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4-(4-halophenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolines 2a-c have been synthesized by two methods and their biochemical and pharmacological properties have been studied. Biochemical investigations showed that all the compounds are strong inhibitors of DA, NE and 5-HT reuptake, the strongest effect being observed with compound 2b (R = Br). 2a-c exhibited a strong antiulcer activity on an experimental model of stress-induced ulcers with minimal doses (0.1 to 3.0 mg/kg), the effect of 2b being 30 times higher as compared to the H2-antagonist Ranitidin. At higher doses (10 to 30 mg/kg) 2b and 2c inhibited the Reserpinptosis. The most active compound in the reuptake inhibition 2b, expressed a high antidepressive activity in some other tests, comparable to that of the antidepressant Nomifensin. 2b has been selected for further pharmacological testing under the code name AN12.

Stereospecific multistep synthesis and resolution of 6,7-dimethoxy-4- phenyl-1,2,3,4-tetrahydroisoquinoline (3) has been achieved from its racemic base. The absolute configurations of the optical antipodes converted into their hydrochloride salt forms have been determined by X-ray diffractometric analysis, thus permitting assignment of the antipodes as the (+)-(4R)-3 and (-)-(4S)-3 enantiomers. The crystal structures of the two enantiomers are related as mirror images and only the (4R)-3.HCl form has been fully determined by three-dimensional X-ray diffraction. In the solid state, the carbon atoms of the two methoxy groups deviate slightly from the benzene-ring plane and the chirally oriented phenyl substituent is almost perpendicularly tilted out of conjugation with the isoquinoline system. Examination of the enantiomers in several biochemical tests for 5-HT, NE and DA uptake inhibition-activity revealed an exclusive preference for the (4S)-enantiomer. These results are in accord with previous suggestions that the S-configurational state of the 4-phenyl substituent is important for biological activity.

In 93 decreased patients, 31 with first myocardial infarction and 62 with repeated myocardial infarction, the following indices were studied: risk factors, previous history, clinical onset, complications, ECG localization, time and cause of death, pathologicoanatomical changes. There was a tendency toward a greater frequency of cardiogenic shock in the patients who died during their first infarction. In the patients who died during a repeated infarction the following events were significantly more frequent: pulmonary thromboembolism (9.6%), dilatation (8.1%), recurrence (8.1%) (p less than 0.01); chronic cardiac failure (25.8%), episodes of clinical death (25.8%) (p less than 0.001); conduction-rhythm disturbances (75.8%) (p less than 0.05). Transmural infarction was found in 96.7% of the patients of the first infarction group vs 82.2% of the patients of the repeated infarction group (p less than 0.05). A statistically significant difference for the time of death was found only for the group patients who died after the 7th day of the infarction--0% for the first infarction group and 25.8% for the repeated infarction group (p less than 0.001). Cardiogenic shock was a significantly more frequent cause of death for the patients of the first infarction group (87.1%) than for the patients of the repeated infarction group.

The authors describe 12 women with endometrioid ovarian carcinoma at the age of 28 to 74 years. Endometrioid carcinoma is accompanied by endometrial carcinoma in 4 women. Five patients are at I stage, 5 patients--at II stage and 1 patient--at III and IV stage. All women are operated and have total hysterectomy with bilateral adnexectomy and 7 women have omectomy and 5 are without omectomy. All are treated by postoperative telegammatherapy: 8 patients-at the region of the pelvis 1--woman-at the pelvis and para-aortal lymph chains, 2 patients--with band irradiation of the whole abdomen and 1 woman is irradiated palliatively. 7 out of 8 patients treated radically and followed over 5 years, are clinically healthy and only 1 is dead and she been at III stage. In the last case there has been mesonephroid component and it has caused probably more malignant course of the disease. An inference is made that the complex treatment of endometrioid carcinoma of the ovary--radical operation and postoperative irradiation, gives good results.

117 patients, 89 men and 28 women, with repeated myocardial infarction were followed up for a two year period. The following were taken into consideration: risk factors, number and localization of previous infarctions, interinfarction period, clinical onset of the new infarction, complications, electrocardiographic changes, time of death, causes of death, pathologicoanatomical localization of the new and old infarctions in comparison with the electrocardiographic localization. Statistically significant differences between the two sexes were found for the death of cardiogenic shock--48.9% for men and 13.3 for women (p less than 0.01) and for chronic cardiac failure as a complication of the second myocardial infarction--50.0% for women and 16.1% for men (p less than 0.001). For all other indices the differences were not statistically significant.

The racemic and optically active 2-chloroethylcarbamoyl derivatives of 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines 6 and 8 were synthesized. The enantiomers of the benzazepine 5 were obtained by consecutive treatment of (+/-)-5 with (-) and (+)-dibenzoyl-tartaric acids. Compounds 6 are strong DA and NE uptake inhibitors while 8 exhibits inhibition towards 5-HT. The inhibitory effect of 6 is characterized by clearly expressed enantioselectivity. So 1-S-6 is a 26, resp. a 40 times stronger inhibitor of DA and NE uptake than 1-S-6. (+/-)-6 shows moderate antiulcer activity on water-immersion stress ulcer.

The action of AN5 on experimental models of gastric ulcers induced by water-immersion stress, indomethacin and reserpine, or by pylorus ligation in rats has been studied. AN5 supresses the formation of ulcers in all experimental models. The strongest antiulcer effect is shown in relation to water-immersion stress-induced ulcers. From the broad pharmacological studies of AN5 on this model it can be seen that even a dose of 0.100 mg/kg has a high antiulcer activity. The increase of the dose leads to a regular increase of the antiulcer activity, the highest suppression of the ulcer index being reached at a dose of 1 mg/kg (86.15%). The comparative studies with ranitidine and cimetidine on the same experimental models of gastric ulcers show that AN5 possesses an antiulcer activity many times higher than that of the above-mentioned drugs.

The racemic and optically active 4'- and 8-substituted tetrahydroisoquinolines 2-5 have been synthesized and their effect on the water-immersion stress ulcer in rats has been studied. All compounds prevent the formation of stress ulcer, the strongest effect being exhibited by compound 4 and its dextrarotatory isomer (R1 = Cl, R2 = NHCOOC2H5). The antiulcer activity of 4 is 30 to 50 times higher than that of the H2 receptor antagonists Cimetidin and Ranitidin used for comparison. The absolute configuration of the optically active compounds 2, 3 and 4 has been determined by means of chemical correlation. The antiulcer activity of 4 is characterized by enantioselectivity, S-(+)-4 is three times as active than R-(-)-4.

A case of 72 year old woman with arterial hypertension is presented. The woman was treated with clonidine and nifedipine. Hypokalemia was found by normal urine excretion of potassium and normal intraerythrocyte potassium contents. It is assumed that the hypokalemia was due to the nifedipine treatment.

Two patients are described with lupus erythematosus, aged over 60. A brief literature survey is presented of the characteristics of SLE in advanced age, analyzed, in the light of the communications by other authors, were the manifestations in the described patients--fever, accelerated ESR, onset with preceding articular syndrome, skin changes as well as the complications--fresh myocardial infarction with the signs of activation of lupus in one of the patients.

The drug Ofloxacin was tried clinically on 54 patients with different bacterial infections. Patients resistant in vitro and in vivo to all available antibacterial drugs were selected. The patients were classified into 4 groups: 1. with uroinfections--31 patients, 2. bacterial infections in patients under prolonged immunosuppressive treatment--10 patients, 3. bacterial infections in patients with other severe diseases--4 patients, 4. patients in whom previous antibacterial treatment was unsuccessful--11 patients. The treatment was carried out with different doses and duration according to the type, localization and severity of the infection. The results were very good in 24 patients and good in 6 patients. The early (on the second day of treatment) sterilization of the urine is pointed out. The very good results in patients with suppressed immunity, the wide antibacterial and clinical range, the convenience of oral application and the minimal side effects are especially emphasized.

The causative agents of uroinfections were studied among the patients at the Clinic of therapy of internal diseases and clinical pharmacology during 1984. Significant bacteriuria was established in 279 out of 485 patients, with 1475 urine inoculations performed, 14 with mixed flora. The highest is the share of E. coli--50,5 per cent, followed by Proteus--25,7 per cent. No essential change was established in the microbiological spectrum of the causative agents of uroinfections as compared with that from 1961-1970. Good susceptibility was established to ampicillin but only of Enterococcus, to chloramphenicol of E. coli, Klebsiella, Enterobacter. The susceptibility of all microorganisms to gentamycin and nalidixic acid was very good. The susceptibility to doxycycline was poor. The treatment is recommended only after precise microbiological study.

The antihypertensive effect of the preparation celiprolol was studied in a double blind experiment versus acebutolol in 60 patients (30 males and 30 females), with an average age 40 years. Only patients with hypertonic diseases, stage I-II, according to WHO classification were included in the study. The treatment Lasted 4 weeks. The criteria for a good effect were the normalization of the blood pressure and the absence of adverse effects. There was no statistically significant difference between the percentages of the reduced blood pressure, attained by both preparations. By the end of 4th week, 56.7 per cent of the treated with celiprolol were with normalized blood pressure, and 46,7 per cent--with acebutolol. The following adverse effects were observed: light gastrointestinal manifestations, weakness, dizziness, tremor, impotence. In some of the patients those effects were transitory but in 4 patients, treated with acebutolol, the treatment was discontinued because of the adverse effects.

The authors describe three female-patients with mesangial IgA-glomerulonephritis with non-typical clinical manifestations and course. Manifest nephrotic syndrome was established in one of them, favourably influenced by glucocorticosteroid treatment, and advanced renal insufficiency--in the other two.

Clinical studies were carried out on the herb combination Dietosan on 40 patients with diabetes mellitus, insulin-independent type. Twenty patients were treated with the species, and another 20--with the disperg. Eighteen patients, out of both groups have taken glybenclamide. A good compensation of diabetes was attained in 4 patients treated only with species and in 7, treated only with the disperg. Three of those treated with species and glybenclamide were well compensated, and two--of those treated with disperg and glybenclamide. A more distinct reduction of blood sugar was observed among those with good compensation treated with the disperg. No adverse and toxic effects were observed during the treatment with the combination at the clinic.

A total of 185 patients were investigated for M. hominis and mycoplasmal infection was established in 28 patients. In 2 of the patients mixed infection with E. coli was established and I with Staphylococcus aureus. Fifteen had pyelonephritis and 6--arterial hypertension, without positive data for pyelonephritis. The patients were treated with gentamycin and tetracycline according to the data of antibiograms of the isolated microorganisms. The criteria for admittance of the presence of mycoplasmal pyelonephritis are discussed.

Plantago major, according to literature data, has expectorant, antiphlogistic, pain-relieving effect. The experimental studies confirmed a spastic effect upon the smooth musculature of bronchi as well. Twenty five patients with chronic bronchitis were examined, with or without spastic character, with light and moderately severe deviations in ventilation indices. The treatment period was 25-30 days. A rapid effect on subjective complaints and objective findings was obtained in 80 per cent. Some indices of external respiration were favourably affected. The preparation is with a good tolerance, with no toxic effect on gastrointestinal tract, liver, kidneys, hemopoiesis.

A method was elaborated for clinical trial of pharmaceuticals for the treatment of infections of kidneys and urinary ducts. The main requirements are as follows: definitive diagnostic criteria for urological infection, monotherapy, systematic control for the drug intake, precisely formulated indices for assessment of the effect, strict follow-up of adverse and toxic effects. The effect was assessed according to a three-stage scale: very good, good and poor, consideration given not only to the clinical and laboratory indices but to adverse effects as well. Pipemidic acid was studied according to that model--the acid being a new chemotherapeutic, similar to nalidixic acid according to chemical composition and action. Out of all 29 patients treated, 19 were with very good effect, with good--6, and with poor--4. The adverse effects were negligible--one patient had light urticarial rash and pruritus.

Twenty four patients with chronic non-specific colitis were treated with a herb combination. As a result from the treatment, the spontaneous and palpable pains along the large intestine disappeared in 95.83 per cent of the patients by the 15th day of their admission to the clinic. Defecation became daily in the patients with obstipation syndrome, but a combination of Rhamus frangula, Citrus aurantium, C. carvi was added to the herb combination already indicated. Defecation was normalized in patients with diarrhea syndrome. The pathological admixtures in feces disappeared.

From the urine cultures of 1238 patients with renal or suspicious for renal disease mycoplasmas were isolated in 119 (9.6%). In 75 patients the mycoplasmas were typified. In 56 patients M. hominis and in 24 patients Ur. urealyticum were isolated. In 52 patients there were data for pyelonephritis, in 46 patients there was no renal infection. In 21 patents there were mycoplasmas and arterial hypertension without sufficient data for pyelonephritis. In the group of patients with pyelonephritis and arterial hypertension the infection with M. hominis, which is considered pathogenic for the kidneys, prevailed. In 23 patients a mixed flora was isolated and in 19 of them there was pyelonephritis. In 33 patients (27.7%) there were data for pyelonephritis and an independent Mycoplasma infection. Cases with Mycoplasma hominis prevailed. It is isolated in 16 out of 20 typified strains. All isolated mycoplasmas showed high sensitivity to tetracycline and gentamycin. 51 patients were treated by antibiotics. 35 patients were treated with methacycline, 33 of them successfully. 10 patients were treated with other antibiotics. The tetracyclines are recommended for the treatment of Mycoplasma infections.

A total of 28 hypernephroid tumours have been diagnosed within a period of 32 months. The data from echographic, intravenous urography, computer tomography and thin-needle aspiration biopsy and renovasography were compared in the patients studied. Two basic variants of echographic picture have been described. It has been concluded that the combination of abdominal ultrasound tomography with thin-needle aspiration biopsy is a valuable method for the diagnostics of hypernephroid cancer. Computer tomography proved to be appropriate in solving the problem of operability, renovasography--pre-operatively, and the rest of the methods--in suspected and undistinguished echographic evaluations.

33 patients with hypertensive crisis were treated with a 2% Nifedipine solution for oral use. 5 patients had taken 5 mg, 16 patients--10 mg and 12 patients--20 mg of the drug. The antihypertensive action was followed up to the 6-th hour. The results show that the antihypertensive action of Nifedipine in doses of 5, 10 and 20 mg begins on the 5-th minute. The maximum antihypertensive action of these three doses is manifested between the 15 and 30 min. The duration of Nifedipine action in a dose of 5 mg is up to the 2-d hour and that of 10 and 20 mg doses is up to the 6-th hour. Only the 20 mg dose leads to a transitory statistically significant increase of the pulse rate with 10-12(-1) (p less than 0.05) between the 15 and 30 min. The side effects of the three doses are insignificant.

A patient with septicemia, caused by Mycoplasma hominis was described. Data were established for pyeloureteral anomalies in both ureters with disturbed left drainage with hydronephrosis II--II stage. Mixed flora was isolated from urine--Mycoplasma hominis and E. coli. Pure culture Mycoplasma hominis was isolated from the hemocultures. The patient was favourably affected by metacyclin treatment--600 mg daily.

31 patients with a urological infection caused by a bacterial strain susceptible to gentamycin were treated by a single injection of 240 mg of gentamycin. 11 patients (35.5%) fully recovered, the infection was eliminated and the clinical symptoms and signs disappeared. Better results were achieved in patients with infection of the lower urinary tract without pyelonephritis, 7 out of 15 patients (46%) recovered. Out of 16 patients with pyelonephritis only 4 were cured (25%). Of 10 patients with nephrolithiasis only 1 was cured, in the remaining 9 patients the treatment was without effect. In the group of patients who recovered the patients with E. coli infection prevailed while in the group of unsuccessfully treated patients other bacteria prevailed. No side effects were found. The conclusion is that the treatment with a single gentamycin dose could be applied successfully in patients with an infection of the lower urinary tract without pyelonephritis, morphologic changes in the urinary system or nephrolithiasis.

A total of 127 patients with arterial hypertension--64 with symptomatic and 63 with essential, were treated with chlophazolin "Pharmachim" at the Clinic of Therapy of Internal Diseases and Clinical Pharmacology for a period of one year. The drug was used alone in part of the patients and in the rest--in combination with other drugs. Satisfactory effect on the clinical symptoms and the level of blood pressure was attained in all patients treated and in only a small part of them diuretics and beta-blockers were necessary so as to attain better effect in coping with the arterial hypertension. In all patients the drug gave no toxic and allergic reactions, the most frequent adverse affects being the dryness of the mouth and sleepiness.

A total of 170 patients were treated--137 only with the herb combination (78 with duodenal ulcer and 59 with gastroduodenitis), 33--with the herb combination together with antacid (21 with duodenal ulcer and 12 with gastroduodenitis). As a result from the treatment, the spontaneous pains disappeared in 90 per cent of the patients--in the group with and in the group without antacid, the dyspeptic complaints faded in over 85 per cent but in the patients, treated with herbs and antacid the mentioned complaints disappeared several days earlier. The palpitation pains, in both groups, disappeared in more than 90 per cent of the patients within the same time. Gastric acidity, in both groups, showed a statistically insignificant tendency to decrease prior and post treatment. The gastroscopically control revealed that the ulcer niche, in both groups, was healed in almost the same percentage of the patients.