Differences in faecal microbiome composition between adult patients with UCD and PKU and healthy control subjects.

Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases causing hyperammonemic encephalopathy. Despite intensive dietary and pharmacological therapy, outcome is poor in a subset of UCD patients. Reducing ammonia production by changing faecal microbiome in UCD is an attractive treatment approach. We compared faecal microbiome composition of 10 UCD patients, 10 healthy control subjects and 10 phenylketonuria (PKU) patients. PKU patients on a low protein diet were included to differentiate between the effect of a low protein diet and the UCD itself on microbial composition. Participants were asked to collect a faecal sample and to fill out a 24 h dietary journal. DNA was extracted from faecal material, taxonomy was assigned and microbiome data was analyzed, with a focus on microbiota involved in ammonia metabolism.In this study we show an altered faecal microbiome in UCD patients, different from both PKU and healthy controls. UCD patients on dietary and pharmacological treatment had a less diverse faecal microbiome, and the faecal microbiome of PKU patients on a protein restricted diet with amino acid supplementation showed reduced richness compared to healthy adults without a specific diet. The differences in the microbiome composition of UCD patients compared to healthy controls were in part related to lactulose use. Other genomic process encodings involved in ammonia metabolism, did not seem to differ. Since manipulation of the microbiome is possible, this could be a potential treatment modality. We propose as a first next step, to study the impact of these faecal microbiome alterations on metabolic stability. TAKE HOME MESSAGE: The faecal microbiome of UCD patients was less diverse compared to PKU patients and even more compared to healthy controls.

International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

BACKGROUND: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. METHODS: A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. RESULTS: Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients' age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: <1y, 36% (n = 46); 1-10y, 59% (n = 74); 11-16y, 3% (n = 4); and >16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. CONCLUSIONS: Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

The effectiveness of a dentifrice without sodium lauryl sulphate on dental plaque and gingivitis - a randomized controlled clinical trial.

OBJECTIVES: The purpose of the study was to evaluate the effect on dental plaque and gingivitis of a dentifrice without sodium lauryl sulphate (SLS) compared to two SLS-containing dentifrices. MATERIAL AND METHODS: For this double-blind, parallel study, 90 volunteers having moderate gingival inflammation (≥40%) were randomly divided among three groups: one group using non-SLS dentifrice containing enzymes, colostrum and low concentrations of zinc and two control groups each using different SLS-containing dentifrices. Dental plaque scores (Turesky modification of Quigley & Hein) and gingivitis scores (Bleeding On Marginal Probing) were assessed at baseline, after 2 and 4 weeks. RESULTS: Eighty-nine participants provided evaluable data. A slight decrease in gingivitis scores was observed for all groups over 4 weeks, which was statistically significant for the non-SLS group. Mean values for dental plaque scores did not show major differences over 4 weeks. For both parameters, no significant differences between groups could be observed at any time point. Patient appreciation was in favour of the SLS groups especially regarding the foaming effect. CONCLUSION: No significant differences could be observed with respect to the effect on plaque and gingivitis between SLS-containing and SLS-free dentifrice containing enzymes, colostrum and low concentration zinc. Patients enjoyed the duration of taste and the 'foaming effect' of SLS-containing dentifrices better.

The effectiveness of dentifrices without and with sodium lauryl sulfate on plaque, gingivitis and gingival abrasion--a randomized clinical trial.

OBJECTIVES: The aim of this study was to compare the efficacy of a dentifrice without sodium lauryl sulfate (SLS) to a dentifrice with SLS in young adults aged 18-34 years on gingivitis. MATERIAL AND METHODS: One hundred twenty participants (non-dental students) with a moderate gingival inflammation (bleeding on probing at 40-70 % of test sites) were included in this randomized controlled double blind clinical trial. According to randomization, participants had to brush their teeth either with dentifrice without SLS or with SLS for 8 weeks. The primary outcome was bleeding on marginal probing (BOMP). The secondary outcomes were plaque scores and gingival abrasion scores (GA) as well as a visual analogue scale (VAS) score at exit survey. Baseline and end differences were analysed by univariate analysis of covariance (ANCOVA) test, between group differences by independent t test and within groups by paired sample t test. RESULTS: BOMP improved within groups from on average 0.80 at baseline to 0.60 in the group without SLS and to 0.56 in the group with SLS. No statistical difference for BOMP, plaque and gingival abrasion was found between both groups. VAS scores for taste, freshness and foaming effect were significantly in favour of the SLS-containing dentifrice. CONCLUSION: The test dentifrice without SLS was as effective as a regular SLS dentifrice on gingival bleeding scores and plaque scores. There was no significant difference in the incidence of gingival abrasion. CLINICAL RELEVANCE: In patients diagnosed with gingivitis, a dentifrice without SLS seems to be equally effective compared to a dentifrice with SLS and did not demonstrate any significant difference in gingival abrasion. In patient with recurrent aphthous ulcers, the absence of SLS may even be beneficial. However, participants indicate that they appreciate the foaming effect of a dentifrice with SLS more.

How strict is galactose restriction in adults with galactosaemia? International practice.

Dietary management of 418 adult patients with galactosaemia (from 39 centres/12 countries) was compared. All centres advised lactose restriction, 6 restricted galactose from galactosides ± fruits and vegetables and 12 offal. 38% (n=15) relaxed diet by: 1) allowing traces of lactose in manufactured foods (n=13) or 2) giving fruits, vegetables and galactosides (n=2). Only 15% (n=6) calculated dietary galactose. 32% of patients were lost to dietetic follow-up. In adult galactosaemia, there is limited diet relaxation.

Clinical and radiological outcome of the cemented Contemporary acetabular component in patients < 50 years of age.

Despite the worldwide usage of the cemented Contemporary acetabular component (Stryker), no published data are available regarding its use in patients aged < 50 years. We undertook a mid- to long-term follow-up study, including all consecutive patients aged < 50 years who underwent a primary total hip replacement using the Contemporary acetabular component with the Exeter cemented stem between January 1999 and January 2006. There were 152 hips in 126 patients, 61 men and 65 women, mean age at surgery 37.6 years (16 to 49 yrs). One patient was lost to follow-up. Mean clinical follow-up of all implants was 7.6 years (0.9 to 12.0). All clinical questionnaire scores, including Harris hip score, Oxford hip score and several visual analogue scales, were found to have improved. The eight year survivorship of all acetabular components for the endpoints revision for any reason or revision for aseptic loosening was 94.4% (95% confidence interval (CI) 89.2 to 97.2) and 96.4% (95% CI 91.6 to 98.5), respectively. Radiological follow-up was complete for 146 implants. The eight year survival for the endpoint radiological loosening was 93.1% (95% CI 86.2 to 96.6). Three surviving implants were considered radiologically loose but were asymptomatic. The presence of acetabular osteolysis (n = 17, 11.8%) and radiolucent lines (n = 20, 13.9%) in the 144 surviving cups indicates a need for continued observation in the second decade of follow-up in order to observe their influence on long-term survival. The clinical and radiological data resulting in a ten-year survival rate > 90% in young patients support the use of the Contemporary acetabular component in this specific patient group.

Reduction of erosion by protein-containing toothpastes.

AIM: To assess the effect of protein-containing toothpastes on the progression of dental erosion in situ (with pellicle) and in vitro (without pellicle). METHODS: A combined split-mouth (extraoral water or toothpaste brushing) and crossover (type of toothpaste) setup was used. Two protein-containing (high/low concentrations of colostrum) and one nonprotein (placebo) toothpaste were investigated. Sixteen volunteers wore intraoral appliances containing 2 human enamel samples on 3 afternoons for pellicle growth during 90 min. One enamel sample was brushed for 5 s with one of the three toothpastes and subsequently exposed to a slurry of the corresponding toothpaste for 2 min. The other sample was exposed to water. Both samples were subsequently exposed to citric acid (extraorally). Loss of calcium and inorganic phosphate were determined. The same sequence of exposures was applied to 16 enamel samples in an in vitro setup without pellicle. RESULTS: With the in situ-formed pellicle, all toothpastes significantly reduced calcium loss compared to water brushing, although no significant differences were found among toothpastes (p = 0.073). For the loss of phosphate, a significant reduction could be found with the use of the high-protein toothpaste compared to the nonprotein toothpaste. Overall there were only slight differences between the toothpastes. Toothpaste effects were less clear in the in vitro experiment. CONCLUSION: The addition of proteins to toothpaste shows some promise for the prevention of erosion. Further research is needed to investigate the performance of the protein-containing toothpastes in longer in situ studies with regard to erosive wear.

Behavioral dimensions of food security.

The empirical regularities of behavioral economics, especially loss aversion, time inconsistency, other-regarding preferences, herd behavior, and framing of decisions, present significant challenges to traditional approaches to food security. The formation of price expectations, hoarding behavior, and welfare losses from highly unstable food prices all depends on these behavioral regularities. At least when they are driven by speculative bubbles, market prices for food staples (and especially for rice, the staple food of over 2 billion people) often lose their efficiency properties and the normative implications assigned by trade theory. Theoretical objections to government efforts to stabilize food prices, thus, have reduced saliency, although operational, financing, and implementation problems remain important, even critical. The experience of many Asian governments in stabilizing their rice prices over the past half century is drawn on in this paper to illuminate both the political mandates stemming from behavioral responses of citizens and operational problems facing efforts to stabilize food prices. Despite the theoretical problems with free markets, the institutional role of markets in economic development remains. All policy instruments must operate compatibly with prices in markets. During policy design, especially for policies designed to alter market prices, incentive structures need to be compatible with respect to both government capacity (bureaucratic and budgetary) and empirical behavior on the part of market participants who will respond to planned policy changes. A new theoretical underpinning to political economy analysis is needed that incorporates this behavioral perspective, with psychology, sociology, and anthropology all likely to make significant contributions.

Successful weight loss in two adult patients diagnosed with late-onset long-chain Fatty Acid oxidation defect.

UNLABELLED: Patients with long-chain fatty acid oxidation defect (LCFAOD) cannot tolerate fasting and are restricted in their physical activity, hence their increased risk of obesity. Experts therefore advise avoidance of catabolic situations and discourage weight reduction in these patients.Two patients with late-diagnosed LCFAOD undergoing treatment at two academic centers successfully lost weight under supervision of a metabolic dietitian. Patient 1 (male, 47 years) diagnosed with CPT 2 deficiency lost 10 kg body weight in a 3-month period with the help of an energy and LCT-restricted, MCT- and carbohydrate-rich diet in combination with an exercise program. CK levels, C16, C18, and C18:1 levels of his acylcarnitine profile and his blood pressure decreased during the period of weight reduction. Patient 2 (male, 39 years) has a VLCAD deficiency. Dietary advice was energy and LCT restriction, MCT and carbohydrate-enriched food with raw cornstarch added during the night. Patient 2 lost almost 40 kg body weight to 87.6 kg (BMI 25.1) in 2 years. CK, insulin, TG, and ALAT blood levels decreased. CONCLUSION: Weight reduction without loss of metabolic control seems possible in late-onset LCFAOD patients. No metabolic crisis occurred in these two patients, while the positive effects of weight reduction were clear. The residual enzyme function in late-onset LCFAOD may be one of the reasons that metabolic decompensation was prevented. In addition, dietary adjustments to prevent excessive fatty acid oxidation likely contributed as well. Therefore, expert supervision by a dietician specialized in metabolic diseases is recommended. Concise SentenceContrary to the current literature, weight loss in patients with late-diagnosed LCFAOD can be successful. A description of two FOAD patients who lost weight without encountering negative side effects at two academic centers is given.

Supermarket revolution in Asia and emerging development strategies to include small farmers.

A "supermarket revolution" has occurred in developing countries in the past 2 decades. We focus on three specific issues that reflect the impact of this revolution, particularly in Asia: continuity in transformation, innovation in transformation, and unique development strategies. First, the record shows that the rapid growth observed in the early 2000s in China, Indonesia, Malaysia, and Thailand has continued, and the "newcomers"--India and Vietnam--have grown even faster. Although foreign direct investment has been important, the roles of domestic conglomerates and even state investment have been significant and unique. Second, Asia's supermarket revolution has exhibited unique pathways of retail diffusion and procurement system change. There has been "precocious" penetration of rural towns by rural supermarkets and rural business hubs, emergence of penetration of fresh produce retail that took much longer to initiate in other regions, and emergence of Asian retail developing-country multinational chains. In procurement, a symbiosis between modern retail and the emerging and consolidating modern food processing and logistics sectors has arisen. Third, several approaches are being tried to link small farmers to supermarkets. Some are unique to Asia, for example assembling into a "hub" or "platform" or "park" the various companies and services that link farmers to modern markets. Other approaches relatively new to Asia are found elsewhere, especially in Latin America, including "bringing modern markets to farmers" by establishing collection centers and multipronged collection cum service provision arrangements, and forming market cooperatives and farmer companies to help small farmers access supermarkets.

Preventing food crises using a food policy approach.

A food crisis occurs when rates of hunger and malnutrition rise sharply at local, national, or global levels. This definition distinguishes a food crisis from chronic hunger, although food crises are far more likely among populations already suffering from prolonged hunger and malnutrition. A food crisis is usually set off by a shock to either supply or demand for food and often involves a sudden spike in food prices. It is important to remember that in a market economy, food prices measure the scarcity of food, not its value in any nutritional sense. Except in rare circumstances, the straightforward way to prevent a food crisis is to have rapidly rising labor productivity through economic growth and keep food prices stable while maintaining access by the poor. The formula is easier to state than to implement, especially on a global scale, but it is good to have both the objective, reducing short-run spikes in hunger, and the deep mechanisms, pro-poor economic growth and stable food prices, clearly in mind. A coherent food policy seeks to use these mechanisms, and others, to achieve a sustained reduction in chronic hunger over the long run while preventing spikes in hunger in the short run.

[Atopic dermatitis in infants not caused by food allergy]. / Constitutioneel eczeem bij kinderen wordt niet veroorzaakt door voedselallergie.

Food allergy is not the primary cause ofatopic dermatitis. This is illustrated in 3 patients with atopic dermatitis, a girl aged 6 months and 2 boys aged 6 and 7 months, respectively, who were referred to our outpatient clinic for evaluation for possible food allergies. All 3 patients were receiving hypoallergenic formula because their parents or health care providers suspected that the atopic dermatitis was caused by a cows' milk allergy. After sufficient explanation of the causes of atopic dermatitis and thorough clarification and use of topical therapy, a remarkable improvement in the severity of the atopic dermatitis was noted. Only 1 patient was allergic to cows' milk as confirmed by a double-blind, placebo-controlled food challenge, but there was no association with the level of eczema activity. It is a common misconception that food allergies and atopic dermatitis are always causally related. In recent years it has become clear that atopic dermatitis may result from defective skin barrier function, for which topical treatment is essential. Unjustified focus on food allergies as the primary cause ofatopic dermatitis increases the risk of unnecessary elimination diets and malnutrition. Only infants with acute allergic symptoms directly related to ingestion, i.e. urticaria and gastrointestinal symptoms, should be evaluated for food allergies by a double-blind, placebo-controlled food challenge.

Pharmacokinetic parameters of tibolone and metabolites in plasma, urine, feces, and bile from ovariectomized cynomolgus monkeys after a single dose or multiple doses of tibolone.

Levels of nonsulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from six ovariectomized, mature female cynomolgus monkeys after a single dose and multiple p.o. doses (including bile) of tibolone using validated gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry assays. In plasma, the predominant nonsulfated metabolite after single and multiple dosing was the estrogenic 3alpha-hydroxytibolone; levels of the estrogenic 3beta-hydroxytibolone were 10-fold lower and of progestagenic/androgenic Delta(4)-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone; levels of 3betaS,17betaS-tibolone were about 2-fold lower, and monosulfated 3-hydroxymetabolites were about 10-fold lower. After multiple doses, areas under the curve of nonsulfated metabolites were lower (2-fold), and those of sulfated metabolites were 25% higher. In plasma, >95% metabolites were disulfated. In urine, levels of all the metabolites after single and multiple doses were low. After a single dose, high levels of 3beta-hydroxytibolone and the 3-monosulfated metabolites (3betaS,17betaOH-tibolone and 3alphaS,17betaOH-tibolone) were found in feces. After multiple dosing, 3alpha-hydroxytibolone increased, and the ratio of 3alpha/3beta-hydroxytibolone became about 1. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone. Levels of all the metabolites in feces were higher after multiple doses than after a single dose. Levels of nonsulfated and 3-monosulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except monosulfates. This may contribute to the metabolite content of the feces after multiple doses. 3beta-Hydroxytibolone and 3alphaS,17betaS-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces, and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. The major excretion route was in feces.

Pharmacokinetic parameters of sulfated tibolone metabolites in postmenopausal women after single and multiple doses of tibolone.

The objective of this study was to determine pharmacokinetic parameters of sulfated tibolone metabolites after single dose and their accumulation after multiple doses of tibolone. Blood samples from postmenopausal women in a single-dose (2.5 mg tibolone), open-label study (n=8) and multiple-dose (placebo, 0.3, 0.625, 1.25, or 2.5 mg/day tibolone for twenty-six cycles of 28 days), randomized, double-blind study (n=15) were analyzed for non-sulfated and sulfated tibolone metabolites by validated gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with tanolam mass spectrometry (LC-MS/MS), respectively. The predominant non-sulfated and sulfated metabolites after a single dose were 3alpha-hydroxy-tibolone and 3alpha,17beta-di-sulfated (di-S)-tibolone. At 3 h, >90% of metabolites were sulfated. Tibolone and Delta(4)-tibolone were detectable for about 6 h. After multiple treatment cycles with different doses, metabolite levels at 10 h were dose-related and levels of di-S metabolites were three- to fivefold higher than after a single dose. Tibolone metabolite levels did not differ between cycles. Inactive di-S tibolone metabolites predominated in blood. No accumulation occurred between cycles 7 and 26.

Análise da política alimentar

Mostra que os problemas alimentares são partes do problema mais vasto do desenvolvimento econômico, e que sua resolução é uma tarefa complexa, envolvendo uma perspectiva de longo prazo sobre como evoluem os sistemas alimentares nos diferentes contextos políticos. Documento em formato PDF, requer Acrobat Reader.

Macro shocks and micro outcomes: child nutrition during Indonesia's crisis.

A survey of households in rural Java is used to assess the nutritional impact of Indonesia's drought and financial crisis of 1997/1998. A time-age-cohort decomposition reveals significant nutritional impacts. However, child weight-for-age (WAZ) remained constant throughout the crisis, despite rapid increases in food prices and the consequent household consumption shock. The evidence is consistent with the hypothesis that within households, mothers buffered children's caloric intake, resulting in increased maternal wasting. However, reductions in the consumption of high-quality foods further resulted in increased prevalence of anemia for both mothers and children. The combined effects were particularly severe for cohorts conceived and weaned during the crisis.

Biotechnology and food systems in developing countries.

Even in a world with adequate food supplies in global markets, which is the situation today, biotechnology offers important opportunities to developing countries in four domains. First, many agronomically hostile or degraded environments require major scientific breakthroughs to become productive agricultural systems. Few of these breakthroughs are likely to be achieved through traditional breeding approaches. Second, biofortification offers the promise of greater quantities and human availabilities of micronutrients from traditional staple foods, with obvious nutritional gains for poor consumers, especially their children. Third, many high yielding agricultural systems are approaching their agronomic potential. Radically new technologies will be required to sustain productivity growth in these systems, and only modern genetic technology offers this hope. Finally, many cropping systems use large quantities of chemical inputs, such as herbicides, pesticides and fertilizers that can be unhealthy for people and soils alike. Biotechnology offers the potential to reduce the need for these inputs in economically and environmentally sustainable ways. Applying these new technologies to society's basic foods raises obvious concerns for both human and ecological health. For some, these concerns have become outright fear, and this has mobilized a backlash against genetically modified foods in any form. These concerns (and fears) must be addressed carefully and rationally so that the public understands the risks (which are not zero) and benefits (which might be enormous). Only the scientific community has the expertise and credibility to build this public understanding.

Pharmacokinetic evaluation of gepirone immediate-release capsules and gepirone extended-release tablets in healthy volunteers.

In an open-label, randomized, crossover study, the pharmacokinetics of gepirone immediate-release (gepirone-IR) and different gepirone extended-release (gepirone-ER, types 1, 2, and 3) formulations were compared. Mean maximum concentration (C(max)) was 6.1 ng/mL for gepirone-IR, which was statistically significantly (p < 0.05) higher than that of two of the ER-formulations (3.7 and 3.6 ng/mL, respectively, for types 2 and 3). The mean time to C(max) (mean T(max)) was 1.3 h for gepirone-IR and ranged from 4.8 to 5.6 h for gepirone-ER. The mean area under the curve of concentration versus time (AUC(30)) was similar and not statistically significantly different between gepirone-IR and ER. For the 1-(2-pyrimidinyl)-piperazine (1-PP) metabolite, C(max) and AUC(30) were statistically significantly (p < 0.05) higher and T(max) was lower for gepirone-IR compared with ER. No significant differences in bioavailability were observed between the IR and the three gepirone-ER formulations, indicating that any of the once-daily gepirone-ER formulations could be substituted for gepirone-IR. This study revealed a reduction in the peak-to-trough fluctuations in plasma gepirone concentrations and maintenance of consistent plasma levels with gepirone-ER.

Mirtazapine in combination with amitriptyline: a drug-drug interaction study in healthy subjects.

OBJECTIVE: To assess the steady-state pharmacokinetics of mirtazapine (30 mg/day orally) and amitriptyline (75 mg/day orally) during combined administration compared with that of either drug administered alone. To evaluate the tolerability and effects on psychometric tests of acute and subchronic administration of both drugs combined and alone. METHODS: In a single-blind, three-way cross-over study, 24 (12 male and 12 female) healthy subjects were randomly assigned to six different sequences of three 9-day treatments, i.e. racemic mirtazapine (30 mg/day), amitriptyline (75 mg/day) or the combination of these drugs. To control for acute pharmacodynamic assessments, during the first treatment period, a placebo group (n = 8; 4 females and 4 males) was added. Serial blood samples were drawn for plasma level measurements that were subsequently subjected to pharmacokinetic analysis. Psychometric tests assessed attentional performance, and a computer-assisted telephone questionnaire assessed self-ratings of drowsiness/alertness and sleep quality. RESULTS: Amitriptyline increased the C(max) of mirtazapine (+ 36%, p < 0.05) in male subjects only. Mirtazapine altered the C(max) of amitriptyline in both male (+ 23%, p < 0.05) and female (- 23%, p < 0.05) subjects. No changes were observed for other pharmacokinetic parameters. Metabolite parameters were not affected. Changes in parent compound levels mainly resulted from effects on absorption. The psychometric test results did not reveal significant changes between combined and single drug treatments. The telephone registrations of VAMRS and LSEQ did not show clinically relevant differences between the active treatments. CONCLUSION: Combined administration of mirtazapine (30 mg/day) and amitriptyline (75 mg/day) alters the pharmacokinetics of either compound to a minor extent. Adding one drug to the other and substituting one drug by the other had no major effects on tolerability. Nevertheless, caution is warranted when combining amitriptyline and mirtazapine.