TDM-based imipramine treatment in neuropathic pain

Tricyclic antidepressants (TCA) are the best-documented treatment of neuropathic pain. TCAs have a pronounced interindividual pharmacokinetic variability and a narrow therapeutic index. The aim of this study was to characterize the plasma concentration-effect relationship of imipramine in neuropathic pain and to determine the usefulness of therapeutic drug monitoring (TDM) of TCA treatment in a population with noncancer chronic pain. To do this, 83 patients with chronic noncancer neuropathic pain were included. Information on previous use of TCA was collected, and patients were tested for the presence of hyperalgesia. Pain intensity and pain relief were recorded, and the Short Form McGill Pain Questionnaire and Major Depression Inventory were completed before and during a TDM-based imipramine treatment. Imipramine dose was increased in steps of 25 mg/d every second week, and blood samples were taken at every dose. Endpoints were best possible pain relief, unacceptable side effects, or insufficient pain relief despite plasma drug level > 500 nmol/L. Dose range used was 10-300 mg/d. The study showed that imipramine 75 mg/d caused a 36-fold interindividual variation in steady-state plasma drug concentrations. In 46 responders (global pain relief > 25%) the plasma drug concentration at which an individual maximal analgesic effect was obtained ranged from 50 to 1400 nmol/L, but for the majority it was below 400 nmol/L. The concentration-effect relationship was similar for patients with central versus peripheral neuropathic pain and independent of the presence of hyperalgesia. Previous treatment failure with non-TDM TCA treatment was not a predictor of poor response to TDM-based treatment. In conclusion, there is a pronounced interindividual variability in concentration-effect relationship for imipramine treatment in neuropathic pain, but the majority of patients obtain a maximal analgesic effect at drug levels below 400 nmol/L. The concentration-effect relationship is similar for patients with central and peripheral neuropathic pain. Further studies are needed to document if TDM improves pain relief; however, TDM reduces the risk for toxicity.     

IgG antibodies against microorganisms and atopic disease in Danish adults: the Copenhagen Allergy Study

BACKGROUND: Seropositivity to food-borne and orofecal microorganisms (hepatitis A virus, Helicobacter pylori, and Toxoplasma gondii ), which are considered to be markers of poor hygiene, has been reported to be associated with a lower prevalence of atopy. In contrast, colonization of the gut with Clostridium difficile, a potential intestinal bacterial pathogen, in early childhood may be associated with a higher prevalence of atopy. OBJECTIVE: The objective of this study was to investigate the association between atopy and exposure to 2 groups of food-borne and orofecal microorganisms: (1) markers of a poor hygiene and (2) intestinal bacterial pathogens. METHODS: A cross-sectional population-based study of 15- to 69-year-olds living in Copenhagen, Denmark, was carried out in 1990 to 1991. Atopy was defined as a positive test result for specific IgE to at least 1 of 6 inhalant allergens. Exposure to microorganisms was assessed as IgG seropositivity to microorganisms. RESULTS: Seropositivity to 2 or 3 markers of poor hygiene (hepatitis A virus, H pylori, and T gondii ) was associated with a lower prevalence of atopy (adjusted odds ratio, 0.5; 95% CI, 0.3 to 0.8). In contrast, seropositivity to 2 or 3 intestinal bacterial pathogens (C difficile, Campylobacter jejuni, and Yersinia enterocolitica ) was associated with a higher prevalence of atopy (adjusted odds ratio, 1.7; 95% CI, 1.2 to 2.6). CONCLUSION: Exposure to markers of poor hygiene was associated with a lower prevalence of atopy, whereas exposure to intestinal bacterial pathogens was associated with a higher prevalence of atopy. These findings raise the hypothesis that different groups of food-borne and orofecal microorganisms may have different effects on the risk of atopy.     

On the increased risk of developing late-onset epilepsy for patients with major affective disorder

BACKGROUND: Based on register data we wanted to investigate whether patients with a diagnosis of affective disorder are at increased risk of developing epilepsy compared to other medically ill control groups. METHODS: By linkage of public hospital registers covering the whole of Denmark from 1977 to 1993, using ICD-8 diagnoses, three study cohorts were identified: Patients with first affective disorder episodes (mania and depression), patients with first osteoarthritis and patients with first diabetes discharge. Time to first diagnosis of epilepsy was estimated with the use of survival analysis. RESULTS: A total of 164,227 patients entered the study base: 13,748 patients with mania or depression, 81,380 patients with osteoarthritis and 69,149 patients with diabetes. The risk of getting a diagnosis of epilepsy was increased for patients with affective disorder compared with the risk for the control groups. However, the increased risk seemed to be due to the effect of comorbid alcohol or drug abuse and not to the effect of the affective illness itself. LIMITATIONS: The results only apply to hospitalised patients. Diagnoses are not validated for research purposes. CONCLUSION: Patients with a diagnosis of affective disorder have an increased risk of developing epilepsy in later life. In patients with affective disorder, comorbid alcoholism/drug abuse seriously increased the risk of a subsequent diagnosis of epilepsy.     

Detection of chromosomal imbalances in hepatocellular carcinoma

Hepatocellular carcinoma is the most common malignant tumor of the liver. The discrimination between well-differentiated hepatocellular carcinoma and reactive lesions and benign tumors may be difficult, especially when performed on the basis of needle biopsies. A promising means of solving this problem is provided by chromosomal analysis of imbalances in hepatocellular carcinoma. This article describes the different approaches to ascertain differential diagnosis by chromosomal studies in a reliable and cost-effective manner. It is shown that in situ hybridization techniques provide a reliable means of defining chromosome alterations. These techniques allow the detection of genetic gains and losses of defined chromosomes in a histopathological context and can serve as a helpful tool in establishing diagnosis of liver cell proliferation.     

Towards a risk map of malaria for Sri Lanka: the importance of house location relative to vector breeding sites

BACKGROUND: In Sri Lanka, the major malaria vector Anopheles culicifacies breeds in pools formed in streams and river beds and it is likely that people living close to such breeding sites are at higher risk of malaria than people living further away. This study was done to quantify the importance of house location relative to vector breeding sites for the occurrence of malaria in order to assess the usefulness of this parameter in future malaria risk maps. Such risk maps could be important tools for planning efficient malaria control measures. METHODS: In a group of seven villages in north central Sri Lanka, malaria cases were compared with community controls for distance from house to breeding sites and a number of other variables, including type of housing construction and use of anti-mosquito measures. The presence of An. culicifacies in bedrooms was determined by indoor insecticide spray collections. RESULTS: People living within 750 m of the local stream, which was the established vector-breeding site, were at much higher risk for malaria than people living further away (odds ratio adjusted for confounding by other variables 5.93, 95% CI: 3.50-8.91). Houses close to the stream also had more adult An. culicifacies in the bedrooms. Poor housing construction was an independent risk factor for malaria. CONCLUSIONS: Risk maps of malaria in Sri Lanka can be based on the location of houses relative to streams and rivers that are potential breeding sites for the malaria vector An. culicifacies. A distance of 750 m is suggested as the cut-off point in defining low- and high-risk villages.     

Reducing acute poisoning in developing countries--options for restricting the availability of pesticides

Hundreds of thousands of people are dying around the world each year from the effects of the use, or misuse, of pesticides. This paper reviews the different options to reduce availability of the most hazardous chemicals, focusing on issues in developing countries. Emphasis is placed on the fatal poisoning cases and hence the focus on self-harm cases. Overall, it is argued here that restricting access to the most hazardous pesticides would be of paramount importance to reduce the number of severe acute poisoning cases and case-fatalities and would provide greater opportunities for preventive programmes to act effectively. The aim should be to achieve an almost immediate phasing out of the WHO Classes I and II pesticides through national policies and enforcement. These short-term aims will have to be supported by medium- and long-term objectives focusing on the substitution of pesticides with safe and cost-effective alternatives, possibly guided by the establishment of a Minimum Pesticide List, and the development of future agricultural practices where pesticide usage is reduced to an absolute minimum. Underlying factors that make individuals at risk for self-harm include domestic problems, alcohol or drug addiction, emotional distress, depression, physical illness, social isolation or financial hardship. These should be addressed through preventive health programmes and community development efforts.