Rolf A. Walstad

Pharmacokinetics and tissue concentrations of ceftazidime in burn patients

SummaryThe pharmacokinetics and tissue concentrations of ceftazidime have been investigated in 8 patients with severe burns (20–80% of body surface area) undergoing skin transplantation 2 to 21 days after injury. Two prophylactic doses of ceftazidime were administered as 1 g i.v. bolus injections with an 8 h interval. Blood, urine, burn blister fluid and tissue were frequently sampled and drug concentrations were analyzed by HPLC. The kinetics of ceftazidime was the same after each dose.In these patients the pharmacokinetics of ceftazidime was greatly altered from that in other patients and there was much interindividual variation. The mean ceftazidime elimination half-life, apparent volume of distribution and total clearance were: 2.7 h, 30.91 (0.38 l·kg−1) and 139 ml·min−1, respectively. A linear correlation was found between creatinine clearance and the renal clearance of the ceftazidime, the mean values being 108 and 95 ml·min−1, respectively. No correlation was found between creatinine clearance and the total clearance of ceftazidime. The mean percentage urine recovery was 69% of the dose. Tissue and burn blister fluid concentrations were above the MIC, and ranged from 40.0 to 3.1 mg·kg−1. A substantial increase in the apparent volume of distribution and non-renal clearance of ceftazidime was observed, probably due to increased capillary permeability and drug loss through the wound surface replacement of prior to surgery and subsequently to lost and blood fluid.

Pulmonary rehabilitation reduces depression and enhances health-related quality of life in COPD patients--especially in patients with mild or moderate disease.

The first objective of the study was to evaluate a 4-week inpatient pulmonary rehabilitation program on exercise capacity, health-related quality of life (HRQL) and psychological distress in patients with COPD. The second objective was to investigate the influence of gender, age, disease severity, co-morbidity, anxiety and depression on improved HRQL after rehabilitation. The study comprised 136 consecutive patients from baseline to follow-up with mild-to-severe COPD. Exercise capacity was measured by the 6-min walking distance test, disease severity by spirometric tests, HRQL by The St. George’s Respiratory Questionnaire and psychological distress by the The Hospital Anxiety and Depression Scale. Variables on socio-demography and co-morbidity were self-reported. Exercise capacity was improved from baseline to follow-up with a score difference of +44 metres (p = 000). Except for the activity score, HRQL was significantly improved: a change of -3.5 for the symptom score (p = 014), —3.1 for the total score (p = 003) and a clinical significant change of — 4.0 for the impact score (p = 002). The anxiety score did not change significantly after rehabilitation (—0.1, p = 545), though there was a significant reduction of the depression score (—0.8, p = 002) and a 10.4% reduction in the prevalence of possible depression cases (p = 017). Patients with forced expiratory volume in 1 second ≥50% predicted were 4.2 times more likely to achieve a clinical significant improved HRQL after rehabilitation than patients with forced expiratory volume in 1 second <50% predicted (95% confidence interval [CI] 1.7—10.3, p = 002). A 4-week inpatient rehabilitation program improves HRQL and exercise capacity and reduces depression in COPD patients. Patients with mild or moderate disease are more likely to achieve an improved HRQL after rehabilitation than patients with severe or very severe disease.

Long-term pharmacokinetics of thio-TEPA, TEPA and total alkylating activity following i. v. bolus administration of thio-TEPA in ovarian cancer patients

SummaryThe 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 consituting <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.

Single and repeated dose pharmacokinetics of thio-TEPA in patients treated for ovarian carcinoma

SummaryTriethylenethiophosphoramide (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 elemination half-life (3.86±0.97 h), which could be of clinical relevance.A first-order elimination process with a short elimination half-life (∼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.

CHARACTERISTICS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE CHOOSING REHABILITATION

OBJECTIVE To identify and compare objective and self-perceived characteristics of patients with chronic obstructive pulmonary disease, who do and do not choose rehabilitation. SUBJECTS The study comprised 205 consecutive patients with mild to very severe chronic obstructive pulmonary disease. They chose either inpatient rehabilitation (n = 161) or ordinary outpatient consultations (n = 44). MEASUREMENTS Disease severity was assessed with spirometric tests, health-related quality of life was assessed with the St Georges Respiratory Questionnaire, and mental status was measured using the Hospital Anxiety and Depression Scale. Socio-demographic and social characteristics, and co-morbidity variables were available. RESULTS Patients in the rehabilitation group had a lower level of overall health-related quality of life (63.8 vs 47.6, p = 0.000) and a higher prevalence of anxiety (34.6% vs 13.6%, p = 0.007) than the outpatients. The outpatients received more psychological support from spouse/partner than patients in the rehabilitation group (70.5% vs 49.1%, p = 0.012). There were no differences in disease severity and co-morbidity. CONCLUSION The decision to choose rehabilitation may be determined by impaired health-related quality of life, psychological distress and lack of psychological support from a significant other. Our findings suggest that patients with chronic obstructive pulmonary disease are conscious of their overall health status and the necessary treatment to maintain or improve it.

Pharmacokinetics and clinical effects of cefuroxime in patients with severe renal insufficiency

SummaryThe pharmacokinetics and clinical effects of cefuroxime were investigated in 5 patients with severe impairment of renal function (creatinine clearance ⪕ 23 ml/min), suffering from an urinary tract infection. Bolus i.v. injections of cefuroxime 750 mg b.i.d. or 750 mg once daily were given to the patients depending on the degree of renal impairment. The concentration of drug in serum and urine was measured during treatment, and pharmacokinetic parameters were evaluated on the second and last days; the parameters obtained on the 2 days did not differ significantly. Drug elimination half-life increased from 4.2 h (creatinine clearance 23.0 ml/min) to 22.3 h (creatinine clearance 5.0 ml/min) with decreasing renal function. The apparent volume of distribution ranged from 11.6 to 17.91, and showed a substantial increase to 29.61 in the patient with the poorest renal function. A linear correlation was found between the total and renal clearance of cefuroxime and the creatinine clearance; the extrarenal clearance was 8.24 ml/min. Concomitant treatment with furosemide did not impair renal function and no evidence of nephrotoxicity was found. The clinical efficacy of the drug was good. Symptoms of infection subsided after 3–4 days and the isolated pathogens were eradicated. No relapse or episodes of reinfection were observed in a following-up period of 3 months. The drug was well tolerated and no side effects or changes in haematological or biochemical values were seen.

Relapse of health related quality of life and psychological health in patients with chronic obstructive pulmonary disease 6 months after rehabilitation

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. Georges 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.

Pharmacokinetics of thio-TEPA at two different doses

SummaryThio-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.

Pharmacokinetics of ceftazidime in patients with biliary tract disease

SummaryAfter administration of ceftazidime as a 1 g i.v. bolus injection, its concentration was measured by HPLC at frequent intervals in serum, bile and tissue from different parts of the biliary tract in 32 patients undergoing operation for biliary tract disease. In bile from the functioning gallbladder and common bile duct, a high concentration of ceftazidime was found, mean 18.5 and 26.6 mg/l, respectively. In bile from the non-functioning gallbladder, a very low concentration was found (<1.5 mg/l). Ceftazidime in the gallbladder wall varied considerably with the type and degree of inflammation judged histologically; the mean level was 21.3 mg/kg. The elimination half-life of ceftazidime was 1.74 h, apparent volume of distribution 20.01 and total plasma clearance 133 ml/min. In bile from T-tube specimens a high concentration was found, the mean peak values being 27.2 mg/l. However, biliary excretion of the drug was low at less than 0.5% of the administered dose. These concentrations of ceftazidime were sufficient to inhibit the in-vitro growth of pathogens, namely theEnterobacteriaecae commonly responsible for biliary tract infection.

Single-Dose Pharmacokinetics of Lomefloxacin in Patients with Normal and Impaired Renal Function

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.