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PubMed1976

Studies in dose-time-volume relationships in bladder and tongue radium implants.

The clinical results of 26 tongue and 31 bladder radium implants were analysed in terms of proposed dose specification parameters that describe the dose-time-volume relationships of the implant. Tongue cases that recurred within two years were mostly those with a relatively short treatment time and in which a relatively large dose reduction factor had to be applied. The dose-time factor did not differ significantly in the groups of bladder implants having different clinical results. A higher incidence of necrosis was noted in bladder cases. This was associated with a significantly higher mean dose and a somewhat greater degree of dose inhomogeneity. Recurrences were generally linked with greater mean dose, target volume and dose inhomogeneity. These unfavourable dose-volume relationships were frequently associated with poor distribution of needles. The reported experimental and clinical findings pertinent to the differential sparing of normal tissues associated with protraction of continuous irradiation are outlined. In the light of these, it is felt that the results of tongue implants could have been improved by omission of the dose-time adjustment factor for treatment time of 3-10 days without undue risk of necrosis. However, bladder results could have been improved by attainment of a better implantation technique while keeping the treatment time within 6-8 days in view of the lower tolerance.

Carcinoma, Squamous Cell↗

PubMed1977

Effects of methanol extraction residue of Bacillus calmette-Guérin in humans.

Forty patients with histologically confirmed neoplastic diseases were treated with the methanol extraction residue of Bacillus Calmette-Guérin (MER). Thirty-six received concomitant chemotherapy. MER was initially given intradermally twice a month, 1 week apart, at a dose of 200 mug into each of five sites draining different lymph node-bearing areas on the anterior body surface. Thirty-seven patients developed local ulcerations at least 0.5 cm in diameter at MER injection sites. Typical lesion evolution was characterized by erythema and induration followed by vesicle formation and central necrosis. Either granulation tissue or a thick nonulcerated eschar preceded healing, leaving a linear, flat scar. Systemic toxicity consisted of malaise, fever, and myalgias on the day of MER administration. No hematological or biochemical changes directly attributable to MER were observed. Dose titrations in decreasing 10-fold dilutions in a linear array in a single anatomical region were carried out on 35 occasions. All patients but three developed at least a 5-mm induration to the 1-mug dose within 2 weeks of titration. Dose reductions were necessary in 19 instances. The minimal dose that produced a 1-cm inflammatory lesion with central necrosis was 0.01 mug. Serial biopsies were performed. These indicated a time-related series of changes from a nonspecific inflammatory lesion to an acute inflammatory response with microabscesses, followed by noncaseating granulomata and ultimately fibrosis. MER is a quantifiable nonviable immunostimulant that obeys dose-response relationships in its cutaneous lesions.

Antineoplastic Agents↗

PubMedDate not supplied

Quasimonochromatic radiation for dental radiography.

Because of the greater sensitivity of commonly used dental films near 40 kv and the inherently greater contrast between bone and other oral tissues that is achieved at lower energies than those conventionally used, a considerable reduction of radiation exposure can be obtained by the use of those quasimonochromatic photons whose energy lies between 30 and 40 kv. The simplest and clinically most efficacious and econimical method of obtaining this quasimonochromatic radiation using fixed-anode tubes involves the use of Ce, 0.008 inch in thickness, as a band-pass filter, with reduction of skin exposure by a third to a half. The considerable dose reduction achieved at an increased exposure time of only 1.2 seconds is significant in view of the fact that both a greater percentage as well as a greater number of people are receiving radiation for oral diagnosis every year. Since the quasimonochromatic rays produced are less energetic than much of the radiation in the unfiltered beam, the radiation doses from scattered radiation to skull, bone marrow, and gonads also are reduced. In addition, the softer photons result in less Compton scattering, reducing the fog and improving the diagnostic quality of the film. Quasimonochromatic radiation may also be used to enhance the contrast wherever iodine contrast medium is needed since iodine absorbs very strongly above its absorption edge near 33 kev, suggesting another use of this technique in the area of oral diagnosis.

Filtration↗

PubMed1978

Physical dependence to barbital compared to pentobarbital. IV. Influence of elimination kinetics.

The withdrawal characteristics of barbital and pentobarbital after "chronically equivalent" treatment suggested that the longer acting barbital was less liable to produce physical dependence. Therefore, to distinguish this potential pharmacodynamic difference from the known pharmacokinetic differences between the two drugs, the rate of elimination of each was adjusted to mimic that of the other. The rate of barbiturate elimination after chronically equivalent pentobarbital dosing was reduced by barbital substitution or by first-order pentobarbital dose reduction, with the result that withdrawal signs became mild and appeared later (3 days postdrug). The rate of barbiturate elimination after chronically equivalent barbital dosing was increased by pentobarbital substitution or by peritoneal dialysis of barbital, with the result that withdrawal signs became severe and appeared sooner (within 1 day). These findings conclusively support the key role of the rate of barbiturate elimination to expose underlying physical dependence to barbiturates. Furthermore, "physical dependence" and its expression in "withdrawal" must be regarded separately to evaluate and compare critically the dependence capability of different drugs.

Animals↗

PubMed1979

Small electron beams in radiation therapy.

The use of lead cutouts to produce small beams in electron therapy results in a reduced dose to the patient. The authors investigated this effect for beams with energies less than 8 MeV and diameters of 3 cm or less. Dose measurements were obtained using film and an ionization chamber. Based on these values, corrections were established to account for dose reduction due to cutout spaces and air spaces between the end of the electron cone and the skin surface. Data were also obtained on the dose increase due to backscattering from internal eyeshields.

Electrons↗

PubMed1976

[The anti-hypertensive effect of timolol maleate (blocadren) in gradated combination with a diuretic].

In a controlled double-blind crossover study followed by an open longterm continuation period, the antihypertensive effect of timolol (Blocadren), a new beta-receptor antagonist, was investigated in 24 ambulatory patients with mild to moderate essential hypertension who were concomitantly receiving Moduretic as baseline diuretic therapy. The addition of timolol to one tablet daily Moduretic resulted in a clinically and statistically significant further reduction of supine and upright systolic and diastolic blood pressures. The average total daily dosage schedule for timolol ranged between 15 and 20 mg, with the same blood pressure lowering effect whether the divided dose was given twice or three times. Significant sinus bradycardia was consistently observed but well tolerated, with only one patient requiring dose reduction. After 48 weeks of treatment (comprising 46 weeks Moduretic and 36 weeks timolol) 20 of 22 patients were normotensive (supine diastolic blood pressure below 90 mm Hg) while in two the hypotensive response proved inadequate. One patient was dropped from the study after 3 days of timolol treatment because of acute bronchial asthma. When specifically questioned, one-third of the patients admitted experiencing cold extremities. One patient exhibited Raynaud's syndrome which was treated symptomatically while continuing in the study. In terms of electrolyte balance, the fixed combination of hydrochlorothiazide and the antikaluretic amiloride (Moduretic) as baseline therapy essentially proved adequate. On occasion, however, two subject revealed hypokalemia requiring short-term oral potassium supplement. During the initial 10 to 16 weeks a steady decline in serum potassium was observed but this stabilized itself thereafter. The concomitant administration of Moduretic and timolol (Blocadren) was shown to be an effective therapeutic regimen in patients with mild to moderate essential hypertension. This combination is particularly suitable for patient compliance in longterm therapy, as timolol can be given twice daily.

Amiloride↗

PubMed1976

The metabolism of zingerone, a pungent principle of ginger.

1. The metabolism of 4-(4-hydroxy-3-methoxyphenyl)butan-2-one (zingerone), a pungent principle of ginger, has been investigated in rats. 2. Oral or intraperitoneal dosage (100mg/kg) of zingerone resulted in the urinary excretion of most metabolites within 24 h, mainly as glucuronide and/or sulphate conjugates. While zingerone itself accounted for roughly 50-55% of the dose, reduction to the corresponding carbinol (11-13%) also occurred. Side chain oxidation took place at all three available sites and oxidation at the 3-position, giving rise to C6-C2 metabolites, predominated. About 95-97% of the dose was accounted for. 3. Appreciable (40% in 12 h) biliary excretion occurred. Biliary studies and studies in vitro using caecal micro-organisms indicated that several O-demethylated metabolites found in the urine are of bacterial origin.

Animals↗

PubMed1977

[On the dose-effect relation of allopurinol (author's transl)].

The hypuricemic action(y) of 1H-pyrazolo(3,4-d)pyrimidin-4-ol (allopurinol) is dependent on the serum concentration of uric acid (x). After treatment with allopurinol at doses of 300 mg daily for 8 days there exists a highly significant correlation corresponding the equation y = 0.875x + 3.950. At a level of 8 mg/dl without any therapy serum uric acid concentration is expected to decrease by an average of 3 mg/dl if allopurinol is applied at daily doses of 300 mg in a preparation with or without any retarding effect. Following a dose reduction to 150 mg allopurinol daily over a period of 8 days, too, the mean diminution of the hypuricemic action amounts only to 0.43 +/- 0.26 mg/dl (S.D.). In some cases, however, long-term therapy with allopurinol at daily doses of 150 mg is insufficient to guarantee a normuricemic state.

Adult↗

PubMed1979

National Cooperative Crohn's Disease Study: adverse reactions to study drugs.

Adverse reactions to the drugs employed in the National Cooperative Crohn's Disease Study were sought prospectively at each patient visit and by retrospective review of all patient charts. Prednisone caused evident side effects in over 50% of patients on high-dose suppressive therapy and in approximately one-third of patients on prophylactic dose. Thirty-two percent of patients on high-dose, and 26% on prophylactic-dose prednisone required dose reduction or withdrawal because of side effects. Comparable figures for sulfasalazine were 14% and 12%, and for azathioprine 32% and 20%. The incidence of nausea, vomiting, or anorexia among patients taking sulfasalazine was 46% and 34%, on high and low dose respectively; however, this incidence was no different than that observed among patients taking placebo. These symptoms occasioned withdrawal from the study of only 4% and 3% of patients on high and low doses of sulfasalazine, respectively. Azathioprine produced leukopenia at a dose of 2.5 mg/kg body weight in 15% of patients and the mean white cell count, lymphocyte count, granulocyte count, and hematocrit all fell significantly in patients on this dose. Pancreatitis occurred in 5% of patients taking azathioprine but in no other patients. Sulfasalazine proved to be the safest effective suppressive drug for Crohn's disease. Prednisone toxicity, though substantial, is acceptable in view of its demonstrated suppressive efficacy. Azathioprine was approximately as toxic as prednisone but no more effective than placebo in suppressing active disease. None of the drugs was effective prophylactically, and all showed appreciable long-term toxicity.

Adult↗

PubMed1979

Effect of increased bioavailability of phenytoin tablets on serum phenytoin concentration in epileptic out-patients.

1. The bioavailability of a brand of phenytoin tablets used in Finland was improved in 1976. In the present retrospective study serum concentrations of phenytoin, measured before and after the change of bioavailability, are compared in 50 epileptic out-patients, who for various reasons used exactly the same dose of phenytoin tablets and of other drugs despite the increased bioavailability of phenytoin. 2. The mean increase of serum phenytoin steady-state concentration was about 70% after the change of bioavailability but there were considerable interindividual differences in the response. The mean increase in serum phenytoin was only 28% in patients with serum phenytoin concentrations 5 microgram/ml or less but the mean increase was 100% in patients with serum phenytoin between 5 and 10 microgram/ml. In patients with serum phenytoin concentrations more than 10 microgram/ml the mean increase in concentration was 60-80% after the improvement of bioavailability. However, in these groups of patients some clinically manifested phenytoin intoxications enforced the patients to the control and to dose reduction obviously before the steady-state concentration of phenytoin was reached. 3. On the basis of our experiences and those reported in the literature some proposals are presented to be considered when the bioavailability of phenytoin or of another drug with a narrow therapeutic range and a dose-dependent kinetics has to be changed.

Biological Availability↗

PubMed1979

[General characteristics and comparative evaluation of the radioprotective properties of aryl alkyl amine adrenomimetics in experiments on mice].

The radioprotective effect (RPE) of some arylalkylamines (AAAs) was studied in experiments on mice. Mesaton and its close analogues were injected subcutaneously 15 minutes prior to irradiation at a dose of 800 rad. The protective effect is exerted by AAAs in low doses (25--50 mumole/kg), the compounds show stable and high RPE (80--80% survival, dose reduction factor being 1.3--1.4) and low toxicity (LD50 = 4--8 mumole/kg). AAAs studied are not less effective than aminothiols. Their pharmacological spectrum--K = LD50/ED50 (200--500) is superior to that of known aminothiols and indolylalkylamines.

Animals↗

PubMed1978

Patient exposures and radiation risks in Swedish diagnostic radiology.

Results are reported of measurements around 1974 on a thousand patient at 13 Swedish hospitals, and additionally at several photofluorographic and dental installations. Energy imparted as well as doses to the thyroid, breast, lung, bone marrow, ovary and testis have been calculated for many types of examination. Collective doses have been calculated and risk estimates made. The energy imparted corresponds to an annual mean body dose to the Swedish population of about 1 mGy (100 mrad), and the genetically significant dose was about the same as the 1955 total of 0.4 mGy; in both cases the uncertainty of the estimate is about +/- 50%. The possibility of dose reduction by a factor of 2 or more using available techniques is demonstrated. The risk of future serious injury is estimated to 0.0002 cases per joule of energy imparted to the patient.

Bone Marrow↗

PubMed1976

A trial of micro-encapsulated and enteric-coated aspirin in rheumatoid arthritis.

In a trial of 48 patients with rheumatoid arthritis, enteric-coated aspirin (4.55 g daily( and micro-encapsulated aspirin (4.50 g daily) proved to be equally effective in reducing morning stiffness, relieving pain, increasing grip strength, reducing ESR, and reducing the need for additional analgesic tablets, compared with placebo. Reduction of joint tenderness was also found, but this was not statistically significant. Proximal interphalangeal joint circumference altered little during the trial. Tinnitus and deafness were commoner with enteric-coated aspirin, but gastric side-effects were similar. Of 39 patients completing the trial, there was an equal patient preference for enteric-coated aspirin and micro-encapsulated aspirin. Salicylate side-effects necessitated withdrawal of six patients from the trial and dose reduction in nine patients. It was concluded that the efficacy and side-effects in rheumatoid arthritis of both aspirin preparations were similar.

Administration, Oral↗

PubMed1979

A pharmacokinetic model for predicting the concentration of methotrexate in plasma subsequent to intrathecal injection.

A pharmacokinetic model has been established in which plasma methotrexate (MTX) concentrations following intrathecal administration are predicted. The model is based upon cerebrospinal fluid MTX concentrations following intrathecal injection of MTX, and plasma MTX levels subsequent to i.v. injection of the drug in dogs. Anticipated plasma MTX levels were compared with actual measured concentrations. The model predicts changes in the plasma MTX concentration curve as a result of varying of the injected dose, reduction in plasma MTX clearance, and reduced transfer of MTX from cerebrospinal fluid to the blood. It is suggested that plasma MTX levels be measured at 3, 5, 7 and 10 h following intrathecal injection to facilitate an early assessment of unusually slow plasma MTX decay. Thus, administration of leucovorin, to prevent systemic toxicity, may be more rapidly commenced. Also, if such measurements indicate that the transfer of MTX from cerebrospinal fluid to the blood is reduced. MTX dose of the subsequent intrathecal injections should be reduced to minimize risks of systemic toxicity and neurotoxicity.

Animals↗

PubMed1978

Pharmacokinetic and therapeutic studies of pivmecillinam in patients with normal and impaired renal function.

Pivmecillinam which is the oral form of mecillinam was evaluated by treatment of 26 patients presenting various types of urinary tract infections and by prophylactic treatment of 12 patients. Pivmecillinam given in a daily dosage of 1.2 g for periods of 1 to 56 weeks was well tolerated in all of the patients including those with impaired renal function without any dose reduction. The original bacterial strain in the urine was eradicated in 100% of the cases. Two patients had a superinfection and 4 had a recurrence during a 3-month follow-up period. The oral absorption of pivmecillinam was investigated in 15 patients with normal or slightly reduced renal function and in 5 patients on maintenance hemodialysis. High serum levels were achieved within 1 to 2 h after administration. Patients with reduced renal function showed retarded elimination rates, suggesting that the dose should be adjusted in this category of patients.

Acute Kidney Injury↗

PubMed1975

Abnormal involuntary movements in relation to anticholinergics and levodopa therapy.

During a study comparing levodopa with and without benserazide in Parkinsonism, 19 of 41 patients (42 per cent) receiving concomitant anticholinergic therapy developed abnormal involuntary movements (AIM), in contrast to 11 of 58 patients (19 per cent) receiving only levodopa. This difference is statistically significant. Discontinuation or dose-reduction of anticholinergics in 10 patients without altering the levodopa-dosage resulted in disappearance or amelioration of the AIM in nine cases. The Parkinsonism, however, aggravated subsequently, necessitating resumption of anticholinergics in five cases. These results establich further the facilitating effect of anticholinergics on the emergence of AIM.

Benserazide↗

PubMed1975

[Effect of aminopropyl-aminoethylthiphosphate on radio-iron utilization following whole-body irradiation of mice in the sublethal dose range].

The effectiveness of the thiophosphate compound WR 2721 was investigated with regard to the radiosensitivity of X-irradiated female mice in the sublethal dose range of 50 to 150 R using the radioiron test (59Fe). An increase of the radioresistance with regard to the radioiron uptake in young erythrocyte populations was obtained only beyond radiation doses of 75 R. In lower dose ranges the animals treated with thiophosphate became even more radiosensitive. At dose values of 100 R and 150 R dose reduction factors (DRF) of 1.3 and 1.5 respectively were obtained. These factors are considerably smaller than the DRF-values found for the survival rate at LD 50/30. A possible mechanism for this result may be due to the different dephosphorylation rate of the thiophosphate in various tissues, as described in literature.

Animals↗

PubMed1978

Multiple adjuvant therapy on a murine fibrosarcoma: actinomycin-D, X-irradiation and local tumor hyperthermia.

The tumoricidal activities of single dose x-irradiation (RAD) and concomitant Actinomycin D (AMD) with or without local tumor hyperthermia (LTH) on an in vivo Methylcholanthreme-induced fibrosarcoma (Meth-A) are described. The addition of LTH enhanced the actions of AMD, RAD and AMD + RAD; the trimodality treatment was most effective. Based on delay of tumor growth, the radiation dose reduction factors for AMD + RAD + LTH compared to RAD; AMD + RAD + LTH, were approximately 2.8, 2.1, and 1.8, respectively. The shape of the curves suggests a further decrease in the ability of the tumor cell to repair sublethal damage with AMD + RAD + LTH. The clinical relevance is not determined.

Animals↗