Minimum Therapeutic Dose Research Articles

PMH6 Economic Outcomes of Antidepressant Use in A Managed Care Organization

Hospitals, health care systems, and policy makers are striving to seek ways to provide cost-effective care for patients with major depressive disorder. OBJECTIVES: The first objective is to investigate the differences between the newer antidepressants regarding treatment completion, average daily dose, dosage titration, switching, and augmentation behavior. The second objective is to compare direct health service expenditures related to the treatment of depression. The inquiry is guided by the following question: Is there a significant difference between antidepressants in regard to overall health care service expenditures for the treatment of depression? METHODS: Retrospective archival data from computerized claims records of a large managed care organization were analyzed. Treatment completion was defined as receiving at least 180 days of therapy at a minimum therapeutic dose as defined by the AHCPR guidelines for detection, diagnosis, and treatment of depression. Patients were included in the analysis if (1) they had an ICD-9 diagnosis code for depression or if (2) they received an antidepressant prescription. Patients were excluded if (1) they were less than 18 years of age, (2) they had a diagnosis indicating schizophrenia or bipolar depression, (3) there were not at least 6 months of follow up data available, or (4) they were ineligible for coverage by the plan. RESULTS: Patients initiated on fluoxetine were more likely to complete therapy than those on paroxetine, sertraline, nefazodone, or venlafaxine (n = 65,792; p < .01). These differences narrowed over time. Results regarding overall health care utilization related to each antidepressant will be presented. CONCLUSIONS: Based on this sample of patients, it appears that patients initiated on fluoxetine are more likely to complete therapy when compared to the other antidepressants.

Effects of TCP on Spatial Memory: Comparison with MK-801

TCP { N-[1-(2-thienyl)cyclohexyl]piperidine}, a PCP (phencyclidine) derivative, has been shown to possess antiepileptic and neuroprotective efficacy against chemically induced seizures. However, it is known that other antagonists of the NMDA receptor impair spatial learning. This study was thus undertaken to explore the eventual effects of TCP on memory. The same study was done with MK-801 {(+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a, d]-cyclohepten-5, 10-imine}, one of the most studied NMDA receptor antagonists, which can be considered as a reference molecule. Three doses of each drug were chosen: 0.05, 0.1, and 0.2 mg/kg for MK-801 and 0.5, 1, and 2 mg/kg for TCP, the second dosage corresponding to the minimal required for antiseizure activity. The drugs were injected IP 30 min each day before a classical procedure of acquisition in a Morris water maze test. At the highest dose of each drug, the animals did not learn the position of the platform. At 0.1 mg/kg MK-801, the rats used a praxis strategy to find the platform but they did not know where the platform was. Contrary to MK-801, TCP at 1 mg/kg did not induce any memory impairment. At the lowest doses used, no memory impairment was found. It thus appears that, at the minimal therapeutic dose effective against chemically induced seizures (0.1 mg/kg for MK-801 and 1 mg/kg for TCP), TCP, contrary to MK-801, does not induce any memory impairment. Furthermore, at all the doses used, TCP presents the particularity that its locomotor side effects are not long lasting, being no longer observed from 30 min after the injection.

The effects of acute levodopa withdrawal on motor performance and dopaminergic receptor sensitivity in patients with Parkinson's disease.

The effects of acute levodopa withdrawal were studied in nine patients with levodopa related on-off oscillations. One patient withdrew from the study due to off period confusion and hallucinations. A marked deterioration in motor disability occurred in all patients following overnight withdrawal of levodopa and a further mild delayed deterioration was present over a mean withdrawal period of 44 hours. Patients with more severe disease were able to tolerate levodopa withdrawal for a shorter period of time than those with milder disease severity. The minimum therapeutic dose of subcutaneous apomorphine needed to produce a similar improvement in patients' mobility, before and after several days of drug withdrawal, did not differ, thus providing no clinical evidence for alterations in striatal dopamine receptor sensitivity after acute levodopa withdrawal.

Clastogenic effect of fenfluramine in mice bone marrow cells in vivo.

Fenfluramine, an amphetamine derivative used in the treatment of obesity, has been evaluated in vivo in the bone marrow cells of Swiss albino mice using two cytogenetic endpoints for assessing its genotoxic and clastogenic potentials. Concentrations of 0.75, 1.5, 3.0, and 5.0 mg/kg b.w. were administered orally for the study of sister chromatid exchange frequencies and chromosome aberrations (CA). SCE frequencies showed a positive dose response; 1.5 mg/kg being the minimum effective concentration. Fen caused a prolongation of cell cycle at all concentrations. Except for the minimum therapeutic dose (0.75 mg), all other doses (1.5, 3.0, and 5.0 mg) showed a significant increase in the percentage of damaged cells over that of the vehicle control. The degree of clastogenicity was directly proportional to the dosage used and inversely related with the duration of treatment. A gradual reduction of the clastogenic potential was observed after 12 and 24 hr of exposure, indicating that the maximum effect occurs at the middle or late synthetic phase of the cell cycle. This study, probably the first detailed screening of the drug for its genotoxicity, shows that Fen is moderately clastogenic and a DNA damaging agent in vivo.

Differential effects of methylphenidate on the growth of neonatal and adolescent rats

Methylphenidate (MPH), the drug of choice in the treatment of Attention Deficit Disorders with Hyperactivity (ADD/H), has raised concern regarding its suspected potential for reducing body stature in growing patients. In a previous study we demonstrated that neonatal rats treated with MPH (35 mg/kg, SC, twice daily) showed an acute growth impairment followed by a rapid growth-rebound phenomenon. This report confirms our earlier findings in neonatal rats and extends the investigation of the growth suppressing effects of MPH to the periadolescent period of development in rats. Specifically, neonatal groups of male and female rats treated with higher and lower doses of MPH than in the original study confirmed the growth impairment and growth rebound phenomena reported earlier. Unlike neonatal rats, rats treated during the periadolescent period of development failed to show any growth impairment. These data suggest that the growth suppressing effects of MPH are the result of an acute toxicity which is readily reversible on discontinuation of the drug. Further, it is concluded that there is a low probability of long term effects on human body stature when the minimal therapeutic dose is used in clinical practice.

Cardiac effects of six actodigin (AY-22,241) - related semisynthetic glycosides

Six actodigin (AY-22,241) - related semisynthetic glycosides (with the C-3 natural linkage of the lactone ring to the steroid nucleus, transposed to C-2) were assayed in failing hearts of canine heart-lung preparations. Two compounds, with additional small modifications in the steroid nucleus, were incapable of reversing heart failure. Two others, an isodigoxigenin and an isogitoxigenin derivative, were only slightly active. However, the two other actodigin-derived compounds, with methyl groups at the lactane's C-4, were very active. Compound 5 had the methyl group in beta position and was 2.5 times more potent than actodigin. Compound 6, with the methyl group in alpha position, had a potency similar to that of actodigin. In the anesthetized and vagotomized dog, their toxic effects (to the point of atrioventricular dissociation) were short lasting and completely reversible. Both of these agents had a wide margin of safety (relationship between the minimal therapeutic, irregularity and lethal doses).

Anthelmintic Activity of Closantel against Ancylostoma caninum in Dogs

The efficacy and minimum therapeutic dose of closantel, an injectable salicylanilide anthelmintic, was evaluated on adult Ancylostoma caninum. Doses of 7.5 and 10 mg/kg had a marked anthelmintic effect on adult stages, removing 99 and 98%, respectively. A second experiment tested the efficacy of closantel against hypobiotic larval stages of A. caninum. A dose of 20 mg/kg did not affect the abundance of arrested hookworm larvae or prevent their subsequent development, but it may have inhibited their full maturation as adult worms so that patent, intestinal infections did not occur. Small numbers of adults were recovered from treated dogs at 29, 43, and 57 days post-treatment, but no eggs were passed in their feces. These studies bear on the practical problem of control of hookworms in dogs.

1107 TREATMENT OF ACRODERMATITIS ENTEROPATHICA(AE) WITH ZINC PICOLINIC ACID(ZnPA)

AE without hypozincemia(variant) was recently shown to respond to viokase which contains PA (Krieger&Evans, J.Pediatr.96:32,80). It promotes Zn absorption in the rat and concentrations in human milk are 20× higher than in cow's milk(Evans, Pediatr Res.14:876, 80). The patient was treated sucessfully with 60mg Zn++ as the sulfate, then for 5 mo. with ZnPA(5mg Zn++)and 3 mo. with 8-20mg PA. Both maintained plasma Zn around 150μg/dl(N:112±13). This prompted a trial of ZnPA in 3 patients with “classical” AE.The minimum therapeutic dose of Zn sulfate that maintained normal plasma Zn was first determined and then discontinued until the rash appeared. ZnPA was then given, using 1/3 dose of Zn+. This caused rapid improvement and has maintained normalcy for 4-6 weeks. Plasma PA was measured in 2 AE and 3 variant AE cases,age 1 to 9 yrs, while they were on 30-45mg Zn++ as the sulfate and well. Normal:1.2-2.0μmoles/dl(4 children, 10 adults). Plasma PA in AE was 0.05&0.45 μmoles/dl, and in variant AE 0.02-0.69 μmoles/dl. These values were thus far below the normal range. Some variability can be attributed to different dietary content of PA since it was shown that oral PA raises plasma PA(in 1 case of AE from 0.05-1.24 μmoles/dl). These data indicate that ZnPA decreases the requirements for Zn in AE, presumably because it acts as a ligand. A genetic defect of PA metabolism may be the cause of AE. Neither PA nor ZnPA are recommended for treatment until the metabolism of this tryptophan metabolite is better understood.

Clinical study with bleomycin: tolerance to twice weekly dosage.

Fifty-nine patients with inoperable malignant neoplasms were treated with bleomycin at dose levels ranging rom 1.25 mg/m2 to 35 mg/m2 of estimated body surface area twice weekly in an attempt to define host tolerance to this new antineoplastic agent. The drug was given for a total of 12 doses, if tolerated, and longer in the presence of objective tumor response. At 4 mg/m*, chills and fever, vomiting, and moderate cutaneous toxicity appeared. At 15 mg/m2, 3 of 11 patients developed dose-limiting skin toxicity. TWO additional patients developed pulmonary infiltrates after prolonged courses of treatment to a total of 546 and 582 mg, respectively. At 26 mg/m2 and higher, prohibitive pulmonary and hematologic toxicity developed during the initial course of study requiring premature termination of scheduled courses. At 35 mg/m2, transient hypertension, confusion, abdominal distention, and urinary burning also developed. Four of 19 patients with squamous cell carcinoma of the head and neck, one patient with squamous cell carcinoma of the skin, 3 of 6 patients with lymphosarcoma, and 1 of 4 patients with testicular carcinoma responded with more than 50% tumor regression. One patient with lymphosarcoma was induced into complete remission. Minimal therapeutic dose levels for lymphosarcoma and for squamous cell carcinoma were 4 mg/m' and 6 mg/m', respectively. This study indicates that optimal dose levels range between 4 and 15 mg/m2 twice weekly. The present study establishes patient tolerance to twice weekly doses of bleomycin and confirms therapeutic benefit for squamous cell carcinoma and lymphosarcoma over a remarkably wide range of doses.

Immunity in trypanosomiasis. III. Sensitivity of antibody-resistant strains to chemotherapeutic drugs.

Antibody-resistant strains are less sensitive to suramin and antrycide than antibody-sensitive strains. When living trypanosomes were exposed to suramin and antrycide in vitro, antibody-resistant strains needed 50 times more drugs than antibody-sensitive trypanosomes in order to make them non-infectious to mice. In therapeutic experiments in mice the minimal therapeutic dose of drugs for antibody-sensitive strains was 0·1 mg. but for resistant strains it was 0·3 mg./20 g. mice. Rabbits treated prophylactically with suramin resisted infection with the antibody-sensitive strain for a period of 4 months, but failed to resist infection with the antibody-resistant strain after 2 months.Rabbits treated prophylactically with antrycide pro-salt, resisted infection with antibody-sensitive strains for a period of 2 months, but failed to resist infection with the antibody-resistant strain even 1 month after injection with the drug. Although trypanosomes can become drug resistant without being antibody resistant it is suggested that, under natural conditions, drug-resistant strains in animals and man develop from antibody-resistant strains, particularly when trypanostatic drugs are used. It is suggested in conclusion from these experiments that strains of trypanosomes which are exposed for some time to antibodies and become antibody resistant after passage through animals like rabbits, as well as those strains frequently passaged through mice, should be used in all tests for the efficiency of chemotherapeutic drugs.

Gas gangrene

Prophylaxis in gas gangrene consists of: (1) débridement and the thorough cleansing of early wounds; (2) prophylactic administration of polyvalent antitoxin in one minimal therapeutic dose in gunshot wounds, wounds associated with devitalized tissues, compound fractures and extensive burns. Treatment of the active infection consists of: (1) incision and drainage of all pus pockets and dead spaces, and débridement with excision of all involved tissues; (2) amputation only if the entire limb is involved in the infection or if the blood supply of the entire limb is impaired; (3) polyvalent antitoxin administered intravenously in dosage from 100,000 to 150,000 units if practical; (4) sulfanilamide and x-ray therapy for their beneficial effects on the contaminating streptococci.

Therapeutic Effect of 4,4'-Diamino-Diphenyl-Sulfone, Corresponding Sulfide and Acetyl Derivatives in Streptococcic Infection

Conclusions1. 4,4′-diamino-diphenyl-sulfone is about 3 times as toxic for the rabbit as is sulfanilamide; 4,4′-diamino-diphenyl-sulfide is 5 times as toxic. 2. The corresponding diacetyl derivatives of sulfone and sulfide are less toxic than sulfanilamide. 3. The minimum therapeutic doses given daily for 5 consecutive days are as follows: for sulfanilamide, 0.005 g, for 4,4′-diamino-diphenyl-sulfone, 0.0005 g, for diamino-diphenyl-sulfide, 0.003 g, for di (acetyl-amino)- diphenyl-sulfone, 0.001 g, and for di(acetyl-amino)-diphenyl-sulfide, 0.002 g. 4. In mice infected with beta-Streptococcus hemolyticus, 4,4′-diamino-diphenyl-sulf one is therapeutically active in a dose 10 times smaller than that required by sulfanilamide. This indicates a considerably higher therapeutic efficacy of the sulfone over sulfanilamide.

Current Literature

Current LiteratureGösta ForssellGösta ForssellStockholmSearch for more papers by this authorPublished Online:29 May 2014https://doi.org/10.1259/0007-1285-1-3-108SectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail AboutAbstractThe Pharmacological and Biological Behaviour of the Radioactive Substances at Internal Treatment.–––F. Gudzent (Acta Radiologica, Vol. VI).–––Among the radioactive substances utilised in medicine––radium and emanation of radium, mesothorium, radiothorium, thorium X (aktinium, uran X)–––the weight is taken as the unit measure for the solids, and the Curie and its derivation, the Eman, as the unit for the gaseous radium–emanations.The physical and chemical behaviour of the radioactive substances in the organism conform to a great extent to that of the longer known and near related isotopic elements. The solid substances are mainly deposited in various parts of the body–bone, bone-marrow, spleen—and to smaller extent in the intestines and the kidneys, while the gaseous elements with no fixed abode are mostly eliminated by the lungs.The therapeutical doses for man are as follows : radium 0.001–0. I mg., thorium X 0.01–0.2 mg. ; the lethal dose is about 0.5 mg. for radium, and 1.0 mg. for thorium X. The minimum therapeutic dose of radium emanation (thorium emanation is practically out of the question) in the ematorium is to be put at 20–40 Eman. The tolerance-dose varies greatly, and its upper limit cannot be determined. The biological effects are very numerous. They concern particularly the blood and the hæmatopoietic organs, the capillaries, the chromaffin system, the metabolism, the growth and the circulatory organs.Curative effects have been found in gout, rheumatism, neuralgia and neuritis, chronic suppuration and inflammation, diseases of the blood, and in many forms of essential hypertonia. Previous article Next article FiguresReferencesRelatedDetails Volume 1, Issue 3March 1928Pages: 75-110 © The British Institute of Radiology History Published onlineMay 29,2014 Metrics Download PDF