Acyclovir treatment of relapsing-remitting multiple sclerosis

Acyclovir treatment was used in a randomized, double-blind, placebo-controlled clinical trial with parallel groups to test the hypothesis that herpes virus infections are involved in the pathogenesis of multiple sclerosis (MS). Sixty patients with the relapsing-remitting form of MS were randomized to either oral treatment with 800 mg acyclovir or placebo tablets three times daily for 2 years. The clinical effect was investigated by an extensive test battery consisting of neurological examinations, neuro-ophthalmological and neuropsychological tests, and evoked potentials. Results were based on intent-to-treat data and the primary outcome measure was the exacerbation rate. In the acyclovir group (n = 30), 62 exacerbations were recorded during the treatment period, yielding an annual exacerbation rate of 1.03. The placebo group (n = 30) had 94 exacerbations and an annual exacerbation rate of 1.57. Thus, 34% fewer exacerbations were encountered during acyclovir treatment. This difference in exacerbation rate between the treatment groups was not significant (P = 0.083). However, this trend to a lower disease activity in acyclovir-treated patients was supported in subsequent data analysis. If the patients were grouped according to exacerbation frequencies, i.e. into low (0–2), medium (3–5) and high (6–8) rate groups, the difference between acyclovir and placebo treatment was significant (P = 0.017). Moreover, in a subgroup of the population with a duration of the disease of at least 2 years providing an exacerbation rate base-line before entry, individual differences in exacerbation rates were compared between the 2-year pre-study period and the study period in acyclovir-treated (n = 19) and placebo (n = 20) patients and acyclovir-treated patients showed a significant reduction of exacerbations (P = 0.024). Otherwise, neurological parameters were essentially unaffected by acyclovir treatment and there were no convincing signs of reduced neurological deterioration in the acyclovir group. This study indicates that acyclovir treatment might inhibit the triggering of MS exacerbations and thus suggests that acyclovir-susceptible viruses might be involved in the pathogenesis of MS. This possibility warrants further investigation.     

Maternal risk of breast cancer following multiple births: a nationwide study in Sweden

The association between multiple births and subsequent maternal breast cancer risk was explored in a nested case-control study in Sweden encompassing 19,368 parous women with breast cancer diagnosed up to age 65 years, and 100,459 parous controls. Among cases and controls, there were 329 and 2,031 women, respectively, with a history of at least one live multiple birth. Compared with singleton mothers, breast cancer risk was 12 percent lower (odds ratio=0.088, 95 percent confidence interval=0.78–0.99) in women who had had a multiple birth. After stratification for age at diagnosis, evidence of a significant inverse association was found only in women aged 54 years or younger. Birth order of the multiple pregnancy had no apparent risk-modifying effect. Age at earliest multiple birth was unrelated to breast cancer risk. The inverse association between twinning and breast cancer risk may reflect protective physiological features of twin pregnancies. Further research is needed to investigate the role, if any, of in creased levels of steroid hormone-binding globulins in mothers of twins and the proposed inhibitory effects of human chorionic gonadotropin and -fetoprotein, both of which are increased during multiple gestations, on breast carcinogenesis. Breast feeding patterns in mothers of twins also may modify their risk of developing breast cancer.Ambors are with the Department of Cancer Epidemiology (Drs Lambe Ekbom, Adami) and Department of Social Medicine (Lambe), University Hospital, Uppsala, Sweden: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA (Drs Hsieb, Tsilib, Adami, Ekbom, Trichopoulos); UMASS Cancer Center, Worcester, MA, USA (Dr Hsieb). Address correspondece to Dr Lambe, Department of Cancer Epidemiology, University Hospital, S-751 85 Uppsala, Sweden. This project is funded by grants from the Swedish Cencer Societv. the Swedish Societv of Medicine. and the Wahlmarks Fund at Uppsala City Council.     

Multiple-dose pharmacokinetics of epirubicin at four different dose levels: studies in patients with metastatic breast cancer

Summary Pharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m². In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (meant _1/2, 21.6±7.9 h; range, 10.6–69 h;n=110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (meant _1/2, 18.1±4.8 h; range, 8.2–38.4 h;n=105).Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (meant _1/2, 13±4.6 h; range, 2.7–29 h;n=104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC=9.44×c ₂+62.5×c ₂₄+157.7 (r=0.953).This work was supported by the Lundbeck Foundation, the Michaelsen Foundation and Farmitalia Carlo Erba Ltd.     

Metabolism of Testosterone During in Vitro Transport Across CACO-2 Cell Monolayers: Evidence for β-Hydroxysteroid Dehydrogenase Activity in Differentiated CACO-2 Cells

Testosterone has previously been used as a model compound for the determination of unstirred water layer thickness in the CACO-2 transport model. We have found, however, that testosterone is metabolized during in vitro transport across the CACO-2 cell monolayers. This suggests that testosterone is not an ideal model substance. Testosterone is metabolized to androstenedione, indicating the formation of 17--hydroxysteroid dehydrogenase by differentiated CACO-2 cells. No reverse metabolism is observed, thus androstenedione is considered superior to testosterone for determination of unstirred water layer thickness in the CACO-2 system. Permeability coefficients for testosterone and androstenedione obtained under identical transport conditions were 66 (±7) * 10 ^–6 (n = 26) and 84 (±7) * 10^–6 (n = 9) cm/sec, respectively. The unstirred water layer thicknesses at different agitation rates are determined for the CACO-2 transport model used in our laboratory utilizing androstenedione as a model compound. The system is capable of controlling the water layer thickness from about 200 to 1000 µm.     

Extra- and Intracellular pH in the Brain During Ischaemia,Related to Tissue Lactate Content in Normo- and Hypercapnic rats

The objective of the present study was to assess the relationship between the amount of lactate accumulated during complete ischaemia and the ensuing changes in extra- and intracellular pH (pHe and pHi, respectively). The preischaemic plasma glucose concentration of anaesthetized rats was varied by administration of glucose or insulin, pHe was determined in neocortex with ion-sensitive microelectrodes, and tissue lactate and CO2 contents were measured, tissue CO2 tension being known from separate experiments. The experiments were carried out in both normocapnic [arterial CO2 tension (PaCO2) approximately 40 mm Hg] and hypercapnic (PaCO2 approximately 80 mm Hg) animals. Irrespective of the preischaemic CO2 tension, DeltapHe was linearly related to tissue lactate content. Depending on the preischaemic glucose concentration, DeltapHe varied from <0.4 to >1.4 units. The results thus fail to confirm previous results that the changes in pHe describe two plateau functions (DeltapHe approximately 0.5 and 1.1, respectively), with a transition zone at tissue lactate contents of 17 - 20 mmol kg-1. Changes in pHi given in this study are based on the assumption of a uniform intracellular space. The pHi changed from a normal value of approximately 7.0 to 6.5, 6.1 and 5.8 at tissue lactate contents of 10, 20 and 30 mmol kg-1. The intrinsic (non-bicarbonate) buffer capacity, derived from these figures, was 23 mmol kg-1 pH-1. Some differences in pH and in HCO3- concentration between extra- and intracellular fluids persisted in the ischaemic tissue. These differences were probably caused by a persisting membrane potential in the ischaemic cells.     

The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys.

Xanomeline is a muscarinic M(1)/M(4) preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whether the lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behavior induced by D-amphetamine and (-)-apomorphine in drug-naive Cebus apella monkeys. Antipsychotic compounds antagonize amphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibited D-amphetamine-induced motor unrest, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when xanomeline was tested in EPS-sensitized Cebus apella monkeys, EPS were not observed at the dose range of xanomeline used in the D-amphetamine-apomorphine combination study (0.5-3 mg/kg). However, when xanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibits D-amphetamine- and (-)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis.     

Effects of recombinant erythropoietin in palliative treatment of unselected cancer patients.

PURPOSE: The purpose is to evaluate relationships between objectively assessed exercise capacity and subjectively assessed scoring of physical functioning and well-being after erythropoietin treatment in cancer patients on palliative care. EXPERIMENTAL DESIGN: Unselected cancer patients (n = 108) who experienced progressive cachexia were randomized to receive either anti-inflammatory treatment alone (indomethacin) or recombinant erythropoietin plus indomethacin to prevent the appearance of disease-induced anemia and thereby protect patients' exercise capacity. Follow-up investigations of nutritional status, exercise capacity, and health-related quality of life assessed by SF-36 and the European Organization for Research and Treatment of Cancer QLQ-C30 were compared. RESULTS: Effective treatment by erythropoietin on top of basal whole body anti-inflammatory treatment was confirmed and indicated by time course changes of biochemical, physiologic, and nutritional objectives, whereas individual self-reported scoring of physical functioning and general health did not indicate a clear-cut effectiveness, particularly at moderately subnormal hemoglobin levels. CONCLUSIONS: Discrepancies between objective and subjective self-reported measures may be either fundamental or indicate scoring limitations for evaluation of therapeutic results. Present results demonstrate a clinical benefit of erythropoietin treatment in cancer patients with subnormal to normal hemoglobin levels, whereas the patients' own subjective scoring was insufficient to sense such improvements. The discrepancy may be either fundamental or methodological but emphasizes the importance to document therapeutic outcome in both subjective and objective perspectives in palliative care of cancer patients.     

The Swedish Council on Technology Assessment in Health Care (SBU) Systematic Overview of Radiotherapy for Cancer including a Prospective Survey of Radiotherapy Practice in Sweden 2001--Summary and Conclusions

A systematic assessment of radiotherapy for cancer was conducted by The Swedish Council on Technology Assessment in Health Care (SBU) and published in 1996. The assessment reviewed the scientific literature up to 1993 on the use of radiotherapy in the treatment of solid tumours, and estimated the costs associated with radiotherapy. It also described the current practise of radiotherapy in Sweden 1992 and compared practise with scientific knowledge. The SBU has now conducted a follow-up study on radiotherapy for cancer, including a review of the scientific literature from 1994 and a prospective survey of radiotherapy practise in Sweden 2001. The following conclusions were drawn: The role of radiotherapy as an important form of treatment for cancer with both curative and palliative intent has been further confirmed.The use of radiotherapy in Sweden has increased and is now at the internationally recommended level.Radiotherapy in Sweden is mostly given in accordance with the scientific evidence but may still be underutilized in certain situations.The resources for radiotherapy are being utilized more efficiently.The costs of radiotherapy are still 5% of the total cost of cancer care, while the cost of an individual treatment (fraction) has decreased.The need for radiotherapy capacity will increase. In addition, half of the treatment equipment will have to be replaced in the next few years.     

A Systematic Overview of Radiation Therapy Effects in Urinary Bladder Cancer

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for urinary bladder cancer is based on data from 3 meta-analyses and 33 randomized trials. The studies include 4 333 patients. The results were compared with those of a similar overview from 1996 including 15 042 patients. The conclusions reached can be summarized as these points: There is moderate evidence for an overall survival benefit with preoperative radiotherapy followed by cystectomy compared to curative radiotherapy based on early studies (1964-1986). Since that time surgical as well as radiation techniques have developed considerably. Therefore, the conclusion may not be relevant to modern treatment of invasive urinary bladder carcinoma.There is only one small study reporting on curative radiotherapy where increased dose per fraction is compared with conventionally fractionated radiotherapy to the same total dose. Thus, no conclusions can be drawn concerning optimal fraction dose.A meta-analysis based on two studies on hyperfractionated radiotherapy gives moderate evidence of a survival benefit at 5 and 10 years and an increased local control rate compared with conventional fractionation.The documentation of local control and overall survival rate after split-course radiation treatment compared to continuous therapy is conflicting. No firm conclusions can be drawn.Four small and early studies have compared radiation treatment using neutrons with photon treatment. The reports favour therapy with photons with respect to overall treatment results. There is moderate evidence for this conclusion.There is fairly strong evidence in early studies that radiation treatment in combination with hyperbaric oxygen does not confer a treatment benefit compared to radiation in normal atmosphere.There is no indication of a treatment benefit with the addition of either hyperthermia or misonidazole.A large number of phase II studies, suggesting an increased possibility for bladder preservation with concomitant chemoradiotherapy compared to radiotherapy alone, have been reviewed in a previous SBU report on chemotherapy. Only one small randomized study has been reported where concomitant chemoradiotherapy with cisplatin is compared to radiation alone. No conclusion on the therapeutic benefit of combined treatment can be drawn. Large randomized studies are needed.There is some evidence that preoperative radiotherapy followed by cystectomy does not confer any significant survival benefit compared to cystectomy alone.There is moderate evidence that palliative radiotherapy of invasive bladder carcinoma can rapidly induce tumour-related symptom relief.There is moderate evidence that palliative hypofractionated radiotherapy, 3 fractions during one week, gives the same relief of symptoms as 10 fractions during 2 weeks.