Six-week treatment with Ukrain in rabbits. Part III: Serum levels of thyroid hormones

The influence of 6-week treatment with Ukrain at doses of 0.3, 1.5 and 3.0 mg/kg i.v. on serum levels of thyroid hormones, i.e., thyroxine and triiodothyronine, was studied in rabbits of both sexes. Ukrain affected the serum levels of both hormones in males. An increase in the thyroxine level was found after Ukrain used at a dose of 1.5 and 3.0 mg/kg i.v., whereas increased triiodothyronine was noted when Ukrain was given at all studied doses. In females the thyroxine level was not altered by Ukrain administration, whereas the triiodothyronine concentration was increased following Ukrain at 0.3, 1.5 and 3.0 mg/kg i.v. it is probable the altered thyroid hormone levels as a result of Ukrain application may contribute to the drug's potent immunomodulatory action.     

Six-week treatment with Ukrain in rabbits. Part I: Morphological parameters

This study was performed to evaluate the effect of 6-week treatment with Ukrain in doses of 0.3, 1.5 and 3.0 mg/kg i.v. on the morphological and biochemical parameters of peripheral blood and morphology of body organs in rabbits. Ukrain application did not change the body organs and total body weight. The drug did not affect biochemical parameters of peripheral blood, except for a minor reduction in the total plasma level and increases in serum uric acid and urea indicating enhanced catabolism of proteins. The peripheral erythrocyte and leukocyte counts were not altered, whereas the percentages of lymphocytes, monocytes, and eozynophils were increased after higher doses of Ukrain. An increase in rod neutrophils and a decrease in the percentage of segmented neutrophils were also noted. These observations indicate a lack of organ toxicity following long-term treatment with Ukrain.     

Intermittent three-month treatment with Ukrain in intact and ovariectomized rats. Part II: Effect on bone mineral density of the femur

Ukrain, an acid alkaloid derivative of Chelidonium majus L., was administered intraperitoneally to ovariectomized and control sexually mature female rats at doses of 7, 14 and 28 mg/kg once daily for 10 days, followed by 10-day break. This procedure was repeated five times. At the end of the Ukrain treatment (24 h after the last dose of the drug) the right femora of the rats were harvested and the bone densitometric parameters of the whole bone and distal metaphysial and intertrochanteric subregions were assessed using the dual energy x-ray absorptiometry densitometric method. The results showed no apparent decrease in bone mineral density in groups of rats studied. A nearly significant (p = 0.08) decrease of bone mineral content was observed in ovariectomized rats treated with 14 mg/kg of Ukrain.     

Pharmacological effects of Ukrain in rats and rabbits

The effect of Ukrain administered in various doses on mean blood pressure (MAP) and breathing rate in rats and rabbits was evaluated. It was found that MAP was reduced and breathing rate increased significantly in both animal species. Maximum tolerated dose (MTD) of Ukrain was 10-fold higher in rats than in rabbits, and it amounted to 3.5 mg x kg(-1) and 0.35 mg x kg(-1), respectively. Possible clinical implications of these findings were discussed.     

Intermittent three-month treatment with Ukrain in intact and ovariectomized rats. Part I: Effect on selected biomechanical parameters of the femur

Ukrain, an acid alkaloid derivative from Chelidonium majus L., was administered intraperitoneally to intact and ovariectomized sexually mature female rats at doses of 7, 14 and 28 mg/kg once daily for 10 days, followed by 10-day break. This procedure was repeated five times. At the end of this Ukrain treatment (24 h after the last dose of the drug), the right femora of the rats were harvested and a three-point bending test until shaft failure was performed under standard conditions. Assembled data, including ultimate strength, ultimate energy at failure and ultimate displacement, were assessed. Strength and energy were adjusted to accommodate differences between groups in the end body weight. These results showed a decrease in adjusted bone strength of ovariectomized rats as compared to sham-operated animals. None of the three long-term doses of Ukrain (i.e., 7 mg/kg, 14 mg/kg and 28 mg/kg) significantly altered the bone strength when it was adjusted to the end body weight of the ovariectomized animals. Intact rats that received a 28 mg/kg dose of Ukrain demonstrated decrease of bone strength of 13.5% when it was adjusted to the end body weight.     

Ukrain treatment in a patient with breast carcinoma. Case report

A 50-year-old female patient with breast cancer (stage IV) was treated with Ukrain because of the impossibility of radiotherapy and chemotherapy. The first course led to a subjective improvement in her general condition, objective changes such as the appearance of border between the tumor and healthy tissues and a decrease in tumor size. Ukrain facilitated the surgeon in performing an operation to remove the primary tumor as well as the metastatic lymph nodes. After the second and third courses of Ukrain, the patient demonstrated clinical remission.     

Parkinsonism--drug treatment: Part II

This article, second in a two-part review, discusses investigational drug therapy and miscellaneous drug management of parkinsonism. Drug therapy should be individualized according to signs and changed as the disease progresses or if the patient develops intolerable side effects. Investigational drugs being examined include sustained-release and injectable dopaminergic formulations. Drug-induced parkinsonism is also examined.     

Ukrain treatment of a patient with retroperitoneal synovial sarcoma. Case report

A 23-year-old woman, diagnosed with a synovial sarcoma of the peritoneum, underwent an operation for tumor extraction. In the postoperative period, Ukrain was injected i.v. at a dose of 10 mg on alternate days, for a total of 10 injections. After a 2-month break, this schedule was repeated. Ukrain treatment was well tolerated by the patient and there were no complications in the postoperative period. The following changes in immunohematological parameters were observed: increased total leucocytes, T lymphocytes and T helpers. Nearly 4 years after Ukrain therapy, the patient is in complete remission.     

Ukrain treatment in a patient with stage IV neuroblastoma. A case report

A 22-month-old boy with stage IV neuroblastoma underwent laparotomy with tumor removal and nephrectomy, followed by treatment with Ukrain. Two months later, a remaining abdominal tumor, a retroperitoneal tumor (approximately 2 x 1 cm), and lung, brain, pelvis, kidney, and distal femur metastases were found. Growth of the neuroblastoma around the spinal cord and growth into the spinal canal was also found. Ukrain was administered in 3-week therapy series with 3-week pauses between each series. Some tumors disappeared, others were smaller, and growth stopped in the remaining tumors. Various metastases were no longer detectable.     

Antimicrobial agents in rats. II. Serum levels of oral cephalosporins.

Cephalexin, cephradine and 7 beta-(D-2-amino-2-[(1,4-cyclohexadienyl)-acetamido])-3-methoxy-3-cephem-4-carboxylic acid (CGP 9000) were tested for their pharmacokinetic behaviour in rats. The cephalosporin serum concentrations were determined at certain times after oral administration of 150 mg/kg by the agar-well-diffusion method. The experiments revealed that the serum levels of cephalexin and cephradine did not differe essentially from one another. They maintained maximum serum concentrations of 30 microgram/ml to 40 microgram/ml during the first hour and than declined with a half-life of 2.5 h. CGP 9000 reached peak concentrations 60 to 90 min postdose and was eliminated with a half-life of 3.5 h. The area under the curve was double as large as those of cephalexin and cephradine. This may be a reason of favourable results in experimental chemotherapy with CGP 9000.     

Intermittent three-month treatment with Ukrain in intact and ovariectomized rats. Part III: Effect on the native electron paramagnetic resonance signal intensity of the femur

Ukrain, an acid alkaloid derivative of Chelidonium majus L., was administered intraperitoneally to ovariectomized and sexually mature female control rats at doses of 7, 14 and 28 mg/kg once daily for 10 days, followed by a 10-day break. This procedure was repeated five times. At the end of the long-term treatment with Ukrain (24 h after the last dose of the drug) the left femora of the rats were harvested. Dried bones were studied by electron paramagnetic resonance (EPR) method. Significant changes in the intensity of the native signal were observed within the groups (ANOVA, p = 0.0001); the lowest value was observed in the ovariectomized rats treated with 28 mg/kg of Ukrain (decrease of 40.8% compared to the ovariectomized group, p = 0.005). A significant increase in the intensity of the signal was observed in the intact 7 mg/kg Ukrain-treated group (34.7% compared to controls, p = 0.004).     

Gender and gonadal status modulation of dorsal raphe nucleus serotonergic neurons. Part II. Regulatory mechanisms

In the companion paper, we showed that the spontaneous firing activity of DRN 5-HT neurons is significantly higher in male (M) than in freely cycling female (CF) rats. Moreover, during pregnancy, it increased in parallel to circulating levels of progesterone, peaking at day 17 of pregnancy (P17). In this second part, we assessed the role of three regulatory mechanisms potentially involved in these modifications of the 5-HT neurons firing activity. During pregnancy, the ED(50) for the response to LSD was decreased by about 70%, indicating a partial desensitization of 5-HT(1A) autoreceptors, which is consistent with the 5-HT neurons higher firing activity. The GABAergic tonic inhibition of 5-HT neurons was assessed using the responses to GABA, bicuculline and isoniazid. Together, they indicate a lower GABAergic tonic inhibition in males and P17 as compared to CF, which is in agreement with their greater 5-HT neurons firing rate. Finally, the efficacy of the long feedback loop, involving postsynaptic 5-HT(1A) receptors, did not seem affected by gender, ovariectomy or pregnancy since the response to systemic 8-OH-DPAT was similar. These results constitute strong evidence of mechanisms by which gender and hormonal fluctuations can modulate the 5-HT neurons function and influence vulnerability to mood disorders.     

Retrospective study of Ukrain treatment in 203 patients with advanced-stage tumors

A total of 203 advanced-stage cancer patients suffering from different types of cancer who had exhausted all conventional forms of therapy were treated with the novel antitumor drug Ukrain over a period of 2.5 years at the Villa Medica Clinic in Germany. Seventy-six patients (37.4%) were simultaneously treated with regional deep hyperthermia in which tumor tissue was heated to > 42.5 degrees C. Patients also received complementary oncological treatment with selen, cimetidine, thyme extract and vitamin A. In view of the advanced stage of the disease, the results of therapy were surprising. Forty-one patients (20.2%) achieved total remission, 122 (60.1%) partial remission and only 40 (19.7%) did not respond to treatment. The highest response rates were in patients with seminoma (three out of four patients had total remission and one had partial remission) and in prostate cancer [14 out of 20 patients (70%) achieved total remissions and five achieved partial remission].     

Serum trace elements in animal models and human depression. Part II. Copper

In the present study we report the results of investigations into the serum copper levels in a clinical study of 19 patients with unipolar depression; 16 normal controls and three animal models of depression: chronic severe stress (CSS), chronic mild stress (CMS) and olfactory bulbectomy (OB) in rats. Unipolar depressed patients exhibit significantly higher serum copper levels than the appropriate controls (depression 1·15±0·17 mg/l; control 0·95±0·09 mg/l). There was no alteration in that value in rat models of depression. The data indicate that the increased serum copper level in the depressed patients might potentially be a marker of that illness. Moreover, animal models of human depression do not show changes in this marker. Copyright © 1999 John Wiley & Sons, Ltd.     

Comparative evaluation of the efficiency of various Ukrain doses in the combined treatment of breast cancer. Report 1. Clinical aspects of Ukrain application

This study was carried out in 75 patients with histologically confirmed breast cancer. Patients were divided into three groups of 25. The control group received symptomatic corrective therapy prior to mastectomy. The two other groups were given neoadjuvant therapy with Ukrain injections. The first group received a total course dose of 50 mg Ukrain at single doses of 5 mg injected every second day (a total of 10 injections) and the second group received a total Ukrain dose of 100 mg but with single doses of 10 mg. Five to seven days after the last injection patients from all groups were subjected to mastectomy according to Halsted, Patey or Madden. No allergic reactions or adverse effects were observed after the first course of injections or the whole course of Ukrain therapy, regardless of the dose. After five to six injections some patients noticed slight burning sensations and insignificant morbidity in the tumor area, which, according to a number of authors, testifies to the therapeutic activity of the preparation. Practically all patients who were administered Ukrain noticed remarkable positive changes in the second half of treatment: improvement in appetite, normalization of sleep, disappearance of general weakness and the appearance of confidence in recovery. After the course of treatment with Ukrain, the contours of the tumorous node became more clearly defined, which facilitated mastectomy. Changes in the tumor tissue were one-sided in their qualitative differences in comparison to the control group and were not dose-dependent. Qualitative and quantitative reactions to Ukrain by both intact lymphatic nodes and those affected by the metastatic process contribute to more quantitative and radical performance of the most important stage of mastectomy--removal of the regional cellulose together with the lymphatic nodes. The results of this study showed the efficiency of both doses (50 and 100 mg) of Ukrain with neither performing significantly better than the other.     

The pharmacological treatment of delusional depression: Part II

This study investigated the pharmacological treatment of delusional depressives by assigning patients on a random double-blind basis to amitriptyline (AT) alone, perphenazine (PER) alone, or AT + PER. As reported in an earlier paper, the combination of AT + PER was the superior treatment with a response rate of 78% compared with 41% for AT alone and 19% for PER alone. This difference is both clinically and statistically significant (p less than 0.01). In this second article, the authors report that the patients on AT + PER had higher plasma levels of AT and its pharmacologically active metabolite nortriptyline (NT) than the patients on AT alone. Although the response rate had a direct relationship to AT + NT plasma levels, an analysis of variance showed that the group of patients treated with AT + PER still had a significantly higher response rate, even after controlling for the plasma levels of AT + NT (p less than 0.05). There was also a correlation between PER plasma levels and clinical response.     

Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part II: the adrenergic response

The aim of the study was to prospectively evaluate the association between the occurrence of post-traumatic stress disorder (PTSD) and the adrenergic response to the traumatic event, and additionally, to explore the link between PTSD and the initial norepinephrine:cortisol ratio. Plasma levels and urinary excretion of norepinephrine (NE) were measured in 155 survivors of traumatic events during their admission to a general hospital emergency room (ER) and at 10 d, 1 month and 5 months later. Symptoms of peri-traumatic dissociation, PTSD and depression were assessed in each follow-up session. The Clinician-Administered PTSD Scale (CAPS) conferred a diagnosis of PTSD at 5 months. Trauma survivors with (n=31) and without (n=124) PTSD had similar levels of plasma NE, urinary NE excretion, and NE:cortisol ratio in the ER. Plasma NE levels were lower in subjects with PTSD at 10 d, 1 month, and 5 months. There was a weak but significant positive correlation between plasma levels of NE in the ER and concurrent heart rate, and a negative correlation between NE in the ER and dissociation symptoms. Peripheral levels of NE, shortly after traumatic events, are poor risk indicators of subsequent PTSD among civilian trauma victims. Simplified biological models may not properly capture the complex aetiology of PTSD.     

Serum creatine phosphokinase levels during treatment with beta-adrenoreceptor blocking agents

We administered four beta-adrenoreceptor blocking agents--pindolol (15 mg/day), propranolol (60 mg/day), carteolol (15 mg/day), and labetalol (150 mg/day)--to essential hypertensive patients, and followed the changes in levels of serum creatine phosphokinase (CPK) and its isoenzymes for 1 year. Blood pressure was reduced almost equally by all drugs, but the changes in serum CPK levels differed. During treatment with pindolol, 20 of 25 patients showed a 20-760% increase in CPK compared with the pretreatment value. Studies on CPK isoenzymes revealed that the elevation was mainly in the skeletal muscle (MM type), while eight of the 25 patients also showed a slight increase in the myocardial type (MB type). Another beta-blocking agent with intrinsic sympathomimetic activity (ISA), carteolol, also increased the CPK levels significantly in 10 of 15 patients. On the other hand, such increases were observed in only four of 27 patients receiving propranolol and three of nine patients receiving labetalol. These results suggest that beta-blocking agents with ISA increase the serum CPK levels more frequently than those without ISA. Therefore, the serum CPK levels should be carefully evaluated in patients receiving beta-blocking agents, especially those with ISA.     

Metabolism of territrem a in liver microsomes from wistar rats: 2. Sex differences and regulation with gonadal hormones and phenobarbital.

The aim of the present study was to assess the effects of sex difference on metabolism of territrem A (TRA) by liver microsomes from 7-wk-old Wistar rats. Metabolism of TRA to 2-dihydro-4beta-demethylterritrem A (MA2) through 4beta-hydroxymethyl-4beta-demethylterritrem A (MA1) and 4beta-oxo-4beta-demethylterritrem A (MAX) was observed in intact male rats. However, in intact female rats only MA1 was formed, although the amount of MA, formed in females was much less than in males. Phenobarbital pretreatment enhanced this step and was not affected by gonadectomy. In the gonadectomized rats of both sexes, MA2 was formed from TRA when the animals were further treated by testosterone and was significantly enhanced by treatment with phenobarbital. However, estradiol treatment or estradiol in combination with phenobarbital treatment did not affect MA2 formation from TRA in gonadectomized rats.