Twice-weekly Treatment Research Articles

Enhancement of mezerein-promoted papilloma formation by treatment with 12-O-tetradecanoylphorbol-13-acetate or mezerein prior to initiation.

The effects of promoter treatments prior to initiation on subsequent promotion by mezerein were examined in SENCAR mice. Groups of mice received two applications of various complete as well as first and second stage promoters given at various time intervals prior to initiation ranging from 3 days to 10 weeks. The mice were then initiated with 2 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA) followed 2 weeks later by twice-weekly treatments with 2 micrograms of mezerein. The papilloma response in mice, receiving pretreatments with 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) either 3 days, 1, 2, 3 or 5 weeks before initiation, was similar to that seen when TPA was given after initiation during stage I of promotion followed by stage II of promotion with mezerein (4-5 papillomas per mouse in all groups). Surprisingly, pretreatment with the stage II promoter, mezerein (2 micrograms), either 2 or 5 weeks prior to initiation, also gave papilloma responses similar to that induced with the standard two-stage promotion protocol (4.7 and 6.4 papillomas per mouse, respectively). The papilloma response was less than that in the standard two-stage promotion protocol when pretreatments with the stage I promoter A23187 (80 micrograms/mouse) were given either 2 or 5 weeks before initiation (2.6 and 2.3 papillomas per mouse, respectively). However, a repeat experiment (currently in progress) with a higher dose of A23187 (160 micrograms/mouse) given 2 weeks prior to initiation indicates that it is more effective than the 80 micrograms dose. When the time interval between pretreatment and initiation was increased to 10 weeks, the papilloma response with TPA and A23187 pretreatment was reduced to below two papillomas per mouse and with mezerein pretreatment to below three papillomas per mouse, indicating the effect was reversible. Histological changes in epidermis of mice which received two applications of these compounds correlated with the tumor response. In this regard, treatment with two applications of TPA and mezerein resulted in an epidermal hyperplasia of similar magnitude (epidermal thickness of 53.5 +/- 1.5 and 50.0 +/- 1.1 microns, respectively). The hyperplasia produced by treatment with two applications of 80 micrograms A23187 (39.4 +/- 1.8 microns) was significantly less. The ability of pretreatments with benzoyl peroxide (20 mg) and chrysarobin (50 micrograms) to affect the subsequent promoting activity of mezerein was also examined.(ABSTRACT TRUNCATED AT 400 WORDS)

Undesirable side effects of isoniazid and rifampin in largely twice-weekly short-course chemotherapy for tuberculosis.

Between January 1976 and June 1981, 814 patients with pulmonary tuberculosis were treated for 9 months with isoniazid (INH) and rifampin (RIF), daily for 1 month and twice weekly for the other 8 months. Overall success was achieved in 95% of the 586 patients who completed therapy: in 15 patients (2.9%), sputum cultures failed to convert to negative during therapy, and 10 patients (1.7%) have relapsed since stopping the chemotherapy. Major toxic effects occurred in 22 patients; in 14 during the daily phase and in 8 during the twice-weekly phase. Hepatic toxicity occurred in 13 patients during daily and in 5 during twice-weekly treatment, and it was caused by RIF in 5, INH in 10, and was undetermined in 3. Hematologic abnormalities developed in 4 patients: in 1 during the daily and in 3 during the twice-weekly phase. Minor side effects, which were not life threatening, were encountered in 62 patients: in 35 during the daily and in 27 during the twice-weekly therapy. These were gastrointestinal intolerance in 18, drug fever in 27 (including 11 with "flu-syndrome" during twice-weekly administration), cutaneous rashes in 14, and headache, general malaise, and weakness in 3. These side effects were produced by RIF in 43, by INH in 18, and the responsible drug was not identified in 1. Hypersensitivity reactions to twice-weekly administration of RIF were infrequent. Clinical surveillance for toxicity is preferred over routine and regular biochemical monitoring.

Inhibition of maturational changes in Leydig cell function by treatment of rats with an agonist of LH-RH.

Daily treatment of immature (30-day-old) male rats for 40 days with 50 ng of an agonist of LH-RH impaired normal development of Leydig cell function. This treatment partly or completely inhibited maturational increases in (1) the serum levels of testosterone, (2) seminal vesicle weight, (3) the in-vitro steroidogenic responsiveness of the testis, and (4) the in-vitro testicular binding of 125I-labelled hCG. In contrast, twice-weekly treatment of immature or adult rats with 50 ng LH-RH agonist had only minor effects on Leydig cell function, although hCG-binding was always significantly reduced. Testicular growth in immature rats was unaffected by daily injection of LH-RH agonist whereas twice-weekly treatment caused a small reduction in weight. None of the treatments had any major consistent effect on the pituitary or serum levels of gonadotrophins and prolactin, although daily treatment with the LH-RH agonist clearly reduced the responsiveness of the pituitary to the agonist, in terms of the amounts of LH and FSH released.

Studies on the mechanism of skin tumor promotion: evidence for several stages in promotion.

The effects of nonpromoting and weakly promoting diterpenes on skin tumor promotion by 12-O-tetradecanoylphorbol 13-acetate (TPA) were investigated. When phorbol and phorbol 12,13-diacetate (both nonpromoting) were given simultaneously with TPA after 7,12-dimethylbenz[a]-anthracene (DMBA) initiation in female mice, they had no effect on TPA promotion. However, the nonpromoter 4-O-methyl-TPA and the weak promoter mezerein were found to inhibit TPA promotion in a dose-dependent manner when given simultaneously with TPA. Because mezerein was found to be an effective inhibitor of TPA promotion when given simultaneously and because it induces many biological responses similar to those to TPA, the capacity of mezerein to act as an incomplete promoter in a two-stage promotion protocol was also investigated. Twice-weekly applications of 1,2, or 5 mug of TPA for 2 weeks after DMBA initiation produced 0, 0, and 0.5 papilloma per mouse, respectively, at 20 weeks. When the twice-weekly applications of TPA for 2 weeks were followed by twice-weekly treatments with 2 mug of mezerein for 18 weeks, the number of papillomas per mouse was 2.2, 3.5, and 9.0, respectively. Twice-weekly applications of 2 mug of TPA for 2 weeks followed by twice-weekly treatments with 1, 2, or 4 mug of mezerein for 18 weeks produced 2.1, 3.5, and 6.8 papillomas per mouse, respectively, in DMBA-treated mice. Twice-weekly doses as high as 40 mug of 4-O-methyl-TPA were not effective in producing tumors when given after a limited treatment with TPA; however, 4-O-methyl-TPA had weak activity as a first-stage promoter. The results suggest that although mezerein by itself is a weak promoter and mimics TPA in many biochemical and morphological effects it is a potent second-stage promoter in a two-stage promotion regimen.

THE EFFECTS OF IRRIGATION, FERTILIZATION AND ORGANIC MATTER ON ROSES GROWN IN FOUR SOILS IN THE GREENHOUSE

Abstract ‘Baccara’ roses were grown for 4 years in 4 soils of different properties, but in the same greenhouse and location: a sandy soil of the coastal region (8% clay), a loessial sandy loam (16% clay), a grumusolic clay loam (39% clay) and a heavy clay grumusol (69% clay). During the first 2 years the 2 lighter soils gave higher yields with better quality than the clay soils. During the last 2 years the loessial soil gave the highest yields. The addition of 70 l/m 2 of peat affected the organic matter content and the water retention properties of the light soils, but not the flower yields. Irrigation twice weekly during the summer gave a small advantage at times on some of the soils, as compared with irrigation once a week. When, during the last year of the experiment, the latter plots were irrigated frequently (every 2–3 days), their yields exceeded those of the twice-weekly treatment. The yield and quality differences were evaluated on a basis of soil physical properties and attending fertility status.

The effects of irrigation, fertilization and organic matter on roses grown in four soils in the greenhouse

‘Baccara’ roses were grown for 4 years in 4 soils of different properties, but in the same greenhouse and location: a sandy soil of the coastal region (8% clay), a loessial sandy loam (16% clay), a grumusolic clay loam (39% clay) and a heavy clay grumusol (69% clay). During the first 2 years the 2 lighter soils gave higher yields with better quality than the clay soils. During the last 2 years the loessial soil gave the highest yields. The addition of 70 l/m 2 of peat affected the organic matter content and the water retention properties of the light soils, but not the flower yields. Irrigation twice weekly during the summer gave a small advantage at times on some of the soils, as compared with irrigation once a week. When, during the last year of the experiment, the latter plots were irrigated frequently (every 2–3 days), their yields exceeded those of the twice-weekly treatment. The yield and quality differences were evaluated on a basis of soil physical properties and attending fertility status.

Sleep deprivation therapy in depression

A study of sleep deprivation therapy was made in 62 females and 15 males, aged 20-72, with monopolar (60 patients) and bipolar (17 patients) types of manic-depressive psychosis. Of these patients, 30 had suffered only the current depression, 29 a maximum of five depressions, and 18 more than five depressions before the sleep deprivation therapy. Twenty-five patients had been treated with antidepressant drugs for less than 10 days, 12 patients for 10-24 days, and 36 patients for more than 24 days. Twenty-four patients were treated with one sleep deprivation, 29 patients with one sleep deprivations per week (average 1.59), and 24 patients with two sleep deprivations per week (average 2.5). The effect of the sleep deprivation therapy was evaluated clinically and by means of Cronholm-Ottosson's rating scale. The effect was found good and lasting in 29%, good but temporary in 38%, and poor in 32% of the cases. The best results were achieved with twice-weekly treatments, the poorest results with once-weekly treatment. The results were equal in monopolar and bipolar cases and were independent of the number of previous depressions as well as antidepressant drug treatment. No side effects have been observed, in particular no conversion to mania. The results of the present investigation indicate that depression and sleep disturbances are symptoms produced by a common factor which, however, it as yet unknown. Sleep deprivation therapy is seen to have at least some effect on all cases of endogenous depression. Sleep deprivation therapy has no side effects and is more quick-acting than any other treatment procedure hitherto known. It should therefore be considered the first treatment offer to all endogenously depressed patients in whom immediate ECT is not necessitated.

Rejection of Mammary Adenocarcinoma Cell Tumors in DBA/2 Mice Immunocompromised by Thymectomy and Treatment with Antithymocyte Serum

Syngeneic mammary adenocarcinoma cells were mixed with killed Corynebacterium parvum organisms and were then transplanted subcutaneously into groups of normal and immunocompromised mice. The tumors formed at the site of injection exhibited normal growth for approximately 12 days followed by rapid and lasting rejection in both normal and immunocompromised animals. The control mice were protected against reinjections of 10-4 to 10-8 cells of the same line of tumor cells. The immunocompromised mice exhibited protection to reinjection of 10-4 cells of the tumor line initially employed. Microscopic examination of histologic sections of 10-day-old tumors in immunocompromised mice arising from administration of tumor cells and C.parvum mixtures revealed infiltration of only macrophages whereas those from normal animals exhibited both macrophages and lymphocytes. The data suggested that primary rejection of these tumors in immunocompromised mice may be the result of macrophage activity together with humoral immunity. These studies also revealed that 59 to 75% of immunocompromised mice exhibit protection against reinjection of the same line of tumor cells if twice-weekly treatment (i.p.) with killed C. parvum was included after inoculation of tumor cells mixed with C. parvum vaccine. These mice, unlike their saline-treated peers, exhibit delayed hypersensitivity reactions which are associated with proliferation of theta antigen-bearing lymphocytes. They also have intact tumor-directed humoral immune reactions.

A controlled clinical trial of daily and intermittent regimens of rifampicin plus ethambutol in the retreatment of patients with pulmonary tuberculosis in Hong Kong A Hong Kong tuberculosis treatment services/Brompton hospital/British medical research council investigation

In a controlled clinical trial, 4 regimens of rifampicin plus ethambutol are being compared with the standard reserve regimen of ethionamide plus pyrazinamide plus cycloserine in the management of patients in Hong Kong with pulmonary tuberculosis whose first-line chemotherapy has failed. The results at 1 year are presented. A total of 575 Chinese adults with sputum-positive pulmonary tuberculosis, with strains resistant to isoniazid, who had previously been treated with first-line drugs but not with the drugs under study, were allocated at random to: 1. a. rifampicin plus ethambutol daily (ER7); 2. b. rifampicin plus ethambutol twice a week (ER2); 3. c. rifampicin plus ethambutol once a week (ER1); 4. d. rifampicin plus ethambutol daily for 2 months and then once a week (ER7ER1); 5. e. ethionamide plus pyrazinamide plus cycloserine daily for 6 months and then ethionamide plus pyrazinamide daily (EtZC). There were 384 patients (107 ER7, 89 ER2, 57 ER1, 69 ER7ER1, 62 EtZC) in the main comparison. The radiographic improvement and monthly sputum culture results were broadly similar in all 5 regimens. At 12 months 89 per cent of 107 ER7, 80 per cent of 89 ER2, 82 per cent of 57 ER1, 91 per cent of 69 ER7ER1 and 95 per cent of 62 EtZC patients had a favourable status. Bacteriological failure on the rifampicin regimens was associated with the early emergence of rifampicin resistance, there being evidence that the Hong Kong strains were less sensitive pretreatment to ethambutol than British strains were. Of 396 patients (91 ER7, 80 ER2, 78 ER1, 85 ER7ER1, 62 EtZC) in the analysis of adverse reactions, 2 of 91 ER7 patients, but no other patient on the other rifampicin regimens, had reactions to ethambutol. Nine (10 per cent) of the ER7 patients had reactions to rifampicin; 111 (46 per cent) of the 243 patients on intermittent rifampicin had reactions to rifampicin, and 34 (55 per cent) of the EtZC patients had adverse reactions. Reactions to daily rifampicin were either cutaneous or transient increases in serum transsaminase levels without jaundice. Six main types of adverse reaction to intermittent rifampicin occurred; cutaneous, abdominal, ‘flu’ syndrome, respiratory, hepatic and purpura. The ‘flu’ syndrome was the commonest, but was less common during twice-weekly treatment (22 per cent of 80 ER2 patients) than during once-weekly treatment (54 per cent of 85 ER1 patients) with the same dose size of rifampicin (P=00001), and less common during once-weekly rifampicin (35 per cent of 85 ER7ER1 patients) when this was preceded by a 2-month daily phase (P = 0.03). Most adverse reactions to intermittent rifampicin were relatively easy to manage clinically, and only 11 patients (5 per cent of 243 on intermittent rifampicin) had to have the drug terminated. Adverse reactions to the EtZC regimen (the commonest of which were cutaneous, hepatic, gastro-intestinal, neuropsychiatric reactions and arthralgia) led to the termination of one drug in 11 and all 3 drugs in 4 of 34 patients with reactions. Circulating rifampicin-dependent antibodies, detected by the indirect antiglobulin method, were found in 1 (2 per cent) of 47 ER7 patients, in 30 per cent of 40 ER2, 41 per cent of 44 ER1, and 32 per cent of 44 ER7ER1 patients and in none of 36 EtZC patients. They were significantly associated with the ‘flu’ syndrome (P=0.001). In the light of this study, twice-weekly rifampicin plus ethambutol, with or without an initial daily phase, is now in use as a reserve regimen in Hong Kong.

Ambulatory tuberculosis chemotherapy on an Indian reservation.

Forty-two White Mountain Apache Indians with tuberculosis were placed on a supervised twice-weekly ambulatory treatment program of streptomycin and isoniazid after short periods of hospitalization. Previously, prolonged off-reservation hospitalization had been the rule due to skepticism that chemotherapy could be maintained in the nonurban setting of an Indian Reservation. Although 12 percent of the scheduled appointments were missed, chest roentgenogram findings remained stable or improved and sputa cultures remained negative. No treatment failures occurred, and no patient has been lost to follow-up in spite of the great distances, cultural conflicts and serious social problems which exist. Monetary savings have amounted to an estimated $9,000 to $14,000 (104 clinic visits @ 3.75 = $389.00 vs 365 × $40.00/day = $14,600.00) per patient treated. The early results show that ambulatory chemotherapy has proved effective, well tolerated and economical in this nonurban setting.

Removal of Plutonium from Mouse Liver by Glucan and DTPA

Glucan from yeast is additive with DTPA (diethylenetriaminepentaacetic acid) in removal of polymeric plutonium-239 from the mouse liver. At 47 days after administration of plutonium, the net removal was 8.5% of the injected dose by glucan alone, 11.5% by twice-weekly DTPA treatments, and 19.5% by combined therapy. A 60 mg/kg dose of glucan, given intravenously, was equally effective when given (a) in a single injection, (b) divided into three daily injections, (c) given 5 days or 3 hr before plutonium, or (d) 5 days after plutonium. A 15 mg/kg dose of glucan was almost as effective as higher doses (30-120 mg/kg). Hepatic plutonium removed by glucan was excreted in the urine in the presence of DTPA, or was apparently translocated to the skeleton without DTPA. As shown earlier for monomeric plutonium in the mouse, liver deposits of polymeric plutonium are excreted primarily through the feces, both with and without DTPA, and skeletal deposits removed by DTPA are excreted through the urine. Twice-weekly injec...

Rifampicin in daily and intermittent treatment of experimental murine tuberculosis, with emphasis on late results

Three experiments are reported in this paper. The first compared the efficacy of the combinations rifampicin-isoniazid, rifampicin-ethambutol and isoniazid-ethambutol, each combination administered daily, twice-weekly and once weekly for six months. In both the daily and the intermittent regimens, rifampicin-isoniazid was the most effective. With this combination the results produced by twice-weekly treatment, after an initial daily stage of one month, were almost as good as those produced by daily treatment throughout.The second experiment demonstrated that the addition of streptomycin to the regime rifampicin-isoniazid, whether given daily or intermittently, carried no clear-cut benefit. After the end of treatment, the stability of the results obtained with rifampicin-isoniazid, although not perfect, was considerably better than the stability observed after treatment with isoniazid-streptomycin of considerably longer duration.The third experiment showed that the addition of rifampicin to isoniazid-streptomycin for a short period (one month) produced a long-lasting benefit.