Therapy-free Interval Research Articles

Five years with continuous combined oestrogen/progestogen therapy. Effects on calcium metabolism, lipoproteins, and bleeding pattern

Objective–To study the effect of long-term continuous combined oestrogen/progestogen therapy on calcium metabolism, lipoproteins, and bleeding pattern in early postmenopausal women. Design–A prospective, open, controlled study. After initial examinations, control examinations were performed every three months for the first two years and every year for the following three (two) years, with determinations of bone mass, serum lipoproteins, and bleeding pattern. Setting– Out-patient research clinic at The Department of Clinical Chemistry, Glostrup Hospital, Denmark. Participants–Eighteen healthy women between 6 months and 3 years after a natural menopause, entered in a trial of continuous long-term hormone replacement therapy and a comparison group of 19 age-matched untreated women. Intervention–The treated group received 2 mg of 17β-oestradiol combined with 1 mg of norethisterone acetate orally each day continuously for 5 years with a 3 month therapyfree interval after the first 2 years. The women were investigated before treatment, then every 3 months for the first 2 years and every year for the next 3 years for determinations of bone mass, serum lipoproteins and bleeding patterns. The comparison group was followed-up in parallel for the first 4 years. Forearm bone mass was measured with single photon absorptiometry. Blood and urine samples were taken in the morning after an overnight fast and tobacco abstinence. Main outcome measures–The effects of hormone therapy on bone mineral content in the forearm, on serum and urine indices of calcium metabolism, on serum levels of total, high (HDL-C) and low (LDL-C) density lipoprotein cholesterol, and bleeding pattern. Results–Bone mineral content in the forearm was stable during the 5 years of treatment, whereas it declined significantly averaging 10% after 4 years in the comparison group. The biochemical estimates of bone turnover decreased to premenopausal level in the hormone group, whereas they remained at a high level in the comparison group. In the hormone group total cholesterol and LDL-C decreased by 20% whereas HDL-C was virtually unchanged. The treatment was associated with minor irregular bleeding in nine women during the first 6 months of treatment, after which no bleeding was experienced. Conclusion–Continuous combined oestrogen/progestogen therapy can keep early postmenopausal women free of bleeding episodes for a period of 5 years, after the first 6 months in which spotting occurs in 25%. The therapy prevented bone loss completely. The changes in serum lipoproteins were concordant with a lipid profile associated with a decreased risk of coronary heart disease.

Carboplatin and cyclophosphamide salvage therapy for ovarian cancer patients relapsing after cisplatin combination chemotherapy

30 ovarian cancer patients with a relapse after prior cisplatin combination chemotherapy were treated in a phase II study with cyclophosphamide 100 mg/m 2 orally on days 1–7 and carboplatin 300 mg/m 2 intravenously on day 8. Treatment was well tolerated. The major side-effect was thrombocytopenia. 28 patients were evaluable for response. The response was 5 CRs (18%), 4 PRs (14%) 15 SDs (53%) and 4 PDs (14%), for an overall response rate of 32%. The overall progression-free survival lasted from 2 to 23 months, median 8 months. Overall survival ranged from 2 to 35+ months, median 12 months. Patients with a therapy-free interval of more than 1 year showed a higher response rate (46%) than patients with a shorter therapy-free interval (20%). It is concluded that platinum containing second-line chemotherapy, after treatment that already contained cisplatin, is only warranted to palliate symptoms.

Five years with continuous combined oestrogen/ progestogen therapy. Effects on calcium metabolism, lipoproteins, and bleeding pattern

To study the effect of long-term continuous combined oestrogen/progestogen therapy on calcium metabolism, lipoproteins, and bleeding pattern in early postmenopausal women. A prospective, open, controlled study. After initial examinations, control examinations were performed every three months for the first two years and every year for the following three (two) years, with determinations of bone mass, serum lipoproteins, and bleeding pattern. Out-patient research clinic at The Department of Clinical Chemistry, Glostrup Hospital, Denmark. Eighteen healthy women between 6 months and 3 years after a natural menopause, entered in a trial of continuous long-term hormone replacement therapy and a comparison group of 19 age-matched untreated women. The treated group received 2 mg of 17 beta-oestradiol combined with 1 mg of norethisterone acetate orally each day continuously for 5 years with a 3 month therapy-free interval after the first 2 years. The women were investigated before treatment, then every 3 months for the first 2 years and every year for the next 3 years for determinations of bone mass, serum lipoproteins and bleeding patterns. The comparison group was followed-up in parallel for the first 4 years. Forearm bone mass was measured with single photon absorptiometry. Blood and urine samples were taken in the morning after an overnight fast and tobacco abstinence. The effects of hormone therapy on bone mineral content in the forearm, on serum and urine indices of calcium metabolism, on serum levels of total, high (HDL-C) and low (LDL-C) density lipoprotein cholesterol, and bleeding pattern. Bone mineral content in the forearm was stable during the 5 years of treatment, whereas it declined significantly averaging 10% after 4 years in the comparison group. The biochemical estimates of bone turnover decreased to premenopausal level in the hormone group, whereas they remained at a high level in the comparison group. In the hormone group total cholesterol and LDL-C decreased by 20% whereas HDL-C was virtually unchanged. The treatment was associated with minor irregular bleeding in nine women during the first 6 months of treatment, after which no bleeding was experienced. Continuous combined oestrogen/progestogen therapy can keep early postmenopausal women free of bleeding episodes for a period of 5 years, after the first 6 months in which spotting occurs in 25%. The therapy prevented bone loss completely. The changes in serum lipoproteins were concordant with a lipid profile associated with a decreased risk of coronary heart disease.

Interaction studies with moclobemide

Drug interactions with moclobemide given to healthy subjects and depressed patients are reviewed. The drugs investigated for safety were antihypertensives, digoxin, oral contraceptives, anticoagulants and benzodiazepines. Cimetidine was studied for the pharmacokinetic effect, and possible interactions with alcohol (stimulation and/or sedation) were included. Finally, since inhibition of monoamine oxidase (MAO) can increase noradrenergic transmission, possible interaction with neuronal reuptake inhibitors such as tricyclic antidepressants (TCAs) was investigated. Whereas replacement of the older, irreversible MAO inhibitors by a TCA was held to be dangerous and to require a therapy-free interval, the studies reviewed here provide evidence that amitriptyline can replace or be added to moclobemide without any sign of impaired tolerance, need for dose reduction or a therapy-free interval. Combined administration of moclobemide and desipramine was also tolerated well. Moclobemide did not interact with the direct-interacting sympathomimetics norepinephrine and isoproterenol and only to a negligible extent with phenylephrine. The combination of moclobemide with antihypertensive agents did not cause postural hypotension or an increase in other side effects. No clinically relevant interaction was observed between moclobemide and phenprocoumon, glibenclamide, oral contraceptives, digoxin or benzodiazepines. Cimetidine increased the concentration of moclobemide in plasma after a single oral dose by about 100%. If moclobemide is to be used in a patient pretreated with cimetidine, treatment should therefore start with the lowest therapeutic dose and then be adjusted to clinical needs. Since moclobemide is devoid of anticholinergic effects, no interaction with alcohol was anticipated. High therapeutic doses (600 mg/day) induced an effect similar to that of low doses of a TCA, but with 100-300 mg no interaction with alcohol was seen, even in elderly people.

Treatment of Cancer Patients with Recombinant Interferon-γ Induces Release of Endogenous Tumor Necrosis Factor-α

1) to investigate serum levels of tumor necrosis factor-alpha in patients treated with recombinant interferon-gamma and 2) to relate changes in TNF serum levels to other biological responses observed during treatment with interferon gamma (IFN-gamma). Five patients suffering from metastasizing renal cell carcinoma. Each patient received three treatment cycles of 10 micrograms, 100 micrograms and 500 micrograms IFN-gamma applied three times at weekly intervals. The treatment cycles were separated by a therapy free interval of two weeks. The order of dose levels was randomly assigned to each patient. Tumor necrosis factor alpha (TNF-alpha), IFN-gamma and neopterin serum levels, monocyte counts in the peripheral blood and body temperature were measured immediately before and 4, 24, 48, 72, and 168 h after each application of IFN-gamma. Results indicated that elevated serum levels of TNF-alpha are induced by 100 micrograms and 500 micrograms IFN-gamma. Repeated application of the same dose led to downregulation of TNF release into the serum. Changes in TNF serum levels did not correlate with the magnitude of febrile reactions, neopterin production or IFN-gamma serum levels.

Acute Effects of Single Doses of Recombinant Interferon-γ on Blood Cell Counts and Lymphocyte Subsets in Patients with Advanced Renal Cell Cancer

The object of this study was to investigate the effects of different single doses of recombinant interferon-gamma (rIFN-gamma) on white blood cell counts, differential blood counts, and the relative composition of T-cell subsets in the peripheral blood of cancer patients. Sixteen patients suffering from metastasizing renal cell carcinoma received 10, 100, or 500 micrograms of rIFN-gamma three times at weekly intervals. After a therapy-free interval of 2 weeks, the next dose level was applied. The order of dose levels was assigned randomly to each patient. White blood cells, differential blood counts, and the number of Leu1, Leu3, Leu2a, Leu7, and HLA DR+ cells were measured immediately before and at 4, 24, 48, 72, 96, and 168 h after the administration of single doses of rIFN-gamma. Results indicated that white blood cells were transiently removed from the blood circulation after administration of IFN-gamma. Monocytes, HLA DR+ cells, and Leu7+ cells were reduced to below 50% of pretreatment values 4 h after application of the cytokine. CD8+ cells and granulocyte counts declined to approximately 70% of pretreatment values 24 h after IFN therapy. The preferential reduction of CD8+ lymphocytes resulted in a temporary increase of the T4/T8 ratio in these patients.

Interferon and genital warts

<h3>To the Editor.—</h3> The editorial by Dr Kirby¹entitled "Interferon and Genital Warts: Much Potential, Modest Progress," leaves untouched some recent developments in the use of interferon for treatment of genital papillomavirus infections. We have found that low doses of recombinant interferon alpha 2a (Hoffmann-La Roche, Basle, Switzerland) or recombinant interferon alpha 2c (Thomae/Boehringer-Ingelheim, Federal Republic of Germany) (1 × 10⁶to 5×.10⁶U/d, subcutaneously) are equally potent, and perhaps even more potent, than high-dose treatment (18 × 10⁶U/d) and that they cause fewer side effects.^2,3In addition, when administered cyclically (for seven days followed by a therapy-free interval of four weeks, repeated approximately three times), low-dose interferon is highly effective with only minimal side effects.³With cyclic treatment, neutralizing antibodies against interferon are only rarely observed (one of 23 patients with genital warts treated with recombinant interferon alpha 2a had such antibodies

Helicopter Rescue for Traffic Accidents in West Germany

Approximately 200,000 emergency patients die annually in the Federal Republic of Germany (FRG) after a sudden illness or a serious accident. According to estimates, more than 20,000 die because effective first aid was not rendered soon enough. We know that two-thirds of all victims of fatal traffic accidents die within 25 minutes after the accident has occurred. In order to improve chances of survival, the therapy-free interval must be as brief as possible.

Efficacy of the bisphosphonate APD in the control of Paget's bone disease

Fifty-four patients with Paget's bone disease have been treated with the bisphosphonate APD. Twenty-six patients had not previously received treatment for Paget's disease; and 28 had been treated before with EHDP alone or in combination with calcitonin. APD was given orally in a mean dose of 500 mg daily (≅ 6.8 mg/kg of body weight) for 4 to 12 months. Bone pain diminished or disappeared in 34 of 39 patients with symptoms. A very significant diminution of the biochemical indices of bone turnover was observed in all patients, but the responses were faster in patients who had not previously received treatment for Paget's disease. After 4 months of treatment the serum levels of alkaline phosphatase of previously untreated patients diminished from 58.8 ± 8.0 to 20.0 ± 3.9 KA units ( P ∠ 0.001) and urinary excretion of hydroxyproline diminished from 108.6 ± 16.9 to 42.4 ± 8.3 mg/24 h ( P ∠ 0.001). In 23 of 26 previously untreated patients the biochemical indices decreased to the normal range (complete response). A reduction of 50% or more without reaching the normal range was observed in the other 3 patients (partial response). Actuarial analysis of the duration of the effect 12 months after stopping APD disclosed that 63% of patients who had achieved a complete response but only 23% of those with a partial response were in biochemical remission. A second course of APD was administered to 11 patients. The results were as effective during the second as the first course in 9 patients, whereas 2 patients had no response to retreatment. It was found that the nonresponders had a shorter therapy-free interval as compared with the good responders. These observations indicate that APD is an effective agent in the long-term control of the activity of Paget's bone disease. No significant side effects have been observed in this group of patients.

Imbalances of T-cell subsets in monoclonal gammopathies.

In 42 patients with untreated or treated multiple myeloma (MM) or benign monoclonal gammopathy (BMG) the lymphocytes and T lymphocyte subsets were determined by monoclonal antibodies and other surface markers. In untreated MM, the T cells (1077/microliters vs 1439/microliters, P less than 0.01) and especially the OKT4+ lymphocytes (700/microliters vs 950/microliters, P less than 0.05) were significantly reduced compared with a control group. The OKT8+ cells were slightly but not significantly decreased. In previously treated MM, the loss of T cells was more pronounced than in the untreated group and was primarily caused by a further reduction of OKT4+ cells. Patients with BMG revealed decreased OKT8+ lymphocytes (304/microliters vs 502/microliters, P less than 0.001), whereas the OKT4+ cells were within the normal range. Therefore, the OKT4/OKT8 ratio was significantly elevated compared with that in untreated MM patients and normal controls (3.31 vs 2.06 vs 2.13; P less than 0.005). To sum up, in MM the results revealed a reduction of T cells, mainly of OKT4+ cells, which is intensified by chemotherapy and persists even after a long therapy-free interval. The different findings of T cell subsets in BMG and MM may be a helpful criterion to differentiate between BMG and MM.

SCE and cell cycle studies in leukemia.

During recent years an increasing number of papers has been published on sister chromatid exchanges (SCEs) in neoplasia. These papers can be divided roughly into 2 major groups, i.e., SCEs in the circulating lymphocytes of cancer patients or their relatives and SCEs in affected cells. A considerable number of authors have investigated SCEs in phytohemagglutinin (PHA)-stimulated lymphocytes of cancer patients, which is comprehensively discussed by Sandberg et al. (1). Here, we want to report on SCE frequencies and cell cycle-specific patterns of the leukemic cells themselves. As SCE induction is a sensitive parameter of DNA damage, the available data have to be carefully interpreted regarding the effects of previous cytostatic treatment and the length of the therapy-free interval before samples are collected.

Atenolol interaction with aspirin, allopurinol, and ampicillin.

Atenolol kinetics were investigated in six healthy subjects after 100 mg orally, as monotherapy a 6-day treatment began 48 hr later. After a therapy-free interval of 4 wk, the same subjects received the same dose of atenolol with 1 gm ampicillin, 500 mg aspirin, and with 300 mg allopurinol. Allopurinol and aspirin did not substantially alter the kinetics of atenolol. After a single oral dose of 100 mg atenolol combined with 1 gm ampicillin, the bioavailability of atenolol was reduced to 36 +/- 5% compared to 60 +/- 8% after monotherapy. During long-term treatment with atenolol and ampicillin the bioavailability of atenolol fell to 24% (P less than 0.01). Mean peak plasma levels were lowered from 511 +/- 59 ng/ml on monotherapy to 344 +/- 33 ng/ml after the combination with ampicillin. The area under the plasma level-time curve, mean steady-state concentration, and urinary recovery were reduced, also. Twelve hours after 100 mg atenolol and 1 gm ampicillin, exercise tachycardia was significantly higher than after atenolol alone. During the 4-wk treatment in six hypertensive patients blood pressure levels of those on atenolol alone were not different from those on the combination therapy with ampicillin.

Chemo-immunotherapy in disseminated malignant testicular tumors

Since 1978 we have treated 26 patients with testicular cancer in stage IV with the following chemotherapy regimen: Vinblastine 6 mg/m2 (day 1 and 2) and bleomycin 30 mg given over 24 hour period (day 1 to day 5). After two cycles this therapy was changed and patients received the combination adriamycin 60 mg/m2 (day 1) and cis-DDP 20 mg/m2 (day 1 to 5) for further two cycles. We achieved 69% (18 of 26 patients) complete remissions. Patients without response or no change received as second treatment modality vincristine 0,8 mg/m2 (day 1) and ifosfamide 1500 mg/m2 (day 1 to 5). Before each chemotherapy in an interval of two days 1 Unit (= 1 KE) of OK-432 (Streptococcus pyogenes) preparation, an immunomodulating agent, was given intravenously. In the therapyfree interval of chemotherapy 2 KE of OK-432 were applied. The maintenance therapy for 1 year consisted of vinblastine and trofosfamide and also OK 432. For the achievement of complete remissions 4 courses of chemotherapy seemed to be sufficient. The inclusion of OK 432 immunotherapy in an already established chemotherapy regimen seems to be qualified due to the reduction of chemotherapy induced side effects (myelosuppression, immunodeficiency) and the immunorestoration achieved before chemotherapy.