Impact of illegal trade on the quality of epoetin alfa in Thailand.

BACKGROUND: Reports from the World Health Organization have suggested that counterfeit medicines pose a serious problem in developing countries. An investigation of anti-erythropoietin antibody-mediated pure red cell aplasia in Thailand found evidence of drug smuggling, which may have serious safety implications. OBJECTIVE: This study assessed the authenticity and quality of epoetin alfa samples in Thailand. METHODS: Samples of epoetin alfa-prefilled syringes were collected from the pharmacies at 2 major hospitals (62 samples), 8 retail pharmacies (41 samples), and Thai authorities (30 samples confiscated from smugglers at 2 airports, and 6 samples from a condominium used by smugglers). These samples were tested against the European Union Pharmacopeia specifications for aggregate content in epoetins of <2%. The integrity of epoetin alfa distribution channels, coldchain processes (maintenance at 2 degrees C-8 degrees C), primary and secondary packaging components (eg, batch number, expiration date, appearance, letter size), and company's confidential features (eg, nature of the ink, type and quality of the paper, other covered features) were also investigated. The main outcome measures were protein aggregate content, determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting; and isoform distribution, assessed by isoelectric focusing and Western blotting. RESULTS: Epoetin alfa samples obtained from the company's cold-chain and authorized distribution channels met all quality standards, as did all epoetin alfa samples obtained from the hospital pharmacies. However, evidence showed that some samples were being smuggled or sold illegally through certain unauthorized retail pharmacies. The epoetin alfa samples obtained from both airports and the condominium were stored improperly at room temperature. Aggregate levels exceeded the specification of <2% in 11 samples from 2 of the retail pharmacies (range, 1.2%-3.1%), 15 samples from the Dongmuang Airport (range, 2.2%-17.0%), and all 6 samples from the condominium (range, 10.5%-19.8%). All samples from the 2 hospitals, 8 retail pharmacies, and Suvarnabhumi Airport had the authentic 6 isoform bands. Samples from Dongmuang Airport and the condominium appeared to have the 6 characteristic bands, but positive confirmation was difficult because of band smearing caused by a high level of aggregates. All features of primary and secondary packaging were found to be authentic. CONCLUSIONS: This investigation found evidence that some epoetin alfa samples were smuggled into Thailand without proper cold chain, contained high levels of protein aggregates, and were sold illegally through certain retail pharmacies. The Thai authorities have intervened to stop such unauthorized products from reaching patients. Strenuous efforts must be made to prevent illegal cross-border smuggling of biopharmaceuticals without proper cold chain because of the serious safety implications for patients in developing countries.

Case-control study of the association between select HLA genes and anti-erythropoietin antibody-positive pure red-cell aplasia.

AIMS: Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele. To confirm a possible association of HLA-DRB1*9 and Ab-positive PRCA, we performed a pharmacogenomic analysis using subjects from an earlier case-control study of risk factors associated with Ab-positive PRCA, which had been performed using subjects from Europe or Canada. The primary goal of the analysis was to test the association between HLA-DRB1*9 and Ab-positive PRCA. A secondary goal was to perform an exploratory analysis in order to identify additional HLA alleles potentially associated with Ab-positive PRCA. PATIENTS & METHODS: Subjects were taken from a case-control study of Ab-positive PRCA in chronic kidney disease patients treated in Europe or Canada. Ab-positive PRCA cases (n=24) were matched to controls (n=81) by timing of treatment exposure and, when possible, by location. RESULTS: The allele frequency of HLA-DRB1*9 was 12.5% in cases vs 1.2% in controls (p=0.002). The frequency of the HLA-DRB1*9/other genotype was 25.0% in cases vs 2.5% in controls (p=0.004; OR: 10.8 [95% CI: 2.2-53.7]). Within the exploratory analysis, six additional HLA alleles (HLA-A*25, HLA-B*53, HLA-C*12, HLA-DQB1*3, HLA-DQB1*6 and HLA-DRB1*4) were also found to be associated with Ab-positive PRCA. CONCLUSION: This study confirmed that HLA-DRB1*9 occurs at a significantly higher frequency in Ab-positive PRCA cases than in controls; however, within this sample set, carrying the *9 allele was neither necessary nor sufficient to cause Ab-positive PRCA.

Is there a dysfunction in the visual system of depressed patients?

BACKGROUND: The aim of the current study was to identify a possible locus of dysfunction in the visual system of depressed patients. MATERIALS AND METHODS: Fifty Major Depressive patients aged 21-60 years and 15 age-matched controls took part in the study The diagnosis was obtained with the SCAN v 2.0. The psychometric assessment included the HDRS, the HAS, the Newcastle Scales, the Diagnostic Melancholia Scale and the GAF scale. Flash Electroretinogram and Electrooculogram were performed in all subjects. The statistical analysis included ANCOVA, Student's t-test and Pearson Product Moment Correlation Coefficient were used. RESULTS: The Electro-oculographic findings suggested that all subtypes of depressed patients had lower dark trough and light peak values in comparison to controls (p < 0.001), while Arden ratios were within normal range. Electroretinographic recordings did not reveal any differences between patients and controls or between subtypes of depression. DISCUSSION: The findings of the current study provide empirical data in order to assist in the understanding of the international literature and to explain the mechanism of action of therapies like sleep deprivation and light therapy.

The relationship of regional cerebral blood flow with subtypes of major depression.

UNLABELLED: The aim of the present study was to search for differences between subtypes of major depression with the use of single photon emission tomography. MATERIALS AND METHODS: Fifty (50) patients aged 21-60 years suffering from Major Depression according to DSM-IV took part in the study. The SCAN v 2.0 was used to assist clinical diagnosis. The psychometric assessment included the HDRS, the HAS, the GAF, the Newcastle scales and the Diagnostic Melancholia Scale (DMS). Single Photon Emission Computerized Tomography (HMPAO SPECT) was used to assess regional cerebral blood flow. The methods of analysis included chi-square test, ANCOVA, and Discriminant Function Analysis. RESULTS: Forty one (82%) depressed patients had abnormal SPECT findings. The most consistent finding in all patients across all subtypes was a global brain hypoperfusion, which did not include the frontal lobes. The most impressive finding was the relative increase of right frontal lobe perfusion in atypicals, in contrast to the relative decrease of perfusion in both the melancholic and the 'undifferentiated' patients in that particular region. The reverse was true for the right occipital lobe. CONCLUSION: The results of the current study provide support for the old hypothesis on the existence of two distinct types of depression, characterized by different underlying psychopathologies, but also provide strong evidence for a neurobiological abnormality underlying atypical depression, the subtype closer to the old concept of 'neurotic' depression, which was considered to be psychological or reactive in origin.

Pattern-reversed visual evoked potentials in subtypes of major depression.

There are no articles in the international psychiatric literature reporting subclinical visual system disorders in depressed patients, although a disturbance of circadian rhythms is one of the prominent theories of the etiopathogenesis of depression. Fifty patients aged 21-60 years suffering from major depression according to DSM-IV criteria, and 20 controls took part in the study. Diagnosis was obtained with the aid of the Schedules for Clinical Assessment in Neuropsychiatry version 2.0. Psychometric assessment included the Hamilton Depression Rating Scale, the Hamilton Anxiety Scale, the 1965 and 1971 Newcastle Scales, and the Diagnostic Melancholia Scale. All subjects had normal electroretinographic and flash-visual evoked potential (VEP) recordings. Pattern-reversed VEPs (PR-VEPs) were recorded from each eye separately. Three-way analysis of covariance, Student's t-test and Pearson product-moment correlation coefficients were used for the analysis. All recordings were within the normal range. N80 and P100 latency were significantly shorter in atypical and significantly longer in melancholic patients. There was a positive correlation between N80 and P100 latency and age of onset and melancholic indices, and a negative correlation with the presence and the number of life events precipitating onset. The results of the current study suggest that PR-VEPs are consistent with other biological data supporting the atypical-melancholic distinction. The most important finding was the strong negative relationship between PR-VEP latency and stressful life events. The current study also provided data inconsistent with the hyperarousal theory and in support of an arousal dysregulation hypothesis for major depression.

Pupil reaction to light in Alzheimer's disease: evaluation of pupil size changes and mobility.

AIMS: The aim of the study is to assess pupil size changes and mobility evaluation as a diagnostic marker in patients with probable Alzheimer's disease (AD). MATERIAL AND METHODS: Twenty-three control subjects and 23 patients with probable AD entered the study. The latter patients had been under observation for 2 years and had undergone all necessary examinations to verify their initial diagnosis. A full record of the pupil's reaction to light was registered. Ten parameters from these data were measured, reported and then compared in both group of subjects. RESULTS: Patients with probable AD had abnormal pupillary function compared with such function in healthy aging. All pupillary light reflex (PLR) variables differed significantly between the two groups (p<0.005) except baseline pupil diameter (D1) and minimum pupil diameter (D2). Maximum constriction acceleration (ACmax) was the best predictor in classifying a subject as normal or as AD with perfect classification ability (area under the curve =1, p<0.001). In addition, the correlation between the percentage recovery-redilatation (%D1) and ACmax was highly negative in the group of AD patients (r = -0.808, p<0.005). CONCLUSIONS: Pupil size changes and mobility examination may be a fast, non-invasive and efficient additional diagnostic marker in AD diagnosis.

Neurobiological and psychological correlates of suicidal attempts and thoughts of death in patients with major depression.

Suicide is a major problem for psychiatry. Depression is the most common mental disorder related to suicidal behavior. The present study aimed at investigating the relationship between the symptomatology related to death, dying, and suicide and neurobiological factors in depressed patients. Fifty patients aged 21-60 years suffering from major depression were investigated. Schedules for Clinical Assessment in Neuropsychiatry version 2.0 and the International Personality Disorder Examination were used to assist the clinical diagnosis. The psychometric assessment included the Hamilton Depression Rating Scale, the Hamilton Anxiety Scale, the 1965 and 1971 Newcastle Depression Diagnostic Scales, the Diagnostic Melancholia Scale, the General Assessment of Functioning Scale, and the Personality Deviance Scale. Psychophysiological methods included electro-oculogram, flash electroretinogram under photopic and scotopic conditions, and pattern-reversal visual evoked potentials. Biological markers included the 1-mg dexamethasone suppression test, the 30-mg dexfenfluramine challenge test, and brain (99m)Tc-HMPAO SPECT. Statistical analysis included one-, two-, and three-way Manova and Mancova and the Scheffé test as post hoc test. Patients without thoughts of death had higher self-confidence levels and less overdependency on others and intropunitiveness. The suicidal patients had a significantly prolonged pattern-reversal visual evoked potential latency in comparison with the other patients. The findings of this were related to the status of the patient at the time of the interview but not to his/her history. They also provide neurobiological data to support the need for a combined presence of self-directed aggression and a higher arousal level or disinhibition of self-directed aggressive thoughts in order for a patient to become suicidal. Further study is needed to test whether psychophysiological methods, which are noninvasive and easy to perform, are of value in the therapeutic planning and monitoring of responses.

Clinical and neuroimaging correlates of abnormal short-latency Somatosensory Evoked Potentials in elderly vascular dementia patients: A psychophysiological exploratory study.

BACKGROUND: Short Latency Somatosensory Evoked Potentials (SEPs) may serve to the testing of the somatosensory tract function, which is vulnerable and affected in vascular encephalopathy. The aim of the current study was to search for clinical and neuroimaging correlates of abnormal SEPs in vascular dementia (VD) patients. MATERIALS AND METHODS: The study included 14 VD patients, aged 72.93 PlusMinus; 4.73 years, and 10 controls aged 71.20 PlusMinus; 4.44 years. All subjects underwent a detailed clinical examination, blood and biochemical testing, brain MRI and were assessed with the MMSE. SEPs were recorded after stimulation from upper and lower limbs. The statistical Analysis included 1 and 2-way MANCOVAs and Factor analysis RESULTS: The N13 latency was significantly prolonged, the N19 amplitude was lower, the P27 amplitude was lower and the N11-P27 conduction time was prolonged in severely demented patients in comparison to controls. The N19 latency was prolonged in severely demented patients in comparison to both mildly demented and controls. The same was true for the N13-N19 conduction time, and for the P27 latency. Patients with subcortical lesions had all their latencies prolonged and lower P27 amplitude. DISCUSSION: The results of the current study suggest that there are significant differences between patients suffering from VD and healthy controls in SEPs, but these are detectable only when dementia is severe or there are lesions located in the subcortical regions. The results of the current study locate the abnormal SEPs in the white matter, and are in accord with the literature.