In vitro dissolution testing of parenteral aqueous solutions and oily suspensions of paracetamol and prednisolone.

The number of intramuscularly applied dosage forms has been continuously increasing during the last decades. However, up to date no in vitro dissolution test method for parenteral dosage forms has been described in the Ph. Eur. or USP. It was the aim of this study to investigate dissolution test setups based on the compendial flow-through cell and the reciprocating holder for this purpose. Both apparatuses were equipped with dialysis membranes to accommodate the drug formulation. The suitability of the dissolution method was evaluated by comparing release profiles with blood level curves that were obtained previously in an in vivo study in rats by our group. Aqueous solutions and oily suspensions of paracetamol and prednisolone were tested in vitro that were also applied in the in vivo study. In the case of the aqueous solutions in which no formal dissolution occurs, transport from the applied depot across a dialysis membrane was investigated. While the drug transport across the dialysis membrane of both drugs in aqueous solution was similar in all applied test methods, differences in the release behavior of paracetamol and prednisolone as an oily suspension were observed. This was mainly due to sedimentation of the particles within the oily depot.

Muscle Injury After Intramuscular Administration of Diclofenac: A Case Report Supported by Magnetic Resonance Imaging.

Intramuscular injection of diclofenac is still frequently practiced, although there is ample evidence that the risk of local tissue intolerability is highly underestimated. The aim of this study was to evaluate local toxicity in a patient using magnetic resonance imaging. A patient who gave written informed consent received a medically indicated intramuscular administration of diclofenac 75 mg/2 mL. Simultaneously with magnetic resonance imaging of the depot, a clinical-chemical evaluation and quantification of diclofenac in plasma was performed. A manifold enhancement of the T2-weighted magnetic resonance signal was observed in a muscle area of approximately 60 mL volume, with maximum signal intensity 30 min after injection, the time of maximum diclofenac plasma exposure. Plasma creatine kinase activity was elevated approximately sixfold within 8 h and normalized within 1 week, whereas the magnetic resonance enhancement disappeared within 5 weeks. Interestingly, the patient did not complain about any clinical symptoms at the injection site. Asymptomatic tissue injury after intramuscular injection of diclofenac, caused by intramuscular dosing, can be reliably evaluated by magnetic resonance imaging and should be applied early during the development of parenteral dosage forms. Clinical Trials Registration Number: BB130/16 (Ethics Committee of the University Medicine Greifswald).

Simultaneous magnetic resonance imaging and pharmacokinetic analysis of intramuscular depots.

The present pilot study introduces a method that might give novel insights in drug absorption processes from intramuscularly administered depots. An oily suspension or an aqueous solution of paracetamol (6 mg/kg body mass), prednisolone or its hemisuccinate sodium salt for the aqueous solutions (10mg/kg body mass) or diclofenac (10mg/kg body mass) was injected into the muscle tissue of the hind leg of female Lewis-rats (n=47). For the oily suspensions the micronized particles were suspended in medium-chain triglycerides. The aqueous solutions were buffered to a pH of 7.4 ± 0.5. Polyethylene glycol was added as a cosolvent in the formulations containing paracetamol (acetaminophen) and diclofenac and sodium chloride was added to the aqueous solutions of prednisolone hemisuccinate sodium to achieve nearly isotonic formulations. The formed depot was visualized by magnetic resonance imaging (MRI) and characterized with regard to volume and surface area. A 7 T-small animal scanner was used and T1-weighted and T2-weighted sequences including a fat saturation were performed. Simultaneously blood samples were taken and the drugs were quantitatively analyzed. The water based solvent and the oily dispersion agent were visible in the MRI images without the use of contrast agents. Since a free hand injection mostly led to an application directly into the fascia, resulting in a fast removal of the depot, MRI-guided injection was conducted. Comparing pharmacokinetic data with MRI data it was observed that maximal blood levels occurred before the solvent and the dispersion agent were removed from the muscle tissue. Thus, the drug is not absorbed together with the depot. Furthermore, no correlation was found between the shape of the depot and the rate of absorption. Consequently, a higher surface area or volume of the depot did not result in a faster release or absorption of the drugs from the tested formulations. In contrast to the paracetamol and prednisolone formulations the formulations containing diclofenac led to a massive accumulation of interstitial fluid around the injection area being a sign for an acute local reaction. Histological analysis of the muscle tissue revealed a clear correspondence between the amount of interstitial fluid and the extent of infiltrating lymphocytes and granulocytes indicating a tissue response. In conclusion combining MRI with pharmacokinetic data is a suitable method to gain deeper insights into drug absorption processes from intramuscular depots. Furthermore, MRI offers a great possibility detecting local side effects caused by an intramuscularly applied dosage form. This might be very useful in preclinical phases during the development of new intramuscular formulations.

Enlarged substantia nigra hyperechogenicity and risk for Parkinson disease: a 37-month 3-center study of 1847 older persons.

OBJECTIVE: To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population. DESIGN: Longitudinal 3-center observational study with 37 months of prospective follow-up. SETTING: Individuals 50 years or older without evidence of PD or any other neurodegenerative disease. PARTICIPANTS: Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment. MAIN OUTCOME MEASURE: Incidence of new-onset PD in relation to baseline transcranial sonography status. RESULTS: There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants. CONCLUSIONS: In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.

Width of the third ventricle assessed by transcranial sonography can monitor brain atrophy in a time- and cost-effective manner--results from a longitudinal study on 500 subjects.

Ventricular width and its enlargement over time are discussed as promising markers for preclinical brain atrophy. The aim of our study was to define whether brain atrophy can reliably be monitored by transcranial ultrasound (TCS). In a prospective longitudinal trial over 5years, 500 healthy persons were examined by a standardized protocol with TCS in addition to an extensive cognitive testing using the Consortium to Establish a Registry of Alzheimer's Disease - Neuropsychological Testing (CERAD-NP). TCS displayed the third ventricle in 96% of all cases at the follow-up with a high intra-individual reproducibility and excellent inter-rater coefficient (0.992). The mean diameter of the third ventricle in subjects with a cognitive decline was significantly wider (6mm±2) than in subjects with normal cognitive testing results (4.6mm±1.8). We demonstrated that the width of the third ventricle, as a marker of brain atrophy can reliably be monitored by using TCS as a non-invasive, time- and cost-effective method. We provide evidence that the assessed width of the third ventricle can differentiate between subjects with a normal cognitive performance and subjects with a cognitive decline. TCS may be a useful screening tool in the early diagnosis of cognitive decline.