Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis.

The object of this study was to monitor the safety and efficacy of long-term use of an oromucosal cannabis-based medicine (CBM) in patients with multiple sclerosis (MS). A total of 137 MS patients with symptoms not controlled satisfactorily using standard drugs entered this open-label trial following a 10-week, placebo-controlled study. Patients were assessed every eight weeks using visual analogue scales and diary scores of main symptoms, and were followed for an average of 434 days (range: 21 -814). A total of 58 patients (42.3%) withdrew due to lack of efficacy (24); adverse events (17); withdrew consent (6); lost to follow-up (3); and other (8). Patients reported 292 unwanted effects, of which 251 (86%) were mild to moderate, including oral pain (28), dizziness (20), diarrhoea (17), nausea (15) and oromucosal disorder (12). Three patients had five 'serious adverse events' between them--two seizures, one fall, one aspiration pneumonia, one gastroenteritis. Four patients had first-ever seizures. The improvements recorded and dosage taken in the acute study remained stable. Planned, sudden interruption of CBM for two weeks in 25 patients (of 62 approached) did not cause a consistent withdrawal syndrome, although 11 (46%) patients reported at least one of--tiredness, interrupted sleep, hot and cold flushes, mood alteration, reduced appetite, emotional lability, intoxication or vivid dreams. Twenty-two (88%) patients re-started CBM treatment. We conclude that long-term use of an oromucosal CBM (Sativex) maintains its effect in those patients who perceive initial benefit. The precise nature and rate of risks with long-term use, especially epilepsy, will require larger and longer-term studies.

Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment.

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and -1.3% in the menstruating group and -7.5 and -10.4% in the amenorrhoeic group (P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and -0.3%, and -3.5 and -5.8% (P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine -3.0% compared with controls -7.4% at three years (P=0.003), but no significant difference was found in the femoral neck: -1.7% versus -2.8%, respectively (P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine -5.8% versus -9.7% (P=0.008) and femoral neck -3.5% versus -5.1% (P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

The effect of clodronate and antioestrogens on bone loss associated with oestrogen withdrawal in postmenopausal women with breast cancer.

In this study we report bone mineral density (BMD) changes during clodronate and antioestrogen treatment in women with breast cancer having discontinued hormone replacement therapy (HRT) at the time of operation compared to women who had not used HRT immediately before the operation. 61 postmenopausal women with operable breast cancer were treated with the adjuvant antioestrogen tamoxifen 20 mg or toremifene 60 mg daily for 3 years. All patients were randomized to clodronate (1.6 g daily orally) or control groups for 3 years. 23 patients had recently (recent users) and 38 never or not for at least 1 year before operation used HRT (non-users). BMD of lumbar spine and femoral neck were measured before antiresorptive therapy (antioestrogens and clodronate) and at 1, 2, 3 and 5 years thereafter. All patients were disease-free at the time of BMD measurements. Patients who had recently used HRT had more significant bone loss as compared to HRT non-users at 3 years in lumbar spine - 3.0% vs. + 1.2% (P< 0.001), but not in femoral neck - 0.4% vs. + 1.7% (P = 0.27). Adding 3-year clodronate treatment to antioestrogen therapy improved BMD marginally at 3 years: lumbar spine + 1.0% vs. -1.7% (P = 0.01) and femoral neck + 2.4% vs. -0.4% (P = 0.12). This was also seen at 5 years of follow-up, 2 years after termination of the antiresorptive therapy: HRT recent users vs. HRT non-users in lumbar spine -6.5% vs. +0.5% (P< 0.0001) and in femoral neck -4.8% vs. -1.5% (P = 0.38); and clodronate vs. controls in lumbar spine -1.0% vs. -3.2% (P = 0.06) and in femoral neck -0.1% vs. -5.2% (P = 0.001, respectively). The type of endocrine therapy (tamoxifen and toremifene) had no significant influence on BMD changes. We conclude from this study that postmenopausal women who have recently discontinued HRT experience more rapid bone loss than HRT non-users. Neither 3-year antioestrogen therapy alone nor antioestrogen together with clodronate could totally prevent the bone loss related to HRT withdrawal in lumbar spine, even though clodronate seemed to retard it.

Bone mass and markers of bone and calcium metabolism in postmenopausal women treated with 1,25-dihydroxyvitamin D (Calcitriol) for four years.

To evaluate the long-term effect of calcitriol treatment on bone mineral density (BMD) of the femoral neck and lumbar spine and the parameters of calcium and bone metabolism in elderly women, 55 healthy, postmenopausal women, all aged 66 years, were enrolled in the study. Eighteen started a 4-year supplementation with 0.5 microg of calcitriol daily and 37 served as controls. Calcium intake of all the subjects was adjusted to 800 mg daily. In 4 years femoral neck BMD increased by 3.0% in the calcitriol group, but decreased by 1.6% in the control group (P = 0.009). The respective changes in lumbar spine BMD were +2.3% and +0.9% (P = 0.067). Two years' treatment with calcitriol increased the intestinal absorption of strontium by 57% (P < 0.001), doubled the urinary excretion of calcium (P < 0. 001), and decreased the mean parathyroid hormone (PTH) level by 32% (P < 0.01). In the calcitriol group the marker of bone formation, serum osteocalcin, decreased by 27% (P < 0.01), and the marker of bone resorption, serum C-telopeptide of type I collagen (CTx), by 33% (P = 0.05) after 2 years. In two subjects the calcitriol dose had to be reduced because of hypercalciuria. We conclude that calcitriol treatment increases bone mass at the femoral neck and lumbar spine, the increases being maintained for up to 4 years. The gain in bone mass results from reduced bone turnover which is partly a consequence of the enhanced intestinal absorption of calcium and suppressed serum PTH levels.

A prospective study of bone loss and turnover after cardiac transplantation: effect of calcium supplementation with or without calcitonin.

Cardiac transplantation exposes recipients to osteoporosis and increased risk of consequent fractures. The purpose of the present study was to examine the magnitude, timing and mechanism of bone loss following cardiac transplantation, and to establish whether bone loss can be prevented by calcium with or without calcitonin. Thirty patients (29 men, 1 woman), aged 26-68 years (mean 48 years), were randomized into three groups of 10 to receive either no additional treatment, oral calcium 1 g twice daily for 12 months or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months. Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward's triangle) was measured by dual-energy X-ray absorptiometry (DXA) at the time of transplantation and 6 and 12 months later. Markers of bone formation [serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal propeptide (PICP) and aminoterminal propeptide (PINP)] and resorption [serum type I collagen carboxyterminal telopeptide (ICTP)], as well as serum testosterone in men, were assayed before transplantation and at 1 week and 1, 3, 6 and 12 months after transplantation. During the first 6 post-transplant months BMD calculated as a percent change from baseline decreased in the control group by 6.4% (p = 0.014) in the lumbar spine, by 6.0% (p = 0.003) in the femoral neck, by 5.0% (p = 0.003) in the trochanter and by 5.5% (p = 0.130) in Ward's triangle. Between 6 and 12 months a further decline in BMD occurred only at the three femoral sites, ranging from 2.2% to 9.8% (p = 0.004-0.079). In comparison with the control group, the group receiving calcium alone lost less bone in the trochanter between 0 and 6 months (p = 0.019), and the group receiving calcium together with calcitonin lost less bone in the femoral neck (p = 0.068) and Ward's triangle (p = 0.076) between 0 and 12 months. Seven (28%) of 25 assessable patients experienced vertebral compression fractures. Calcium with or without calcitonin had no effect on changes in biochemical parameters; consequently, the three study groups were combined. The markers of bone formation increased, the elevations in mean values being 59% for B-ALP at 1 month (p = 0.009), 152% for PICP at 1 week (p < 0. 0001) and 27% for PINP at 1 week (p = 0.021). After a temporary decline at 3 months B-ALP (p = 0.0002) and PINP (p < 0.0001) at 1 year were nearly doubled compared with baseline values. Throughout the study the marker of bone resorption, serum ICTP, was above normal, with a peak (mean values 67-69% above baseline) at 1 week (p = 0.0002) to 1 month (p < 0.0001). The mean concentration of total testosterone was decreased by 48% (p < 0.0001) 1 week and by 28% (p = 0.0005) 1 month after transplantation, but this was mainly explained by the concomitant drop in serum albumin. High bone turnover underlies bone loss after cardiac transplantation. Bone loss is most rapid during the first 6 post-transplant months. In the upper femur this bone loss may be reduced by treatment with calcium and calcitonin.

A prospective study of bone loss and turnover after allogeneic bone marrow transplantation: effect of calcium supplementation with or without calcitonin.

Transplantation of solid organs including heart, kidney, and liver is associated with rapid bone loss and increased rate of fracture; data on bone marrow transplantation recipients (BMT) are scarce. The purpose of the present study was to examine the magnitude, timing, and mechanism of bone loss following allogeneic BMT, and to study whether bone loss can be prevented by calcium with or without calcitonin. Sixty-nine patients undergoing allogeneic BMT for malignant blood diseases were enrolled into the study. Forty-four (22 women, 22 men) completed 6 months, and 36 patients 1 year follow-up. They were randomized to receive either no additional treatment (n = 22), or oral calcium 1 g twice daily for 12 months (n = 12) or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months (n = 10). Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward's triangle) was measured by dual-energy X-ray absorptiometry (DXA). Bone turnover rate was followed with markers of bone formation and resorption (serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal (PICP) and aminoterminal propeptide (PINP), serum type I collagen carboxyterminal telopeptide (ICTP)). Serum testosterone was assayed in men. Calcium with or without calcitonin had no effect on bone loss or bone markers; consequently the three study groups were combined. During the first 6 post-transplant months BMD decreased by 5.7% in the lumbar spine and by 6.9% to 8.7% in the three femoral sites (P < 0.0001 for all); no significant further decline occured between 6 and 12 months. Four out of 25 assessable patients experienced vertebral compression fractures. Markers of bone formation reduced: B-ALP by 20% at 3 weeks (P = 0.027), PICP by 40% (P < 0.0001) and PINP by 63% at 6 weeks (P < 0.0001), with a return to baseline by 6 months. The marker of bone resorption, serum ICTP was above normal throughout the whole observation period, with a peak at 6 weeks (77% above baseline, P < 0.0001). In male patients serum testosterone decreased reaching a nadir (57% below baseline) at 6 weeks (P = 0.0003). In conclusion, significant bone loss occurs after BMT. It results from imbalance between reduced bone formation and increased bone resorption; hypogonadism may be a contributing factor in men. Bone loss can not be prevented by calcium with or without calcitonin.

The serum selenium concentrations in children and young adults: a long-term study during the Finnish selenium fertilization programme.

OBJECTIVE: To investigate the effects of the Finnish nationwide selenium (Se) fertilization programme on the Se status of the population. DESIGN AND SUBJECTS: Serum Se concentrations from 1985-1992 from 1568 healthy children and young adults in southwestern Finland were determined using direct electrothermal atomic absorption spectrometry. RESULTS: The mean concentration in young adults increased from 1.04 micromol/L in 1985 to 1.59 micromol/L in 1990. Children younger than 15 y had lower concentrations than adults, with an increase from 0.87 micromol/L in 1985 to 1.31 micromol/L in 1990. The younger the children, the lower the Se concentrations tended to be. At the age of about seven months no significant difference was noted between breast-fed and formula-fed infants. From 1991, when the amount of Se added to fertilizers was reduced and less foreign high-Se cereal was imported, the Se concentrations decreased in all age groups. CONCLUSIONS: The nationwide Se supplementation programme has succeeded in elevating the Se intake and the serum Se concentrations in the Finnish population.

Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients.

PURPOSE: In the majority of premenopausal breast cancer patients, an adjuvant chemotherapy-induced early menopause occurs, which is known to be a strong predictor of osteoporosis. We present data on the effect of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy on bone mineral density (BMD) and the efficacy of clodronate on the prevention of bone loss in 148 premenopausal breast cancer patients without skeletal metastases. MATERIALS AND METHODS: Patients were randomized to receive oral clodronate 1,600 mg/d or to a control group. In addition, patients were treated with six cycles of CMF therapy. BMD of the lumbar spine and femoral neck was measured by dual-energy x-ray absorptiometry (DEXA) before therapy and at 1 and 2 years. RESULTS: Changes in the BMD of lumbar spine and femoral neck were -5.9% and -2.0% without clodronate and -2.2% and +0.9% with clodronate at 2 years (P = .0005 and .017, respectively). Patients who developed amenorrhea after chemotherapy had a rapid bone loss, which was significantly reduced by clodronate. In controls, bone loss was 9.5% in the lumbar spine and 4.6% in the femoral neck, while in the clodronate group, bone loss was 5.9% and 0.4%, respectively, at 2 years. Patients with preserved menstruation had only marginal changes in BMD. CONCLUSION: Chemotherapy-induced ovarian failure causes rapid bone loss in premenopausal breast cancer patients. Women older than 40 years are at particularly high risk. Clodronate significantly reduces this bone loss.

Clodronate improves bone mineral density in post-menopausal breast cancer patients treated with adjuvant antioestrogens.

The effect of clodronate on bone mineral density (BMD) was studied in 121 post-menopausal breast cancer women without skeletal metastases. In addition, two antioestrogens, tamoxifen and toremifene, were compared in their action on bone mineral density. Patients were randomized to have an adjuvant antioestrogen treatment either 20 mg of tamoxifen or 60 mg of toremifene daily for 3 years. In addition all patients were randomized to have 1600 mg of oral clodronate daily or to act as control subjects. BMD of the lumbar spine and femoral neck were measured by dual-energy radiographic absorptiometry before therapy and at 1 and 2 years. At 2 years, clodronate with antioestrogens markedly increased BMD in the lumbar spine and femoral neck by 2.9% and 3.7% (P = 0.001 and 0.006 respectively). There were no significant changes in BMD in the patients given antioestrogens only. No significant differences were found between tamoxifen and toremifene on bone mineral density. Clodronate with antioestrogens significantly increased bone mass in the lumbar spine and femoral neck. Both antioestrogens, tamoxifen and toremifene, similarly prevented bone loss in the lumbar spine and femoral neck.

Serum selenium, zinc and copper in Swedish and Finnish orienteers. A comparative study.

Serum selenium, zinc and copper concentrations of 127 highly-trained Swedish orienteers have been analysed and compared with the corresponding values of 30 elite Finnish orienteers, and those of 111 healthy Finnish medical students. The mean serum selenium levels of Finnish orienteers, 1.35 mumol l-1, and students, 1.38 mumol l-1, were statistically significantly higher than those of Swedish orienteers, 1.09 mumol l-1. The serum levels of selenium were lower than 1.0 mumol l-1 in 27% of Swedish orienteers. This is obviously due to the lower selenium intake of the population in Sweden, where the soil selenium content is known to be low. Serum levels of zinc were within the reference interval in both Swedish and Finnish orienteers (mean values 14.8 and 14.1 mumol l-1, respectively). However, Finnish students had significantly lower serum levels of zinc, 12.5 mumol l-1. The mean serum concentration of copper was statistically significantly higher in females than in males.

Effect of nationwide selenium supplementation in Finland on selenium status in children with juvenile rheumatoid arthritis. A ten-year follow-up study.

A study was performed on the effect of increased selenium intake on the serum selenium level of 212 children with juvenile rheumatoid arthritis (JRA) and of 214 controls in a follow-up study during the Finnish nationwide selenium fertilization programme, which was started in 1984. The mean serum level of selenium increased from 0.90 mumol l-1 in 1985 to 1.56 mumol l-1 in 1990 in the children with JRA. The corresponding selenium levels in the controls were 0.87 mumol l-1 in 1985 and 1.33 mumol l-1 in 1990. Boys had slightly higher selenium levels in all the age groups among the patients and the controls. During the entire 10-year observation period, the patients with JRA had slightly higher mean levels of selenium than the controls. The age of the children did not have any significant effect on the selenium level in either group. The present study shows that the main factor affecting the serum level of selenium was the dietary intake of selenium both in patients and in healthy controls.

Serum selenium levels in diabetic children. A followup study during selenium-enriched agricultural fertilization in Finland.

The effect of increased selenium uptake on serum selenium in diabetic children was investigated during the first 9 yr of the Finnish nationwide selenium fertilization program, which started in 1984. Serum selenium concentrations were followed in 237 diabetic children (mean age 8.1 yr) and 214 controls from 1984 to 1992. The control group consisted of 107 siblings of the diabetics and of 107 other healthy children of corresponding age groups. Selenium was determined by direct electrothermal atomic absorption spectrophotometry. The effect of the increased uptake was seen in both diabetic and in control persons. Before the autumn of 1985, diabetic patients had significantly higher serum selenium levels than their siblings or the other healthy controls. Toward the end of year 1987, this difference had disappeared. After that, serum selenium levels continued to increase until the year 1990. In 1990 the mean selenium serum level of diabetic patients was 1.36 mumol/L and that of controls 1.33 mumol/L. The duration of diabetes did not have any effect on selenium serum levels. Slightly higher serum selenium in new diabetic patients before the start of therapy was explained by the dehydration state. The patients who were younger than 3 yr had slightly lower selenium serum levels when compared with older age groups. This difference was observed, however, only during the first 3 yr of the study. After that, when the selenium intake increased in general, no age-dependent differences were found anymore. There were no significant differences in serum selenium levels between males and females in either diabetic patients or in controls.

The effect of nationwide selenium enrichment of fertilizers on selenium status of healthy Finnish medical students living in south western Finland.

In Finland commercial fertilizers have been enriched with sodium selenate since July 1, 1984 in order to compensate for the poor selenium content of the soil. Fertilizers that are used for the production of hay and fodder were supplemented with 6 mg/kg of selenium, whereas fertilizers used for the production of cereals were supplemented with a higher dose, 16 mg/kg fertilizer. The effects of selenium fertilization were first seen in diary products in June 1985, and from the beginning of August 1985, the effect was evident also in wheat flour, beef, and bovine liver. In this study the selenium status of 108 healthy young adults has been systematically documented since November 1985, at which time the mean selenium serum level (S-Se) was 1.05 umol/L. A steady increase was observed until November 1989, when the maximum level, with a mean of S-Se 1.6 umol/L was reached. After that, a slight decrease has occurred. The mean serum selenium level in autumn 1991 in a new group of 35 students was 1.58 umol/L. This decrease can be explained by the high amount of imported cereals in 1988 and 1989, which was reflected also in the serum selenium levels. The glutathione peroxidase activity in erythrocytes in 1989-1990 was at the same level as in 1985 and 1986.

Finnish approach to the treatment of acute otitis media. Report of the Finnish Consensus Conference.

The theme of the first consensus conference to be held in Finland was the treatment of acute otitis media. The statements and recommendations accepted by the conference, which was organized according to the National Institutes of Health model, are presented in this report. On the basis of scientific knowledge, clinical experience, and conditions in Finland, the conference delegates concluded that penicillin V, in large doses, is still the drug of first choice in this disease. The importance of surgical drainage of the middle ear was stressed, as was the necessity of careful follow-up of the patient until the condition is completely healed. Decongestants were considered rather useless. In the prevention of recurrent attacks, adenoidectomy but not tonsillectomy was regarded as being of help, tympanostomy of probable benefit, antimicrobial (sulfonamide) prophylaxis worth considering in selected cases, but the effect of pneumococcal vaccination poor. The conference delegates agreed that uncomplicated acute otitis media should, as before, usually be treated by physicians taking care of children at the primary health care level.

Low residual diet and hydration improving double contrast examination of the colon.

Light food diet and low residual diet with hydration, both combined with Proctosal and Bisacodyl cleansing, were compared in 268 patients in the preparation of the colon for double contrast examination. Low residual diet with hydration resulted in significantly less residual fecal material, no flocculation of the barium coating and significantly denser mucosal coating. The examination had to be repeated more often (8.6%) after light food diet than after low residual diet with hydration (1.7%), but there was no statistically significant difference in the diagnostic accuracy. The hydration is important in avoiding patient discomforts and flocculation of the barium coating. Despite the use of laxatives, a strict diet restriction is needed to obtain consistently clean colon.

Dimethylpolysiloxane as an adjuvant in double-contrast barium enema.

The value of Dimethylpolysiloxane (Simethicone) in the reduction of gas bubbles and foam formation, and in the prevention of flocculation of contrast medium during the double-contrast barium enema examination is presented. Altogether 600 unselected patients were studied, 300 with barium suspension diluted with 10 vol % of distilled water only, and 300 with the same suspension into which dimethylpolysiloxane was added. Simethicone significantly reduced gas bubbles and foam formation. It also prevented flocculation and cracking of mucosal coating, while it had no effect on the density of mucosal coating.