Australian Schizophrenia Care and Assessment Programme: real-world schizophrenia: economics

OBJECTIVE: The treatment of patients with schizophrenia consumes a considerable proportion of health service budgets, yet there have been few attempts to prospectively analyse the costs associated with this condition. Amid the current debate about where to invest scarce treatment resources to achieve optimal outcomes, real-world studies, such as the Schizophrenia Care and Assessment Programme (SCAP) contrast with hypothetically based models and provide comprehensive and broad-ranging data. METHOD: Direct health-care costs were prospectively studied in a cohort of 347 patients with schizophrenia in Dandenong, Australia over 3 years. Indirect costs were estimated from patient self-reported information. RESULTS: The average annual societal cost was AU $32,160 per participant in the first year of the study, AU $27,190 in the second year and AU $29,181 in the third year. Indirect costs accounted for 46% of the total costs in the first year, 52% of the total costs in the second year and 50% of the total costs in the third year. The most expensive component of treatment was inpatient hospital care, which accounted for 42%, 34% and 36% of the total costs in the first, second and third year, respectively. CONCLUSIONS: Considerable resources are required for the provision of treatment for patients with schizophrenia. But for the majority of people in this cohort, funding assertive treatment programmes and measures to reduce hospitalization was accompanied with enhanced functioning and quality of life, as well as a reduction in long-term societal and government costs. The distribution of health-care costs is highly skewed, with a relatively small proportion of patients (39%) consuming the majority of resources (80%). Improving rates of employment for this patient group could hold substantial benefits in reducing the overall economic and personal impact of this disorder.     

Vitamin deficiencies in acutely intoxicated patients in the ED

Objective

Physicians often administer intravenous multivitamins to intoxicated patients in the emergency department (ED); however, this practice is not supported by evidence from any prior study. We determined the prevalences of vitamin deficiencies in patients presenting to our ED with alcohol intoxication.

Methods

This study was a prospective, cross-section, observational study of a convenience sample of ED patients presenting with acute alcohol intoxication. Patients were tested for B₁₂, folate, and thiamine levels as add-ons to their blood samples.

Results

Seventy-seven patients were included in the final analysis. The mean age was 46 years, and 19% were female; the mean blood alcohol level was 280 mg/dL. Of 75 patients, no one (0%) had low B₁₂ or folate levels (95% confidence interval, 0-0.05); 6 (15%) of 39 patients had low thiamine levels (95% confidence interval, 0.06-0.31). Of these 6 patients, none exhibited clinical signs of thiamine deficiency.

Conclusions

In our ED, patients with acute ethanol intoxication do not have B₁₂ or folate deficiencies. A significant minority (15%) of patients have thiamine deficiency; its clinical significance is unclear. Widespread administration of multivitamins is unwarranted by these findings, but thiamine may be considered.     

Possible involvement of sigma-1 receptors in the anti-immobility action of bupropion, a dopamine reuptake inhibitor

Sigma receptors particularly, sigma-1 subtype is known to modulate the release of catecholamines in the brain and may participate in the mechanism of action of various antidepressants. The present study investigated the possible involvement of sigma receptors in modulating the anti-immobility-like effect of bupropion (a dopamine reuptake inhibitor) using the forced swim test (FST) in mice. Bupropion produced dose-dependent (10–40 mg/kg, i.p.) reduction in immobility period and the ED₅₀ value was found to be 18.5 (7.34–46.6) mg/kg, i.p. (+)-Pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma-1 receptor agonist, produced synergistic response when it was co-administered with a subeffective dose of bupropion (10 mg/kg, i.p.). On the contrary, pretreatment with progesterone (10 mg/kg, s.c.), a sigma-1 receptor antagonist neurosteroid, rimcazole (5 mg/kg, i.p.), another sigma-1 receptor antagonist, or BD 1047 (1 mg/kg, i.p.), a novel sigma-1 receptor antagonist, reversed the anti-immobility effects of bupropion (20 mg/kg, i.p.). The various modulators used in the study did not show any effect per se on locomotor activity except bupropion which at a higher dose (15–40 mg/kg, i.p.) significantly increased the locomotor activity. The results for the first time demonstrated the involvement of sigma-1 receptors in the anti-immobility effects of bupropion.     

Chondroprotective Potential of Fruit Extracts of Phyllanthus emblica in Osteoarthritis

There is a need for effective nutraceuticals for osteoarthritis care. The fruit of Phyllanthus emblica is used as a powerful rejuvenator in Ayurvedic medicine. This study measured the chondroprotective potential of P. emblica ('Amalaki') fruits in vitro. We used aqueous extracts of unprocessed P. emblica fruit powder (powder A), and the powder obtained after hot water extraction and drying of powder A (powder B). Chondroprotection was measured in three different assay systems. First, we tested the effects of both fruit powders on the activities of the enzymes hyaluronidase and collagenase type 2. Second, an in vitro model of cartilage degradation was set-up with explant cultures of articular knee cartilage from osteoarthritis patients. Cartilage damage was assayed by measuring glycosaminoglycan release from explants treated with/without P. emblica fruit powders. Aqueous extracts of both fruit powders significantly inhibited the activities of hyaluronidase and collagenase type 2 in vitro. Third, in the explant model of cartilage matrix damage, extracts of glucosamine sulphate and powder B (0.05 mg/ml) exhibited statistically significant, long-term chondroprotective activity in cartilage explants from 50% of the patients tested. This result is important since glucosamine sulphate is the leading nutraceutical for osteoarthritis. Powder A induced a statistically significant, short-term chondroprotective activity in cartilage explants from all of the patients tested. This is the first study to identify and quantitate new chondroprotective activities of P. emblica fruits. These data provide pilot pre-clinical evidence for the use of P. emblica fruits as a chondroprotective agent in osteoarthritis therapy.     

HER2-Positive Early Breast Cancer and Trastuzumab: A Surgeon’s Perspective

Although the treatment of patients with early-stage breast cancer is provided by a multidisciplinary team, surgeons must ensure they are well informed about all aspects of patient care. For example, understanding the importance of human epidermal growth factor receptor 2 (HER2) gene amplification and/or protein overexpression and the effect on patient prognosis can guide therapeutic decision making. In addition, surgeons should also be knowledgeable about the wide variety of available postsurgical treatments, from traditional chemotherapy and radiotherapy to novel agents such as the HER2-targeted monoclonal antibody trastuzumab. Trastuzumab was recently approved for adjuvant treatment of invasive, HER2-positive, node-positive breast cancer. Its approval was based on the combined results of two large-scale trials, which demonstrated that adding trastuzumab to chemotherapy significantly improves disease-free and overall survival. Knowledge about the indications, schedules, and safety profiles of therapies such as trastuzumab will enable surgeons to optimize the timing of surgery in relation to these therapies, and to make informed decisions about the team member to whom a particular patient should ideally be referred for postsurgical care. In the future, results from large-scale trials evaluating the clinical utility of neoadjuvant trastuzumab will become available. Early results from ongoing phase III trials of the addition of trastuzumab to presurgical chemotherapy suggest that high response rates, including pathologic complete responses, are achievable. If trastuzumab is approved for use in neoadjuvant regimens, the need for surgeons to be well informed about the appropriate use of this particular agent will become even more important.     

Solitary Fibrous Tumor of the Breast and Mammary Myofibroblastoma: The Same Lesion?

Abstract:  Benign stromal tumors of the breast are rare mesenchymal neoplasms that have significant clinical and morphologic overlap. We report the case of a spindle cell tumor occurring in the mammary gland with mixed features of solitary fibrous tumor and mammary myofibroblastoma. The significance of this finding as well as the pathologic and radiologic diagnostic strategies used to differentiate these two lesions are presented based on a review of pertinent literature.     

Possible involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant activity of berberine chloride

Berberine is an isoquinoline alkaloid isolated from Berberis aristata, a major herb widely used in Indian and Chinese systems of medicine. Berberine possessed a wide range of biological activity including antidiarrheal, antimicrobial, anti-inflammatory effects and some central nervous system activity as well. The present study was designed to explore the antidepressant activity and its possible mechanism of action. Further, the involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of berberine chloride was investigated. The antidepressant activity was assessed in forced-swim and tail-suspension tests. Total immobility period was recorded during a six-min test. Berberine (5-20 mg/kg, i.p.) produced a reduction in immobility period in both the tests. When berberine (5 mg/kg, i.p.) was co-administered with other antidepressant drugs, it enhanced the anti-immobility effect of subeffective doses of imipramine (2 mg/kg, i.p.), desipramine (5 mg/kg, i.p.), tranylcypromine (4 mg/kg, i.p.), fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.) in forced-swim test. However, berberine did not modify the effects of mianserine (32 mg/kg, i.p.) or trazodone (2 mg/kg, i.p.), the two atypical antidepressant drugs. The neurochemical analysis revealed that berberine (5 mg/kg, i.p.) increased the levels of norepinephrine, serotonin or dopamine in the mouse whole brain. The antidepressant-like effect of berberine (5 mg/kg, i.p.) in forced-swim test was prevented by pretreatment with L-arginine (750 mg/kg, i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg, i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of berberine (2 mg/kg, i.p.). In addition, treatment of mice with methylene blue (10 mg/kg, i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of berberine (2 mg/kg, i.p.) in the forced-swim test. Furthermore, the reduction in the immobility period elicited by berberine (5 mg/kg, i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg, i.p.) [phosphodiesterase 5 inhibitor]. The various modulators and their combination with berberine did not produce any changes in locomotor activity. Our findings demonstrated that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin or dopamine) and further, the antidepressant-like effect of berberine in the forced-swim test involved an interaction with the L-arginine-NO-cGMP pathway.     

U-74500A (lazaroid), a 21-aminosteroid attenuates neuroleptic-induced orofacial dyskinesia

21-Aminosteroid, or lazaroid, is one of a novel class of antioxidant drugs designed to inhibit iron-dependent lipid peroxidation in biological lipid environments. They have shown promising results in several animal models of traumatic, ischemic and hemorrhagic injury of the central nervous system. Neuroleptic-induced orofacial dyskinesia is an animal model of tardive dyskinesia whose pathophysiology has been related to oxidative stress in the basal ganglia. In this study, we have examined the protective role of U-74500A [pregna-1,4,9(11)-triene-3,20-dione, 21-(4-(5,6-bis(diethylamino)-2-pyridinyl)-1-piperazinyl)-16-ethyl-HCl (16-alpha)], a 21-aminosteroid having antioxidant property in attenuating the behavioral and biochemical effects of chronic haloperidol and chlorpromazine administration. Haloperidol (1 mg/kg/day i.p.) and chlorpromazine (5 mg/kg/day i.p.) administered for 21 days caused a significant increase in vacuous chewing movements (VCMs), tongue protrusion (TP) and the number of facial twitchings (FT) observed on day 22. U-74500A (1, 2 and 5 mg/kg i.p.), administered every day, along with haloperidol (1 mg/kg/day i.p.) and chlorpromazine (5 mg/kg/day), attenuated the increase of VCMs and related behaviors on day 22. Haloperidol and chlorpromazine significantly increased lipid peroxidation in various brain areas such as the cortex, striatum and subcortical parts characterized by an increase in MDA levels. The coadministration of U-74500A limited the effect of haloperidol and chlorpromazine on MDA levels in the cortex and striatum but not in the subcortical parts. U-74500A, an aminosteroid, may have therapeutic use in typical neuroleptic-induced tardive dyskinesia-like effects.     

Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands

Structure-based design and synthesis of a number of potent and selective memapsin 2 inhibitors are described. These inhibitors were designed based upon the X-ray structure of memapsin 2-bound inhibitor 3 that incorporates methylsulfonyl alanine as the P2-ligand and a substituted pyrazole as the P3-ligand. Of particular importance, we examined the ability of the substituted isophthalic acid amide derivative to mimic the key interactions in the S2-S3 regions of the enzyme active sites of 3-bound memapsin 2. We investigated various substituted phenylethyl, alpha-methylbenzyl, and oxazolylmethyl groups as the P3-ligands. A number of inhibitors exhibited very potent inhibitory activity against mempasin 2 and good selectivity against memapsin 1. Inhibitor 5d has shown low nanomolar enzyme inhibitory potency (Ki=1.1 nM) and very good cellular inhibitory activity (IC50=39 nM). Furthermore, in a preliminary study, inhibitor 5d has shown 30% reduction of Abeta40 production in transgenic mice after a single intraperitoneal administration (8 mg/kg). A protein-ligand X-ray crystal structure of 5d-bound memapsin 2 provided vital molecular insight that can serve as an important guide to further design of novel inhibitors.