Could Amifostine Prevent Experimental Radiotherapy-Induced Acute Pericarditis?

BACKGROUND: Amifostine is a powerful antioxidant that is one of the documented three chemo-radio prototectants recommended for clinical use. There is no data exploring amifostine in prevention of acute pericardial damage. We aimed to investigate whether amifostine has protective effect against acute pericardial injury due to radiotherapy in an experimental rat model. METHODS: Twenty-four rats were divided into four groups: control group, radiotherapy-only group, amifostine-only group, radiotherapy+amifostine group. In groups receiving radiotherapy, hearts were irradiated with a Co 60 teletherapy device at a distance of 80 cm and 20 Gy at a depth of 2 cm. Thirty minutes before interventions, 200 mg/kg amifostine or same volume 0.9% NaCl were administered intraperitoneally. Subjects were sacrificed 24 hours after the procedure. Pericardial histopathological changes were investigated by light microscopy. RESULTS: There was focal inflammation of >= 50% in all rats exposed-to-radiotherapy. All groups receiving radiotherapy revealed a significant increase in pericardial inflammation compared to the groups that did not receive irradiation (p<0.05). There was no difference between the radiotherapy-only group and amifostine+radiotherapy group for pericardial inflammatory response (p>0.05). CONCLUSION: Acute pericarditis was detected in all rats receiving radiotherapy. There was no positive effect of amifostine administration before radiotherapy on acute pericardial inflammation.

The histopathologic, pharmacologic and urodynamic results of mesenchymal stem cell's injection into the decompensated rabbit's bladder.

OBJECTIVES: We researched the survival of bone marrow-derived mesenchymal stem cells (MSCs) and the results of MSCs' injected into decompensated bladders in a rabbit model. METHODS: Partial bladder neck obstruction (PBNO) and subsequent decompensation of the bladder was achieved by wrapping the bladder neck with autologous rectus fascia. In the first aspect of the experiment 18 rabbits underwent MSC injection into the decompensated bladder to prove the survivability of injected MSCs. For this purpose MSCs were isolated, transfected with Green Fluorescent Protein (GFP), and injected into the detrusor layer. Once viability was assessed in the first phase, an additional 10 rabbits underwent PBNO in the second phase. Five of these animals underwent subsequent MSC injection (group 3, stem cell) and 5 did not (group 2, obstruction). Both groups were compared to 5 controls (group 1). Urodynamics were performed in all groups. After the animals were sacrificed the groups were compared via morphometric analysis, contractile response to carbachol and KCl, and muscarinic receptor type analysis. RESULTS: On morphometric analysis, collagenous area rates were 43, 53 and 37% in group 1, 2 and 3, respectively. There was no statistically significant difference between groups in terms of bladder weight, bladder capacity and vesical pressure. The contractile effects of KCl and muscarinic agonist carbachol were significantly higher in groups 1 and 3 than group 2. The response to carbachol was antagonized by muscarinic M(1) and M(3) receptor antagonist pirenzepine and abolished by muscarinic M(3) receptor antagonist 4-DAMP in all groups. CONCLUSIONS: The injection of MSCs decreased the collagenous area, increased detrusor contractility. Functional M(3) receptors were also expressed in MSCs-injected bladder smooth muscle as well as in control group.

Vasorelaxant effect of a self-etch adhesive system through calcium antagonistic action.

Etch-and-rinse adhesives can cause vasorelaxation via mechanisms occurring in the endothelium and smooth muscle, including the release of nitric oxide (NO). This effect might promote or aggravate bleeding if such adhesives are placed inadvertently on iatrogenic pulp microexposures. The present study assessed the vasoactive potential of a newer generation self-etch adhesive, Clearfil Protect Bond (CPB), on isolated rat aorta. Cumulative concentrations of the primer, bond, and mixture of CPB elicited concentration-dependent relaxation of phenylephrine-induced active tonus in the rat aorta, demonstrating that the tested self-etch adhesive can lead to vasorelaxation of pulp vessels that is mediated by Ca(2+) antagonistic effect. The vasorelaxant effect of CPB or its components was mediated neither via endothelium-dependent NO and prostanoid-dependent mechanisms nor by K(+) efflux through K(+) channels. Mechanical removal of the endothelium did not significantly alter the relaxation induced by CPB. Assuming these data can be extrapolated to the clinical situation, CPB, either in mixed form or by its components, can lead to vasorelaxation of pulp vessels that is mediated by a Ca(2+) antagonistic effect. If CPB is placed inadvertently on pulp microexposures during direct pulp capping, this effect might promote bleeding that might impair healing and, via plasma exatravasation, might compromise resin infiltration and polymerization.

The concentration-dependent contractile effect of methylene blue in the human internal mammary artery: a quantitative approach to its use in the vasoplegic syndrome.

OBJECTIVE: To quantitate the contractile effect of methylene blue on isolated human internal mammary artery (IMA) as used in the vasoplegic syndrome. DESIGN: An in vitro experimental study. SETTING: Cardiovascular Pharmacology Laboratory, Department of Medical Pharmacology. PARTICIPANTS: IMA segments were used from 24 patients undergoing coronary artery bypass surgery. INTERVENTIONS: The responses to methylene blue, norepinephrine, and acetylcholine were recorded isometrically by a force-displacement transducer in an isolated organ bath. MEASUREMENT AND MAIN RESULTS: Methylene blue (10 nmol/L-100 micromol/L) produced concentration-dependent contraction in the arteries. The maximal contraction to methylene blue was 44.2% +/- 3.8% of KCl (68 mmol/L) maximum contraction; the pEC(50) (-log(10) of 50% effective concentration) value was 5.5 +/- 0.1. Methylene blue caused an insignificant leftward shift of the concentration-response curve of norepinephrine. Acetylcholine-induced relaxation in submaximal contracted rings with phenylephrine recovered nearly 6 hours after the methylene blue challenge. CONCLUSION: Methylene blue caused concentration-dependent contraction in human IMAs. Furthermore, the inhibition of ACh-induced relaxation for 6 hours after the methylene blue challenge points out an additional mechanism (ie, receptor occupation). The concentration-dependent contractile effect of methylene blue justifies its use in the vasoplegic syndrome. The findings also suggest that the time course of contraction is longer than the exposure to methylene blue.

The vasodilator effect of testosterone on the human internal spermatic vein and its relation to varicocele grade.

PURPOSE: Several animal and human studies in vivo and in vitro indicate that testosterone has vasodilatory effects on different vessels. However, the effect of testosterone on the internal spermatic vein is not clear. In addition, the role of testosterone in the pathophysiology of varicocele is not established. We investigated the effect of testosterone on the internal spermatic vein in vitro in patients with varicocele and analyzed its relation to varicocele grade. MATERIALS AND METHODS: Isolated internal spermatic veins were collected from patients who underwent varicocelectomy and orchiectomy. The preparations (3 to 4 mm rings) were mounted in an organ bath containing 10 ml Krebs-Henseleit solution on an L-shaped brace for tension measurement along the former circumferential axis. Changes in venous tension in the presence of testosterone (0.1 to 300 microM) were recorded isometrically by a force displacement transducer. RESULTS: Cumulative concentrations of testosterone (0.1 to 300 microM) elicited concentration dependent relaxation of 45 mM KCl induced active tone in the internal spermatic vein (mean +/- SEM 60.97% +/- 5.05% of the KCl induced contraction). Relaxation to testosterone (1 to 300 microM) was significantly higher in 5 cases of grades 0 and 1 varicocele than in 15 of grades 2 and 3 varicocele (maximum relaxation response 78.58% +/- 8.25% vs 55.10% +/- 5.3% of the KCl induced contraction). CONCLUSIONS: To our knowledge the current report is the first to describe testosterone induced relaxation of the human internal spermatic vein. The vasodilatory effect of testosterone on the human internal spermatic vein decreases in high grade varicoceles.

Antinociceptive effects of fluoxetine and paroxetine with their related actions on glycemia in mice.

OBJECTIVES: Clinical and experimental trials have demonstrated that some of selective serotonin reuptake inhibitors (SSRIs) have some suspicious effects on blood glucose levels in different directions. Especially fluoxetine and sertraline are studied in this point of view. These drugs are also used in treatment of depression and peripheral neuropathy in diabetic patients. Paroxetine and fluoxetine, members of this drug group, besides having antidepressant effects were shown to have antinociceptive effects in animals and humans. They can be used in the treatment of chronic pain as an adjuvant drug or alone. But less is known about their actions on pain in case of diabetes. The aim of this study is to investigate the antinociceptive effects of fluoxetine and paroxetine in diabetic and non-diabetic mice while monitoring their effects on blood glucose levels. METHODS: Mice of either sex were randomly used in experiments. The antinociceptive effects of paroxetine and fluoxetine were evaluated using hot plate test both in diabetic and non-diabetic mice. The effects of these drugs on blood glucose levels were also evaluated in another group of mice both in diabetic and non-diabetic mice. RESULTS: Fluoxetine and paroxetine showed significant antinociceptive effect at all doses and at all times tested in non-diabetic mice, but they could not successfully show this effect in diabetic mice. They also had controversial effects on blood glucose levels. CONCLUSION: Although they showed increasing or decreasing effects on blood glucose levels in non-diabetic and diabetic mice, they showed antinociception on hot-plate test showing dissociation between blood glucose levels and analgesia.

Acute alterations in biochemistry, morphology and contractility of rat isolated urinary bladder via increased intra-abdominal pressure.

OBJECTIVE: To determine the acute effects of increased intra-abdominal pressure (IAP) on the biochemistry, morphology and contractility of the rat isolated urinary bladder using an experimental laparoscopy model. METHODS: We divided 24 adult female Sprague-Dawley rats into three groups. The control group (group I) was not subjected to increased IAP. In groups II and III, IAPs of 10 and 20 mm Hg, respectively, were established by carbon dioxide pneumoperitoneum for 60 min. Thirty minutes after desufflation, the rat urinary bladder dome was removed for in vitro pharmacological investigation, measurement of malondialdehyde (MDA) levels and histopathological examination. Statistical comparisons between groups were performed. RESULTS: Tissue MDA levels in groups II and III were significantly higher than in the control group. In group II, only the lamina propria was significantly damaged. However, the epithelium, lamina propria, and serosa were significantly damaged in group III. Acetylcholine potentiated contractions in both IAP groups. Increased responses to electrical field stimulation in the IAP groups were significant only in group II. CONCLUSIONS: In this experimental model, 10 and 20 mm Hg of IAP induced by pneumoperitoneum increased MDA levels and caused important changes in the morphology and contractile response of the urinary bladder.

Effect of gender on antinociceptive effect of paroxetine in hot plate test in mice.

PURPOSE: Many studies have reported both a gender difference in the rates of depression and its treatment by using any of the widely used antidepressant drug groups. Some studies suggest that females respond more poorly to tricyclic antidepressants than males and appear to respond better to selective serotonin reuptake inhibitors (SSRI). There is no study investigating the analgesic/antinociceptive effects of antidepressant drugs on the basis of gender difference. In this study, we aimed to investigate the antinociceptive effect of paroxetine on the basis of gender difference. METHODS: The antinociceptive effect of paroxetine was tested using hot plate test in Balb/c mice (30-40 g). The animals were divided into eight groups on the basis of gender. FINDINGS: While paroxetine did not induce an antinociceptive effect in both sex at a dose of 1 mg kg(-1), it showed significant antinociceptive effects in both sex at a dose of 5 or 10 mg kg(-1). None of the doses of paroxetine revealed a gender difference in its antinociceptive action. CONCLUSION: There are several studies showing positive or negative evidence on the gender difference of paroxetine's antidepressant effect, but in the literature there is no study about the gender difference of paroxetine's or any other SSRI drug's antinociceptive effect. In conclusion, our results do not show any gender difference in antinociceptive effect of paroxetine that may be important especially when it would be used as an adjuvant agent in some painful conditions.

The acute alterations in biochemistry, morphology, and contractility of rat-isolated terminal ileum via increased intra-abdominal pressure.

AIM AND SCOPE: To determine the acute effects of increased intra-abdominal pressure (IAP) on the biochemistry, morphology, and contractility of the isolated terminal ileum of rats. BACKGROUND: Laparoscopic procedures are used clinically in diagnostic and treatment modalities and experimentally as a model of ischemia-reperfusion injury induced by the elevation of IAP. Although some clinical and in vivo experimental studies investigate the results of ischemia-reperfusion injury whether induced by elevated IAP or clamping, there is no in vitro study that has investigated the acute effects of high IAP mimicked by a laparoscopic intervention in any of the intra-abdominal organs (like terminal ileum) on the basis of contractility which represents the motility. METHODS: Twenty-four adult with either sex Sprague-Dawley rats were divided into three groups. The control group (Group I) was not subjected to any IAP. In Groups II and III, an IAP of 10 and 20 mmHg, respectively, was established by carbon dioxide pneumoperitoneum for a period of 60 min. Thirty minutes after the desufflation, the terminal ileum was removed for in vitro pharmacological investigation, measurement of malondialdehyde (MDA) values, and histopathological examination. Statistical comparisons among groups were done using the Kruskal-Wallis variance analysis, with post hoc comparison performed with the Mann-Whitney U-test. RESULTS: Tissue MDA value and the damage scores of mucosa and submucosa were significantly increased in both IAP groups. The smooth muscle layer was significantly damaged only in Group III. The contractions obtained by electrical field stimulation (EFS) were inhibited in both IAP groups, and the contractions to acetylcholine were inhibited in Group III when compared to the control group. CONCLUSIONS: In conclusion, we can say that pneumoperitoneum induced IAP may inhibit contractile responses, cause structural alterations which may be related to ischemia-reperfusion injury in rat terminal ileum.

The contracting and relaxing responses of human internal mammary artery grafts harvested by two different methods.

Perioperative spasm of internal mammary artery is a common experience in coronary artery bypass grafting. Many techniques were described of harvesting the internal mammary artery to prevent vasospasm. We investigated the comparison of the contracting and relaxing responses of human internal mammary artery grafts harvested by two different methods. Patients were divided into two groups depending on the harvesting technique. In the first and second groups arteries were harvested by classical and carbon dioxide insufflation techniques, respectively. In both groups, endothelial function of arteries was assessed by precontracting the rings with phenylephrine (10(-5)M) and dilatating them by cumulative acetylcholine (10(-8) to 10(-5)M) concentrations. Cumulative concentration-response curves for phenylephrine (10(-8) to 10(-4)M), noradrenaline (10(-9) to 10(-4)M), and 5-hydroxytryptamine (10(-9) to 10(-4)M) were obtained in all groups. Endothelial integrity of arteries were histopathologically evaluated. In both groups, acetylcholine caused concentration-dependent relaxations in rings precontracted with phenylephrine (10(-5)M). In arteries harvested by carbon dioxide insufflation technique, acetylcholine caused significantly higher relaxations compared to the rings obtained by classical technique (p<0.05). In all rings of study groups, phenylephrine, noradrenaline and 5-hydroxytryptamine caused concentration-dependent contractions. There was not any significant difference in concentration-dependent responses of these contracting pharmacological agents between the groups. Histopathological evaluation revealed no major arterial damage in both groups. Carbon dioxide insufflation technique does seem not only to protect the integrity of the endothelium and the whole vessel, but also prevent the possible vasospasm of the internal mammary artery segments.

A case of rosiglitazone exposure in the second trimester of pregnancy.

AIM: Data about rosiglitazone use in pregnancy is limited. We aimed to present a pregnant woman who exposed to rosiglitazone in the second trimester and the fetal outcome. SUBJECT: The case was a 42-year-old, multigravid Caucasian woman with a history of diabetes mellitus type II for 4 years prior to her current pregnancy. Her diabetes was managed by diet and exercise and she has not received any drug therapy until the 13th week of her sixth (present) and unplanned pregnancy. The case was exposed to rosiglitazone (4 mg/day) between 13th and 17th gestational weeks. After the diagnosis of pregnancy at the 17th week, rosiglitazone was stopped and insulin therapy was started. At the 37th week, she had a healthy male infant (4500 g, 50 cm). The baby was examined and no major or minor malformations were observed. CONCLUSION: This is the first case present in the literature exposed to rosiglitazone in the second trimester of her pregnancy. The data from the present case may contribute to the existing limited knowledge about rosiglitazone in pregnancy.

Psychotropic drugs in pregnancy: a case-control study.

Psychotropic drug exposure during pregnancy is a common problem. Among the 601 cases exposed to drugs during pregnancy, who were followed by our Toxicology Information and Follow-up Service, 124 cases had used psychotropic drugs for depression, anxiety, or psychotic disorders. As the control group, 248 women, who did not use any drugs were selected. Of the 124 cases, 80 (64.5%) had healthy babies, and 17 (13.7%) decided to terminate the pregnancy. Spontaneous abortions, intrauterine death (in the 38th week) and premature deliveries were observed in the 9 (7.3%), 1 (0.8%) and 3 (2.4%) cases, respectively, in the drug exposure group. Pregnancies of the 14 (11.3%) cases were continuing during the preparation of this manuscript. Of the 248 controls, 151 (60.9%) had healthy babies, 9 (3.6%) experienced spontaneous abortion and 3 (1.2%) decided to terminate their pregnancies, 3 (1.2%) had premature deliveries, and we observed one (0.4%) congenital abnormality, 81 (32.7%) cases were still pregnant. Odds Ratio (95% confidence interval) for spontaneous abortion was found to be 1.35 (1.27-11.82) in the cases exposed to psychotropic drugs (P=0.02). No developmental problems were observed in the babies followed for 12 months. These data may give information about the early- but not the late-term effects of psychotropic drugs used in pregnant women.

Newer antidepressants in pregnancy: prospective outcome of a case series.

Antidepressant drug choice in pregnancy is a complex problem especially for new drugs. Among 590 cases exposed to drugs during pregnancy who were followed by our center, 21 cases used newer antidepressants, i.e., venlafaxine, mirtazapine, nefazodone. We present the gestational findings and fetal outcomes of these cases. Ten cases had used venlafaxine, one case had used both venlafaxine and mirtazapine, eight had used mirtazapine alone or with some other drugs and two had used nefazodone, in the first trimester. Of the 21 cases, 17 (80.9%) had healthy babies, 3 (14.3%) decided to terminate the pregnancy, and 1 (4.8%) spontaneous abortion was observed in a case exposed to mirtazapine, alprazolam, diazepam and trifluoperazine. All obstetrical findings were normal during the pregnancy of each case. No congenital abnormality and developmental problem was observed in the babies followed up for 12 months. The aim of the present study is to contribute the data to the limited knowledge available in the literature regarding human pregnancy.

Sibutramine use in pregnancy: report of two cases.

BACKGROUND: Sibutramine is a drug used for the medical treatment of obesity. No data are available on sibutramine use in pregnancy. We report the fetal outcomes of two pregnant women exposed to sibutramine. CASES: The first woman was exposed to 10 mg/day of sibutramine during gestational weeks 4-6. The second woman was exposed to 10 mg/day of sibutramine during gestational weeks 5-8. At weeks 37 and 39, they delivered healthy infants. CONCLUSIONS: To our knowledge, this is the first report of sibutramine exposure in pregnancy. These cases may contribute to the knowledge about sibutramine use during pregnancy.

Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman.

The subject is a diabetic and hypertensive woman treated early during an unplanned pregnancy with a multi-drug regimen that included three drugs with no prior history for use in pregnant women (rosiglitazone, gliclazide, atorvastatin). She was under care for chronic hypertension, which she suffered for 14 years, and diabetes mellitus, hypercholesterolemia, anxiety disorder, morbid obesity and epilepsia for 5 years. She was exposed to rosiglitazone (4mg/day), gliclazide (60mg/day), and atorvastatin (40mg/day) in addition to acarbose, spironolactone, hydrochlorothiazide, carbamazepine, thioridazine, amitryptiline, chlordiazepoxide, and pipenzolate bromide during the first 7 weeks of gestation while unaware of pregnancy. Pharmacotherapy was adjusted following clinical recognition of pregnancy during the 8th week. She gave birth to a normal healthy infant at the 36th week of gestation. This is the first reported case of human exposure to rosiglitazone, gliclazide, and atorvastatin during pregnancy. Although the normal pregnancy outcome does not address the safety of these drugs for use in pregnancy, these data contribute to a limited knowledge regarding human exposure to these antidiabetic drugs.

Use of polypharmacotherapy in pregnancy: a prospective outcome in a case.

PURPOSE: Little is known about the risks associated with prenatal exposure to atypical antipsychotics. Our objective is to present a case of exposure to risperidone and quetiapine in pregnancy, and additionally to some other drugs. CASE: Our case (36-year old) has suffered schizophrenia (DSM-IV) for 5 years and used these drugs (risperidone, quetiapine, mirtazapine, thioridazine, diazepam, hydroxyzine, clomipramine, fluvoxamine, alprazolam, carbamazepine, biperiden, haloperidol, ampicillin+sulbactam, enoxaparin, oxerutine) in her third pregnancy. Because of her psychotic condition, Mrs. N.B. was not aware of her pregnancy until 22nd week and the pregnancy could not be terminated. She had a female infant (3000 g, 50 cm) with APGAR scores of 8-9 at the first and fifth minutes at 37th week with an uncomplicated vaginal delivery. The baby was normal. CONCLUSION: This case may contribute to the existing knowledge regarding use of atypical antipsychotics in pregnancy.

Paroxetine alters KCl- or ATP-induced contractile responses of isolated vas deferens in rats chronically treated with ethanol.

Chronic ethanol administration affects many organ systems, including sexual organs. One of these organs is the vas deferens whose contractility can also be altered by selective serotonin re-uptake inhibitors (SSRIs). The aim of the present study, is to evaluate whether paroxetine (PX), a SSRI, can modify the contractile responses of isolated vas deferens obtained from rats chronically treated with ethanol to the contractile agents, potassium chloride (KCl) and adenosine triphosphate (ATP). For 21 days, alcohol was applied with a modified liquid diet to sexually mature male Sprague-Dawley rats (200-240 g). The vas deferens of the rats were excised at the end of day 21 and suspended in the organ baths by classical pharmacological methods. The responses to contractile agents tested were decreased by chronic ethanol treatment in all groups compared to their untreated matches. PX (10(-7) and 10(-6)M) potentiated the contractions to KCl (20-180 mM) and ATP (10(-6) to 10(-3)M) in epididymal portion but its higher concentrations (10(-5) and 10(-4)M) inhibited the responses, both in the control and chronically ethanol treated rat groups. Prazosin (PR), an alpha adrenergic receptor blocker, could not inhibit PX-induced potentiation in lower concentrations of KCl but could inhibit the potentiation occurred at higher concentrations of KCl in epididymal portion both in the control and chronically ethanol treated rat groups. PR also inhibited PX-induced potentiation on the responses to ATP in epididymal portion both in the control and chronically ethanol treated rat groups. In conclusion, all the results obtained in this study, suggest that chronic ethanol treatment decreased the contractility of vas deferens but did not alter the action pattern of PX on responses to KCl and ATP in rat vas deferens. On the other hand, the potentiation of responses to contractile agents induced by PX can be partially considered as the result of inhibition of noradrenaline re-uptake.

Protective effect of melatonin against fractionated irradiation-induced epiphyseal injury in a weanling rat model.

The effects of melatonin, a free-radical scavenger and a general antioxidant, on radiation-induced growth plate injury have not been studied previously. The purpose of this study was to determine the potential benefits of sparing longitudinal bone growth by fractionated radiotherapy alone compared with pretreatment with melatonin that provides differential radioprotection of normal cells. Weanling 4-wk-old (75-100 g) male Sprague-Dawley rats were randomly assigned to one of three groups: Group R received fractionated radiation alone (n = 8); groups M5 (n = 8) and M15 (n = 7) received 5 or 15 mg/kg melatonin prior to fractionated radiation, respectively. The distal femur and proximal tibia in the right leg of each animal were exposed to a therapeutic X-irradiation dose (25 Gy total in three fractions) with the contralateral left leg as the non-irradiated control. Melatonin was administered intraperitoneally to the animals 30 min before radiation exposure. Six weeks after treatment, the rats were killed and the lower limbs disarticulated, skeletonized, radiographed, and bone growth was calculated based on measurement of the bone lengths. Fractionated radiation resulted in a mean percent overall limb growth loss of 41.2 +/- 9.5 and a mean percent overall limb discrepancy of 11.2 +/- 2.2. The administration of 5 or 15 mg/kg melatonin before each of the three fractions of radiotherapy reduced the mean percent overall limb growth loss to 33.9 +/- 5.8 and 32.2 +/- 4.5, respectively, and the mean percent overall limb discrepancy to 9.4 +/- 1.6 and 8.9 +/- 1.1, respectively; these values were significantly different compared with irradiation alone (range: P = 0.01-0.04). When compared with Group R, the growth arrest recovered by 5 or 15 mg/kg melatonin was 19.7 and 24.1% for the tibia, 7 and 18.6% for the femur, and 17.7 and 21.8% for the total limb, respectively. These results support further investigation of melatonin in combination with fractionation for potential use in growing children requiring radiotherapy to the extremity for malignant tumors.