Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: a randomized study. Cooperative Study Group.

This clinical trial was designed to investigate if maintenance therapy with alfa-interferon could prolong the plateau phase in patients with multiple myeloma. In addition, the tolerability of interferon treatment and its effect on survival were evaluated. From September 1987 to September 1989 a total of 314 patients were accrued to a multi-institutional randomized clinical trial. All patients entered into the protocol received standard melphalan-prednisone (MP) induction therapy. Response was noted in 184 (59%) and a plateau phase achieved in 155 (49%). From the latter group, 125 eligible patients were randomized to either interferon alfa-2b or no maintenance. The patients were followed for an average of 51 months (minimum 36 months) from the time of randomization. The plateau phase was significantly prolonged in the group of patients treated with interferon (median 13.9 v 5.7 months from the time of randomization; P < 0.0001). The interferon therapy was tolerated fairly well, moderate granulocytopenia and a chronic fatigue syndrome being the most frequent side-effects (22% v 18% W.H.O. grade 3 toxicity). The median survival from randomization was almost identical in both groups (36 v 35 months). The study shows that interferon maintenance therapy given to multiple myeloma patients who have achieved a response to initial treatment with MP prolongs the plateau phase duration with tolerable toxicity. The clinical value of this finding should be interpreted with caution, because survival was not prolonged. Further studies are required to clarify the role of interferon in the treatment of multiple myeloma.

Interferon therapy during the plateau phase of multiple myeloma: an update of the Swedish study.

A multicentre clinical trial was carried out in order to evaluate the effect of interferon (IFN) in patients with multiple myeloma. Patients (n = 120) who had shown response to conventional intermittent melphalan-prednisone induction therapy, and achieved a plateau phase, were randomized at that point to receive either interferon alfa-2b in a dose of 5 million units (MU) three times per week or no therapy. This report presents the results of an interim analysis, performed when the patients had been followed for a median of 20 months. The duration of the plateau phase was significantly longer in the IFN arm (59 weeks), compared to the no therapy arm (26 weeks). A total of 34 deaths have occurred, 13 in the IFN arm and 21 in the no therapy arm. In spite of the high median age of the patients studied (70 years), most patients were able to tolerate a full or only slightly reduced IFN dose.

Effects of adjunctive verapamil administration in chronic schizophrenic patients.

1. The efficacy of adjunctive verapamil on psychopathological symptoms and tardive dyskinesia was investigated in 22 chronic schizophrenic patients, who had partially responded to neuroleptics. 2. After 28 days verapamil administration (240 mg/day) a significant improvement was found in anxiety-depression, and in some positive and negative symptoms. Three of the 22 patients showed clinically pronounced global improvement. 3. The treatment was ineffective in tardive dyskinesia.

Evaluation of the possible interaction of the antifungal triazole SCH 39304 with oral contraceptives in normal healthy women.

The possible interaction of the newly developed triazole antifungal SCH 39304 with low-dose combined oral contraceptives (OCs) was studied in 15 healthy women. Serum levels of ovarian and adrenocortical steroids and sex hormone-binding globulin (SHBG) were analyzed in samples collected during the OC cycles immediately before, during and after the administration of SCH 39304. The drug was given as a single 400-mg oral dose on day 7 in the second cycle. SCH 39304 did not interfere with the ovulatory inhibitory action of low-dose combined OCs as judged from serum progesterone values. Administration of SCH 39304 caused minor decreases in serum SHBG, cortisol and dehydroepiandrosterone sulfate. The mechanism(s) behind these minor changes is not known.

Demonstrated Benefit of Continuous Interferon-Alpha-2b Therapy in Hairy Cell Leukemia. A Two-Year Follow-Up.

Interferon-alpha-2b (IFN) was given to a series of 50 patients with hairy cell leukemia (HCL). The IFN dose for both induction and maintenance was 2.0 × 10(6) IU/m(2) s.c. three times weekly. At 24 months 38 patients remained in the study. The proportion of complete responders (CR) increased during the follow-up, and had at 24 months reached 58%, while 28% at the same time had a partial (PR) and 14% a minor response (MR). During the two years of continuous IFN treatment none of the 38 patients showed any signs of relapse. The response rate was similar between splenectomized (n = 15) and non-splenectomized (n = 23) patients, but the rise in platelets was much steeper and reached a significantly higher plateau in patients, who previously had undergone splenectomy. The IFN therapy was generally well tolerated, but when evaluated at 24 months at least some (mostly mild) toxicity was noted in 76% of the patients. None of the patients developed neutralizing antibodies to IFN.

Predicting neuroleptic response from a combination of multilevel variables in acute schizophrenic patients.

A predetermined set of 22 sociodemographic, psychosocial, clinical, neurocognitive and biochemical potential predictor variables was tested in 98 schizophrenic patients admitted for relapse. The patients were treated with neuroleptics, mostly with haloperidol, for 28 d. Ten of the 22 variables correlated significantly with the neuroleptic response. Using stepwise multiple regression analyses, an optimal combination of 5 predictors was found to be in hierarchical order: disturbances of premorbid adjustment, intensity of positive symptoms at admission, family history of schizophrenia, working ability during the year before admission and serum dopamine-beta-hydroxylase. The 5 best predictors explained 29% of outcome variance, and all 22 variables together explained 35%. Such neurological characteristics as neurological soft signs, handedness, abnormal voluntary movements, spontaneous blink rate and cognitive impairment did not predict the treatment response. Several psychopathological, psychosocial and clinical predictors known from the literature could also be confirmed by cross-validation.

Neurological features, cognitive impairment and neuroleptic response in schizophrenic patients.

The relationship between neurological and cognitive features and the outcome of a 28-day neuroleptic treatment were studied in 98 chronic schizophrenic patients admitted for relapse. Handedness, neurological soft signs, and the cognitive rating on the Mini Mental State assessed in a stable state did not correlate with the neuroleptic response. The findings do not provide a basis for predicting the short-term outcome of the treatment.

Clinical evaluation with long-term follow-up of flutamide and estramustine as initial treatment of metastatic carcinoma of the prostate.

Thirty patients with metastatic cancers but with no serious cardiovascular (CV) conditions were randomly assigned to receive treatment either with flutamide (250 mg x 3) (F) or with estramustine (280 mg x 2) (E). Clinical examination, bone scan, laboratory measurements were performed before randomization and at regular intervals thereafter. During an observation period of between 1 and 2.5 years, F was discontinued in one case (7%) because of icterus, and E in three cases (20%) because of CV complications. Of the remaining 14 F-treated patients, 13 responded initially. Eleven of them relapsed, and five died of cancer. In the corresponding group of 12 E-treated patients, there were 11 primary responders. Of these, only two relapsed and died, as did the only nonresponder. The difference between the two groups with regard to relapse is significant (p less than 0.01), but not with regard to mortality. In the present material, there was an initial favorable response to F without signs of CV complications and with maintained libido in most cases. However, due to the significantly increased risk for relapse compared with E, F cannot be recommended as single therapy except in cases where estrogens are contraindicated or when interference with libido and potency is unacceptable.

Clinical symptomatology and drug compliance in schizophrenic patients.

The differences in the psychopathologic status of 26 complaint and 32 noncomplaint schizophrenic patients were evaluated on the basis of rating scales used at discharge. Noncomplaint patients had significantly higher scores for grandiosity, lack of feeling of illness and insight into it. Their score for global psychopathological state and disturbance in social adjustment was also significantly higher. The compliant patients had significantly higher score for self-rated depression.

Clinical evaluation of flutamide and estramustine as initial treatment of metastatic carcinoma of prostate.

The efficacy and side effects of flutamide were compared with estramustine in patients with advanced prostatic carcinoma. Thirty patients with metastatic cancers but with no serious cardiovascular (CV) conditions were randomly assigned to receive treatment either with flutamide (250 mg X 3) or with estramustine (280 mg X 2). Clinical examination, bone scan, laboratory measurements, including coagulation studies were performed prior to randomization, every three months during year one, and at six-month intervals thereafter. The two groups were comparable with respect to age and tumor characteristics. However, more patients presented with skeletal pain among those later treated with flutamide. During an observation period of between one and two and one-half years, flutamide was discontinued in 1 case (7%) because of icterus, and estramustine in 3 cases (20%) because of CV complications. Of the remaining 14 flutamide-treated patients, 13 responded initially. Eleven of them relapsed, and 5 died of cancer. In the corresponding group of 12 estramustine-treated patients, there were 11 primary responders. Of these, only 2 relapsed and died as did the only nonresponder. The difference between the two groups with regard to relapse is significant (P less than 0.01), but not with regard to mortality. All estramustine-treated patients lost their libido, whereas only 20 per cent of the patients treated with flutamide did so. In the present limited material there was an initial favorable response to flutamide without signs of CV complications and with maintained libido in most cases. However, due to significantly increased risk for relapse compared with estramustine, flutamide cannot be recommended as single therapy except in cases where estrogens are contraindicated or when interference with libido and potency is unacceptable.

The effect of cyproterone acetate on pituitary-ovarian function and clinical symptoms in hirsute women.

Ten hirsute women in fertile age were given 50 mg cyproterone acetate (CA) on day 5--14 and 50 micrograms ethinyl oestradiol (EE2) on day 5--21 except during the first treatment cycle when EE2 was given on day 15--21. The treatment lasted for 12 months. Clinical examination and hormone analysis were undertaken every third month. LRH tests were performed prior to treatment with CA in late follicular phase and after one week of administration of the drug. Subjective improvement of hypertrichosis was reported in 7 women, objectively a significant decrease in hair scores was observed. Short-term effects of CA alone included significantly decreased serum levels of oestrogens while FSH, LH, 4-androstene-3,17-dione and testosterone remained unaffected. Long-term administration of CA and EE2 resulted in significantly decreased serum levels of FSH, LH and oestrogens whereas 4-androstene-3,17-dione and testosterone were not affected. The gonadotrophin response to LRH did not reveal any significant difference before and after treatment. 4-Androstene-3,17-dione and testosterone did not change during the LRH tests but increased levels of oestrogens were observed at the end of the test during the CA treatment. Since CA alone causes decreased oestrogen levels without any suppression of the basal gonadorrohin levels, it is speculated that CA directly affects the ovarian steroid biosynthesis. On the other hand the adrenal androgens seem to be unaffected by the drug.

Effects of the estrogenicity of levonorgestrel/ethinylestradiol combinations of the lipoprotein status.

Ninety-eight women seeking contraceptive advice were randomly allocated to 6 months of treatment with one of the following four combinations of ethinylestradiol (EE) and levonorgestrel (NG): 20/250, 30/250, 30/150, and the so-called triphasic drug. The EE/NG ratios were 0.08, 0.12, 0.20 and 0.36 respectively. Blood lipids, HDL-cholesterol and sex hormone binding globulin (SHBG) were determined twice before treatment and after 1, 3 and 6 months of medication. Plasma triglyceride levels were moderately elevated in all groups, with the highest increase in the women taking the triphasic drug. The HDL-cholesterol and HDL-cholesterol to cholesterol ratios were both markedly reduced, by 20/250 and 30/250, while 30/150 and the triphasic drug caused only minor reductions. The mean change in HDL-cholesterol showed a good correlation with the mean changes of SHBG (r = 0.916) and with the EE/NG ratios (r = 0.979). It is concluded that both SHBG and the EE/NG ratio may be used as an index of the estrogenicity of a combined oral contraceptive drug. As reduced HDL-cholestrol levels and HDL-cholesterol to cholesterol ratios have been shown to be directly correlated to the risk of developing ischemic cardiovascular disease it would seem important that the estrogenicity of such a drug should be sufficiently high.

Lipoprotein changes may be minimized by proper composition of a combined oral contraceptive.

Lipids, high-density lipoprotein (HDL) cholesterol, and sex hormone-binding globulin (SHBG) were determined in 98 women treated with combined oral contraceptives containing ethinylestradiol (EE) and levonorgestrel (NG) in the following combinations: 20/250, 30/250, 30/150, and a so-called three-phase drug. The EE/NG ratios were 0.08, 0.12, 0.20, and 0.35, respectively. The HDL cholesterol and the HDL cholesterol to cholesterol ratios were markedly reduced by 20/250 and 30/250, whereas 30/150 and the three-phase drug caused only minor reductions. The mean change in HDL cholesterol showed a good correlation with the mean changes in SHBG (r = 0.916) and with the EE/NG ratios (r = 0.979). It is concluded that SHBG may be used as an index of estrogenicity of a combined oral contraceptive agent and that EE and NG may be balanced in such a way that undesirable effects on lipid metabolism are minimized.

HCG, progesterone and 17-beta-estradiol levels during extra-amniotically induced early abortion by a new prostaglandin derivative (Sulprostone).

A new prostaglandin E2 derivative (Sulprostone) was given extra-amniotically to 17 healthy women, who were 7-8 weeks pregnant, in order to assess the plasma profile of HCG, 17 beta-estradiol (E2), and progesterone and to evaluate the effectiveness and overall acceptability of the method in relation to different dose levels. On the lowest dose level (5 micrograms) only 3 of 7 patients aborted within a 3-to 6-day period. At higher dose levels (10 and 15 micrograms, respectively) 9 out of 10 women exhibited clinical evidence of an abortion. In the group who aborted, E2, progesterone, and HCG decreased continuously, whereas in the nonabortion group decreased levels were found 3 and 6 h after administration of the drug, but already after 24 h the values had again increased. Practically all treated women experienced lower abdominal discomfort, 7 (41%) reported the pains being severe. Vomiting and/or diarrhea occurred in 4 patients (24%). Similarly to other hitherto tested prostaglandins in humans, this new analogue exhibits its effect primarily through direct stimulatory effect on the uterine smooth muscle, resulting in subsequent decline in the concentrations of HCG, E2, and progesterone. In the group of successful inductions the decrease of the HCG concentration was close the half-time of HCG, indicating a permanent damage to the placenta. Despite the high success rate at a dose of 10 micrograms or more, the side effects, mainly abdominal cramps. were too severe to make this method feasible for the induction of early abortion when comparing to the available routine procedure of rapid vacuum curettage used on an outpatients basis.

PIP: A new (PG) prostaglandin E2 derivative (Sulprostone) was given extraamniotically to 17 healthy women, who where 7-8 weeks pregnant, in order to assess the plasma profile of HCG, 17beta-estradiol (E2), and progesterone and to evaluate the effectiveness and overall acceptability of the method in relation to different dose levels. On the lowest dose level (5 mcg) only 3 of 7 patients aborted within a 3-6 day period. At higher dose levels (10 and 15 mcg respectively) 9 out of 10 women exhibited clinical evidence of an abortion. In the group who aborted, E2, progesterone, and HCG decreased continuously, whereas in the nonabortion group decreased levels were found 3 and 6 hours after administration of the drug, but already after 24 hours the values had again increased. Practically all treated women experienced lower abdominal discomfort; 7 (41%) reported the pains being severe. Vomiting and/or diarrhea occurred in 4 patients (24%). Similarly to other hitherto tested PGs in humans, this new analogue exhibits its effect primarily through direct stimulatory effect on the uterine smooth muscle, resulting in subsequent decline in the concentrations of HCG, E2, and progesterone. In the group of successful inductions the decrease of the HCG concentration was close to the 1/2-time of HCG, indicating permanent damage to the placenta. Despite the high success rate at a dose of 10 mcg or more, the side effects, mainly abdominal cramps, were too severe to make this method feasible for the induction of early abortion when compared to the available routine procedure of rapid vacuum curettage used on an outpatients basis.

Administration of dehydroepiandrosterone enanthate to oophorectomized women--effects on sex hormones and lipid metabolism.

Eight bilaterally oophorectomized women were given a depot injection of 200 mg DHEA-enanthate to study the effect on endocrine and lipid metabolism. A decrease in sex-hormone binding globulin (SHBG) and an increase in androstenedione was found 14 and 30 days after the injection. No changes could be detected in LH, FSH, oestrone, oestradiol or oestriol. Testosterone showed a tendency towards an increase. As compared to pre-treatment values, plasma lipids were unaltered after 30 days. A decrease in high density lipoproteins (HDL), cholesterol and in very low density lipoproteins (VLDL), free cholesterol, total cholesterol and phospholipids were seen in the lipid composition of the lipoproteins on day 30. These findings are in agreement with previous data reported after the administration of drugs with androgen-like effects. The relative fatty acid composition of plasma lecithin revealed only minor changes while the fatty acid composition of cholesterol esters indicated a decreased portion of essential fatty acids. These results suggest, in agreement with previous studies, an impaired endogenous cholesterol formation in the liver. The results from the analysis of the fatty acid composition of lecithin and cholesterol esters might indicate a decreased percentage of exogenous (dietary) cholesterol ester in plasma.

[Fertility regulation using triphasic administration of ethinyl estradiol and levonorgestrel in comparison with the 30 plus 150 mcg fixed dose regime (Author's transl)]. / Association trephasique d'ethyniloestradiol et de levonorgestrel, comparee a un produit monophasique de 30 + 150 mcg sur le plan contraceptif.

PIP: 489 women from Sweden (n = 296) and from Great Britain and Germany (n = 193) took part in a test of 2 O.C. (oral contraceptive) preparations. 254 women used the triphasic SH B 264 AB preparation, while 235 women used Neovletta. A total of 2777 cycles was observed, during which no pregnancies occurred. The mean menstrual duration decreased nearly 2 days among Neovletta patients and 1 1/2 days among SH B 264 AB users (p .001). The rate of amenorrhea after 3 and 6 cycles was 1.6% and .5% respectively among SH B 264 AB users and 1.4% and 2.1% respectively among Neovletta users. Menstrual bleeding decreased. The rate of amenorrhea was significantly (p .001) greater among Neovletta users. The volume of menstrual bleeding decreased for users of both preparations. The incidence of bleeding irregularities was greater among those using Neovletta. 14.7% of the women discontinued O.C. use during the study, ca. 8% due to medical reasons, at about the same rate for both preparations. SH B 264 AB users more often reported side effects; the most frequent side effects for both preparations were headaches, mastodynia, and nausea.^ieng

Plasma lipids and high density lipoproteins during oral contraception with different combinations of ethinyl estradiol and levonorgestrel.

Seventy-five menstruating women seeking contraceptive advice were randomly allocated to treatment with combined oral contraceptives containing either ethinyl estradiol 50 micrograms + levonorgestrel 250 micrograms (50/250), ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms (30/150) or ethinyl estradiol 50 micrograms + levonorgestrel 125 micrograms (50/125). The concentrations of cholesterol, triglycerides, phospholipids, high density lipoprotein (HDL)-cholesterol and HDL-phospholipids were determined after one, three and six months and compared to the mean of two determinations of the same parameters before medication. Triglycerides increased by 18--42 per cent after 1--6 months of treatment with 50/125. The HDL-cholesterol and HDL-phospholipids were reduced by 10 per cent during 50/250 treatment. No other parameters showed any consistent alteration in any of the treatment groups. Raised triglyceride concentration and/or decreased HDL concentration increases the risk for cardiovascular disease. It is therefore suggested that in order not to alter the HDL concentration a combined oral contraceptive agent should not contain more gestagen-androgen than corresponding to 125--150 micrograms of levonorgestrel. To avoid a rise of the triglyceride level the weight relation between levonorgestrel and ethinyl estradiol should be about 5:1.

PIP: This study evaluates the effects of 3 different combinations of ethinyl estradiol (EE) and gestagen levonorgestrel on the plasma concentrations of some lipids and lipoproteins. 75 healthy menstruating women from the Dept. of Obstetrics and Gynecology of Linkoping University were randomly assigned to 3 different treatment groups and were given either 1) EE 50 ug + levonorgestrel 250 ug (50/250); 2) EE 30 ug + levonorgestrel 150 ug (30/150); or 3) EE50 ug + levonorgestrel 125 ug (50/125). Fasting blood samples were collected before medication and on the 20th or 21st treatment day of cycles 1, 3 and 6. No significant alterations of the mean blood pressure, blood hemoglobin concentrations or erythrocyte sedimentation rate were observed in any of the groups. After 1-6 months of treatment with 50/125, triglyceride increased by 18-42%. In the group treated with 50/250, HDL-cholesterol and HDC phospholipids were reduced by 10%. No other parameter exhibited any consistent changes in any of the treatment groups. Elevated triglyceride concentrations and/or decreased HDL concentration increases cardiovascular risk. So as not to alter the HDL concentration, it is recommended that a combined oral contraceptive should not contain more gestagen-androgen than corresponding to 125-150 ug. of levonorgestrel. A proportion of around 5:1 between levonorgestrel and EE may be needed to balance the changes of production and elimination of triglycerides.