Arsenic toxicity: Molecular targets and therapeutic agents

High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As2+ are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As2+-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered

A review on coordination properties of thiol-containing chelating agents towards mercury, cadmium, and lead

The present article reviews the clinical use of thiol-based metal chelators in intoxications and overexposure with mercury (Hg), cadmium (Cd), and lead (Pb). Currently, very few commercially available pharmaceuticals can successfully reduce or prevent the toxicity of these metals. The metal chelator meso-2,3-dimercaptosuccinic acid (DMSA) is considerably less toxic than the classical agent British anti-Lewisite (BAL, 2,3-dimercaptopropanol) and is the recommended agent in poisonings with Pb and organic Hg. Its toxicity is also lower than that of DMPS (dimercaptopropane sulfonate), although DMPS is the recommended agent in acute poisonings with Hg salts. It is suggested that intracellular Cd deposits and cerebral deposits of inorganic Hg, to some extent, can be mobilized by a combination of antidotes, but clinical experience with such combinations are lacking. Alpha-lipoic acid (alpha-LA) has been suggested for toxic metal detoxification but is not considered a drug of choice in clinical practice. The molecular mechanisms and chemical equilibria of complex formation of the chelators with the metal ions Hg2+, Cd2+, and Pb2+ are reviewed since insight into these reactions can provide a basis for further development of therapeutics

The aging kidney—as influenced by heavy metal exposure and selenium supplementation

The aging process in the kidneys has been well studied. It is known that the glomerular filtration rate (GFR) declines with age in subjects older than 50–60 years. However, there is still insufficient knowledge regarding the response of the aged kidney to environmental toxicants such as mercury, cadmium, and lead. Here, we present a review on the functional decline and proposed mechanisms in the aging kidney as influenced by metal pollutants. Due to the prevalence of these toxicants in the environment, human exposure is nearly unavoidable. Further, it is well known that acute and chronic exposures to toxic metals may be detrimental to kidneys of normal adults, thus it may be hypothesized that exposure of individuals with reduced GFR will result in additional reductions in renal function. Individuals with compromised renal function, either from aging or from a combination of aging and disease, may be particularly susceptible to environmental toxicants. The available data appear to show an association between exposure to mercury, cadmium and/or lead and an increase in incidence and severity of renal disease in elderly individuals. Furthermore, some physiological thiols, as well as adequate selenium status, appear to exert a protective action. Further studies providing improved insight into the mechanisms by which nephrotoxic metals are handled by aging kidneys, as well as possibilities of therapeutic protection, are of utmost importance

Examining of Thallium in Cigarette Smokers

Abstract Smoking is one of the sources of thallium which is considered as a toxic heavy metal. The aim of this study was to determine urinary thallium levels and related variables in smokers, compared to a control group. The study was conducted on 56 participants who had smoked continuously during the year before they were referred to Kashan Smoking Cessation Clinic. Fifty-three nonsmokers who were family members or friends of the smokers were selected as the control group. Urinary thallium was measured in both groups (n = 109) using atomic absorption spectrophotometry. The mean value (with SD) for urinary thallium in the smokers (10.16 ± 1.82 μg/L) was significantly higher than in the control group (2.39 ± 0.63 μg/L). There was a significant relationship between smoking duration and urinary thallium levels (P = 0.003). In a subgroup of smokers who was addicted to opium and opium residues (n = 9), the mean level of thallium (37.5 ± 13.09 μg/L) was significantly higher than in the other smokers (4.93 ± 4.45; P = 0.001). Multiple regression analysis showed opioid abuse, insomnia, and chronic obstructive pulmonary disease (COPD), together were strong predictors of urinary thallium levels in smokers. There was no significant difference in thallium level in hookah smokers (P = 0.299) or in those with COPD compared to other smokers (P = 0.375). Urinary thallium levels of smokers with clinical signs of depression, sleep disorders, memory loss, and sweating were higher than those of smokers without these signs. Since thallium, as other toxic metals is accumulated in the body, and cigarette smoking also involves carcinogenic exposures and health hazards for passively exposed people, the need for cigarette control policies is emphasized. Keywords: Thallium Smoking Urinary level Poisonin

Clinical trials on onabotulinumtoxinA for the treatment of chronic migraine

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A 4-year follow-up of patients with medication-overuse headache previously included in a randomized multicentre study

The aim of this study was to evaluate the long-term outcome in 61 patients with medication-overuse headache (MOH) who 4 years previously had been included in a randomized open-label prospective multicentre study. Sixty patients still alive after 4 years were invited to a follow-up investigation. Fifty patients (83%) participated. Sixteen visited a neurologist, 22 were interviewed through telephone, 2 gave response by a letter, and 10 were evaluated through hospital records. The influence of baseline characteristics on outcome 4 years later was evaluated by non-parametric tests. p values below 0.01 were considered significant. At follow-up, the 50 persons had a mean reduction of 6.5 headache days/month (p < 0.001) and 9.5 acute headache medication days/month (p < 0.001) compared to baseline. Headache index/month was reduced from 449 to 321 (p < 0.001). Sixteen persons (32%) were considered as responders due to a ≥50% reduction in headache frequency from baseline, whereas 17 (34%) persons met the criteria for MOH. None of the baseline characteristics consistently influenced all five outcome measures. Total Hospital Anxiety and Depression Scale (HADS) score at baseline was predictors (p < 0.005) for being a responder after 4 years. At 4 years’ follow-up, one-third of the 50 MOH patients had ≥50% reduction in headache frequency from baseline. A low total HADS score at baseline was associated with the most favorable outcome

Chelators in Iron and Copper Toxicity

Purpose of Review Chelation therapy is used for diseases causing an imbalance of iron levels (for example haemochromatosis and thalassaemia) or copper levels (for example Menkes’ and Wilson’s diseases). Currently, most pharmaceutical chelators are relatively simple but often have side effects. Some have been taken off the market. This review attempts to find theory and knowledge required to design or find better chelators. Recent Findings Recent research attempting to understand the biological mechanisms of protection against iron and copper toxicity is reviewed. Understanding of molecular mechanisms behind normal iron/copper regulation may lead to the design of more sophisticated chelators. The theory of metal ion toxicity explains why some chelators, such as EDTA, which chelate metal ions in a way which exposes the ion to the surrounding environment are shown to be unsuitable except as a means of killing cancer cells. The Lewis theory of acids and bases suggests which amino acids favour the attachment of the hard/intermediate ions Fe2+, Fe3+, Cu2+ and soft ion Cu+. Non-polar amino acids will chelate the ion in a position not in contact with the surrounding cellular environment. The conclusion is that only the soft ion binding cysteine and methionine appear as suitable chelators. Clearly, nature has developed proteins which are less restricted. Recent research on naturally produced chelators such as siderophores and phytochemicals show some promise as pharmaceuticals. Summary Although an understanding of natural mechanisms of Fe/Cu regulation continues to increase, the pharmaceutical chelators for metal overload diseases remain simple non-protein molecules. Natural and synthetic alternatives have been studied but require further research before being accepted

Management of primary chronic headache in the general population: the Akershus study of chronic headache

Primary chronic headaches cause more disability and necessitate high utilisation of health care. Our knowledge is based on selected populations, while information from the general population is largely lacking. An age and gender-stratified cross-sectional epidemiological survey included 30,000 persons aged 30–44 years. Respondents with self-reported chronic headache were interviewed by physicians. The International Classification of Headache Disorders was used. Of all primary chronic headache sufferers, 80% had consulted their general practitioner (GP), of these 19% had also consulted a neurologist and 4% had been hospitalised. Co-occurrence of migraine increased the probability of contact with a physician. A high Severity of Dependence Scale score increased the probability for contact with a physician. Complementary and alternative medicine (CAM) was used by 62%, most often physiotherapy, acupuncture and chiropractic. Contact with a physician increased the probability of use of CAM. Acute headache medications were taken by 87%, while only 3% used prophylactic medication. GPs manage the majority of those with primary chronic headache, 1/5 never consults a physician for their headache, while approximately 1/5 is referred to a neurologist or hospitalised. Acute headache medication was frequently overused, while prophylactic medication was rarely used. Thus, avoidance of acute headache medication overuse and increased use of prophylactic medication may improve the management of primary chronic headaches in the future

One-year prevalence and the impact of migraine and tension-type headache in Turkey: a nationwide home-based study in adults

Several studies have shown that the prevalence of migraine and tension-type headache (TTH) varied between different geographical regions. Therefore, there is a need of a nationwide prevalence study for headache in our country, located between Asia and Europe. This nationwide study was designed to estimate the 1-year prevalence of migraine and TTH and analyse the clinical features, the impact as well as the demographic and socio-economic characteristics of the participant households in Turkey. We planned to investigate 6,000 representative households in 21 cities of Turkey; and a total of 5,323 households (response rate of 89%) aged between 18 and 65 years were examined for headache by 33 trained physicians at home on the basis of the diagnostic criteria of the second edition of the International Classification of Headache Disorders (ICHD-II). The electronically registered questionnaire was based on the headache features, the associated symptoms, demographic and socio-economic situation and history. Of 5,323 participants (48.8% women; mean age 35.9 ± 12 years) 44.6% reported recurrent headaches during the last 1 year and 871 were diagnosed with migraine at a prevalence rate of 16.4% (8.5% in men and 24.6% in women), whereas only 270 were diagnosed with TTH at a prevalence rate of 5.1% (5.7% in men and 4.5% in women). The 1-year prevalence of probable migraine was 12.4% and probable TTH was 9.5% additionally. The rate of migraine with aura among migraineurs was 21.5%. The prevalence of migraine was highest among 35–40-year-old women while there were no differences in age groups among men and in TTH overall. More than 2/3 of migraineurs had ever consulted a physician whereas only 1/3 of patients with TTH had ever consulted a physician. For women, the migraine prevalence was higher among the ones with a lower income, while among men, it did not show any change by income. Migraine prevalence was lower in those with a lower educational status compared to those with a high educational status. Chronic daily headache was present in 3.3% and the prevalence of medication overuse headache was 2.1% in our population. There was an important impact of migraine with a monthly frequency of 5.9 ± 6, and an attack duration of 35.1 ± 72 h, but only 4.9% were on prophylactic treatment. The one-year prevalence of migraine estimated as 16.4% was similar or even higher than world-wide reported migraine prevalence figures and identical to a previous nation-wide study conducted in 1998, whereas the TTH prevalence was much lower using the same methodology with the ICHD-II criteria