Tuberculosis drug safety and pharmacovigilance in health system of Kosova: A cross-sectional analysis.

BACKGROUND: Tuberculosis (TB) remains a significant worldwide social and life-threatening epidemiological problem. Because this disease requires multiple drug treatment and prolonged therapy for several months, followed by a high probability of adverse effects (AEs), we assessed AE monitoring for anti-TB drugs in the Health Care System of Kosova. METHODS: This survey was a cross-sectional analysis performed at the primary, secondary and tertiary health care levels in Kosova. We included 930 registered tuberculosis patients within three levels of this health system in our study. Furthermore, we interviewed 62 physicians and 71 nurses at TB health facilities. Data were collected from official TB registers and personal contact with patients for 12 months. RESULTS: The representative age group was 19 to 29 years (30.49%), followed by a group of patients aged >60 years (23.23%). Among 930 patients treated with TB drugs, the total incidence of adverse AEs was 29.03%. Female TB patients had a higher rate of AEs than did male patients (33.56% vs 28.84%, respectively). The highest incidence of registered AEs was recorded in the gastrointestinal system (270, 80.83%), followed by the central nervous system (CNS, 7.50%) and was lower in other organ systems. The reporting of anti-TB drug effects by medical staff (TB medical doctor and TB medical nurse) at different levels of TB medical settings occurred among 62.90% of medical doctors and 81.69% of nurses. Only 53.23% of medical doctors and 46.48% of nurses completed pharmacovigilance training. CONCLUSION: The pharmacovigilance approach in Health System of Kosova is not comprehensible and not systematic. The relatively low incidence of AEs among TB patients is due under reporting of these by medical staff. The knowledge, attitudes, and adherence of medical staff reveal low awareness for pharmacovigilance activities, and this concern should be addressed to reinforce this important issue for the safe treatment of TB patients.

High-Dose Vitamin D-Mediated Hypercalcemia as a Potential Risk Factor in Central Nervous System Demyelinating Disease.

The exact cause of multiple sclerosis (MS) is unknown; however, it is considered to be an inflammatory disease of the central nervous system (CNS) triggered by a combination of both environmental and genetic factors. Vitamin D deficiency is also discussed as a possible disease-promoting factor in MS, as low vitamin D status is associated with increased formation of CNS lesions, elevated number of relapses and accelerated disease progression. However, it remains unclear whether this association is causal and related and most importantly, whether vitamin D supplementation in MS is of direct therapeutic benefit. Recently, we could show that in a murine model of MS, administration of a moderate vitamin D dose was of clinical benefit, while excessive vitamin D supplementation had a negative effect on disease severity. Of note, disease exacerbation was associated with high-dose vitamin D caused secondary hypercalcemia. Mechanistically dissecting this outcome, we found that hypercalcemia independent of vitamin D similarly triggered activation of disease-perpetuating T cells. These findings caution that vitamin D should be supplemented in a controlled and moderate manner in patients with MS and concomitantly highlight calcium as a novel potential MS risk factor by itself. In this review, we will summarize the current evidence from animal and clinical studies aiming to assess whether vitamin D may be of benefit in patients with MS. Furthermore, we will discuss any possible secondary effects of vitamin D with a particular focus on the role of calcium on immune cells and in the pathogenesis of CNS demyelinating disease.

Medicinal uses, pharmacology, and phytochemistry of Convolvulaceae plants with central nervous system efficacies: A systematic review.

Central nervous system (CNS) disorders play a major impact on individual lives and place a severe strain on health care resources. Convolvulaceae is a family comprising approximately 1,600-1,700 species grouped in 55-60 genera, and many species are reported to have an effect on CNS functions. A systematic review of the literature studies was carried out to summarize available evidences on Convolvulaceae plants with CNS efficacies. This review is based on various data sources such as Google Scholar, Web of Science, Scopus, PubMed, and Wanfang Data. A total of 200 related articles were included in this review. According to the research result, 54 Convolvulaceae species are suggested to display CNS efficacies historically, and 46 species have been evaluated for their CNS efficacies. In addition, 67 compounds from 16 Convolvulaceae species are recognized to possess CNS efficacies. Despite great progress made through pharmacology and phytochemistry studies on CNS active Convolvulaceae species, more exploratory research is needed to gain a better understanding of the CNS efficacies of this plant family.

Vitamin B-12 status and neurologic function in older people: a cross-sectional analysis of baseline trial data from the Older People and Enhanced Neurological Function (OPEN) study.

BACKGROUND: Aging is associated with a progressive decline in vitamin B-12 status. Overt vitamin B-12 deficiency causes neurologic disturbances in peripheral and central motor and sensory systems, but the public health impact for neurologic disease of moderately low vitamin B-12 status in older people is unclear. Evidence from observational studies is limited by heterogeneity in the definition of vitamin B-12 status and imprecise measures of nerve function. OBJECTIVE: We aimed to determine whether vitamin B-12 status is associated with electrophysiologic indexes of peripheral or central neurologic function in asymptomatic older people with moderately low vitamin B-12 status. DESIGN: We used a cross-sectional analysis of baseline data from the Older People and Enhanced Neurological Function study conducted in Southeast England. This trial investigated the effectiveness of vitamin B-12 supplementation on electrophysiologic indexes of neurologic function in asymptomatic older people (mean age: 80 y) with moderately low vitamin B-12 status (serum vitamin B-12 concentrations ≥107 and <210 pmol/L without anemia, n = 201). Vitamin B-12 status was assessed with the use of total vitamin B-12, holotranscobalamin, and a composite indicator of vitamin B-12 status (cB-12). Electrophysiologic measures of sensory and motor components of peripheral and central nerve function were assessed in all participants by a single observer. RESULTS: In multivariate models, there was no evidence of an association of vitamin B-12, holotranscobalamin, or cB-12 with any nerve conduction outcome. There was also no evidence of an association of vitamin B-12 status with clinical markers of neurologic function. CONCLUSION: This secondary analysis of high-quality trial data did not show any association of any measure of vitamin B-12 status with either peripheral or central neurologic function or any clinical markers of neurologic function in older people with moderately low vitamin B-12 status. The results of this study are unlikely to be generalizable to a less healthy older population with more severe vitamin B-12 deficiency. This trial was registered at www.controlled-trials.com as ISRCTN54195799.

Ethnopharmacological study of medicinal plants used in the treatment of CNS disorders in Sinai Peninsula, Egypt.

ETHNOPHARMACOLOGICAL RELEVANCE: To provide ethnopharmacological information on the use of medicinal plants for central nervous system (CNS) disorders in the Sinai Peninsula region (Egypt). To collect, analyze and evaluate the ethnobotanical knowledge about these medicinal plants in the Sinai Peninsula region with 61,000 km (2) and 379,000 inhabitants. METHODOLOGY: Field work was concluded between March 2006 and May 2011, using semi-structured questionnaire with 700 informants (mean age: 59; 100% men) from 117 settlements of 17 Bedouin tribes. Transects walks in wild herbal plant collection areas and bibliographical review on the collected plants were also conducted. The Interview/ Inhabitant index (I/P), relative importance value of the species and informant consensus factor (FIC) were calculated. RESULTS: More than 300 species were traditionally used in folk medicine in the Sinai Peninsula; 101 of these species belonging to 40 families were reported as useful in different CNS disorders. Only 5 species are endemic of the studied area. All different part plants were used, leaves and aerial parts being the most frequent. Most of the remedies were prepared as infusion or decoction, while oral administration was the most common way to be used. Gastrointestinal (67.3%) and respiratory disorders (42.57%) were also reported as frequently treated by Bedouins with herbal remedies. CONCLUSIONS: Only a few species were found where the traditional use is supported by pharmacological studies (Acacia nilotica, Achillea fragrantissima, Ajuga iva or Mentha longifolia). No bibliographical references in the scientific literature were found for 22 species (21.78%); finally, several studies were published with different pharmacological activities than those provided by Bedouins.

[Neuro-urological dysfunction of the lower urinary tract in CNS diseases: pathophysiology, epidemiology, and treatment options]. / Neurourologische Funktionsstörungen des unteren Harntraktes bei Erkrankungen des ZNS : Pathophysiologie, Epidemiologie und Therapieoptionen.

The lower urinary tract (LUT) is regulated by a complex neural network that is subject to supraspinal control. Neurological disorders, especially of the central nervous system (CNS), can rapidly lead to disruption of this control. Multiple sclerosis, Parkinson's disease, multiple system atrophy, and stroke are neurological disorders which quite frequently cause dysfunction of the LUT. With respect to the pathophysiology of bladder dysfunction in CNS diseases there are various hypotheses regarding the individual disorders: disturbances of neural communication between the frontal cortex and pontine micturition center, between the pontine micturition center and the lumbosacral parts of the spinal cord, and between the basal ganglia, thalamus, and anterior cingulate gyrus appear to play a pivotal role in the development of bladder dysfunction. The symptoms and urodynamic presentation of LUT dysfunction can vary considerably depending on the disease and disease progression and can change in the course of the disease. The incidence and prevalence of LUT dysfunctions rise with increasing progression of the underlying neurological disease.Various conservative, minimally invasive, and open surgical procedures are available to prevent harmful sequelae and to improve the quality of life of these patients. As yet, however, few data exist on most of the treatment options in cases of the above-mentioned CNS diseases. Intermittent self-catheterization and antimuscarinic medications are among the most important conservative treatment options. Injection of botulinum neurotoxin type A into the detrusor muscle and increasingly sacral or pudendal neuromodulation are among the most important minimally invasive treatment options. Surgical methods include reconstructive continent or incontinent urinary diversion.When planning therapy the patient's current needs and neurological limitations as well as possible disease progression must be taken into consideration. It is often advisable to consult with and enlist the cooperation of the attending neurologist when planning treatment.

Metabolismo talámico y situación neurológica tras un traumatismo craneoencefálico. Estudio mediante PET-FDG y morfometría basada en vóxel / Thalamic metabolism and neurological outcome after traumatic brain injury. A voxel-based morphometric FDG-PET study

Objetivos: Estudiar la relación entre el metabolismo talámico y la situación neurológica en pacientes que han sufrido un traumatismo craneoencefálico (TCE). Material y métodos: Se incluyó a 19 pacientes que habían sufrido un TCE grave y 10 sujetos control. De los 19 pacientes, 6 presentaban un grado de alerta bajo (estado vegetativo o estado de mínima conciencia), mientras que 13 mostraban un grado de alerta normal. A todos los pacientes se les realizó una tomografía con emisión de positrones (PET) con 18-fluorodesoxiglucosa (18F-FDG) 459,4 ± 470,9 días después del TCE. Las imágenes de PET-FDG se normalizaron en intensidad, creándose posteriormente una plantilla metabólica del grupo entre todos los sujetos. El trazado talámico se generó automáticamente con una máscara de la región de interés. Se comparó el metabolismo talámico de los dos grupos de pacientes respecto al grupo control, para ello se utilizó un método de análisis basado en vóxel, con significación estadística, p < 0,05 corregido para múltiples comparaciones. Resultados: Los pacientes con grado de alerta bajo mostraron menor metabolismo talámico (coordenadas MNI-Talairach, 12, -24, 18; T = 4,1), con respecto a los sujetos control, que los pacientes con grado de alerta adecuado (14, -28, 6; T = 5,5). Estas diferencias en el metabolismo fueron más acentuadas en las regiones internas del tálamo. Conclusiones: La PET-FDG puede ser una herramienta útil para valorar la situación neurológica después de un TCE. El método utilizado permite una evaluación objetiva y cuantitativa de imágenes de PET-FDG para grupos de sujetos. Nuestros resultados confirman la vulnerabilidad del tálamo a sufrir los efectos de las fuerzas de aceleración-desaceleración generadas durante un TCE (AU)

Objective: To study the relationship between thalamic metabolism and neurological outcome in patients who had sustained a traumatic brain injury (TBI). Methods: Nineteen patients who had sustained a severe TBI and ten control subjects were included in this study. Six of the 19 patients had a low level of consciousness (vegetative state or minimally conscious state), while thirteen showed normal consciousness. All patients underwent a PET with 18F-FDG, 459.4 ± 470.9 days after the TBI. The FDG-PET images were normalized in intensity, with a metabolic template being created from data derived from all subjects. The thalamic trace was generated automatically with a mask of the region of interest in order to evaluate its metabolism. A comparison between the two groups was carried out by a two sample voxel-based T-test, under the General Linear Model (GLM) framework. Results: Patients with low consciousness had lower thalamic metabolism (MNI-Talairach coordinates: 12, -24, 18; T = 4.1) than patients with adequate awareness (14, -28, 6; T = 5.5). Control subjects showed the greatest thalamic metabolism compared to both patients groups. These differences in metabolism were more pronounced in the internal regions of the thalamus. Conclusions: The applied method may be a useful ancillary tool to assess neurological outcomes after a TBI, since it permits an objective quantitative assessment of metabolic function for groups of subjects. Our results confirm the vulnerability of the thalamus to suffering the effects of the acceleration-deceleration forces generated during a TBI. It is hypothesized that patients with low thalamic metabolism represent a subset of subjects highly vulnerable to neurological and functional disability after TBI (AU)

Exploratory safety pharmacology: a new safety paradigm to de-risk drug candidates prior to selection for regulatory science investigations.

The primary objective of Safety Pharmacology is to ensure the safety of medicines on physiological functions in order to protect humans against adverse drug reactions. Safety Pharmacology became a major non-clinical discipline in 2000 when the International Conference on Harmonization approved the S7A guideline. This regulatory document requires pharmaceutical companies to undertake Safety Pharmacology assessment under Good Laboratory Practice (GLP) in order to guarantee the absence of unmanageable risks on vital organ function for compounds to be tested on humans. These regulatory studies often reveal liabilities impacting on the smooth transition of drug candidates from the discovery phase into the clinical arena. However, if these safety issues were uncovered prior to regulatory science assessment, the chemistry of poorly safe molecules could be modified during the lead optimisation phase for preventing later occurring attrition accidents. This article proposes the establishment of a spin-off specialty of Regulatory Safety Pharmacology, for which the name 'Exploratory Safety Pharmacology' is proposed. The objective of this discipline would be to conduct early safety investigations on potential drug candidates by applying, outside the constraints of GLP, in silico, in vitro, ex vivo and in vivo platforms translating clinical liabilities into simple, fast and cost-effective screening assays. This approach should result in early hazard detection with rapid turnaround of the data, enabling medicinal chemists to mitigate the safety liabilities of new compounds in an iterative manner. Hence, the ultimate aim of Exploratory Safety Pharmacology activities is to transform Regulatory Safety Pharmacology investigations into risk-known exercises.

[Barthel index as a length of stay predictor in neurological rehabilitation]. / Der Barthel-Index als Verweildauer-Prädiktor in der neurologischen Rehabilitation.

The present study investigated impact factors on the length of stay in neurological rehabilitation. 161 patients were enrolled in a six months period. As a major result, admission Barthel Index correlated highly significantly with length of stay (correlation coefficient -0.34). Besides diagnosis and age, gender had a significant influence on the duration, too. While the Barthel did not differ significantly, women stayed 2.9 days longer than men. In summary, the admission Barthel Index predicts length of stay in neurological rehabilitation.

Hematologic problems in psychosomatic medicine.

Vitamin B12 deficiency is associated with problems in cognition, mood, psychosis, and less commonly, anxiety. Folate deficiency primarily is associated with problems in mood. Patients who have sickle cell disease, a disease of chronic pain, experience difficulties with depression, anxiety, stigma, and are at risk for substance abuse and dependence. Patients with hemophilia have benefited from advances in treatment; however, their morbidity and mortality were compounded in those who received blood products contaminated with HIV, or hepatitis B and C. Psychiatrists who practice psychosomatic medicine should expect to encounter patients with the above problems, as they are frequently seen in medical settings. Finally, most of the commonly used psychotropic medications have uncommon but potentially important hematologic side effects or may interact with the anticoagulants used in medically ill patients.

What are the risks of biologic therapy in rheumatoid arthritis? An update on safety.

The tumor necrosis factor-alpha (TNF-alpha) blockers infliximab and etanercept and the recombinant interleukin 1 (IL-1) receptor antagonist anakinra are effective in patients with active rheumatoid arthritis (RA). Here, information in the medical literature and public domain is used to consider the safety of these biologic agents. TNF-alpha inhibition with infliximab has been associated with reactivation of tuberculosis and possibly development of other opportunistic infections (histoplasmosis, listeriosis. and pneumocystis). Exacerbations of multiple sclerosis and other central nervous system events have been reported with etanercept and infliximab. Recently, a review of preliminary data from an ongoing phase II study suggests that infliximab may worsen congestive heart failure. On the basis of clinical trials, there appears to be a higher incidence of serious infections seen in anakinra patients compared with controls; the particular combination of anakinra and etanercept may be associated with a higher incidence of serious infections and clinically significant leukopenia. Additional data are needed to understand whether all these safety issues are unique to an individual biologic agent or representative of a class effect. At this time, treating physicians must carefully weigh the benefits of these new biologics against their risks, particularly in patients at risk of infection.

Chronic arsenic toxicity in Bangladesh and West Bengal, India--a review and commentary.

Fifty districts of Bangladesh and 9 districts in West Bengal, India have arsenic levels in groundwater above the World Health Organization's maximum permissible limit of 50 microg/L. The area and population of 50 districts of Bangladesh and 9 districts in West Bengal are 118,849 km2 and 104.9 million and 38,865 km2 and 42.7 million, respectively. Our current data show arsenic levels above 50 microg/ L in 2000 villages, 178 police stations of 50 affected districts in Bangladesh and 2600 villages, 74 police stations/blocks of 9 affected districts in West Bengal. We have so far analyzed 34,000 and 101,934 hand tube-well water samples from Bangladesh and West Bengal respectively by FI-HG-AAS of which 56% and 52%, respectively, contained arsenic above 10 microg/L and 37% and 25% arsenic above 50 microg/L. In our preliminary study 18,000 persons in Bangladesh and 86,000 persons in West Bengal were clinically examined in arsenic-affected districts. Of them, 3695 (20.6% including 6.11% children) in Bangladesh and 8500 (9.8% including 1.7% children) in West Bengal had arsenical dermatological features. Symptoms of chronic arsenic toxicity developed insidiously after 6 months to 2 years or more of exposure. The time of onset depends on the concentration of arsenic in the drinking water, volume of intake, and the health and nutritional status of individuals. Major dermatological signs are diffuse or spotted melanosis, leucomelanosis, and keratosis. Chronic arsenicosis is a multisystem disorder. Apart from generalized weakness, appetite and weight loss, and anemia, our patients had symptoms relating to involvement of the lungs, gastrointestinal system, liver, spleen, genitourinary system, hemopoietic system, eyes, nervous system, and cardiovascular system. We found evidence of arsenic neuropathy in 37.3% (154 of 413 cases) in one group and 86.8% (33 of 38 cases) in another. Most of these cases had mild and predominantly sensory neuropathy. Central nervous system involvement was evident with and without neuropathy. Electrodiagnostic studies proved helpful for the diagnosis of neurological involvement. Advanced neglected cases with many years of exposure presented with cancer of skin and of the lung, liver, kidney, and bladder. The diagnosis of subclinical arsenicosis was made in 83%, 93%, and 95% of hair, nail and urine samples, respectively, in Bangladesh; and 57%, 83%, and 89% of hair, nail, and urine samples, respectively in West Bengal. Approximately 90% of children below 11 years of age living in the affected areas show hair and nail arsenic above the normal level. Children appear to have a higher body burden than adults despite fewer dermatological manifestations. Limited trials of 4 arsenic chelators in the treatment of chronic arsenic toxicity in West Bengal over the last 2 decades do not provide any clinical, biochemical, or histopathological benefit except for the accompanying preliminary report of clinical benefit with dimercaptopropanesulfonate therapy. Extensive efforts are needed in both countries to combat the arsenic crisis including control of tube-wells, watershed management with effective use of the prodigious supplies of surface water, traditional water management, public awareness programs, and education concerning the apparent benefits of optimal nutrition.

Childhood convulsions: a hospital survey on traditional remedies.

A study of one hundred and thirty five children with convulsions admitted in the University of Port Harcourt Teaching Hospital, Nigeria over a 15-month period, October 1986 to December 1987 showed that 65 (48%) of the children received some traditional remedy at home prior to presentation in hospital. Crude oil and palm kernel oil either singly or in combination were the most commonly administered remedies. The central nervous system was more affected by remedies containing crude oil than others (P < 0.05). Administration of cow's urine to convulsing children, reported from other parts of Nigeria, was not observed in the present study and would appear to be uncommon in this part of the country.

The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with the M-BACOD regimen.

One hundred thirty-four assessable patients with stage II-IV large-cell lymphoma (LCL) were treated with the combination chemotherapy regimen methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) between July 1981 and May 1986. The m-BACOD regimen substituted moderate-dose methotrexate (200 mg/m2 x 2) for the high-dose methotrexate used in the preceding M-BACOD regimen; all other drugs were administered as with m-BACOD. Eighty-two patients (61%) in the completed m-BACOD trial achieved a complete response (CR). With a median follow-up of 3.6 years, 62 patients (76%) continue in CR. Predicted survivals of 1, 3, and 5 years for the entire m-BACOD group are 80%, 63%, and 60%, respectively, with a 5-year disease-free survival (DFS) of 74% for the patients who achieve CR. The results obtained with m-BACOD are comparable with those obtained in the preceding M-BACOD trial, which now has a median follow-up of 8.0 years. The reduction in methotrexate dosage in m-BACOD patients was not associated with an increased incidence of CNS relapse. Long-term follow-up of the 215 M/m-BACOD patients indicates that the regimens are not associated with an increased incidence of secondary malignancy. Prolonged follow-up also indicates that advanced-stage patients have a persistent rate of late relapse of about 7.0% per year for years 2 to 5 of their follow-up and that stage II patients have an approximate 2.1% per year rate of late relapse. Application of the previously described prognostic factor model to the 215 M/m-BACOD patients from the completed trials identifies a high-risk group of patients with a CR rate and predicted 5-year survival (38% and 24%, respectively) that are significantly worse than those of the group as a whole (65% and 57%, respectively).