Home-based intravenous treatment with reslizumab for severe asthma in the Netherlands - An evaluation.

The anti-IL-5 biologic reslizumab for the treatment of severe eosinophilic asthma is administered intravenously. In the current study home administration of intravenous reslizumab was evaluated in 24 patients included between 2019 (July) and 2020 (July). This is the first study to show that intravenous reslizumab can be administered safely and successfully in an outpatient setting. Notably, not all patients prefer home administration and severe asthma patients may have different needs when it comes to choosing treatment at home or in the hospital.

[Poisoning with organophosphate compounds]. / Intoxicatie met organofosforverbindingen.

A 50-year-old man swallowed 200 ml of an insecticide containing the organophosphates dimethoate and phenitrotion in an attempted suicide. On admission, signs of a cholinergic syndrome were observed: miosis, rhinorrhoea, and fasciculations. This was followed by bradycardia with hypotension and vomiting. The patient was treated with the antidotes atropine and obidoxime. Decreasing consciousness necessitated intubation, mechanical ventilation and other supportive measures. Although the serum concentrations of both organophosphate compounds rapidly decreased, the activity of cholinesterase showed a prolonged inhibition. The clinical course was complicated by hypotension, acute respiratory distress syndrome, nosocomial pneumonia, and an epileptic seizure. A period with muscle weakness and a persisting depressive disorder then followed. This case is characteristic for acute intoxications with irreversible acetylcholinesterase inhibitors, such as organophosphate compounds. The treatment of these potentially severe intoxications includes rapid decontamination and the administration of high doses of atropine followed by obidoxime. Mechanical ventilation and circulatory support are also indicated.

The completeness of medication histories in hospital medical records of patients admitted to general internal medicine wards.

AIMS: Accurate recording of medication histories in hospital medical records (HMR) is important when patients are admitted to the hospital. Lack of registration of drugs can lead to unintended discontinuation of drugs and failure to detect drug related problems. We investigated the comprehensiveness of medication histories in HMR with regard to prescription drugs by comparing the registration of drugs in HMR with computerized pharmacy records obtained from the community pharmacy. METHODS: Patients admitted to the general ward of two acute care hospitals were included in the study after obtaining informed consent. We conducted an interview on drugs used just prior to hospitalization and extracted the medication history from the HMR. Pharmacy records were collected from the community pharmacists over a 1 year period before the admission. Drugs in the pharmacy records were defined as possibly used (PU-drugs) when they were dispensed before the admission date and had a theoretical enddate of 7 days before the admission date or later. If any PU-drug was not recorded in the HMR, we asked the patient whether they were using that drug or not. RESULTS: Data were obtained from 304 patients who had an average age of 71 (range 40-92) years. The total number of drugs according to the HMR was 1239, 43 of which were not used. When compared with the pharmacy records we found an extra 518 drugs that were not recorded in the HMR but were possibly in use. After verification with the patients, 410 of these were indeed in use bringing the total number of drugs in use to 1606. The type of drugs in use but not recorded in the HMR covered a broad spectrum and included many drugs considered to be important such as cardiovascular drugs (n = 67) and NSAIDs (n = 31). The percentages of patients with 0, 1, 2, 3, 4, 5-11 drugs not recorded in the HMR were 39, 28, 16, 8, 3.6 and 5.5, respectively. Of the 1606 drugs in use according to information from all sources, only 38 (2.4%) were not retrievable in the pharmacy records when the complete year prior to hospitalization was evaluated. CONCLUSIONS: The medication history in the hospital medical record is often incomplete, as 25% of the prescription drugs in use is not recorded and 61% of all patients has one of more drugs not registered. Pharmacy records from the community pharmacist can be used to obtain more complete information on the medication history of patients admitted to the hospital.

A nation-wide study on the practice of euthanasia and physician-assisted suicide in community and hospital pharmacies in The Netherlands.

PURPOSE: In recent years the attitudes and practices of euthanasia (E) and physician-assisted suicide (PAS) among health care workers have been evaluated in different countries. There is, however, still an information gap on the role of pharmacists in these matters. The aim of our study was to study the attitudes and practices of E and PAS among pharmacists. METHODOLOGY: We conducted a nation-wide survey into the practice, including adherence to guidelines, of E and PAS in community and hospital pharmacies (CP and HP) in the Netherlands. Furthermore, the attitude of community pharmacists concerning this subject was evaluated. Anonymous questionnaires were sent to a random sample of 50% (n = 755) of all CP and to all (n = 101) HP. RESULTS: The response rates were 52% and 51% for CP and HP, respectively. Most of the CP-respondents (95%) agreed with the concept of E and PAS and would dispense drugs for these purposes. When the data were extrapolated to all pharmacies, there were 1351 and 340 dispensing of drugs for E and PAS per year in CP and HP (94% of all requests), respectively. In most cases the pharmacist had been notified of the condition of the patient (CP: 93%, HP 87%) and a written request was obtained (CP: 74%, HP: 79%). The drugs were often handed personally to the physician (CP: 98%, HP: 86%). Involvement of pharmacy technicians was more common in HP than in CP (31% versus 6%). The most frequently dispensed drugs were muscle relaxants with barbiturates (CP: 47%, HP 71%), barbiturates only (CP: 19%, HP: 6.1%), and muscle relaxants with benzodiazepines (CP: 14%, HP: 7.6%). CONCLUSION: Most pharmacists are supportive of E and PAS and are prepared to fill prescriptions written for these purposes.

Validation of pharmacy records in drug exposure assessment.

The validity of drug exposure measurement based on pharmacy records was investigated taking into account completeness of data, drug compliance, and different methods of drug exposure measurement in pharmacy records. Data on prescription drug use were collected from home inventories and community pharmacies in a survey on drug use and compliance in 115 elderly people. To compare drug exposure in pharmacy records with exposure in the home inventory, three different methods for exposure measurement in pharmacy records were used. Two employed a fixed time window of 30 and 90 days, respectively, and the third method was based on the calculated duration of use of a prescription ("legend time"). Drug exposure in the home inventory was taken as the gold standard and sensitivity, specificity, and positive predictive values of the different methods were calculated for the most frequently used drugs and drug categories. The specificity and positive predictive value of all three methods was generally high (0.93-1.00 and 0.67-1.00, respectively). The 90-day fixed method and the legend time method generally showed high sensitivity (range: 0.67-1.00 and 0.63-0.83, respectively) for drugs that were used on a chronic basis, while the 30-day fixed method had poor sensitivity (range: 0.29-0.69). Drugs that were used according to the home inventory but not according to the pharmacy records methods could be almost completely retrieved in the pharmacy records of a one-year period showing that these records were virtually complete with regard to prescription drugs. We conclude that computerized pharmacy records can be a reliable source of the true drug exposure as estimated in a home inventory, when adequate attention is paid to the definition of the exposure time-window and when these records are comprehensive with regard to prescription drugs.

Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function.

Pamidronate is a second-generation bisphosphonate that undergoes negligible biodegradation and is eliminated exclusively by renal excretions. Nineteen cancer patients were stratified according to baseline creatinine clearance (Clcr): group I, Clcr > 90 mL/min (n = 6); group II, Clcr 61 mL/min to 90 mL/min (n = 6); group III, Clcr 30 mL/min to 60 mL/min (n = 3); group IV, Clcr < 30 mL/min (n = 4). All patients received a single, 90-mg dose of pamidronate disodium administered in a 4-hour intravenous infusion. Plasma and urine samples were collected at intervals up to 36 and 120 hours, respectively, after the start of infusion and were assayed for pamidronate, using validated high-performance liquid chromatography. Pamidronate's pharmacokinetics were characterized by a short distribution phase (2-3 hours) followed by rapid elimination of the drug in urine. Elimination of pamidronate was slower in patients in group IV with a mean +/- standard deviation area under the plasma concentration-time curve (AUC0-36) of 19.0 +/- 4.60 micrograms.hr/mL compared with 8.1 +/- 3.13 micrograms.hr/mL in patients in group I. A linear relationship in Clcr was observed for AUC0-36 (r = 0.67), urinary excretion (r = 0.69), and renal clearance (r = 0.81). Renal clearance was proportional to Clcr for patients in all four renal-function groups. In the treatment of bone metastases of malignancy, successive doses of pamidronate are generally separated by weeks; thus, plasma accumulation in patients with renal impairment is not expected to be clinically relevant. A reduction in dose of pamidronate disodium should not be necessary in cancer patients with renal impairment.

Selective decontamination of the digestive tract: effect of cessation of routine application at an ICU.

BACKGROUND: Selective decontamination of the digestive tract (SDD) with non-absorbable antibiotics was extensively used at intensive care units (ICU) in Europe to prevent nosocomial infections in critically ill patients. After three recent meta-analyses in which it was demonstrated that SDD did not influence hospital stay and mortality in these patients several ICU's decided to stop the routine use of SDD. OBJECTIVE: To examine the effects of the cessation of SDD on nosocomial infections, mortality and hospital stay at an ICU in post-operative patients. DESIGN: Retro- and prospective follow-up. PATIENTS: Post-operative patients with mechanical ventilation (MV) for > or = 5 days at an ICU were included. The retrospective group (SDD group) comprised of 138 patients (mean age 66, range 10-91; 78% male) and the prospective group (non-SDD group) of 142 patients (mean age 67 range 18-85; 65% male). The SDD regime consisted of colistin, tobramycin and amphotericin B. Cessation of the SDD was accompanied by a shortening of the routine intravenous cefuroxime prophylaxis. RESULTS: There was a nonsignificant increase from an average 21 to 23 days ICU stay in the non-SDD group when compared with the SDD group (p > 0.05). Of the 280 patients 97 (35%) died on the ICU. The risk of death was lower in the non-SDD group (adjusted hazard ratio 0.7 with 95% Cl 0.5-1.1). There was a trend towards an increase in infections as a cause of death in the non-SDD group (38% of the ceased patients versus 20% in the SDD group) (p > 0.05). The incidence of respiratory tract infection (per 1000 person days) was 80 (95% Cl 48-113) in the non-SDD group versus 19 (95% Cl 8-22) in the SDD group (adjusted hazard ratio 4.5 (95% Cl 2.9-7.1)). CONCLUSION: The cessation of the routine application of SDD in post-operative patients mechanically ventilated for 5 days or more did nod adversely affect survival nor increased length of stay at the ICU. There may have been a shift to infections as a cause of death after cessation of SDD.

Non-compliance in elderly people: evaluation of risk factors by longitudinal data analysis.

Studies on risk factors for drug non-compliance have not taken into account the possibility of correlated outcomes. We therefore conducted a study into risk factors for non-compliance by using analysis techniques that adjust for these correlations (longitudinal data analysis). Data were obtained from interviews and pharmacy records in a cross-sectional survey in Amsterdam. The subjects were 157 elderly people aged 70 years or older. Of these subjects, 37 were residents of a home for the elderly, 40 were community-dwelling elderly who needed to be visited regularly by a district nurse, and 80 were community-dwelling elderly who did not need to be visited by a district nurse. Most drugs (78%) were used according to the directions; the remainder (22%) were not used as intended. Odds ratios (95% confidence intervals) for non-compliance for moderate and poor/wrong knowledge of the purpose of a drug as compared with good/correct knowledge were 2.8 (1.2-6.7) and 4.2 (1.5-12), respectively. Drug regimens of two times daily and more than two times daily were associated with odds ratios for non-compliance of 4.5 (1.6-12) and 4.2 (1.7-11), respectively, compared to a regimen of once daily. Compliance increased if a drug was prescribed by a specialist instead of a general practitioner odds ratio 0.1 (0.04-0.4)]. There was no significant relation between compliance and the number of drugs prescribed to a patient, sex, age, living situation, patient group, or perceived effect. This study, which was based on longitudinal data analysis, demonstrates that in elderly people non-compliance with drug therapy is related to the knowledge of purpose of a drug, the complexity of a drug regimen, and the type of prescriber. The positive association between compliance and the number of drugs prescribed found in former studies was not confirmed.

Analysis of diclofenac and four of its metabolites in human urine by HPLC.

An HPLC method for the determination of diclofenac (DCF) and four of its metabolites (3'-hydroxydiclofenac, 4'-hydroxydiclofenac, 5-hydroxydiclofenac, and 3'-hydroxy-4'-methoxydiclofenac) in human urine is described. Following base hydrolysis, the samples were neutralized and extracted. Evaporated extracts were reconstituted in mobile phase containing ascorbic acid, and chromatographed, using flow-rate programming, on a reversed-phase column. Absolute recovery (average), was at least 78% for diclofenac and ranged from 75 to 85% for the four metabolites. Standard curves showed linearity over the range of concentrations of 0.2 to 40 ug/mL, using 0.25 mL of urine. Specificity was demonstrated by examining chromatograms of extracts of blank urine from 8 volunteers and 24 study subjects. Good accuracy was observed for all compounds over the concentration range of 0.2 to 40 ug/mL using 0.25 mL of urine. Based on accuracy and precision criteria, the limit of quantitation for all 5 analytes was 0.4 ug/mL, using 0.25 mL of urine. Analysis of urine from subjects with normal and reduced renal function who received diclofenac orally demonstrated that total diclofenac and metabolites excreted in the urine represented approximately 31% and 4% of an oral dose of diclofenac, respectively.

Absorption of flurbiprofen in the fed and fasted states.

The oral absorption of flurbiprofen, an antiinflammatory nonsteroidal compound, was compared in the fasted vs the fed state. When ingested as an aqueous solution of the sodium salt, absorption kinetics followed a monoexponential pattern in half of the subjects and a bimodal pattern with a lag time before the onset of the second phase of absorption in the other half of the subjects. When ingested in the free acid form as a tablet either with water (fasted state) or with water 15 min after 330 ml of apple juice (fed state), flurbiprofen absorption was always bimodal, and the lag time before the onset of the second phase was shown to be dependent on the gastric emptying time (r = 0.623, P less than 0.01). The gastric emptying times were significantly longer when the drug was administered in the fed state (average GET = 57 min in the fasted state and 102 min in the fed state; P less than 0.01). These results suggest that gastric emptying effects are one important way in which absorption of drugs can be affected by meal intake.

Effect of food on the bioavailability of adinazolam from a sustained release formulation: effect of meal timing and lack of dose dumping.

Food effects on adinazolam absorption from sustained release (SR) adinazolam mesylate tablets were assessed in 28 healthy male volunteers. Subjects received 15 mg SR tablets, 15 mg immediate release tablets, 15 mg oral solution, administered after an overnight fast, and 15 mg SR tablets after a high fat breakfast. Treatments were administered in a crossover design. Plasma adinazolam and N-desmethyladinazolam (NDMAD) concentrations were determined by HPLC. Adinazolam and NDMAD AUC values were unaffected by food. Cmax for SR tablets was increased 33 per cent and 18 per cent for adinazolam and NDMAD, respectively, when administered postprandially. Tmax occurred later in the fed state; no dose dumping was observed. Meal timing effects on adinazolam absorption from SR tablets were assessed in 24 healthy subjects, who received 30 mg SR tablets 1 h before, 0.5 h after, 2 h after a high fat meal, and in the fasted state. Postprandial administration had no effect on AUC, but resulted later and higher adinazolam and NDMAD Cmax. Differences in these values were less than 11 per cent. Administration of SR tablets before meals yielded Cmax and Tmax values which were similar to the fasted state. Results suggest that meal timing does not substantially affect adinazolam absorption from the SR tablet.

Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with chronic renal failure.

Six patients with chronic renal failure (CRF group) and four healthy subjects (HS group) were given 5 mg oral and intravenous doses of bumetanide in a random, crossover design. The CRF group had significantly lower plasma and renal clearances, resulting in a five-to sixfold reduction in the fractional urinary excretion of the drug. The percent free drug in plasma for the CRF group was more than double that for the HS group, and significant correlations were observed for volume of distribution at steady state vs. percent free (r = 0.661; P less than 0.05), nonrenal clearance vs. percent free (r = 0.796; P less than 0.01), and renal clearance vs. creatinine clearance (r = 0.995; P less than 0.001). Although bioavailability was relatively consistent among the HS (0.664 +/- 0.112) and CRF (0.689 +/- 0.149) groups, the absorption-time profiles were more irregular for both groups. Cumulative sodium excretion and overall efficiency of response to bumetanide did not differ significantly between the two routes of administration in either group.

Urine glycoprotein crystal growth inhibitors. Evidence for a molecular abnormality in calcium oxalate nephrolithiasis.

One reason that some people are prone to calcium oxalate nephrolithiasis is that they produce urine that is subnormal in its ability to inhibit the growth of calcium oxalate crystals. We have identified in human urine a glycoprotein (GCI) that inhibits calcium oxalate crystal growth strongly, and at low concentrations (10(-7) M); in this study, we have isolated GCI molecules from the urine of normal people and patients with calcium oxalate stones. GCI from stone formers is abnormal in three ways: it contains no detectable gamma-carboxyglutamic acid (Gla), whereas normal GCI contains 2-3 residues of Gla per mole; about half of the GCI in urine of patients inhibits crystal growth 4-20 times less than normal GCI as judged by its performance in a kinetic growth assay, in vitro; at the air-water interface, patient GCI has a film collapse pressure approximately half of normal. GCI molecules from the urine of patients with calcium oxalate nephrolithiasis are intrinsically abnormal, and these abnormalities could play a role in the genesis of stones.

Determinants of bumetanide response in the dog: effect of indomethacin.

Four male unanesthetized dogs each weighing 22.0-29.0 kg received 0.250 mg/kg iv of bumetanide before (treatment I) and after (treatment II) indomethacin pretreatment. Lactated Ringer's solution was administered intravenously throughout both treatments at a flow rate of 2 ml/min to avoid fluid and electrolyte depletion. Unchanged bumetanide and indomethacin concentrations were analyzed using high-performance liquid chromatography. Sodium was measured by flame photometry and creatinine by colorimetry. Indomethacin pretreatment did not significantly change the pharmacokinetics of bumetanide, affecting neither the total amount of drug nor time course of drug delivered into the urine. In contrast, indomethacin pretreatment resulted in a dramatic reduction in the 4-hr sodium excretion and urine volume. Therefore, a pharmacokinetic interaction may be eliminated as a possible mechanism for the attenuation, by indomethacin, of the natriuretic and diuretic response of bumetanide. Instead, it appears that indomethacin diminishes the response to bumetanide via prostaglandin inhibition.

Effect of probenecid on the dose-response relationship of bumetanide at steady state.

The present investigation was undertaken to clarify the determinants of the pharmacologic responses to bumetanide. The urinary excretion rate, plasma concentration and natriuretic and diuretic effects of bumetanide were evaluated under steady-state conditions in four mongrel dogs, before (Treatment I) and after (Treatment II) probenecid administration. To avoid fluid and electrolyte imbalance, urinary losses were replaced i.v. by equal volumes of lactated Ringer's solution over the time interval of the subsequent collection period. Probenecid administration caused a dramatic reduction in the renal clearance of bumetanide (5.05 +/- 1.11 for Treatment I vs. 0.716 +/- 0.285 ml/min . kg for Treatment II; P less than .002), resulting in significantly higher plasma concentrations (3-fold) and significantly lower urinary excretion rates (2.5-fold) of the diuretic. This was accompanied by concomitant reductions in bumetanide-induced diuresis and natriuresis. The results from this study demonstrate that adequate luminal levels of bumetanide are required for the pharmacodynamics of the drug.

Application of effect-compartment model to bumetanide-indomethacin interaction in dogs.

Analyses of bumetanide's dose-response relationship have been complicated by the hysteresis observed between the drug's urinary excretion rate and its sodium excretion. This apparent time lag reflects the disequilibrium between the urine concentration and effect compartment (biophase) which occurs during the early distribution phase. In the present article, an expanded pharmacodynamic model has been introduced in which the hypothetical effect compartment is linked, by a first-order process (Kue), to the urine compartment. Drug dissipation from the effect compartment occurs by means of the first-order rate constant, Keo. This representation accommodates bumetanide's luminal site of action in the kidney tubule as well as the drug's temporal component. Application of this model to the bumetanide-indomethacin interaction in dogs is examined.

Determinants of bumetanide response in the dog: effect of probenecid.

The pharmacokinetics and pharmacodynamics of intravenous bumetanide (0.250 mg/kg), alone (treatment I) and after probenecid pretreatment (treatment II), were studied in four mongrel dogs. Lactated Ringer's solution was administered by vein throughout both treatments at a flow rate of 2 ml/min to avoid fluid and electrolyte depletion. Bumetanide and probenecid concentrations were analyzed by HPLC, sodium by flame photometry, and creatinine by colorimetry. Although the probenecid markedly reduced the plasma and renal clearances of bumetanide, as well as the fraction excreted unchanged in the urine, there was no significant difference between treatments I and II in the 4-hr natriuretic and diuretic responses. However, analysis of the dose-response curves between treatments I and II showed that sodium excretion was better correlated with bumetanide urinary excretion rate than with plasma concentration. The reasons for a poor correlation between treatments during the early time periods are discussed.

Leukocytic hypersensitivity in experimental group A streptococcal infections.

Skin hypersensitivity to streptococcal antigens was demonstrated in 15 New Zealand red rabbits that were sensitized by intracutaneous injections with group A streptococci, and leukocytic hypersensitivity, as determined by in vitro inhibition of leukocyte migration, was demonstrated in 11 of the rabbits. The skin hypersensitivity persisted for at least 8 weeks, whereas the leukocytic hypersensitivity generally waned rather rapidly. The leukocytic hypersensitivity reappeared in the infected rabbits that had developed this hypersensitivity. However, it did not reappear on reimmunization with living streptococci of the type originally employed, whereas it did reappear with living but not heat-killed streptococci of another M type.