Does Impaired Plantar Cutaneous Vibration Perception Contribute to Axial Motor Symptoms in Parkinson's Disease? Effects of Medication and Subthalamic Nucleus Deep Brain Stimulation.

OBJECTIVE: To investigate whether impaired plantar cutaneous vibration perception contributes to axial motor symptoms in Parkinson's disease (PD) and whether anti-parkinsonian medication and subthalamic nucleus deep brain stimulation (STN-DBS) show different effects. METHODS: Three groups were evaluated: PD patients in the medication "on" state (PD-MED), PD patients in the medication "on" state and additionally "on" STN-DBS (PD-MED-DBS), as well as healthy subjects (HS) as reference. Motor performance was analyzed using a pressure distribution platform. Plantar cutaneous vibration perception thresholds (VPT) were investigated using a customized vibration exciter at 30 Hz. RESULTS: Motor performance of PD-MED and PD-MED-DBS was characterized by greater postural sway, smaller limits of stability ranges, and slower gait due to shorter strides, fewer steps per minute, and broader stride widths compared to HS. Comparing patient groups, PD-MED-DBS showed better overall motor performance than PD-MED, particularly for the functional limits of stability and gait. VPTs were significantly higher for PD-MED compared to those of HS, which suggests impaired plantar cutaneous vibration perception in PD. However, PD-MED-DBS showed less impaired cutaneous vibration perception than PD-MED. CONCLUSIONS: PD patients suffer from poor motor performance compared to healthy subjects. Anti-parkinsonian medication in tandem with STN-DBS seems to be superior for normalizing axial motor symptoms compared to medication alone. Plantar cutaneous vibration perception is impaired in PD patients, whereas anti-parkinsonian medication together with STN-DBS is superior for normalizing tactile cutaneous perception compared to medication alone. Consequently, based on our results and the findings of the literature, impaired plantar cutaneous vibration perception might contribute to axial motor symptoms in PD.

Effect of Compaction Pressure on the Enzymatic Activity of Pancreatin in Directly Compressible Formulations.

Tableting of biomolecules is a challenging formulation phase due to their sensitivity to various process parameters, such as compression pressure, process dynamics, or the temperature generated. In the present study, pancreatin was employed as a model enzyme mixture, which was formulated in tablet form utilizing the synergistic effects of brittle and plastic excipients (dibasic calcium phosphate and microcrystalline cellulose, respectively). The effect of varying compaction pressure and lubricant concentration on the generated temperature and enzymatic activity was evaluated. The tablets were analyzed for pancreatin content and the activity of two enzymes (protease and amylase) using pharmacopoeial tests. This study indicated that the formulations proposed here allow tableting over a wide range of compaction pressures without adversely affecting pancreatin content and its enzymatic activity.

The Use of Calcium Phosphate-Based Starter Pellets for the Preparation of Sprinkle IR MUPS Formulation of Rosuvastatin Calcium.

Sprinkle formulations represent an interesting concept of medicinal products aimed at the steadily growing population of patients suffering from swallowing difficulties (dysphagia). In the present work, immediate-release sprinkle MUPS (multiple-unit pellet system) containing rosuvastatin calcium as a model drug substance was successfully developed. The formulation was prepared by drug layering technique using novel calcium phosphate-based starting pellets (PharSQ® Spheres CM) of three different particle sizes. The study showed that the developed multiparticulates were characterized by uniform distribution of coating layers thickness, as well as fast dissolution rate (more than 85% of rosuvastatin calcium dissolved within 30 min, as required by the relevant USP/NF monograph). Rosuvastatin calcium, like other statins, has a bitter, unpleasant taste. Investigations conducted with an electronic tongue suggested that the developed formulation achieved the desired taste-masking efficiency. The effect was found to be particle size-dependent, improving as the size of the multiparticulates increased.

Towards the Continuous Manufacturing of Liquisolid Tablets Containing Simethicone and Loperamide Hydrochloride with the Use of a Twin-Screw Granulator.

Continuous manufacturing is becoming the new technological standard in the pharmaceutical industry. In this work, a twin-screw processor was employed for the continuous production of liquisolid tablets containing either simethicone or a combination of simethicone with loperamide hydrochloride. Both active ingredients present major technological challenges, as simethicone is a liquid, oily substance, and loperamide hydrochloride was used in a very small amount (0.27% w/w). Despite these difficulties, the use of porous tribasic calcium phosphate as a carrier and the adjustment of the settings of the twin-screw processor enabled the optimization of the characteristics of the liquid-loaded powders and made it possible to efficiently produce liquisolid tablets with advantages in physical and functional properties. The application of chemical imaging by means of Raman spectroscopy allowed for the visualization of differences in the distribution of individual components of the formulations. This proved to be a very effective tool for identifying the optimum technology to produce a drug product.

Anticipatory Postural Adjustments and Compensatory Postural Responses to Multidirectional Perturbations-Effects of Medication and Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Postural instability is one of the most restricting motor symptoms for patients with Parkinson's disease (PD). While medication therapy only shows minor effects, it is still unclear whether medication in conjunction with deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves postural stability. Hence, the aim of this study was to investigate whether PD patients treated with medication in conjunction with STN-DBS have superior postural control compared to patients treated with medication alone. METHODS: Three study groups were tested: PD patients on medication (PD-MED), PD patients on medication and on STN-DBS (PD-MED-DBS), and healthy elderly subjects (HS) as a reference. Postural performance, including anticipatory postural adjustments (APA) prior to perturbation onset and compensatory postural responses (CPR) following multidirectional horizontal perturbations, was analyzed using force plate and electromyography data. RESULTS: Regardless of the treatment condition, both patient groups showed inadequate APA and CPR with early and pronounced antagonistic muscle co-contractions compared to healthy elderly subjects. Comparing the treatment conditions, study group PD-MED-DBS only showed minor advantages over group PD-MED. In particular, group PD-MED-DBS showed faster postural reflexes and tended to have more physiological co-contraction ratios. CONCLUSION: medication in conjunction with STN-DBS may have positive effects on the timing and amplitude of postural control.

Exploiting synergistic effects of brittle and plastic excipients in directly compressible formulations of sitagliptin phosphate and sitagliptin hydrochloride.

Direct compression (DC) is the simplest and most economical way to produce pharmaceutical tablets. Ideally, it consists of only two steps: dry blending of a drug substance(s) with excipients followed by compressing the powder mixture into tablets. In this study, immediate-release film-coated tablets containing either Sitagliptin phosphate or Sitagliptin hydrochloride were developed using DC technique. After establishing the optimum ratio of ductile and brittle excipients, five formulations were compressed into tablets using a rotary press and finally film coated. Both powders and tablets were examined by standard pharmacopoeial methods. It has been shown that the simultaneous use of excipients with different physical properties, i.e. ductile microcrystalline cellulose and brittle anhydrous dibasic calcium phosphate, produces a synergistic effect, allowing preparation of Sitagliptin DC tablets with good mechanical strength (tensile strength over 2 N/mm2), rapid disintegration (shorter than 2 min), and fast release of the drug substance (85% of the drug is dissolved within 15 min). It was found that the type of calcium phosphate excipient used had a large effect on the properties of the sitagliptin tablets. All formulations developed showed good chemical stability, even when stored under stress conditions (50 °C/80% RH).

Directly compressible formulation of immediate release rosuvastatin calcium tablets stabilized with tribasic calcium phosphate.

Reliable and stable tablet formulations for rosuvastatin calcium (RSC) in four strengths: 5 mg, 10 mg, 20 mg, and 40 mg have been developed. Rosuvastatin is a cholesterol-lowering statin drug and is known to be unstable during storage. The possibility of its stabilization with inorganic salts of multivalent metals has already been reported in the literature. In the present study, a special grade of tribasic calcium phosphate excipient was used to chemically stabilize RSC in a directly compressible immediate release tablet formulation. The developed tablets exhibited good mechanical properties (breaking force ranging from 177 N to 250 N depending on tablet strength), rapid disintegration (less than three minutes) and fast dissolution rate (85% of the drug substance dissolved within 15 minutes) as well as satisfactory chemical stability during storage under stress conditions (50 °C/80% RH), even compared to the reference commercial product.

Studies on the pH-Dependent Solubility of Various Grades of Calcium Phosphate-based Pharmaceutical Excipients.

Calcium phosphate-based pharmaceutical excipients, including calcium hydrogen phosphate anhydrous and dihydrate, calcium hydroxide phosphate have been well established in pharmaceutical technology for a very long time. Nowadays, they are of increasing interest to the pharmaceutical industry because, in addition to their advanced functional properties, they offer beneficial biocompatible and biodegradable properties. Yet, there is limited availability of embracing information regarding the solubility of these popular excipients, especially in variable pH conditions, reflecting those of the gastrointestinal tract (GIT). The study has shown that the solubility of calcium phosphates as well as their dissolution rate decreases significantly with increasing pH of dissolution fluids. The highest solubility was observed for dibasic calcium phosphate dihydrate, the lowest for tribasic calcium phosphate. This article provides also a comparison of various calcium phosphate types originating from different manufacturers, which may prove to be useful and help formulation scientists to design new medicinal products.

Development of a Biphasic-Release Multiple-Unit Pellet System with Diclofenac Sodium Using Novel Calcium Phosphate-Based Starter Pellets.

Novel calcium phosphate-based starter pellets were used to develop a biphasic-release multiple-unit pellet system (MUPS) with diclofenac sodium as a model drug in the form of hard gelatin capsules. For comparative purposes, corresponding formulations based on the inert cores made of microcrystalline cellulose, sucrose and isomalt were prepared. The developed system consisted of two types of drug-layered pellets attaining different release patterns: delayed-release (enteric-coated) and extended-release. Dissolution characteristics were examined using both compendial and biorelevant methods, which reflected fed and fasting conditions. The results were collated with an equivalent commercial product but prepared with the direct pelletization technique.

Postural performance and plantar cutaneous vibration perception in patients with idiopathic normal pressure hydrocephalus.

OBJECTIVE: To investigate whether impaired plantar cutaneous vibration perception contributes to postural disturbance in idiopathic normal pressure hydrocephalus (iNPH). METHODS: Three different groups were tested: iNPH-patients (iNPH), iNPH-patients after surgical shunt therapy (iNPH shunt), and healthy subjects (HS). Postural performance was quantified during quiescent stance on a pressure distribution platform. Vibration perception threshold (VPT) was measured using a modified vibration exciter to apply stimuli to the plantar foot. RESULTS: Regarding postural performance, iNPH showed significantly higher values for all investigated center of pressure (COP)-parameters compared to HS, which suggests impaired postural control. Shunted patients presented a tendency towards better postural control in contrast to non-shunted patients. VPTs did not differ significantly between all investigated groups, which suggests comparable plantar cutaneous vibration perception. CONCLUSION: Patients with iNPH suffer from poor postural stability, whereas shunting tends to affect postural performance positively. Plantar cutaneous vibration perception seems to be comparable between all investigated study groups. Consequently, postural disturbance in iNPH cannot clearly be ascribed to defective plantar cutaneous input.

Effects of plantar hypothermia on quasi-static balance: Two different hypothermic procedures.

Inducing hypothermia to examine its effects on balance is performed with various approaches. However, data interpretations of underlying postural mechanisms often do not consider the applied hypothermic protocol. In this context, the effects of diminished plantar mechanoreceptor activity on quasi-static balance performance were investigated, examining the applicability of a continuously cooling thermal platform in comparison with conventional ice pads. Increased instability for the thermal platform compared to cooling with ice pads was hypothesized, since we expected increased temperatures for the ice pad group directly after balance tests. Similar scores on a Visual Analogue Scale (VAS) were predicted regarding subjective pain. Results showed that both cooling procedures successfully induced plantar hypothermia. However, the thermal platform was more effective with respect to reaching and maintaining the desired temperature throughout the trials, especially when comparing temperatures before and after balance tests. Therefore, balance tests indeed demonstrated increased COP parameters exclusively after permanent cooling via the thermal platform as early as after the first 10 min of cooling. Reduced plantar input may result in this postural instability, but without the need of other sensory systems to compensate. The VAS generally demonstrated higher pain scores for the ice pads, rejecting our hypothesis. This is an important finding, since pain is known to influence balance. Therefore, permanent and controllable cooling via the thermal platform should be taken into consideration when conducting related research.

closo-borane conjugated regulatory peptides retain high biological affinity: synthesis of closo-borane conjugated Tyr(3)-octreotate derivatives for BNCT.

Despite the improvements in cancer therapy during the past years, high-grade gliomas and many other types of cancer are still extremely resistant to current forms of therapy. Boron neutron capture therapy (BNCT) provides a promising way to destroy cancer cells without damaging healthy tissue. However, BNCT in practice is still limited due to the lack of boron-containing compounds that selectively deliver boron to cancer cells. Since many neuroendocrine tumors show an overexpression of the somatostatin receptor, it was our aim to synthesize compounds that contain a large number of boron atoms and still show high affinity toward this transmembrane receptor. The synthetic peptide Tyr (3)-octreotate (TATE) was chosen as a high-affinity and internalizing tumor targeting vector (TTV). Novel boron cluster compounds, containing 10 or 20 boron atoms, were coupled to the N-terminus of TATE. The obtained affinity data demonstrate that the use of a spacer between TATE and the closo-borane moiety is the option to avoid a loss of biological affinity of closo-borane conjugated TATE. For the first time, it was shown that closo-borane conjugated regulatory peptides retain high biological affinity and selectivity toward their transmembrane tumor receptors. The results obtained and the improvement of spacer and boron building block chemistry may stimulate new directions for BNCT.