Large Initial Doses Research Articles

Minimizing metastatic risk in radiotherapy fractionation schedules

Metastasis is the process by which cells from a primary tumor disperse and form new tumors at distant anatomical locations. The treatment and prevention of metastatic cancer remains an extremely challenging problem. This work introduces a novel biologically motivated objective function to the radiation optimization community that takes into account metastatic risk instead of the status of the primary tumor. In this work, we consider the problem of developing fractionated irradiation schedules that minimize production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming framework is utilized to determine the optimal fractionation scheme. We evaluated our approach on a breast cancer case using the heart and the lung as organs-at-risk (OAR). For small tumor values, hypo-fractionated schedules were optimal, which is consistent with standard models. However, for relatively larger values, we found the type of schedule depended on various parameters such as the time when metastatic risk was evaluated, the values of the OARs, and the normal tissue sparing factors. Interestingly, in contrast to standard models, hypo-fractionated and semi-hypo-fractionated schedules (large initial doses with doses tapering off with time) were suggested even with large tumor α/β values. Numerical results indicate the potential for significant reduction in metastatic risk.

Alternative models for estimating the radiotherapy retreatment dose for the spinal cord

Purpose: To review the available experimental animal and patient data on response of the spinal cord to re-irradiation in order to identify appropriate data sets to investigate the clinical potential of models that would allow evaluation of the increase in the retreatment dose with elapsed time from the initial exposure.Materials/methods: Analysis of published data on irradiated rat and primate spinal cord identified results for the rat cervical spinal cord that could be compared, where the development of myelopathy was caused by selective white matter necrosis. This data, although limited, provide some important insights. Two models, derived from simple differential equations, provide a time- and dose-dependency for recovery and could be fitted to these data. These models predict the remaining tolerance, in a phase space above the line that connects the 100% biological effectiveness (BEDTOL) tolerance dose of the first and second treatment courses when these are plotted together. A third, much simpler, linear model, assumed that recovery was time but not initial dose dependent.Results: The experimental results showed a non-linear time dependency for the change in biological effectiveness (BED) of the re-irradiation dose. Comparison of the three different models paid particular attention to changes in the re-irradiation dose, when the initial radiation dose was either low or high. For each model, cautious data interpretations were also introduced to reduce the effects of the near completeness of recovery with time derived from the important experiments with primates, which include few data points. Model 1 predicts the least recovery following low initial doses, but with greater recovery following larger initial doses. Model 2 allowed no further irradiation after an initial full tolerance dose, but also greater than expected recovery following the use of smaller priming doses. Model 3 gives unrealistically high doses when used after an initial full tolerance irradiation dose.Conclusions: These results show that it is possible to model these time-dependent relationships for the spinal cord and that Model 1 is probably the most realistic, especially when it is used conservatively. To give greater confidence as to which of the three presented methods is best, further experiments and/or more analysis of human data are necessary. In the meantime clinicians will need to exert caution and judgement as to the choice of the re-irradiation BED, bearing in mind the other clinical factors that influence radio-tolerance. Further research is necessary to provide the safest recommendations and best clinical outcomes. Some suggestions as to what needs to be done are given.

Population Pharmacokinetics of Fusidic Acid: Rationale for Front-Loaded Dosing Regimens Due to Autoinhibition of Clearance

The objectives of this analysis were to develop a population pharmacokinetic (PK) model to describe the absorption and disposition of fusidic acid after single and multiple doses and to determine the effect of food on the rate and extent of bioavailability. Plasma PK data from three phase 1 studies (n = 75; n = 14 with and without food) in which healthy subjects received sodium fusidate (500 to 2,200 mg) as single or multiple oral doses every 8 h (q8h) or q12h for up to 7 days were modeled using S-ADAPT (MCPEM algorithm). Accumulation of fusidic acid after multiple doses was more than that predicted based on single-dose data. The PK of fusidic acid was best described using a time-dependent mixed-order absorption process, two disposition compartments, and a turnover process to describe the autoinhibition of clearance. The mean total clearance (% coefficient of variation) was 1.28 liters/h (33%) and the maximum extent of autoinhibition was 71.0%, with a 50% inhibitory concentration (IC(50)) of 46.3 mg/liter (36%). Food decreased the extent of bioavailability by 18%. As a result of the autoinhibition of clearance, steady state can be achieved earlier with dosing regimens that contain higher doses (after 8 days for 750 mg q12h and 1 day for 1,500 mg q12h on day 1 followed by 600 mg q12h versus 3 weeks for 500 mg q12h). Given that large initial doses autoinhibit the clearance of fusidic acid, this characteristic provides a basis for the administration of front-loaded dosing regimens of sodium fusidate which would allow for effective concentrations to be achieved early in therapy.

Treatment for Childhood-Onset Graves' Disease in Japan: Results of a Nationwide Questionnaire Survey of Pediatric Endocrinologists and Thyroidologists

To determine the present condition of treatment of childhood-onset Graves' disease in Japan, a nationwide questionnaire survey was conducted among councilors of the Japanese Society for Pediatric Endocrinology and the Japan Thyroid Association. Responses were received from 125 individuals, and the rate of collection of questionnaires was 47%. Methimazole was selected for first-line initial antithyroid drug therapy by 92% of respondents. Antithyroid drugs tended to be given at larger initial doses and over longer periods of time to childhood-onset patients than to adult patients, and these tendencies were more pronounced for pediatric endocrinologists. Combination therapy with an antithyroid drug and thyroxine was used more frequently by pediatric endocrinologists. Thyroidologists had more experience with radioiodine therapy than pediatric endocrinologists. Opinions regarding preparation of guidelines for the initial dose of methimazole in childhood-onset Graves' disease were almost equally divided among the following: the dose of methimazole should be adjusted according to the severity of disease as in adult cases, methimazole should be started at a dose of 1mg/kg per day in all patients, and the dose should be determined based on results of a randomized study. The present condition of treatment of childhood-onset Graves' disease in Japan was clarified.

Aminoglycoside Dosing Considerations in Intensive Care Unit Patients

Factors affecting aminoglycoside dosing requirements in critically ill adult patients were reviewed. A literature search was performed from 1979 to 1992 and articles pertaining to aminoglycoside dosing were obtained. Only studies appearing in peer-reviewed journals were selected. Topics selected included: bactericidal kill kinetics, once-daily dosing regimens, critical illness, toxicity, aminoglycosides, intensive care unit, and lung penetration. Studies suggest that larger initial aminoglycoside doses are necessary in critically ill patients (tobramycin/gentamicin 3 mg/kg or amikacin 9 mg/kg) to achieve adequate peak serum concentrations. Current studies have not shown an increase in the incidence of aminoglycoside toxicity when using these larger initial doses. Follow-up monitoring is dependent upon the patient's physiology and risk factors for aminoglycoside-induced toxicity.

A Pharmacokinetic Explanation for Increasing Recovery Time Following Larger or Repeated Doses of Nondepolarizing Muscle Relaxants

The authors used pharmacokinetic and pharmacodynamic modeling to explain the time course of neuromuscular blockade following single or multiple doses of three nondepolarizing muscle relaxants. Published and unpublished pharmacokinetic and pharmacodynamic data for 13 normal subjects were used to simulate the duration of neuromuscular blockade (time from administration of the muscle relaxant to 25% recovery of control twitch tension) following six successive doses of atracurium (150-400 micrograms/kg initially, followed by 100 micrograms/kg), vecuronium, or pancuronium (30-80 micrograms/kg initially, followed by 20 micrograms/kg). With atracurium, duration of action was similar for the second and sixth doses, regardless of the initial dose. With vecuronium (initial doses of 30-80 micrograms/kg) and pancuronium (initial doses of 30-60 micrograms/kg), duration of action was longer after the sixth dose than after the second; with larger initial doses of pancuronium (70 and 80 micrograms/kg), duration of action was similar following the second and sixth doses. The authors also determined two recovery times (time for twitch tension to recover from 5-25% and from 25-75% of control value) for varying single doses of atracurium, vecuronium, or pancuronium. When the dose of atracurium was increased from 200 to 400 micrograms/kg, neither recovery time increased. When the dose of vecuronium was increased from 40 to 80 micrograms/kg, 5-25% recovery time increased from 6.0 +/- 2.5 min to 8.8 +/- 4.0 min (mean +/- SD) and 25-75% recovery time increased from 8.7 +/- 4.3 min to 12.6 +/- 4.4 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone in the Treatment of Refractory Ventricular Arrhythmias

Large initial doses of amiodarone hydrochloride for the treatment of ventricular arrhythmias refractory to conventional therapy were demonstrated to shorten the time to achieve control of the arrhythmia. As compared with a lower-dose regimen, the mean time to achieve partial control (suppression of ventricular tachycardia) was 10.6 +/- 5.2 days in the highest-dose group (group C), 9.5 +/- 6.4 days in the medium-dose group (group B), and 16.9 +/- 9.1 days in the lowest-dose group (group A). Complete control (suppression of virtually all ventricular ectopy) was similarly earlier in groups B and C (16.1 +/- 7.5 days and 16.0 +/- 11.3 days, respectively) as compared with group A (31.0 +/- 10.1 days). The final mean dose for long-term treatment was independent of the initial dose schedule (551 +/- 245 mg/day; range, 200 to 1,200 mg/day). The large doses were shown to be well tolerated and without serious side effects.

Refractory ergonovine-induced coronary vasospasm: Importance of intracoronary nitroglycerin

Recent experience has suggested that the ergonovine maleate test is a safe procedure for the diagnosis of variant angina pectoris, because ergonovine-induced coronary vasospasm has generally been reversible by sublingual nitroglycerin. This report describes five cases of ergonovine-induced coronary vasospasm that were refractory to sublingual nitroglycerin. Four of these patients had cardiac arrest. In two patients the vasospasm was responsive to intracoronary nitroglycerin administration. Three patients died as a result of the test. The two survivors differed from the nonsurvivors in the total dose of ergonovine given (0.1 and 0.15 mg versus 0.17, 0.3 and 0.3 mg, respectively) and in the method of administration of ergonovine. The survivors were given serial doses of 0.05 mg each, whereas the three nonsurvivors received either larger initial doses (0.1 followed by 0.07 mg) or progressive incremental doses (0.05, 0.1 and 0.15 mg serially). Sublingual nitroglycerin, given to all five patients, and intravenous nitroglycerin, given to three of the five, were ineffective in reversing vasospasm. Intracoronary nitroglycerin favorably altered the course of the survivors. Thus, the ergonovine maleate test is not benign and may cause severe coronary vasospasm that is unresponsive to sublingual and intravenous nitroglycerin, but may be reversed by intracoronary nitroglycerin.

Pancuronium Bromide Side Effects

To the Editor.— Dr. Beam (223:1044, 1973) and Drs. Orkin and Pegg (224:630, 1973) recently reported excessive tachycardia after the intravenous administration of pancuronium bromide in two patients who already had accelerated heart rates. Although pancuronium does have a tendency to increase the heart rate, as a rule, only clinically moderate tachycardia is encountered after reasonable (.04 to.06 mg/kg) doses of this agent. Despite this, pancuronium should not be used in patients who already have tachycardia, or in whom even moderate acceleration of the heart rate may be dangerous. The more marked tachycardias reported with the use of pancuronium in patients with normal heart rates were encountered with relatively large doses. 1,2 Since.06 mg/kg pancuronium produces satisfactory conditions for endotracheal intubation in two to three minutes and excellent muscular relaxation of 25 to 35 minutes duration, there seems to be no valid reason for the use of larger initial doses.

Pyrimethamine: An alternative to radiophosphorus in the treatment of polycythaemia rubra vera

Summary 1. Pyrimethamine has been used in the treatment of twenty-two patients with polycythaemia rubra vera. The drug can be extremely effective, producing rapid and complete relief of symptoms, and thromboses do not occur during periods of adequate control. However, maintenance therapy is necessary. 2. Thrombocytopaenia prevented adequate treatment in five patients, but dangerous thrombocytopaenia can be prevented by using small initial doses and regular follow-up blood counts. The effect can be reversed by stopping the drug, and recovery may be accelerated by giving folic or folinic acid. On no account must large initial doses of pyrimethamine be given in an attempt to reduce the red cell mass quickly. 3. Other complications occur, but they are less serious, and rarely do they prevent adequate treatment. These include nausea and vomiting and skin reactions. Stopping pyrimethamine abruptly may be followed by a rapid rise in the platelet count to dangerously high levels. 4. Radiophosphorus provides an easier method of control, from the patient's point of view, as there is no need for maintenance therapy with frequent blood counts. 5. Pyrimethamine may be preferred to radiophosphorus in the treatment of the young patient, who would otherwise receive a large amount of irradiation over the course of many years. 6. Many patients have been treated for a considerable time with radiophosphorus, whereas pyrimethamine is of recent introduction. Further follow-up is necessary before it can be considered to be as safe.

Oral phenylbutazone in the treatment of acute gouty arthritis

T HE beneficial action of phenylbutazone in acute gouty arthritis has been noted in many early clinical trials in various rheumatologic disorders.8*12~13,16 Further studies have confirmed and extended these initial observations and indicate that this synthetic pyrazolone derivative is particularly effective in controlling symptoms of acute gouty attacks.1,a,4,6,g,10,11 Table I summarizes reports from the American literature in which the clinical response of acute gout to phenylbutazone could be evaluated. In those cases treated within the first week of the acute attack, phenylbutazone relieved 82 per cent of the 315 reported attacks. Kuzell,’ Steinbrocker4 and Gutman have commented on the early subjective pain relief which precedes objective resolution of the other signs ofjoint inflammation. Our observations indicate that this early control of pain is a constant and significant advantage of phenylbutazone and may be obtained earliest with relatively large initial drug doses. Determinations of serum phenylbutazone level and serum urate concentration made at the time of clinical pain relief indicate that the drug’s effectiveness in relieving the pain of acute gout is related to the attainment of a relatively low but constant serum drug level and is unrelated to its uricosuric effect. This presentation describes our experiences in treating sixty consecutively observed acute attacks of gout with various doses of phenylbutazone administered orally.

Chloramphenicol in paratyphoid A; observations with a note on the clinical aspects of the disease.

Chloramphenicol (Chloromycetin) at present is the best therapeutic agent available for typhoid. Because it is not the ideal one, some early observers felt that the drug was useful chiefly in the first few days of fever. Given later it presumably controlled the symptoms without significantly influencing the pattern of recovery. Salmonella typhosa may persist in the blood and feces, and relapse may occur during treatment.* It was thought also that early treatment retarded the immune response to infection. The incidence of relapse was unchanged in treated patients and in some instances was actually higher.3Nine per cent of Watson's 110 patients responded poorly or not at all to therapy, and toxicity from the drug occurred in 10% in the form of nausea, vomiting, urticaria, and oral moniliasis. Large initial doses seemed to be harmful in severe cases. Despite the reported shortcomings of antibiotic therapy just mentioned, statistics compiled from

TESTOSTERONE PROPIONATE IN TREATMENT OF RECURRENT CANCER OF THE BREAST

DURING the sixteen months from October 1946 through January 1948, 12 women under care at the Henry Ford Hospital for breast cancer, recurrent after radical operation, were given testosterone propionate 1 and the resulting effects closely watched. Individual doses were mostly 150 mg. Aggregate total doses were from 450 to 6,225 mg. Injections were intramuscular in alternate buttocks. Given slowly, they have not produced pain, soreness or any late untoward local reactions. Only in the first 2 patients treated were there objectionable general reactions to the drug, and those were the result of unnecessary abruptness with large initial doses. There have been slight masculinizing effects in 3 patients, principally of the voice, none sufficient to create a problem. Of the 12 patients treated, 6 have died, but only 1 of the entire group failed to show some observable beneficial clinical response. In 6 of the 12, clinical improvement was striking,

Observations on the blood and urine levels of sulphapyridine (M & B 693) in the treatment of gonorrhœa

1. A series of 50 cases of gonorrhœa treated by large initial doses of sulphapyridine is recorded. 2. The basal blood and urine sulphapyridine levels during treatment are recorded. These figures refer to the free sulphapyridine present in the blood and urine. 3. Cases not responding to sulphapyridine therapy were found to give blood and urine concentrations comparable with those of successfully treated cases. 4. A consecutive basal blood and urine level reading over a 48-hour period in a case developing severe haematuria with recovery is reported. 5. Three control groups of cases are recorded.

Treatment of chorea minor, with a special view to employment of large doses of luminal

Summary.41 children, 6—14 years old (13 boys and 28 girls), are treated with luminal. As a normal method, large initial doses, (up to 30 eg daily) are given for 14 days or till the eruption of an exanthema (about 9 days), whereafter luminal is given in smaller doses (15—10 eg daily) for a shorter or longer period. In more than half of the children treated in this way clinical recovery was obtained within 2 weeks in more than three fourths of the children it was obtained within 3 weeks.Apart from 2 cases, in one of which there was a brief spell of hæmaturia in connection with the exanthema, while the other patient had an attack of febrile angina in connection with the exanthema, no serious complications were observed, especially not involving the respiratory passages.Luminal therapy with large initial doses has thus proved to be a very effective and safe treatment in all cases of chorea, but it is suitable only for hospitals or clinics.An attempt is made to account for the pathogenesis of the choreic movements; and a hypothetical explanation is given of the reason for the antichoreatic effect of luminal.

Luminal Treatment of Chorea minor

Summary: 48 children ((5—14 years old) have been treated with luminal. As normal method, large initial doses are given for 2 weeks or till eruption of exanthema, then decreasing doses. Clinical recovery was obtained in every case, in half of the cases within 2 weeks, and in more than three fourth within 3 weeks. Exanthema appealed in 17 cases, accompanied by fever in 16. Mild and brief relapses were seen in 5 cases. No serious complications were observed. An attempt is made to elucidate the pathogenesis of the choreal jerks, and a hypothetical explanation is given of the cause of the antichoreal effect of luminal.

RHYTHMICITY AND AUTOMATISM IN THE MAMMALIAN LEFT AURICLE

1. Automaticity and responsiveness to various pharmacological agents were examined in isolated muscular strips from the outer wall of the left auricle of mammalian hearts. Simultaneous mechanical and electrical recording was often employed.2. Of 65 preparations studied, 7 beat spontaneously; the others remained quiescent except for occasional isolated contractions. Fifteen were histologically examined (Professor Aschoff); none of them, even those which contracted rhythmically spontaneously, contained specific nodal tissue.3. The strips responded to single condenser discharges or to continued faradic stimulation. The response sometimes outlasted the period of stimulation.4. Adrenaline increased the number and force of the irregular contractions and sometimes produced rhythmic activity. Previous treatment with adrenaline facilitated the setting up of regular rhythmic response to single electrical stimuli.5. Histamine in larger initial doses often, but not invariably, produced rhythmic activity.6. Barium invariably produced rhythmic activity. Calcium abolished spontaneous contractions and prevented the rhythmic response to histamine.7. Strophanthin did not produce rhythmic responses.8. Veratrine and aconitine always produced rhythmic activity of high frequency.9. In man, under pathological conditions, the left auricle may possibly initiate single auricular extra‐systoles and maintain rhythmic activity.We express our thanks to Professor Samson Wright for his help in preparing this paper for the press.