Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study.

BACKGROUND: The first-line medication gabapentin and the acetylcholinesterase inhibitor donepezil represent a new promising combination to improve treatment outcomes for patients with severe neuropathic pain. The drugs have previously shown synergism following co-administration in nerve-injured rats. METHODS: The clinical relevance of adding donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The study comprised two consecutive periods of minimum 6 weeks: (1) titration of gabapentin to the highest tolerable dose or maximum 2400 mg daily, and (2) addition of donepezil 5 mg once daily to the fixed gabapentin dose. Efficacy and tolerability were assessed by ratings of pain intensity, questionnaires for pain and health-related quality of life, and reporting of adverse events. Pain scores were also analysed using mixed-effects analysis with the software NONMEM to account for intersubject variability. RESULTS: Eight patients commenced treatment with donepezil, of which two withdrew because of adverse events. Addition of donepezil resulted in clinically relevant reductions of pain (> 11 units on a 0-100 scale) and improved mental wellness in three of six patients. The remaining three patients had no obvious supplemental effect. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P < 0.0001 combination vs. monotherapy). CONCLUSION: Donepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. The promising results support controlled clinical trials of the drug combination. The usefulness of mixed-effects analysis in small-scale trials and/or for data with high intersubject variability was also demonstrated.

Structural, physicochemical, and pasting properties of starches from potato plants with repressed r1-gene.

The aim of this work was to investigate the effect on starch molecular and physicochemical properties of down regulation of the R1 protein in potato (Solanum tuberosum L. cv. "Dianella") tubers. Most prominent is a 90% suppression of the phosphate content in the isolated potato tuber starch. The amylopectin chain length distribution profile as determined by HPAEC/PAD was not affected, but the amylose content was increased in the most down-regulated plants. The pasting properties of the transgenic starch revealed a pronounced decrease in peak viscosity and increased setback viscosity as measured using a rapid Visco analyzer. The starch gels displayed an increased hardness and stickiness with a maximum at 1.7 nmol of Glc-6P mg-1 of starch compared to the control lines. At very low phosphate levels (1.4 nmol of Glc-6P mg-1 of starch), the gel hardness was decreased as a result of increased gel brittleness. The increase in gel brittleness is believed to be an effect of an increased proportion of free amylopectin blocklets in the starch as determined by SEC/RI. The possible links between the structural and physicochemical parameters are discussed.

Increased body fat mass and suppression of circulating leptin levels in response to hypersecretion of epinephrine in phenylethanolamine-N-methyltransferase (PNMT)-overexpressing mice.

Epinephrine is a major stress hormone that plays a central role in the control of metabolic function and energy homeostasis. To evaluate the role of epinephrine and the physiological and pathophysiological consequences of sustained elevation of epinephrine on metabolic and endocrine function, we studied several metabolic parameters and circulating leptin levels in a newly developed transgenic mouse model of phenylethanolamine-N-methyltransferase (PNMT) overexpression. A 100-fold overexpression of PNMT and subsequent elevation of epinephrine levels resulted in a marked suppression of circulating leptin levels in the transgenic animals (1.14 +/- 0.05 vs. 2.17 +/- 0.35 ng/ml; P < 0.01), which correlated negatively with plasma epinephrine (r = -0.82; P < 0.05), thus providing evidence for an inhibitory action of epinephrine on leptin production in vivo. In parallel, we found a marked increase in the body fat content of the transgenic animals (12.54 +/- 1.5 vs. 6.22 +/- 0.2%; P < 0.01) that was accompanied by enlarged adipocytes, indicating an increased lipid storage in PNMT transgenic mice. Interestingly, however, transgenic animals had normal body weight and did not exhibit major alterations in carbohydrate metabolism, as evidenced by analysis of random and fasted blood glucose levels, plasma insulin and C peptide levels, and insulin tolerance test. The metabolic alterations observed were not secondary to changes in food intake or increased activity of the hypothalamic-pituitary-adrenal axis, as there were no differences in these parameters. In summary, sustained primary overproduction of epinephrine resulted in suppression of plasma leptin levels and increased lipid storage in the PNMT transgenic mice. The concerted action of the sympathoadrenal system and reduced leptin may contribute to defending energy reservoirs while maintaining a normal body weight, which may be of vital importance under conditions of stress and energy deficiency.

The in vivo and in vitro effects of rhG-CSF on allergic, haematological and biochemical variables.

UNLABELLED: The objective was to evaluate the influence of treatment with rhG-CSF on allergic indexes. This was done by open trial of 5 days' treatment with rhG-CSF (5 microg/kg/day s. c.). 10 patients (6 men), aged 28 to 54 years, with rhinoconjunctivitis due to grass pollen allergy, participated in the investigation. Main measures were blood count, basophil histamine release, skin test and conjunctival provocation test. RESULTS: The treatment resulted in significant increases in numbers of neutrophils (590%), basophils (280%), eosinophils (250%) and lymphocytes (71%). Total blood histamine was increased, but basophil histamine releasability was decreased. Serum alkaline phosphatase increased 92% and serum lactate dehydrogenase increased 35% (both significant). There were no significant changes in the skin tests and the conjunctival provocation tests. Two months after the treatment all tests had returned to baseline levels. Five of the patients (50%) reported side effects, one withdrew. In conclusion treatment with rhG-CSF increases the number of circulating blood cells other than neutrophils without causing changes in indexes of allergic reactivity.

Vitamin D deficiency in pregnant and breast-feeding women and their infants.

We describe the cases of five consecutive infants with symptomatic vitamin D deficiency and their mothers. Four of the infants were light skinned, all had poor sunlight exposure, and all were breast-fed or had diets low in vitamin D. All mothers had vitamin D deficiency. Regardless of race, infants with poor sunlight exposure and diets lacking in vitamin D are at risk for vitamin D deficiency. Mothers of these infants should be evaluated for vitamin D deficiency. Vitamin D supplementation of the breast-feeding mother at risk and her infant is recommended.

Increased numbers of circulating basophils with decreased releasability after administration of rhG-CSF to allergic patients.

Preliminary studies in hematological patients have indicated that treatment with rhG-CSF reduces basophil releasability ex vivo. We examined this phenomenon further, in allergic patients. Ten patients with grass pollen rhinoconjunctivitis were given rhG-CSF (5 micrograms/kg/day s.c.) for 5 days, and examined before and after treatment. Basophil counts increased from 5 to 19 x 10(9)/l (P < 0.01). Total blood histamine increased from 80 to 160 micrograms/l (P < 0.01), corresponding to a decrease in average basophil histamine content from 1.5 to 0.81 pg/cell (P < 0.01). Isolated mononuclear cells showed a significantly decreased histamine release (HR) when stimulated with A23187 and grass. Whole blood experiments showed a similar decreased HR to grass and anti-IgE (P < 0.01). However, we found an increase in total blood histamine. We conclude that treatment with rhG-CSF (1) increases the number of circulating blood basophils, (2) reduces the average histamine content per basophil, and (3) reduces the basophil releasability. These findings could be due to the mobilization of immature basophils from the bone marrow.

Drug utilization in breast-feeding women. A survey in Oslo.

In a retrospective questionnaire survey of 885 women who had given birth 3-5 months before, fewer of those who were still breast-feeding at 4 months (n = 645) were using drugs than those who had stopped breast-feeding before 4 months (n = 240), during the 2 week period preceding registration. The average number of doses (Defined Daily Doses/1000 women/day) was 166 and 307, respectively, in that period. The number of doses taken was significantly associated with the use of oral contraceptive agents (p less than 0.005) and young maternal age (p less than 0.05). Most of the variation in drug use between breast-feeding and not breast-feeding mothers was probably due to the greater use of contraception by the latter. The number of drugs used per mother in the 4 month period seemed to be best predicted by her and her infant's disorders. Long-term medication in breast-feeding women included many drugs for which there is incomplete or no data about milk transfer, e.g. salbutamol, clemastine, dexchlorpheniramine, phenylpropanolamine, cromoglycate and levomepromazine. The disorders most extensively treated with drugs in this period were dyspepsia, haemorrhoids and inflammation of the breast. The finding that smoking was associated with early weaning and consumption of alcohol with prolonged breast-feeding calls for further investigation. More information on these drug and health issues to the breast-feeding mother is highly desirable.