Designed proteinoid polymers and nanoparticles encapsulating risperidone for enhanced antipsychotic activity.

BACKGROUND: Nanoparticles (NPs) incorporating drug formulations can be used to facilitate passage through biological barriers including the blood-brain barrier (BBB) and increase drug delivery and bioavailability. Hence, NP-based administration may enhance the efficiency of current antipsychotics. Encapsulation within NPs can resolve aqueous solubility problems that not only reduce permeability through the BBB but also affect targeting. The present study describes a new drug delivery system based on proteinoid NPs to explore the possibility of improving drug efficacy. Risperidone (RSP) is a commonly used atypical antipsychotic medication, and was therefore selected for encapsulation by proteinoid NPs. RESULTS: Proteinoid polymers with high molecular weight and low polydispersity were synthesized from L-amino acids and poly-L-lactic acid (PLLA) by thermal step-growth polymerization mechanism. RSP-loaded proteinoid NPs were then prepared using a self-assembly process in the presence of RSP, followed by PEGylation. The optimal PEGylated RSP-loaded NPs were characterized in terms of diameter and size distribution, drug loading, ζ-potential, cytotoxicity, biodistribution, and psychopharmacological effects. The findings indicate significantly higher antipsychotic activity of drug-loaded proteinoid NPs compared to free RSP. CONCLUSIONS: Proteinoid NPs enhance RSP delivery and may potentially increase drug efficiency by reducing dosage and side effects.

The spectrum of staphylococcal scalded skin syndrome: a case series in children.

Staphylococcal scalded skin syndrome (SSSS) is a disease caused by certain toxigenic strains of Staphylococcus aureus. While the classic severe phenotype is widely recognized in children, SSSS in fact exists on a spectrum with mild and moderate variants. Misunderstanding the phenotypic spectrum of SSSS may result in misdiagnosis of an otherwise treatable condition. To increase awareness of the heterogeneity of SSSS, we report four cases that together represent a range of clinical presentations.

In utero presentation of aggressive systemic mastocytosis in a neonate.

Mastocytosis is a clinically heterogenous disease characterized by mast cell hyperplasia in skin, bone marrow and/or visceral organs. Cutaneous mastocytosis is more frequently observed in children, whereas indolent systemic mastocytosis is more commonly observed in adults. Aggressive systemic presentation, particularly of the neonate, is exceptionally rare. We present a rare case of congenital aggressive systemic mastocytosis. The patient was a 37-week-old male, born by caesarean section owing to hepatosplenomegaly and ascites diagnosed in utero, who exhibited extensive cutaneous and systemic manifestations of mastocytosis at birth. Mutation analysis of c-KIT identified D816V mutation in exon 17. Although initial bilateral bone marrow aspirates demonstrated no mast-cell infiltrates or haematological neoplasm, subsequent bone-marrow biopsies postmortem exhibited multifocal mast-cell aggregates. Clinical course was complicated by bacteraemia and cardiorespiratory failure, leading to death at 10 weeks.

Targeted drug delivery of near IR fluorescent doxorubicin-conjugated poly(ethylene glycol) bisphosphonate nanoparticles for diagnosis and therapy of primary and metastatic bone cancer in a mouse model.

BACKGROUND: Most primary and metastatic bone tumors demonstrate increased osteoclast activity and bone resorption. Current treatment is based on a combination of surgery, radiotherapy and chemotherapy. Severe side effects are associated with chemotherapy due to use of high dosage and nonspecific uptake. Bisphosphonates have a strong affinity to Ca2+ ions and are widely used in the treatment of bone disorders. RESULTS: We have engineered a unique biodegradable bisphosphonate nanoparticle (NPs) bearing two functional surface groups: (1) primary amine groups for covalent attachment of a dye/drug (e.g. NIR dye Cy 7 or doxorubicin); (2) bisphosphonate groups for targeting and chelation to bone hydroxyapatite. In addition, these engineered NPs contain high polyethyleneglycol (PEG) concentration in order to increase their blood half life time. In vitro experiments on Saos-2 human osteosarcoma cell line, demonstrated that at a tenth of the concentration, doxorubicin-conjugated bisphosphonate NPs achieved a similar uptake to free doxorubicin. In vivo targeting experiments using the NIR fluorescence bisphosphonate NPs on both Soas-2 human osteosarcoma xenograft mouse model and orthotopic bone metastases mCherry-labeled 4T1 breast cancer mouse model confirmed specific targeting. In addition, therapeutic in vivo experiments using doxorubicin-conjugated bisphosphonate NPs demonstrated a 40% greater inhibition of tumor growth in Saos-2 human osteosarcoma xenograft mouse model when compared to free doxorubicin. CONCLUSIONS: In this research we have shown the potential use of doxorubicin-conjugated BP NPs for the targeting and treatment of primary and metastatic bone tumors. The targeted delivery of doxorubicin to the tumor significantly increased the efficacy of the anti-cancer drug, thus enabling the effective use of a lower concentration of doxorubicin. Furthermore, the targeting ability of the BP NPs in an orthotopic xenograft mouse model reinforced our findings that these BP NPs have the potential to be used for the treatment of primary and metastatic bone cancer.

Near IR fluorescent conjugated poly(ethylene glycol)bisphosphonate nanoparticles for in vivo bone targeting in a young mouse model.

Bisphosphonate (BP) compounds are widely used in the treatment of bone disorders. This group of drugs with a high affinity to Ca(+2) ions is rapidly attracted to bone mineral, especially in areas of high resorption. We have engineered unique biodegradable BP nanoparticles (NPs) by dispersion co-polymerization of the monomers methacrylate-PEG-BP) and (3-Aminopropyl)mathacrylamide) with the crosslinker monomer tetra ethylene glycol diacrylate. These NPs possess a dual functionality: (1) covalent attachment of a dye (e.g. near IR dye) or a drug to the nanoparticles through the primary amine groups on the surface of the NPs; (2) chelation to the bone mineral hydroxyapatite through the BP on the surface of the NPs. This study describes the uptake of the unique near IR fluorescent Cy 7-conjugated BP NPs in bone of a young mouse model. Blood half-life studies revealed a relatively long half-life (approximately 5 h) due to a high concentration of PEG in the BP NPs as well as a relatively long whole body clearance (approximately 2 weeks). Body distribution studies showed a specific uptake of the BP NPs in bone. These unique engineered BP NPs are planned to be utilized in future work for diagnostic and drug delivery systems that are targeted to bone disorders.

Pilot study of a community pharmacist led program to treat hepatitis C virus among people who inject drugs.

Background: People who inject drugs (PWID) are a key population for treatment with direct-acting antiviral medications (DAAs) to eliminate hepatitis C virus (HCV). We developed a Pharmacist, Physician, and Patient Navigator Collaborative Care Model (PPP-CCM) for delivery of HCV treatment; this study describes clinical outcomes related to HCV treatment (initial evaluation, treatment initiation, completion, and cure), as well as patient satisfaction. Methods: We conducted a single-arm prospective pilot study of adult PWID living with HCV. Participants completed baseline and six-month follow-up surveys, and treatment and outcomes were abstracted from electronic health records. Primary outcome was linkage to pharmacist for HCV evaluation; secondary outcomes included DAA initiation, completion, and cure, as well as patient-reported satisfaction. Results: Of the 40 PWID enrolled, mean age was 43.6 years, 12 (30 %) were female, 20 (50 %) were non-white, and 15 (38 %) were unhoused. Thirty-eight (95 %) were successfully linked to the pharmacist for initial evaluation. Of those, 21/38 (55 %) initiated DAAs, and 16/21 (76 %) completed treatment. Among those completing treatment who had viral load data to document whether they achieved "sustained virologic response", i.e. cure, 10/11 (91 %) were found to be cured. There was high satisfaction with 100 % responding "agree or strongly agree" that they had a positive experience with the pharmacist. Conclusion: Nearly all participants in this pilot were successfully linked to the pharmacist for evaluation, and more than half were started on DAAs; results provide preliminary evidence of feasibility of pharmacist-led models of HCV treatment for PWID. Clinicaltrialsgov registration number: NCT04698629.

Ibipinabant attenuates ß-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight.

AIM: To test the antidiabetic efficacy of ibipinabant, this new cannabinoid receptor 1 (CB1) antagonist was compared with food-restriction-induced weight loss, rosiglitazone (4 mg/kg) and rimonabant (3 and 10 mg/kg), using parameters of glycaemic control in male Zucker diabetic fatty (ZDF) rats. METHODS: Body weight, food and water intake, fasted and non-fasted glucose and insulin, glucose tolerance and glycosylated haemoglobin (HbA1c) were all assessed over the course of the 9-week study. Pancreatic insulin content and islet area were also evaluated. RESULTS: At the end of the study, vehicle-treated ZDF rats were severely hyperglycaemic and showed signs of ß-cell decline, including dramatic reductions in unfasted insulin levels. Ibipinanbant (10 mg/kg) reduced the following relative to vehicle controls: fasting glucose (-61%), glucose excursion area under the curve (AUC) in an oral glucose tolerance test (OGTT, -44%) and HbA1c (-50%). Furthermore, non-fasting insulin, islet area and islet insulin content were all increased (71, 40 and 76%, respectively) relative to vehicle controls by the end of the study. All of these effects were similar to those of rimonabant and rosiglitazone, where ibipinabant was slightly more effective than rimonabant at the lowest dose and somewhat less effective than rosiglitazone at all doses. These antidiabetic effects appear independent of weight loss because none of the parameters above were consistently improved by the comparable weight loss induced by food restriction. CONCLUSIONS: Ibipinabant may have weight loss-independent antidiabetic effects and may have the potential to attenuate ß-cell loss in a model of progressive ß-cell dysfunction.

Systematic review of the association between lung function and Type 2 diabetes mellitus.

AIMS: To describe the association between lung function and Type 2 diabetes mellitus. METHODS: We identified English language studies evaluating the association between lung function and diabetes mellitus in the MEDLINE database from 1 January 1975 to 31 December 2009. We evaluated study quality based on established criteria (54 studies were reviewed, 34 met the inclusion criteria). RESULTS: Cross-sectional studies showed that adults with diabetes mellitus have lower forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), with reductions in FVC more consistent than FEV1 and lower diffusion capacity (DLCO) compared with their non-diabetic counterparts. The reduced lung function in patients with diabetes is inversely related to blood glucose levels, duration of diabetes and its severity and is independent of smoking or obesity. Findings in cohort studies have been less consistent, with only a few studies identifying an increased rate of lung function decline in adults with diabetes. In addition, other cohort studies have reported an association between decreased lung function and incident insulin resistance and diabetes. Studies evaluating biological mechanisms to explain the association between lung impairment and diabetes identified microangiopathy of the alveolar capillaries and pulmonary arterioles, chronic inflammation, autonomic neuropathy involving the respiratory muscles, loss of elastic recoil secondary to collagen glycosylation of lung parenchyma, hypoxia-induced insulin resistance and low birthweight, as being associated with both insulin resistance and impaired lung function. CONCLUSIONS: There is an association between diabetes mellitus and decreased lung function, but the definitive direction as well as the exact pathophysiological mechanism to explain this association requires further investigation.

Neurochemical correlate of a spatial preference in rats.

Spatial (left or right) preferences were determined for rats given foot shock in a T-maze. The animals were killed, and left and right striata were assayed separately for dopamine and left and right teldiencephalic regions were assayed for norepinephrine. Dopamine content was significantly higher (by 12 percent) in the striata contralateral to rats' side preferences than in the ipsilateral striata; there was no such difference for teldiencephalic norepinephrine. The small asymmetry in striatal dopamine content is not due to any learning- or stress-related change induced by the testing procedure but is probably inherent in normal rats. Some spatial behavior appears to be the manifestation of a normal and specific difference in the activity of left and right nigrostriatal systems.

Facilitation of recovery by -methyl-p-tyrosine after lateral hypothalamic damage.

Rats with bilateral lateral hypothalamic lesions die of starvation in approximately 7 days after surgery. Rats that were treated with alpha-methyl-p-tyrosine for 3 days prior to lateral hypothalamic surgery spontaneously eat, drink, and gain weight after surgery. These data suggest that recovery of function after lateral hypothalamic damage involves denervation supersensitivity.

Oxytocin: effects of degradation on radioimmunologic and biologic activity.

Incubation with thioglycollate destroyed biologic activity of oxytocin, but left immunologic activity intact. Incubation with plasma of pregnant women at term or with placental extract destroyed biologic and immunologic activities. Dissociation of biologic from immunologic sites is suggested.

Naloxone antagonism of the thermoregulatory effects of phencyclidine.

Phencyclidine elicits hyperthermia at low doses and hypothermia at high doses in rats. Naloxone antagonizes both effects. Phencyclidine's effects on thermo-regulation are probably mediated by an interaction with a mu opiate receptor.

Lateralization of reward in rats: differences in reinforcing thresholds.

Fourteen rats with bilaterally implanted lateral hypothalamic electrodes were allowed to self-stimulate each side of the brain during daily test sessions. Rotation (circling behavior) during self-stimulation sessions was also recorded. All rats rotated in preferential direction regardless of the side of the brain stimulated, and, in each case, the direction was the same as that subsequently determined in response to d-amphetamine. All rats had asymmetries in self-stimulation thresholds related to the direction of rotation. Thresholds were lower on the side contralateral to the direction of rotation, and entire rate-intensity functions were displaced to the left on that side. The results, discussed in terms of lateralization of affect, suggest a model in which quantitative differences in neuronal firing can be translated into apparent qualitative specialization, with the two sides of the brain appearing to be specialized for high and low mood, respectively.

Cocaine-induced rotation: sex-dependent differences between left- and right-sided rats.

Cocaine elicited dose-related rotation (circling) in naïve rats. The maximum effect was greater than observed previously with other drugs. Overall, females were more sensitive to cocaine than males. However, right-biased females were more sensitive than left-biased females, whereas left-biased males were more sensitive than right-biased males. The results suggest that sex-dependent differences in brain asymmetry may be an important determinant of cocaine sensitivity.

Navigating the chasm between religious and secular perspectives in modern bioethics.

In the past 3 years, three landmark laws relating to bioethics have been passed in the Israeli parliament. These are the Terminally Ill Patient Law (in 2005) and the Organ Donation Law and the Brain Death/Respiratory Law (in 2008). To reach consensus on these difficult issues in a multicultural society such as Israel was not an easy undertaking. Using learning from previous failed attempts, compromise, dialogue and work done in the absence of hysteria and publicity were crucial to the process. In all three laws, compromises were obtained between the secular and religious factions, from which an acceptable law was developed. The Israeli experience is a model of a country working to synthesise an ancient tradition with the complexities of modern life and could serve as an example for other countries struggling with similar issues.

A case against justified non-voluntary active euthanasia (the Groningen Protocol).

The Groningen Protocol allows active euthanasia of severely ill newborns with unbearable suffering. Defenders of the protocol insist that the protocol refers to terminally ill infants and that quality of life should not be a factor in the decision to euthanize an infant. They also argue that there should be no ethical difference between active and passive euthanasia of these infants. However, nowhere in the protocol does it refer to terminally ill infants; on the contrary, the developers of the protocol take into account the future quality of life of the infant. We also note how the Nazi Euthanasie Programm started with the premise that there is some life not worthy of living. Therefore, in our opinion, the protocol violates the traditional ethical codes of physicians and the moral values of the overwhelming majority of the citizens of the world.

Accuracy of three-dimensional soft tissue prediction for Le Fort I osteotomy using Dolphin 3D software: a pilot study.

Three-dimensional (3D) soft tissue prediction is replacing two-dimensional analysis in planning for orthognathic surgery. The accuracy of different computational models to predict soft tissue changes in 3D, however, is unclear. A retrospective pilot study was implemented to assess the accuracy of Dolphin 3D software in making these predictions. Seven patients who had a single-segment Le Fort I osteotomy and had preoperative (T0) and >6-month postoperative (T1) cone beam computed tomography (CBCT) scans and 3D photographs were included. The actual skeletal change was determined by subtracting the T0 from the T1 CBCT. 3D photographs were overlaid onto the T0 CBCT and virtual skeletal movements equivalent to the achieved repositioning were applied using Dolphin 3D planner. A 3D soft tissue prediction (TP) was generated and differences between the TP and T1 images (error) were measured at 14 points and at the nasolabial angle. A mean linear prediction error of 2.91±2.16mm was found. The mean error at the nasolabial angle was 8.1±5.6°. In conclusion, the ability to accurately predict 3D soft tissue changes after Le Fort I osteotomy using Dolphin 3D software is limited.