/h ml-1), indicating the need for drug monitoring during therapy. [ABSTRACT FROM AUTHOR]

Thio-TEPA pharmacokinetics were studied at doses of 20 mg and 30 mg in six patients treated for ovarian cancer. Considerable interindividual variation was encountered in its pharmacokinetics, which were dose-independent within the dose range studied and similar to those reported at far higher doses. Interindividual dosing of thio-TEPA based on an initial AUC estimation is suggested. [ABSTRACT FROM AUTHOR]

A double blind, double dummy, randomized cross-over pharmacokinetic study comparing verapamil 120 mg, conventional tablets administered twice daily and verapamil 240 mg sustained release tablets once daily was performed in 12 patients with essential hypertension. After frequent blood sampling, analyses of verapamil and norverapamil were made with high pressure liquid chromatography. The absorption rate of the sustained release formulation was significantly slower than for the conventional formulation. Also the mean residence time was significantly longer for the sustained release tablet. It can be concluded that verapamil sustained release tablets meet with the following requirements for these formulations: (1) a slower absorption with an acceptable bioavailability relative to conventional tablets (89%); (2) no initial high peak concentration; (3) little fluctuation in the plasma concentration compared to the conventional formulation; (4) no differences in the elimination half lives for the two formulations; (5) maintenance of a therapeutic plasma level for a longer period of time than for the conventional formulation; (6) no increase in unwanted side effects. [ABSTRACT FROM AUTHOR]

The quinolone antibiotic lomefloxacin was administered as a 400 mg single oral dose to 12 subjects with renal impairment (creatinine clearance 5-65 mL/min/1.73 m2) and to 13 healthy subjects (creatinine clearance 80-135 mL/min/1.73 m2). The concentrations of lomefloxacin in plasma and urine were determined by high-pressure liquid chromatography up to 48 hours post-administration. Linear correlations were found between lomefloxacin plasma and renal clearances and creatinine clearance. The mean nonrenal clearance of lomefloxacin (approximately 32 mL/min/1.72 m2) was not influenced by renal function. The mean plasma clearances of lomefloxacin in healthy subjects and in a subgroup of patients with severe renal impairment (creatinine clearance 5-15 mL/min/1.73 m2) were 209 and 43 mL/min/1.73 m2, respectively. The decrease in plasma clearance of lomefloxacin was explained fully by the decrease in renal clearance. The elimination half-life of lomefloxacin increased significantly with the degree of renal impairment, from 7.5 hours in normal subjects to 26.9 hours in subjects with severe renal impairment. The maximum serum concentration and the time to maximum serum concentration were not significantly affected by renal function. The pharmacokinetics of lomefloxacin are dependent on renal function, and appropriate dosage adjustment is necessary when creatinine clearance is less than 30 mL/min/1.73 m2. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to evaluate the short- and long-term effects of 4-week inpatient rehabilitation on health-related quality of life (HRQL), anxiety and depression in patients with chronic obstructive pulmonary disease (COPD) and investigate the influence of clinical and socio-demographical factors on unaltered or improved HRQL after discharge., Methods: A total of 111 consecutive cases with mild-to-very severe COPD were recruited from three rehabilitation centres and measured at baseline (t1), 4 weeks (t2) and 6-month follow-up (t3). Disease severity was assessed by spirometric tests, HRQL by The St. George's Respiratory Questionnaire (SGRQ) and anxiety and depression by The Hospital Anxiety and Depression Scale (HADS). Socio-demography and co-morbidity was also reported. Changes in SGRQ and HADS scores from baseline to follow-up were analysed by paired-sample t-test, and logistic regression was used to investigate the influence of different factors on HRQL after discharge., Results: Health-related quality of life and depression improved between t1 and t2: a change of -3.6 for the SGRQ impact score (p = 0.009), -2.8 for the SGRQ total score (p = 0.012), a clinical relevant change of -4.0 for the SGRQ symptom score (p = 0.012) and a reduction of -0.7 for the HADS depression score (p = 0.011). Between t2 and t3, all SGRQ and HADS scores deteriorated with enhancement of SGRQ impact score (+3.5, p = 0.016), SGRQ total score (+2.5, p = 0.029), HADS anxiety score (+1.1, p = 0.000), HADS depression score (+0.6, p = 0.022) and HADS total score (+1.7, p = 0.000). No significant differences between t1 and t3 were found, except for HADS anxiety score (+0.9, p = 0.003). Patients living alone were 2.9 times more likely to maintain or improve HRQL 6 months after rehabilitation than patients living with someone (95% CI 1.1-7.8, p = 0.039)., Conclusion: Short-term benefits on HRQL and depression after rehabilitation relapsed at 6-month follow-up, but without any further deterioration from baseline. Living alone may be beneficial to maintain or improve HRQL after discharge., (© 2011 The Authors. Scandinavian Journal of Caring Sciences © 2011 Nordic College of Caring Science.)

In the study described, the pharmacokinetics of two oral betalactams, cefuroxime axetil and phenoxymethylpenicillin, were compared with respect to their penetration into tonsil tissue. Seventeen patients were given cefuroxime axetil 500 mg single dose and 16 patients were given phenoxymethylpenicillin 650 mg single dose, at different time intervals before tonsillectomy. The tonsils were freeze-dried and the drug concentrations in serum and tissue determined by a high performance liquid chromatographic method. Cefuroxime axetil showed a slightly better penetration ratio (mean 35%, median 32%) than phenoxymethylpenicillin (mean 31%, median 24%) however the difference was not statistically significant. The bioavailability of cefuroxime axetil was low due to being administered in the fasting state. The relatively low penetration ratios of both drugs into samples of whole tissue can be explained by the localization of betalactam antibiotics primarily in the extracellular fluid, with low penetration into normal cells. Both drugs were found to reach concentrations in tonsil tissue above the minimum inhibitory concentration for Group A beta-haemolytic streptococci after a single oral dose. In addition to streptococci, Haemophilus influenzae and beta-lactamase producing Staphylococcus aureus were isolated in a significant number of the tonsils. These bacteria may play a pathogenic role, but this was not investigated.

Labetalol (Trandate) is a new antihypertensive agent with both alpha- and beta-adrenoceptor blocking properties. In a double-blind cross-over study the antihypertensive action and side-effects of labetalol and propranolol were compared in 18 previously untreated outpatients with hypertension, WHO stage I--III. Mean daily dose of labetalol was 667 mg and of propranolol 129 mg. Labetalol reduced systolic and diastolic blood pressure in the seated and upright position significantly more than propranolol. The pulse rate reduction was greater with propranolol. Side-effects were more pronounced with propranolol. The antihypertensive effect, effect on pulse rate and pharmacokinetics of a single oral dose of 400 mg labetalol were studied in 6 patients with normal and 6 patients with impaired renal function (creatinine clearance less than 20 ml/min), all belonging to WHO stage I--II. A significant fall in pulse rate and systolic and diastolic blood pressure was observed in both groups, the duration being more than 25 h. No difference was found between the two groups. From the serum concentration-time curves the elimination rate constant, elimination half-life and area under the curve were calculated. The mean values of the two groups did not differ significantly. A pronounced interindividual variation was found in both groups.

Acute endophthalmitis was unilaterally induced in 8 rabbits by intravitreal injection of 5 micrograms Escherichia coli endotoxin. A reproducible increase in aqueous humour polymorphonuclear neutrophils and total protein content was observed after 24 h (mean +/- SD: 2400 +/- 274 X 10(6)/l and 3.7 +/- 0.4 g/l, respectively). In the opposite eye only minor changes occurred, making it suitable as a paired control. The intraocular penetration of ceftazidime was then studied in 30 rabbits after i.v. injection of 50 mg/kg body weight. The mean penetration into aqueous humour of the eyes with and without endophthalmitis was 64 and 10%, respectively. In the vitreous body the corresponding penetration was 5 and 1%. The concentration of ceftazidime achieved in the intraocular structures was sufficient to inhibit the growth of pathogens, i.e. Enterobacteriaceae, commonly responsible for intraocular infections.

Twenty patients with partially reversible bronchial obstruction due to chronic obstructive lung disease participated in a study comparing serum levels, clinical and side-effects of a sustained-release formulation of theophylline with placebo. Prior to the study, theophylline dosages were individually adjusted to give serum levels of 55 to 75 mumol/l 4 hours after tablet intake. Theophylline or placebo was then administered every 12 hours with crossover after 6 weeks. During the study, patients were examined in the morning every second week and lung function tests carried out before and after salbutamol inhalation. Doses required to achieve the desired serum concentration showed great inter-individual variations, but the obtained levels were stable during the whole study. Lung function tests were significantly better in the theophylline period. After inhalation of salbutamol, values were also better in the theophylline period but the differences were less marked and of no statistical significance. Subjective improvement from theophylline was not observed. Side-effects reported were mild and caused no withdrawals.

The penetration of ceftazidime into the aqueous humour and the vitreous body of the rabbit eye, after intravenous (i.v.) bolus or subconjunctival injection, was investigated. A dose of 50 mg/kg body weight was administered. After i.v. administration the mean penetration into the aqueous humour was 13% of the plasma values. After subconjunctival injection into the left eye, mean levels of 14% and 25% of the plasma concentrations were found in the right and left eye, respectively. The concentrations in the vitreous body were in all cases below the ceftazidime detection limit (1 mg/l), i.e. less than 1% of the plasma levels. The mean penetration of ceftazidime into human aqueous humour (measured during cataract extraction) was 19% after 2 g i.v. bolus injection. Ceftazidime levels sufficient to inhibit the growth of most pathogens commonly responsible for intraocular infections, including Pseudomonas spp., were consistently found in the aqueous humour. However, inadequate concentrations were achieved in the vitreous body.

Twelve healthy volunteers were treated with two different sustained-release formulations of theophylline (Nuelin Depot 350 mg and Theo-Dur 300 mg) twice daily in an open cross-over study. The serum levels in steady state without and with concomitant administration of antacid were studied. Antacid did not influence the serum theophylline levels in the Theo-Dur treatment period, while in the Nuelin Depot treatment period antacids caused a significantly larger increase in serum levels of theophylline after drug intake. The difference between morning and peak concentrations were also much higher with the combination Nuelin Depot/antacid. This implies that physicochemical factors such as gastrointestinal fluid pH might influence the degradation and/or absorption of some slow-release theophylline formulations as reflected in serum concentrations, and thereby contribute to the therapeutic and side effects of such drugs.

The pharmacokinetics of piretanide, a new loop diuretic, were studied in four patients with GFR 4.7-14.8 ml/min. An oral dose of piretanide 18 mg was given at 08.00 h in two patients and at 08.00 h and 14.00 h in two. Blood samples were drawn after 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. Serum concentrations of piretanide were estimated by radioimmunoassay. The peak serum concentration of piretanide (1-2 h after drug administration) was 510-880 ng/ml, independent of renal function. Elimination half life (t1/2) was 1.2-4.1 h, area under the curves (AUC(0,24)) 1.63-2.44 micrograms ml-1 h, volume of distribution (Vz) 0.30--0.741#kg, total plasma clearance (CL) 122.8-184.0 ml/min and renal clearance (CLR) 1.5-5.2 ml/min. The clinical effects of oral treatment with piretanide 18 mg twice daily were compared with bumetanide 3 mg twice daily in eight patients with renal failure (GFR 2.2-24.5 ml/min). Both drugs equally increased the 24 h output of urine (delta V), sodium (delta UNaV), chloride (delta UC1V), potassium (delta UKV) and calcium (delta UCaV). Fractional excretion of sodium (ENa%) was doubled by piretanide in patients with GFR less than 8 ml/min while a five fold increase was found in patients with GFR greater than 8 ml/min. The onset of effect was the same for both drugs, but the duration exceeded 6 h only for piretanide. Both drugs were most effective on the first of two consecutive treatment days. Delta UC1V was always greater than delta UNaV and urinary phosphate excretion was unchanged, as expected of a loop diuretic without significant proximal effects. Metabolic or clinical side effects were not noticed.

Tiaprofenic acid (Surgam) steady state pharmacokinetics was investigated in eight elderly patients with three different dosage regimens: 200 mg twice daily, 400 mg twice daily and 200 mg three times daily. The following dose independent pharmacokinetic parameters were evaluated from a two-compartment open model; absorption lag time: 0.23 +/- 0.08 h, absorption rate constant: 4.32 +/- 0.51 h-1, distribution rate constant: 1.31 +/- 0.13 h-1 and elimination half-life: 4.66 +/- 0.42. An increase in dose produced a significant and proportional increase in tiaprofenic acid peak and trough serum concentrations at steady state. In contrast to the above mentioned dose independent parameters, the area under the serum concentration-time curve showed a small (12%), but significantly higher increase than expected when the dosage regimen was increased from 200 mg X 2 to 400 mg X 2. This was, however, considered to be of no clinical relevance. Anticipating a 19% reduction of tiaprofenic acid bioavailability due to the intake of food, approximations of total body clearance and apparent volume of distribution can be made to 30.0 +/- 2.0 ml/min and 11.8 +/- 2.0 l, respectively. In spite of the small disproportional increase (12%) observed in the area under the serum concentration-time curve, it can be concluded that tiaprofenic acid shows a well defined pharmacokinetics in old people with acceptable interindividual variations and with a fast building-up to constant and predictable steady state levels within the dosage regimens investigated. A linear relationship was demonstrated between creatinine clearance and tiaprofenic acid total body clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

A heavy smoking male patient with moderate to severe theophylline poisoning is presented. Repeated doses of oral charcoal were given in addition to usual supportive treatment. During this treatment the elimination half-life of the drug (T1/2) was 2 hours. The toxic symptoms disappeared rapidly when the serum concentration was reduced to the therapeutic concentration range. T1/2 was approximately 24 hours in the same patient in a steady state study without oral charcoal treatment. Repeated doses of oral charcoal seem to increase theophylline elimination and should be administered in moderate to severe theophylline poisoning in addition to the usual supportive treatment and correction of metabolic disturbances.

Nasal resistance to air flow has been used to evaluate the effect of beclomethasone dipropionate aerosol on allergen induced nasal stenosis. Sixteen patients with allergic rhinitis due to pollen were investigated in a randomized double-blind cross-over study with beclomethasone dipropionate aerosol and placebo aerosol. Only patients reacting to challenge were chosen. The study was carried out in the pollen-free season. After 1 week on either active or placebo aerosol a basic resistance value was determined followed by allergen challenge. Nasal resistance was determined 15 min and 7 hr after challenge. The aerosols were changed and after another week the procedure was repeated. There was significant preference (P less than 0.01) for beclomethasone dipropionate aerosol.