Serum concentrations of psychotropic drugs in neonates as a PROgnOstic Factor for admission to the neonatology ward and withdrawal symptoms: PROOF-1.

The aim is to determine whether serum drug concentrations obtained from the neonate's umbilical cord can be used as a prognostic factor for admission to the neonatology ward and the occurrence of withdrawal symptoms. A retrospective observational monocenter cohort study was carried out among pregnant women using psychotropic drugs and their baby. Binary logistic regression was used for the multivariate analysis. Of the 186 neonates included, 22.6% (n=42) were admitted to the neonatology ward, 6.5% (n=12) because of withdrawal. Among women with therapeutic concentrations of psychotropic medication, 22.0% (n=5) of the neonates had withdrawal symptoms. When comparing neonates with therapeutic versus undetectable drug concentrations, an odds ratio of 3.1 (95% confidence interval: 1.1-8.6) was found for admission to the neonatology ward and an odds ratio of 20.5 (95% confidence interval: 2.2-186.1) for the occurrence of withdrawal symptoms. Therapeutic concentrations of psychotropic drugs in neonates' umbilical cord blood correspond with higher odds for admission to the neonatology ward and the occurrence of withdrawal symptoms compared with neonates with undetectable drug concentrations. The measurement of drug concentrations in the neonate may contribute toward the general clinical assessment of the physician to predict the necessity of admission to the neonatology ward and the risk of withdrawal symptoms.

A multifaceted intervention to reduce drug-related complications in surgical patients.

AIM: The P-REVIEW study was a prospective, multicenter, open intervention study, designed to determine whether a multifaceted intervention of educating the prescriber combined with medication review and pharmaceutical visits to the ward by the hospital pharmacist could lead to a reduction in drug-related complications among surgical patients. METHODS: A total of 6780 admissions of 5940 patients to surgical, urological and orthopaedic wards during the usual care period and 6484 admissions of 5711 patients during the intervention period were included. An educational programme covering pain management, antithrombotics, fluid and electrolyte management, prescription in case of renal insufficiency and antibiotics was developed. National and local hospital guidelines were included. Hospital pharmacists performed medication safety consultations, combining medication review of high-risk patients and a visit to the physician on the ward. RESULTS: A significantly lower proportion of admissions with one or more clinically relevant, potentially preventable, drug-related problems (including death, temporary or sustained disability, increased length of hospital stay or readmission within 30 days) occurred in the intervention period (1.1% (73/6484) compared to the usual care period [1.6% (106/6780)] (P = 0.029). The relative risk (RR) was 0.72 (95% CI 0.53-0.97). Several types of drug-related problems occurred less frequently. Costs incurred as result of time spent on study-related activities were not different before and after the intervention. CONCLUSIONS: The P-REVIEW study shows that education and support of the prescribing physician with respect to high-risk patients in surgical departments leads to a significant, clinically relevant benefit for patients without generating additional costs.

Untangling the web of European regulations for the preparation of unlicensed radiopharmaceuticals: a concise overview and practical guidance for a risk-based approach.

Radiopharmaceuticals are highly regulated, because they are controlled both as regular medicinal products and as radioactive substances. This can pose a hurdle for their development and clinical use. Radiopharmaceuticals are fundamentally different from other medicinal products and these regulations are not always adequate for their production. Strict compliance may have a huge resource impact, without further improving product quality. In this paper we give an overview of the applicable legislation and guidelines and propose a risk-based approach for their implementation. We focus on a few controversial Good Manufacturing Practice topics: cleanroom classification, air pressure regime, cleanroom qualification and microbiological monitoring. We have developed an algorithm to assess the combined risk of microbiological contamination of a radiopharmaceutical preparation process and propose corresponding Good Manufacturing Practice classification levels. In our opinion, the risk of carry-over of radiopharmaceuticals by individuals cannot be contained by pressure differences, and complicated regimes with underpressured rooms are not necessary in most situations. We propose a sterility assurance level of 10 for radiopharmaceuticals that are administered within a working day, irrespective of their use. We suggest the adoption of limits for environmental monitoring of microbial contamination, as proposed by Bruel and colleagues, on behalf of the French Society of Radiopharmacy. Recently launched regulatory documents seem to breathe a more liberal spirit than current legislation and recognize the need for the use of risk assessment. We argue that future legislation be further harmonized and state risk assessment as the gold standard for implementation of drug quality regulations for the preparation of unlicensed radiopharmaceuticals.

The effects of kidney transplantation on sleep, melatonin, circadian rhythm and quality of life in kidney transplant recipients and living donors.

BACKGROUND: Sleep disturbance is an important medical problem in patients with end-stage renal disease. It might be related to the disruption of the body's circadian clock since nocturnal levels of its key biomarker melatonin are markedly reduced. We aimed at investigating whether a change in renal function due to kidney transplantation or donation would modify sleep, melatonin levels, circadian rhythmicity, and quality of life in kidney transplant recipients (KTR) and living donors (LD). METHODS: In KTR, we assessed saliva melatonin concentrations, sleep quality and daytime sleepiness prior to and at 2 weeks and 3 months after transplantation. In LD, we assessed these parameters prior to and at 3 months after donation. We additionally assessed 24-hour core body temperature (cBT), 24-hour blood pressure profile, and quality of life (QoL) prior to and 3 months after transplantation. RESULTS: Twenty-three KTR and 23 LD completed the study. Regarding sleep, the amount of nighttime awake minutes tended to be reduced in recipients after transplantation (p = 0.05). Nocturnal melatonin concentrations did not change with transplantation or donation. Blood pressure dipping profile and the two circadian markers dim-light melatonin onset and time of core body temperature minimum did not change. Nevertheless, KTR reported that daytime sleepiness and QoL had improved. CONCLUSION: Objectively nocturnal sleep quality marginally improved after transplantation. Subjectively patients reported improved QoL and daytime sleepiness scores. Changes in renal function were not associated with modified melatonin secretion or circadian rhythmicity.

Bench to bedside development of GMP grade Rhenium-188-HEDP, a radiopharmaceutical for targeted treatment of painful bone metastases.

Bone-targeting therapeutic radiopharmaceuticals are effective agents for treatment of painful bone metastases. Rhenium-188-HEDP is such a therapeutic radiopharmaceutical and has advantages over commercially available alternatives in terms of efficacy, safety and the ability to be produced on-site, allowing rapid treatment upon presentation of patients with pain. Unlike many other radiopharmaceuticals, there are no standardized preparation methods for Rhenium-188-HEDP. It is known, however, that drug composition may not only affect stability of the final drug product, but it may also influence bone affinity and, thus, efficacy. Furthermore, for support of clinical studies with Rhenium-188-HEDP as an investigational medicinal product, preparation of this radiopharmaceutical has to be performed under GMP conditions. To our knowledge, no group has reported on the preparation of Rhenium-188-HEDP under GMP conditions or on stock production of sterile non-radioactive starting materials. We present the production of GMP grade Rhenium-188-HEDP for application of this therapeutic radiopharmaceutical in routine clinical practice and for support of clinical studies. In addition, bio-distribution data of Rhenium-188-HEDP in mice and in patients with bone metastases originating from prostate cancer are presented.

The quantitative effect of serum albumin, serum urea, and valproic acid on unbound phenytoin concentrations in children.

Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity.

Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial.

AIM: The disturbed circadian rhythm in haemodialysis patients results in perturbed sleep. Short term melatonin supplementation has alleviated these sleep problems. Our aim was to investigate the effects of long-term melatonin supplementation on quality of life and sleep. METHODS: In this randomized double-blind placebo-controlled trial haemodialysis patients suffering from subjective sleep problems received melatonin 3 mg day(-1) vs. placebo during 12 months. The primary endpoint quality of life parameter 'vitality' was measured with Medical Outcomes Study Short Form-36. Secondary outcomes were improvement of three sleep parameters measured by actigraphy and nighttime salivary melatonin concentrations. RESULTS: Sixty-seven patients were randomized. Forty-two patients completed the trial. With melatonin, no beneficial effect on vitality was seen. Other quality of life parameters showed both advantageous and disadvantageous effects of melatonin. Considering sleep, at 3 months sleep efficiency and actual sleep time had improved with melatonin compared with placebo on haemodialysis days (difference 7.6%, 95% CI 0.77, 14.4 and 49 min, 95% CI 2.1, 95.9, respectively). At 12 months none of the sleep parameters differed significantly from placebo. Melatonin salivary concentrations at 6 months had significantly increased in the melatonin group compared with the placebo group. CONCLUSIONS: The high drop-out rate limits the strength of our conclusions. However, although a previous study reported beneficial short term effects of melatonin on sleep in haemodialysis patients, in this long-term study the positive effects disappeared during follow up (6-12 months). Also the quality of life parameter, vitality, did not improve. Efforts should be made to elucidate the mechanism responsible for the loss of effect with chronic use.

Erlotinib and pantoprazole: a relevant interaction or not?

AIMS: There is increasing evidence that erlotinib exposure correlates well with treatment outcome. In this report we present a case of therapeutic drug monitoring of erlotinib in a patient with a gastric ulcer, treated with the proton pump inhibitor pantoprazole. This agent may cause an unwanted, but not always unavoidable, interaction since absorption of erlotinib is pH dependent. METHODS: Erlotinib trough concentrations were monitored in a patient during treatment with orally and intravenously administered pantoprazole. RESULTS: Erlotinib trough concentrations were diminished during high dose intravenously administered pantoprazole, but returned to normal when the dose was reduced and pantoprazole was administered orally. CONCLUSIONS: More studies are needed to assess the dose dependency of the interaction between pantoprazole and erlotinib. Furthermore, we advise to monitor closely erlotinib plasma concentrations and adjust the erlotinib dose accordingly when a clinically relevant interaction is suspected and no proper dosing guidelines are available.

The effects of melatonin on sleep-wake rhythm of daytime haemodialysis patients: a randomized, placebo-controlled, cross-over study (EMSCAP study).

AIM: The aim of this study was to investigate the effects of exogenous melatonin on sleep-wake rhythm in haemodialysis patients. METHODS: The study design is a randomized, double-blind, placebo-controlled, cross-over study of 3 x 6 weeks melatonin 3 mg at 22.00 h every night. Haemodialysis patients were asked to fill out a sleep questionnaire and to wear an actometer to record their sleep problems objectively. Furthermore, melatonin concentrations in saliva were sampled the night after daytime haemodialysis and the consecutive night. Actometers, the sleep questionnaire and melatonin concentrations were repeated during the study. RESULTS: In total, 20 patients (six female, median age 71 years) completed the investigation. On nights after daytime dialysis, objective sleep onset latency decreased significantly from a median of 44.5 (placebo) to a median of 15.5 min with melatonin (P < 0.01). Sleep efficiency increased from 67.3 to 73.1% with melatonin (P < 0.05). Actual sleep time increased from 376 min (placebo) to 388 min with melatonin (P < 0.01), and sleep fragmentation decreased from 4.5 to 3.1 (P < 0.01). Furthermore, subjective sleep parameters improved also. Patients reported less time needed to fall asleep (P < 0.05) and fewer wake periods (P < 0.05) on the nights with and without daytime dialysis and an increase in sleep time on the night of daytime dialysis (P < 0.05). Furthermore, the nocturnal melatonin rise was recovered. CONCLUSION: Treatment with melatonin resulted in an improvement of subjective and objective sleep parameters, as well as a recovered nocturnal melatonin rhythm.