Small Daily Doses Research Articles

Kinetic considerations in the choice of treatment schedules for neuraxis radiotherapy

Neuraxis radiotherapy of radiosensitive tumours such as medulloblastoma is usually carried out using conventionally sized fractions and a shrinking field technique. Plowman and Doughty (Br. J. Radiol., 64 (1991) 603-607) have proposed a partial transmission block (PTB) technique which entails the use of small daily doses over a conventional time period. Radiobiological analysis suggests that, although the PTB technique may be adequate for slowly growing tumours, therapeutic efficacy is likely to be compromised where the tumour doubling time is short. Accelerated hyperfractionation (twice daily fractions) provides a possible alternative to both conventional scheduling and the PTB technique. Direct measurement of the kinetics of tumour cells in CSF, where possible, may provide useful guidance in the choice of regimes.

Maintaining the Patency of Double-Lumen Silastic Jugular Catheters for Haemodialysis

A system has been developed for maintaining the patency of double lumen silastic jugular catheters in patients with refractory vascular access problems. Most patients receive a small daily dose of aspirin. Selected patients also receive warfarin to maintain a prothrombin time (PT) of 15, 20, or 30 seconds. Inadequate blood flow due to thrombus obstruction can be overcome by the intravenous administration of urokinase, 250.000 units. This can be administered safely to outpatients provided that heparin is not given simultaneously. Occasionally a second dose may be required. By adopting this policy all catheter obstructions have been overcome. The danger of iatrogenic bleeding cannot be discounted. Warfarin therapy must be very closely monitored.

Principles and Practice of Radiation Oncology

Ionizing radiations have been used to treat cancer patients for almost a century now. At first they were used by all types of physicians and physicists and various practitioners, and results were reported in anecdotal fashion. In the early years of this century, information was accumulated slowly and painfully, as experience taught us what patients could and could not tolerate. The concept of protracted fractionation, which now is universally recognized as the chief scientific basis of this clinical specialty, was introduced by Coutard in France in the 1920s. Regaud, in Paris, had documented that an intense single dose of radiation delivered to the scrotum of the ram was insufficient to necrotize the skin of that sensitive organ but was sufficient to sterilize the animal, while a much smaller daily dose, delivered in a series of daily fractions, not only led to complete sterility but had no permanent effect on the

Hepatic morphologic and biochemical changes induced by subacute cocaine administration in mice.

The initial event and site of cocaine-induced hepatic injury have not been elucidated. In an attempt to identify the minimal effective dose and the site of injury, we have examined the livers of mice exposed to small daily doses of cocaine, using morphological and biochemical methods. All doses of cocaine greater than 5 mg/kg were able to cause significant elevation of serum glutamic pyruvic transaminase. Light microscopy revealed a progression of centrilobular necrosis as the dose increased from 10-30 mg/kg. The initial morphologic changes observed prior to necrosis included aggregation of intermediate filaments and dilation of rough endoplasmic reticulum with loss of ribosomes. Immunohistochemistry, using antibodies to cytokeratins, showed staining of individual hepatocytes in livers from cocaine-treated animals but not in controls. In contrast to earlier reports, we found little, if any, disruption of mitochondria. In vitro, the direct application of cocaine, norcocaine, and N-hydroxynorcocaine on isolated mitochondria had no effect on the ADP:O or respiratory control ratios, at concentrations up to 2.0 mM. Our studies demonstrate that any early cellular alterations in cocaine-induced hepatic injury are manifested in intermediate filaments and endoplasmic reticulum with no evidence of mitochondrial involvement.

Blindness in patients after external beam irradiation for pituitary adenomas: Two cases occurring after small daily fractional doses

We report two cases of blindness occurring within 10 months of completion of radiation with 45 Gy in 1.80 Gy fractions given five times weekly. The literature on blindness as a complication of pituitary irradiation is reviewed. There have been no reported cases of total visual loss occurring as a consequence of treatment with fractional doses of less than 2 Gy. Visual loss due to radiation damage usually occurs within two years of completion of treatment in contrast to visual loss due to recurrence or empty sella syndrome, which usually occur more than two years after the completion of therapy. Other causes of blindness not related to the radiation, and potentially reversible must be considered. However, these causes usually have a distinctively different clinical picture. Fraction size, total dose, and treatment time are all important factors when considering the biological effects of radiation to the pituitary region.

Hypocalcemic Effect of Physiological Concentrations of Corticosterone in Adrenalectomized-Parathyroidectomized Rats*

We have confirmed the serum calcium-raising effect of adrenalectomy in young male rats 5-6 h after parathyroidectomy that was first observed by others many years ago. (The phenomenon has also been reported in cats, dogs, and mice.) In addition, we have shown that adrenalectomy raises the serum ionized calcium as well as total calcium and that the effect occurs in young female as well as in young male rats. Furthermore, we have found that the serum calcium-raising effect of adrenalectomy occurs if the adrenalectomy is performed several days before parathyroidectomy or 6 h after parathyroidectomy, as well as at the same time as the parathyroidectomy. When the rats were adrenalectomized 7-9 days before parathyroidectomy and given small daily life-maintaining doses of corticosterone or cortisone acetate, this glucocorticoid treatment did not reverse the adrenalectomy effect. This led us to think at first that the effect of adrenalectomy must be due to the loss of an unknown adrenal factor rather than to loss of glucocorticoid. Additional experiments, however, in which corticosterone or hydrocortisone was administered by continuous release pellets, demonstrated conclusively that a small continuous supply of corticosterone (within the physiological range as determined by immunoassay of plasma) was sufficient to reverse the adrenalectomy effect. The results with hydrocortisone were similar at even lower doses than of corticosterone. Somewhat higher doses of corticosterone or hydrocortisone reduced the serum calcium even below the parathyroidectomy level. In a preliminary investigation of the specificity of the glucocorticoid effect we found that aldosterone, dehydroepiandrosterone, or estradiol had no effect on serum calcium under similar conditions. We conclude that the fall in serum calcium after parathyroidectomy in rats is due in part to the hypocalcemic effect of endogenous corticosterone. Thus, the loss of corticosterone after adrenalectomy explains the serum calcium-raising effect of adrenalectomy in parathyroidectomized rats. These results also suggest that glucocorticoids at physiological levels have a significant effect on calcium metabolism in general.

Blindness in patients after external beam irradiation for pituitary adenomas: Two cases occurring after small daily fractional doses

Blindness in patients after external beam irradiation for pituitary adenomas: Two cases occurring after small daily fractional doses

Short term linear growth in asthmatic children during treatment with prednisolone.

To see whether small daily doses of prednisolone have any adverse effect on short term linear growth in children with mild asthma. Double blind, random order crossover trial of two dosages of prednisolone. During run in and washout periods patients were given placebo. All treatment periods were of two weeks' duration. Outpatient clinic referrals in a secondary referral centre. 14 Children (10 boys) aged 7-11 years with normal growth velocity during the previous year, no signs of puberty, and no history of receiving systemic or topical steroids during the two months before the study. One child was excluded because his pulmonary function deteriorated and another was withdrawn because of varicella. 2.5 and 5.0 mg prednisolone daily given in divided dosage in the morning and evening. Growth of the lower leg as measured twice a week by knemometry. A significant reduction in mean growth velocity of the lower leg occurred in both prednisolone treatment periods. The mean difference between the run in period and the treatment period with 2.5 mg prednisolone daily was 0.63 mm/week (95% confidence interval 0.47 to 0.80 mm/week) and between the run in period and the treatment period with 5.0 mg prednisolone daily 0.57 mm/week (0.38 to 0.77 mm/week). Small daily doses of prednisolone suppress short term linear growth in children with mild asthma. The clinical relevance of this finding needs further study.

The influence of dose interval on the immunosuppressive potency of methylprednisolone: an experimental organ transplant study in isogenous rats

Groups of isogenous Brown-Norway rats received heterotopic heart transplants from (Brown-Norway/Wistar Furth) x F1 hybrid rats. Methylprednisolone was administered IV in a daily dose of 5-40 mg/kg, using a dose interval of 24, 12, or 0 h (continuous infusion). Continuous infusion proved to be superior when small daily doses were used and then caused a more than threefold increase in graft survival. High daily doses created a substantial mortality with all dose intervals. Moreover, the equipment used for continuous drug administrations was unreliable beyond 4 weeks of infusion.

Recurrent nocturnal hypoglycemia in an insulin-dependent diabetic patient receiving a small daily dose of insulin

Recurrent nocturnal hypoglycemia in an insulin-dependent diabetic patient receiving a small daily dose of insulin

The influence of dose interval on the immunosuppressive potency of methylprednisolone: an experimental organ transplant study in isogenous rats

Groups of isogenous Brown-Norway rats received heterotopic heart transplants from (Brown-Norway/Wistar Furth) x F1 hybrid rats. Methylprednisolone was administered IV in a daily dose of 5-40 mg/kg, using a dose interval of 24, 12, or 0 h (continuous infusion). Continuous infusion proved to be superior when small daily doses were used and then caused a more than threefold increase in graft survival. High daily doses created a substantial mortality with all dose intervals. Moreover, the equipment used for continuous drug administrations was unreliable beyond 4 weeks of infusion.

Acute alterations in murine neuromuscular transmission following exposure to a nonparalytic dose of dithiobiuret

Treatment of rats for 5 to 6 days with dithiobiuret (DTB, 1 mg/kg/day, ip) causes a flaccid, ascending neuromuscular weakness which is associated with a decreased end-plate potential (EPP) amplitude, quantal content, miniature end-plate potential (MEPP) frequency, and prolongation of MEPP and EPP rise and decay times. Whereas small daily doses of DTB reliably cause this paresis, a single large dose, approximating the LD50, and far in excess of the cumulative dose given chronically to induce paralysis, causes no apparent muscle weakness. It was of interest to determine whether subtle changes in neuromuscular transmission are produced by DTB under dosing conditions in which gross muscle weakness is not apparent. As such the present study had two goals: first, to determine whether a single large dose of DTB (25 mg/kg, ip) altered neuromuscular transmission at times when the animal did not exhibit paresis; and second, to determine whether bath application of DTB, at concentrations approximating those in the animal following a single large dose, altered junctional transmission at early exposure times. EPPs and MEPPs were recorded, from hemidiaphragms taken 1, 4, 8, or 24 hr following treatment of rats with a single dose of DTB or vehicle or from untreated rats which were exposed to 200 μ m or 1.85 m m DTB by bath application. One hour after a single large dose of DTB, EPP amplitude and MEPP frequency and amplitude were all decreased. Rise and decay times for MEPPs were prolonged in muscles taken 4 hr after treatment. By 4, 8, and 24 hr after treatment, EPP amplitude, MEPP amplitude, and MEPP frequency returned toward control levels. Bath application of DTB initially increased EPP amplitude, MEPP amplitude, and MEPP frequency; however, with continued exposure EPP amplitude decreased to below control levels. Block of EPPs occurred after approximately 10 or 37 min of exposure to 1.85 m m or 200 μ m DTB, respectively. MEPP frequency also decreased with continued exposure to DTB, yet remained above control levels for the duration of DTB exposure. Bath application of DTB caused a slowing of decay times of MEPPs similar to that observed following in vivo exposure. These results demonstrate that a single large dose of DTB initially induces neuromuscular effects similar to those observed in rats paralyzed following chronic treatment with DTB but these effects, with the exception of effects on rise and decay times of synaptic potentials, tend to reverse by 24 hr following exposure. Bath exposure to high concentrations of DTB causes very early effects on transmission, some of which mimic those seen in the paralyzed rat. Thus, acute exposure to DTB causes transient deficits of neuromuscular transmission at times when muscle weakness is not yet observed at the level of the whole animal. These results correlate well with results of earlier studies demonstrating cumulative dose and latency thresholds for the onset of muscle weakness with DTB, possibly indicating that DTB levels must be maintained in the animal for a given period of time to allow the early effects observed here to progress to the more generalized muscle weakness observed with chronic dosing.

Effect of storage on tabletted microencapsulated aspirin granules

The antithrombotic effect of aspirin has been demonstrated through the use of small daily doses of the drug. Slow release formulations were shown to be adequate dosage form for this purpose. In this study, two sustained release formulations of aspirin were prepared and compared to plain aspirin tablets for their drug release and behavior upon storage at 40°C/90% relative humidity (R.H.). The polyacrylate-polymethacrylate based polymers were found suitable for the preparation of a sustained release aspirin product. The release characteristics of the drug were adequate to meet its antithrombotic effect. Storage-related changes observed in this study should help in better understanding and proper treatment of such formulations for the sake of obtaining more stable products with predictable uniform drug release.

Thrombocytopenia—A Rare But Potentially Serious Side Effect of Initial Daily and Interrupted Use of Rifampicin

Thrombocytopenia is occasionally caused by rifampicin, when high-doses are given twice-weekly. This complication is rare when the medication is given in small daily doses, or following a prolonged interruption of therapy. Two cases of rifampicin-induced thrombocytopenia are reported. One occurred within four days of the initiation of small daily doses and the other following a prolonged interruption of therapy.

Comparison of Once‐Daily Captopril or Enalapril in Mild Essential Hypertension

The purpose of this study was to assess the effect of a daily low dose of the angiotensin-converting enzyme (ACE) inhibitors, captopril or enalapril, in mild essential hypertension. Nine men with seated diastolic blood pressure between 95 and 104 mm Hg on placebo participated in the study. After one month of placebo, captopril 25 mg was administered; blood pressure, heart rate, ACE activity and plasma renin activity were measured hourly for 4 hours. Each patient then received captopril 50 mg once daily for 8 weeks and similar measurements were made 24 hours post-dose every 2 weeks. After another month of placebo, the identical protocol was repeated after enalapril 5 mg. Although blood pressure and ACE activity decreased significantly (P less than 0.05) within 2-4 hours of the acute doses of each inhibitor, neither captopril or enalapril produced significant reductions 24 hours after the small daily dose. Thus, neither ACE inhibitor alone was adequate to control blood pressure in mild hypertension when given once daily during 8 weeks of treatment.

Continuous intraventricular morphine- or peptide-infusion for intractable cancer pain.

The continuous intraventricular administration of small daily doses of morphine by means of an implantable pump is an effective method of obtaining considerable pain reduction for patients suffering from otherwise untractable carcinoma pain. We consider this method of treatment to be an excellent alternative to the epidural and intrathecal application. Particularly in cases with obstruction of the spinal canal or in cases suffering from untractable pain in the face, neck or upper thoracic area. During the period of treatment, none of the patients involved in the study developed tolerance to morphine or specific opiate side effects. The programmable pump allows precise dosage which is adjusted to the requirements of the individual patient. The high cost of a pump is a justifyable investment in patients in good general condition with a life expectancy longer than 3 months. In most cases the patient may be cared for at home, making further hospitalization unnecessary.

948 HYPERACTIVE PLATELETS ASSOCIATED WITH STROKE IN CHILDREN

We have investigated platelet activity in 13 children (mean age 11 yrs.) who had one or more episodes of unexplained stroke, with arteriograms revealing medium size arterial occlusions. Six children had no associated risk factors while 7/13 had one (migraine, hyperlipldemia, mitral valve prolapse, oral contraceptives). Platelet activity was assessed using electron microscopy (whole blood TEM platelet function test) and platelet aggregometry. The TEM platelet function test snowed platelet hyperactivity in 11 of 13 subjects, with a marked shift from round or abortive forms to spread forms and increase in spontaneous platelet aggregates. In contrast, platelet aggregometry using decreasing concentrations of ADP and epinephrine showed hypo or normo-responsiveness in the majority (11/13) of patients studied. This may reflect in vivo activated & ‘exhausted’ platelets being refractory to such agonists in vitro. Seven of 11 children with marked platelet hyperactivity who received small doses of aspirin and persantine had normalization of platelet activity and clinical improvement. We conclude there is a relationship between platelet hyperactivity and stroke in children. Aspirin in small daily doses (80 mg) may prove useful in preventing recurrent micro infarcts.

The paradoxes in patterns and mechanism of bone marrow regeneration after irradiation: 1. Different volumes and doses

Bone marrow regeneration (BMR) following irradiation has been largely studied as a dose-effect phenomenon, however, a large literature has simultaneously developed utilizing a wide variety of volumes, both in clinical studies and in experimental studies. In human situations radiation treatment fields and the amount of bone marrow organ exposed have ranged from total body irradiation (small daily and total doses) to large field (half-body) single high doses encompassing 50% of the bone marrow, to segmental or localized field (50-25%). Volume factors, more than dose, determine patterns of suppression and regeneration which have been documented by a variety of assay systems. Experimental evidence is presented which indicates that high dose irradiation (500-1000 cGy) to large volumes of bone marrow (50%) does not completely suppress bone marrow regeneration but results in a rapid compensatory response. The nadir response of bone marrow CFUc-GM stem cell compartment was directly proportional to increasing doses of irradiation (200-2000 cGy) delivered to a single limb. Immediate depression of CFUc-GM was followed by an increase proliferative phase with the most notable difference observed in doses less than or greater than 1000 rad. Following doses of 500 and 1000 rad to large field (half-body), an immediate depression was again observed followed by an immediate and greater compensatory response particularly after the 1000 rad dose. Comparisons ae made between the small and larger volumes at similar doses and indicate a greater overall compensatory response after the larger field irradiation, being more rapid in onset particularly after the 1000 rad dose. Although in-field regeneration of bone marrow occurs after single dose radiation to different volumes of bone marrow, experimental and clinical evidence from protracted conventional doses of irradiation to different volumes of bone marrow (greater or less than 50%) indicate significantly different response mechanisms. From our laboratory and clinical investigations it can be determined that bone marrow is extremely sensitive to radiation insult and has different compensatory mechanisms to "fine tune" its response in proportion to the volume insulted.

Periodicity of chronic ethanol administration as a variable in the induction of dependence in rats

The effect of periodicity of chronic ethanol intragastric administrations on the induction of physical and behavioral dependence on ethanol has been assessed in two groups of rats. In the two groups, rats initially selected for an identical sensitivity to ethanol, were administered daily 10 g per kg b.w. during 15 days. In one group, this daily dose was administered in six intragastric pulses of 1.7 g/kg each, 3 hours apart. In the other group, the same 10 g/kg daily dose was administered in three pulses of 3.33 g/kg, 6 hours apart. In control rats determinations of blood ethanol level in these two treatment conditions showed that the daily area of blood alcohol was 2.5 times higher in the first condition than in the second one. After the 15 days of chronic forced administration, experimental rats were subjected during 6 days to an alternate eight hours single bottle presentation of 10% ethanol solution and water. In this final test of the induced behavioral dependence, rats chronically treated by small frequent doses, displayed the highest intake of ethanol solution versus water. It is concluded that periodicity of a chronic administration or intake of ethanol is an important parameter in the induction of dependence, and the frequent administration of a small daily dose distributed in higher and less frequent unitary administrations.

Changes in Aerobic Pharyngeal Flora Related to Parenteral Ampicillin with Particular Reference to the Emergence of Gram‐Negative Bacilli

AbstractThe pharyngeal flora was evaluated semiquantitatively by differentiating the grown colonies on blood agar plates, in 7 patients undergoing intravenous ampicillin treatment.Intravenous ampicillin in larger daily doses of 200 to 300 mg/kg caused marked changes that eradicated α‐streptococci in most cases, and gram‐negative bacilli appeared in 13 out of 14 cultures with high prevalences. Changes observed by smaller daily doses were less extensive, which indicated a does reponse reltionship. Staphylococcus aureus was isolated with high prevalences in 3 of the total of 12 cultures in the course of ampicillin.Since these changes denote suppression of the normal flora and overgrowth af ampicillin‐resistant organisms in the respiratiory tract, which potentiate the development of supernifection, expected advantages must be weighed against these undesired effects, particularly when ampicillin is prescribed for long periods and larger doses. Culture of the pharyngeal swab would be a useful guide for the check of the bacterial overgrowth.