The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study

The development of therapeutic strategies to effectively treat negative symptoms remains one of the primary goals in the treatment of schizophrenia. Mirtazapine is the first of a new class of dual action compounds, the noradrenergic and specific serotonergic antidepressants (NaSSa), whose activity is related to the enhancement of noradrenergic and serotonergic transmission by a presynaptic alpha2 antagonism and postsynaptic 5-HT2 and 5-HT3 antagonism, respectively. This study was a 8-week double-blind, randomized, placebo-controlled trial of 30 mg adjunctive mirtazapine to clozapine therapy in 24 patients with DSM-IV schizophrenia. The main finding at the end of the trial was a significant reduction on the Scale for the Assessment of Negative Symptoms (SANS) total scores in the mirtazapine group compared to placebo (P<0.01) with a significant improvement on the SANS subscales avolition/apathy and anhedonia/asociality. The Brief Psychiatric Rating Scale total score at week 8 showed superiority of mirtazapine over placebo. These findings suggest a potential role for mirtazapine as an augmentation strategy in the treatment of negative symptoms of schizophrenia.     

A human and mouse pregnane X receptor reporter gene assay in combination with cytotoxicity measurements as a tool to evaluate species-specific CYP3A induction

Recent studies have demonstrated that a member of the nuclear receptor family, pregnane X receptor (PXR) is a key regulator of the expression of cytochrome P450 3A (CYP3A) in humans and rodents. It is also known that species specificity in the induction of CYP3A by xenobiotics is likely a consequence of differences at the level of PXR activation. Because of the importance of CYP3A4 in drug metabolism, the development of rapid and accurate in vitro assays for predicting the effects of compounds on CYP3A4 expression or activity in humans has been a long-standing goal within pharmaceutical industries. PXR activation measurements using an in vitro reporter gene approach appears to provide a rapid and relatively inexpensive means for predicting whether compounds will induce CYP3A levels in vivo. In this study, using an HepG2 cell based human and mouse PXR reporter gene assay, 23 compounds were tested for their potential to activate hPXR or mPXR. Data demonstrated that potent activators of hPXR had virtually no activity on mPXR and efficient activators of mPXR had weak activity on hPXR. In addition, a third category of moderate/weak activators of both hPXR and mPXR was identified. Exemestane was a strong activator of mPXR ( approximately 22-fold activation) with only minor effect on hPXR ( approximately 5-fold activation). The importance of cell viability measurements as part of the PXR reporter gene assay was demonstrated as significant cytotoxicity or inhibition of cell proliferation might underestimate the potential for PXR activation.     

Induction of oxidative stress in murine cell lines by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX)

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), the potent bacterial mutagen produced during chlorination of drinking water, was tested for the induction of oxidative stress in two murine cell lines: NIH 3T3 (fibroblasts) and L929 (fibrosarcoma cells). Following 1 h MX treatment at concentrations between 100 and 1000 microM, cellular stress conditions were monitored by measuring reactive oxygen species formation (ROS) and reduced glutathione levels (GSH). The kinetics of ROS formation and GSH depletion was investigated from 10 min to 1 h. MX caused detachment of cells at 1000 microM in L929 cells and at 300 microM in NIH 3T3 cells but the viability of the cells, measured by the trypan blue assay, decreased only by 20 and 7%, respectively, in 1h. MX increased ROS production in L929 cells in a dose-dependent manner, by 120% at 500 microM of MX in 1 h. The maximum ROS production was attained already in 10min. In NIH 3T3 cells, the ROS production was slightly, but not statistically significantly stimulated at 200 microM between 20 and 60 min. Concomitantly, MX decreased the intracellular content of GSH dose-dependently in both cell lines, by 48% in L929 cells at 500 microM of MX and 32% in NIH 3T3 cells at 200 microM of MX in one hour. The majority of this GSH depletion had occurred in 10 min. These findings indicate that MX induces oxidative stress in mammalian cells in vitro though the sensitivity of cells may differ for this effect.     

Detection of Chlamydia pneumoniae in atherosclerotic coronary arteries

Chlamydia pneumoniae has recently been associated with the development of coronary heart diseases by sero-epidemiological studies and by direct detection of the organism in atherosclerotic tissues. The aim of our study was to employ a semi-nested PCR approach to investigate the presence of C. pneumoniae in both normal and atherosclerotic coronary arteries of humans obtained at autopsy. Moreover, we have evaluated the role of infection with C. pneumoniae in relation to the extent of coronary atherosclerosis. One hundred and eighty coronary artery specimens were collected at autopsy from 60 consecutive subjects (three arterial segments from each subject). Atherosclerosis in each arterial segment was graded histologically by the Stary classification. Thirty normal coronary arteries were also taken at autopsy as control. PCR results evidenced the presence of C. pneumoniae DNA in atherosclerotic coronary arteries in 19 (31.7%) of 60 subjects examined, while none of the 30 subjects with non-atherosclerotic tissues was positive (p=0.001). Moreover, of the 180 atherosclerotic specimens examined, C. pneumoniae DNA was detected in 3.4% (2/59) of mild atherosclerotic lesions, and in 14.0% (17/121) of advanced atherosclerotic lesions (p=0.05). Our results demonstrate that the presence of C. pneumoniae DNA may be associated with the severity of coronary atherosclerosis.     

Structure-activity relationships for euphocharacins A-L, a new series of jatrophane diterpenes, as inhibitors of cancer cell P-glycoprotein

The Mediterranean spurge Euphorbia characias L. afforded twelve new diterpenes based on a jatrophane skeleton named euphocharacins A-L. Their chemical structures were elucidated by extensive nuclear magnetic resonance and mass spectrometry methods. Euphocharacins A-L were tested as inhibitors of the daunomycin-efflux activity of P-glycoprotein from cancer cells. The results were used to extend the structure-activity relationship established for this class of compounds, highlighting the positive effects of propyl and benzoyl groups at positions 3 and 9, respectively, and evidencing the negative effect of a free hydroxyl group at position 2. Among the tested compounds, euphocharacins C and I showed an activity higher than cyclosporin to inhibit Pgp-mediated daunomycin transport.     

Support systems: older adults with neurogenic communication disorders

As the population of older adults increases, there is a corresponding increase in the number of individuals with communication disorders resulting from brain damage. The purpose of this article was to describe the effects of aphasia and dementia on language and communication, and to suggest support systems for improving communication and maximizing residual language abilities. For both these disorders, we address the psychosocial environment, the roles of professionals and caregivers, individual versus group therapy, and support groups. Finally, we report on 2 specific support groups, one for aphasia and one for Alzheimer's dementia, with which the authors have been involved for many years.     

The cerivastatin withdrawal crisis: a "post-mortem" analysis

In August 2001, cerivastatin was removed from European and USA markets because of a higher risk of rhabdomyolysis associated with its use in comparison with other statins. The objective of this study was to compare cholesterol-lowering drug use in Italy before and after the withdrawal of cerivastatin from the market, and to evaluate if the withdrawal influenced patients compliance and physicians prescribing habits. After August 2001, 48% of cerivastatin users discontinued any statin treatment. The major risk factor for discontinuation was a concomitant use of fibrate during the first 7 months of 2001 (OR = 2.3; 95% CI = -2.9). Comparing the discontinuation of statin therapy between 2001 and 2000 we can estimate that there was a 5% increase, corresponding to about 200,000 patients, who discontinued statin therapy during autumn 2001 because of cerivastatin emergency.     

Lactobacilli for prevention of urogenital infections: a review

Urogenital infections are a worldwide shared problem that represent the most common reason for a woman to decide to visit to gynaecologist or urologist. The origin of the uropathogens in uncomplicated urinary tract infection and bacterial vaginosis is the fecal flora. Key element of pathogenesis namely the ability of the pathogens to survive exposure to the microflora that exists on the external urogenitalia, in which lactobacilli predominate. Some health food appear to contain > or = 1 common Lactobacillus strain; L. rhamnosus GR-1 was found to be the best of a group of 34 Lactobacillus strains isolated from dairy, poultry, health food. Recently has been reported the first clinical evidence that probiotic lactobacilli can be delivered to the vagina following oral intake. These L. strains possess the ability to adhere to and colonize tissues and the capacity to inhibit the pathogenesis of disease-causing organisms that make them effective probiotic agents. In particularly, two strains, Lactobacillus GG and Lactobacillus rhamnosus GR-1 appear to be effective at colonizing and protecting the intestine and urogenital tract, respectively, against microbial infection. Treating and preventing urogenital infection by instillating probiotic organisms has great appeal to patients and caregivers. The ability to administer orally L. rhamnosus GR-1 and L. fermentum RC-14, which colonize the intestine and vagina, provides a major step in the right direction for patients as it potentially allows for the self administration of therapy.     

Long-term outcome for patients with non-metastatic Ewing's sarcoma treated with adjuvant and neoadjuvant chemotherapies. 402 patients treated at Rizzoli between 1972 and 1992

We evaluated the long-term results obtained in 402 patients with non-metastatic Ewing's sarcoma (ES) of the bone treated in a single institution with adjuvant and neoadjuvant chemotherapies between 1972 and 1992. Multivariate analyses showed male gender, age older than 14 years, high serum lactate dehydrogenase (LDH) level, axial location of the tumour, use of radiotherapy alone as a local treatment, and poor histological response to chemotherapy, to be independent, adverse prognostic factors for event-free survival (EFS). At a mean follow-up of about 18 years (10-30 years), 177 patients (44.0%) remained continuously free of disease, 2 died of doxorubicin-induced cardiotoxicity and 8 developed a second neoplasm (5 died, and 3 are alive and free of disease). 215 patients relapsed with metastases and/or local recurrence: 14 are alive and free of disease, 1 is alive with uncontrolled disease, and 200 died. The overall survival (OS) at real follow-ups of 5-, 10-, 15- and 20-years was 57.2, 49.3, 44.9 and 38.4%, respectively. We conclude that since local or systemic relapses, treatment-complications and second malignancies are more common after 5 years or more from the beginning of treatment; a long-term follow-up is mandatory for patients with ES.     

Can breast-feeding protect against schizophrenia? Case-control Study

BACKGROUND: Human milk, unlike formula feeds, contains long-chain polyunsatured fatty acids, such as docosahexaenoic acid and arachidonic acid which are essential in the development of the central nervous system. If human milk is the optimal food for brain development, and if schizophrenia is a neurodevelopment disorder, might people who become schizophrenic in adult life be less likely to have been breast-fed? AIMS: To compare the incidence and length of breast-feeding in patients, siblings and normal controls and to examine the relationship between the duration of breast-feeding and age at onset of schizophrenia. METHOD: 113 schizophrenic patients were recruited, as were 140 siblings of the patients and 113 nonschizophrenic controls. The breast-feeding history of the patients, their siblings and controls was obtained through interviews with the mothers of the patients and controls. RESULTS: There were no significant differences between groups in the incidence of breast- feeding. The duration of breast-feeding was positively correlated with the age at onset of illness (r = +0.25, p < 0.02). CONCLUSION: Breast-feeding is no less common in those who develop schizophrenia in later life. However, breast milk might postpone the onset of the illness in schizophrenic patients.