Comparison of antiemetic efficacy between single and repeat treatment with dexamethasone in patients receiving carboplatin-based combination chemotherapy.

A retrospective study was carried out to compare the preventive effects of single and repeat treatment with dexamethasone (DEX) on delayed nausea and emesis in patients who had received carboplatin (CBDCA)-based combination chemotherapy. Sixty-four patients were evaluated. Efficacy was assessed using the nausea and emesis score, food intake score and the requirement for antiemetic medication. These forward scores were categorized as three-grade during the first 5 days after chemotherapy. Acute nausea and emesis were well controlled in both groups on day 1. Mean values of the nausea and emesis score on day 3 evening and the food intake score on day 4 morning in the repeat-treatment group was 1.31 ± 0.93 and 3.46 ± 1.03, respectively, which were significantly better when compared with the single-treatment group (2.00 ± 1.52; P = 0.028 and 2.79 ± 1.12; P = 0.018, respectively). Multivariate logistic regression analysis revealed that less frequent dispensing of antiemetic medication was significantly associated with the repeat-treatment group (adjusted odds ratio, 0.153; 95% confidence interval, 0.026-0.734; P = 0.018). These results suggest that repeat-dose DEX may be more effective than single-dose DEX for the prevention of delayed nausea and emesis after CBDCA-based combination chemotherapy.

Behavioral pharmacological properties after recovery from the loss of righting reflex induced by benzodiazepine receptor agonists in mice.

In this study we examined the behavioral pharmacological side effects after recovery from the loss of righting reflex induced by three benzodiazepine receptor agonists - zolpidem, brotizolam and flunitrazepam - in ddY mice. All agents caused marked motor incoordination in the rotarod test and muscle flaccidity in the traction test until 15 min after recovery of righting reflex. Thereafter, the short-acting hypnotics zolpidem and brotizolam showed a faster recovery than the long-acting benzodiazepine flunitrazepam. However, head twitch responses were observed in the mice treated with flunitrazepam, but zolpidem and brotizolam had no such effect. The flunitrazepam-induced head twitch response was antagonized by ketanserin, a 5- HT(2A) receptor antagonist. These results indicate that flunitrazepam, a long-acting benzodiazepine that is nonselective for type I and II benzodiazepine receptors, induces head twitch responses with muscle flaccidity after recovery from the loss of righting reflex caused by these drugs. In addition, these findings suggest the involvement of a 5-HT(2A)-GABA(A) receptor/benzodiazepine interaction in this phenomenon.

Topical application of royal jelly has a healing effect for 5-fluorouracil-induced experimental oral mucositis in hamsters.

The aim of this study was to evaluate the effects of bee products such as honey, royal jelly and propolis on 5-fluorouracil-induced experimental oral mucositis in hamsters. Oral mucositis was induced in hamsters through a combination of 5-fluorouracil and mild abrasions that were made on the cheek pouch. Honey, royal jelly and propolis were thereafter topically administered to the oral mucosa, and then the healing process was examined by measuring the size of the mucositis. Honey (1%, 10% and 100%) and propolis (0.3%, 1% and 3%) ointments did not reduce the size of the mucositis in comparison to the vaseline-treated control group. However, the royal jelly (3%, 10% and 30%) ointments significantly improved the recovery from 5-fluorouracil-induced damage in a dose-dependent manner. These results suggest the possibility that the topical application of royal jelly has a healing effect on severe oral mucositis induced by chemotherapy.

Evaluation of the clinical application of cystatin C, a new marker of the glomerular filtration rate, for the initial dose-setting of arbekacin.

OBJECTIVE: Recent studies have shown that serum cystatin C is a better marker for measuring the glomerular filtration rate (GFR) than the conventional method, using serum creatinine concentration. The purpose of this study is to evaluate the clinical application of serum cystatin C as a marker of GFR to determine the initial dosage of arbekacin, an antibiotic primarily excreted via the kidneys. In this study, the predictability of serum arbekacin peak and trough concentrations were assessed using estimated population mean GFR values calculated from either serum creatinine (Cockcroft-Gault equation) or cystatin C (Sjöström equation) concentrations. METHOD: Ninety-five patients treated with arbekacin for methicillin-resistant Staphylococcus aureus infection were divided into three groups according to their GFR values estimated by the serum cystatin C concentration as follows: normal to mild (GFR > 70 mL/min, n = 40), moderate (30

Hoek's formula, a cystatin C-based prediction formula for determining the glomerular filtration rate, is the most effective method for original adjusting the dosage of vancomycin.

OBJECTIVE: Some formulas using the serum cystatin C level to estimate the GFR have recently been reported. However, there has been no report of a serum cystatin C-based formula for adjusting the dosage of the drugs cleared by the kidney. In this study, we compared the predictive performance of the serum vancomycin trough concentration predicted using serum cystatin C-based formulas. METHOD: The data were collected from 158 hospitalized patients. Five formulas have been published to predict the GFR using serum cystatin C. The cystatin C-based formulas were divided into two groups, formulas with or without anthropometric data. We predicted the serum vancomycin trough concentrations using VCM-TDM S_edition ver. 1.00 software. RESULTS: In formulas with anthropometric data, the mean absolute error (MAE) using Hoek's formula was 2.38, the MAE using Grubb's 1 formula was 4.13, the MAE using Sjöström's formula was 2.90, and the MAE using Cockcroft and Gault formula based on creatinine was 4.42. On the other hand, in formulas without an anthropometric data group, the MAE using Larsson's formula was 3.07, and the MAE using Grubb's 2 formula was 3.63. CONCLUSION: These results suggested that Hoek's formula is the most useful formula for determining the initial dosage settings for vancomycin.

Changes in the plasma diazepam concentration and its anticonvulsant effect after the discharge of a diazepam suppository from the rectum in rats.

One of the clinical problems regarding the use of suppositories for patients is the discharge of the medication itself after the insertion of the suppository. The effects of the discharge of diazepam (DZP) suppositories from the rectum on the plasma DZP concentration and its anticonvulsant action were investigated in rats. The plasma DZP concentration reached a maximum at approx. 30 min after the rectal administration of a 5 mg/kg DZP suppository. The discharge of the DZP suppository from the rectum at 5 or 10 min after rectal administration significantly reduced the plasma DZP concentration and the anticonvulsant action of the DZP suppository against pentylenetetrazol-induced seizures. However, when the suppository was discharged from the rectum after 20 min, the plasma DZP concentration and the anticonvulsant action were only slightly but not significantly decreased. These results suggest that the discharge of the DZP suppository in the early phase, within 20 min, decreases the plasma concentration and the anticonvulsant action of the DZP suppository in rats. Therefore, when the suppository is discharged from the rectum immediately, sufficient observation and proper treatment are necessary.

[Assessment of anti-tremorogenic drugs using nicotine-induced tail-tremor model and elucidation of the mechanism].

Repeated administration of nicotine causes a tremor only in the tail (tail-tremor) of rats. The tremor is accompanied with locomotor hyperactivity without rigidity and immobility of the whole body, suggesting the involvement of the mechanism associated with the movement. The tail-tremor induced by nicotine was suppressed by nicotinic acethylcholine (nACh) receptor antagonists, but not by muscarinic acethylcholine (mACh) receptor antagonists. Moreover, the tail-tremor was suppressed by beta-adrenoceptor antagonists and benzodizepines. The tremor at rest is observed only in Parkinson's disease, which is improved by the use of mACh receptor antagonists. An essential tremor is one of the typical tremor connected with the movement (postural tremor) and improved with beta-adrenoceptor antagonists. These findings and results suggest that the nicotine-induced tail-tremor is useful for the study of the essential tremor as an animal model. On the other hand, daily administration of nicotine resulted in an augmentation of the tail-tremor. The development of the tail-tremor was suppressed by nACh receptor antagonists, N-methyl-D-aspartate (NMDA) receptor antagonists and nitric oxide (NO) synthase inhibitors. These results suggest that central nACh receptors are essential for the onset and further development of the tail-tremor induced by repeated administration of nicotine, and that NO formation mediated by NMDA receptors is involved in the developmental mechanisms.

Effect of immobilization stress on anticonvulsant actions and pharmacokinetics of zonisamide in mice.

The effects of immobilization stress on anticonvulsant actions and pharmacokinetics of zonisamide were investigated in mice. Oral administrations of zonisamide (10, 20, and 50 mg/kg) dose-dependently reduced incidence of tonic extension (TE) induced by maximal electroshock seizure (MES). Immobilization stress for 2 h immediately after the administration of zonisamide further enhanced the anticonvulsive actions of it. On the other hand, the serum zonisamide concentrations in stressed group were lower during the first 30 min after the administration compared with that in nonstressed control group. Thereafter, there were no significant differences in the serum concentrations between two groups. The brain zonisamide concentration and the concentration ratio of brain/serum at 2 h after administration of zonisamide (50 mg/kg) were significantly higher in stressed group, rather than that in the nonstressed control group without changing the serum concentration. These results suggest that immobilization stress enhances anticonvulsant actions of zonisamide, and that increases of brain zonisamide concentration by immobilization stress may be related with this phenomenon.

Cessation of chronic nicotine administration enhances wet-dog shake responses to 5-HT2 receptor stimulation in rats.

RATIONALE: The involvement of central serotonergic systems has been hypothesized clinically to contribute to nicotine withdrawal symptoms. However, involvement of the serotonin2 (5-HT(2)) receptor system in nicotine withdrawal is not clear. OBJECTIVES: The changes in wet-dog shake responses induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT(2) receptor agonist, following nicotine cessation was investigated in rats. METHODS: DOI (1 mg/kg SC) was administered 24 h after the final treatment of saline or nicotine (0.5 mg/kg per day SC) for 7 or 21 days. RESULTS: Cessation of nicotine administration for 7 or 21 days increased DOI-induced wet-dog shake responses. A single administration of nicotine (0.5 mg/kg SC) had no effect on DOI-induced wet-dog shakes. The enhancement by the cessation of nicotine treatment for 7 days was abolished by coadministration of nicotine. Mecamylamine (3 mg/kg IP), a nicotinic receptor antagonist, precipitated DOI-induced wet-dog shake responses in rats chronically treated with nicotine but not with saline. CONCLUSIONS: These findings suggest that cessation of chronic nicotine produced increased sensitivity to 5-HT(2) receptor systems, and that the 5-HT(2) receptor systems may be involved in the nicotine withdrawal symptoms.

Involvement of 5-hydroxytryptamine(1A) receptors in nicotine-induced tail tremor in rats.

Involvement of the serotonergic system in tail tremor induced by repeated administration of nicotine was investigated in rats. Tail tremor induced by nicotine (0.5 mg/kg, s.c.) was suppressed by a 5-HT(1A) receptor antagonist, N-¿2-[4-(2-methoxyphenyl)-1-piperazinyl-]ethyl¿-N-(2-pyridinyl)cycloh exanecarboxamide trihydrochloride (WAY-100635; 0.3-3 mg/kg, i.p.), but not by a 5-HT(2) receptor antagonist, ketanserin (0.1-0.3 mg/kg, i.p). The 5-HT(1A) receptor agonists, buspirone (1-20 mg/kg, i.p.), gepirone (1-10 mg/kg, i.p.), tandospirone (1-10 mg/kg, i.p.) and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.01-0.1 mg/kg, s.c.), enhanced the tail tremor. The enhancement of tail tremor by buspirone (10 mg/kg, i.p.) was blocked by WAY-100635 (0.3-3 mg/kg, i.p.). These findings suggest that nicotine-induced tail tremor is mediated by 5-HT(1A) receptors and that 5-HT(1A) receptor antagonists are effective in the treatment of tremor.

Inhibition of neuronal dopamine uptake by some antiallergic drugs.

The effects of 10 antiallergic drugs (astemizole, azelastine, ebastine, emedastine, epinastine, ketotifen, oxatomide, terfenadine, pemirolast and tranilast) on neuronal dopamine uptake were examined. Some drugs examined showed a concentration-dependent inhibition of [3H]dopamine uptake into synaptosomal preparations of the rat striatum. The inhibition constant (Ki) values were 231-876 nM for ebastine, terfenadine, oxatomide and astemizole. The specific binding of [3H] (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine) (GBR12935) to the rat striatal membranes was also inhibited by these antiallergic drugs. There was a good correlation between the degrees of inhibition of [3H]dopamine uptake and [3H]GBR12935 binding. Then, the behavioral excitement induced by L-DOPA (100 mg/kg, s.c.) plus pargyline hydrochloride (80 mg/kg, i.p.) in mice was significantly enhanced by i.p. treatment with ebastine (10 mg/kg) and astemizole (5 mg/kg). These results suggest that the neuronal dopamine uptake is inhibited by some antiallergic drugs, especially ebastine.

Steady-state serum concentrations of carbamazepine and valproic acid in obese and lean patients with epilepsy.

Steady-state serum concentrations of carbamazepine (CBZ) and valproic acid (VPA) were investigated in normal weight (body mass index; BMI 20 to 25), lean (smaller than 20 BMI) and moderately obese subjects (greater than 25 BMI) who received either 400 mg/day of CBZ or 800 mg/day of VPA. The CBZ serum concentration in lean subjects was significantly higher than that in normal weight subjects. However, no significant differences in VPA serum concentration were found between the three groups. The CBZ serum concentration decreased with increases in total body weight, and the VPA serum concentration decreased with increases in ideal body weight. However, both serum concentrations were not correlated with BMI. These results suggest that VPA doses should be calculated using ideal body weight and that degree of obesity may affect CBZ serum concentration rather than VPA serum concentration.

Repeated mazindol and methamphetamine administration produces cross-sensitization to stereotyped behavior induced by these agents in rats.

The cross-sensitization to stereotyped behavior between mazindol (MZD) and methamphetamine (MAP) was investigated in rats. MZD (5 and 10 mg/kg/day, p.o.), MAP (5 and 10 mg/kg/day, p.o.) and saline (1 ml/kg, p.o.) were administered once daily for a week. Challenge with MZD (10 mg/kg, p.o.) on the 8th day caused markedly stereotyped behavior in MAP-pretreated group compared with the saline-pretreated control group. MAP (10 mg/kg, p.o.)-induced stereotyped behavior on the 8th day was also greater in MZD-pretreated group rather than the saline-pretreated control group. These results suggest that repeated MZD and MAP administration cross-sensitizes to their stereotype-producing effects.

Involvement of the central catecholaminergic system in nicotine-induced tail-tremor in rats.

The effect of 6-hydroxydopamine on repeated nicotine-induced tail-tremor was investigated in rats. Tail-tremor induced by nicotine (0.5 mg/kg/day, subcutaneously) became more pronounced in intensity with daily administration for 9 days. Rats pretreated with 6-hydroxydopamine (250 micrograms, intracerebroventricularly) showed almost the maximum degree of tail-tremor during the whole experimental period. However, in rats pretreated with 6-hydroxydopamine plus desipramine, enhancement of tail-tremor was slight in the beginning but increased with the daily nicotine administration. Fourteen-day administration of nicotine did not result in significant changes in noradrenaline and dopamine levels in the cortex, hypothalamus, striatum and nucleus accumbens. These results suggest that nicotine-induced tail-tremor is associated with the supersensitivity of postsynaptic catecholaminergic receptors in the central nervous system, and that the noradrenergic system may be more important than the dopaminergic system in this phenomenon.

Involvement of nitric oxide in development of tail-tremor induced by repeated nicotine administration in rats.

Daily administration of nicotine (0.5 mg/kg per day s.c.) to rats caused a tremor that appeared only in the tail (tail-tremor) and which became more marked over 8 days. Nitric oxide (NO) synthase inhibitors, Nw-nitro-L-arginine (10 mg/kg per day i.p.) or Nw-nitro-L-arginine methyl ester (20 and 40 mg/kg per day i.p.), administered each day before nicotine attenuated the development of the tail-tremor. However, neither Nw-nitro-L-arginine (2-10 mg/kg i.p.) nor Nw-nitro-L-arginine methyl ester (10-40 mg/kg i.p.) affected the tail-tremor that developed after 14 days of repeated nicotine administration. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 ((+)-5-methyl-10,11,-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine hydrogen maleate) at 0.2 mg/kg per day (i.p.), or competitive antagonist, CPP (3-[(+/-)-2-carboxypiperazin-4-yl] propyl-1-phosphonic acid) at 2 mg/kg per day (i.p.), administered each day before nicotine attenuated the development of the tail-tremor. MK-801 (0.01-0.2 mg/kg i.p.) but not CPP (0.5-4 mg/kg i.p.) suppressed the tail-tremor that developed after 14 days of repeated nicotine administration. These results suggest that NO formation mediated by NMDA receptors is involved in the mechanisms underlying the tail-tremor induced by the repeated administration of nicotine.

[Assessment of anti-tremorogenic drugs--nicotine-induced tail-tremor model].

The repeated administration of nicotine at small doses, which do not produce whole body tremor or convulsion, causes tremor only in the tail (tail-tremor) of rats. The tremor is accompanied by locomotor hyperactivity without rigidity and immobility of the whole body, suggesting that the nicotine-induced tail-tremor model is useful for studying the mechanism underlying tremor associated with movement. The tail-tremor induced by nicotine was suppressed by mecamylamine, a nicotinic antagonist, but not by atropine or scopolamine, muscalinic antagonists. Moreover, the tail-tremor was suppressed by the beta-blockers propranolol and pindolol, as well as the benzodiazepines diazepam and clonazepam. Tremor at rest is observed only in Parkinson's disease, which is improved with anti-muscalinic drugs. Essential tremor is one of the typical tremors connected with movement (postural and kinetic tremor) and is improved with beta-blocker. These findings and results suggest that nicotine-induced tail-tremor is useful for the study of essential tremor in animal models.

Role of central nicotinic and beta-adrenergic receptors in the onset and further development of tail-tremor induced by repeated nicotine administration to rats.

The effects of nicotinic and beta-adrenergic receptor antagonists on tail-tremor induced by repeated nicotine administration were investigated in rats. The daily administration of nicotine (0.5 mg/kg/day, s.c.) for 8 days resulted in an augmentation of tail-tremor. However, repeated administration of dimethyl phenyl piperazinium iodide (1 mg/kg/day, s.c.) for 8 days did not cause tail-tremor. Mecamylamine (0.5 mg/kg, i.p), administered before the nicotine injection on each day, abolished the tail-tremor. After discontinuation of the mecamylamine treatment, nicotine injections caused tail-tremor augmentation. Propranolol (20 mg/kg, i.p.), administered before the nicotine on each day, suppressed the appearance of tail-tremor. After the discontinuation of propranolol treatment, the degree of tail-tremor induced by a single injection of nicotine on day 9 was much greater in the propranolol-treated group than in the saline-treated control group. Neither carteolol (20 mg/kg, i.p.) nor metoprolol (20 mg/kg, i.p.) treatment showed such effects. Intraspinal injection of 6-hydroxydopamine markedly enhanced the tail-tremor induced on the first day of nicotine injection. This effect became more intense on subsequent administration of nicotine. The enhanced tail-tremor following 6-hydroxydopamine treatment was abolished by mecamylamine (0.5 and 1 mg/kg, i.p.), and was suppressed by propranolol (5-20 mg/kg, s.c.) in a dose-dependent manner. These results suggest that central nicotinic receptors are essential for the onset and for the further development of tail-tremor induced by the repeated administration of nicotine, and that beta 2-adrenoceptors are associated with the tremor mechanism. Moreover, spinal noradrenergic mechanisms may be involved in the manifestation of this phenomenon.

[Behavioral changes induced by repeated administration of mazindol, an anorexiant, in rats].

Behavioral changes in locomotor activity and stereotyped behaviors induced by daily administration (for 7 days) of mazindol (5 and 10 mg/kg, po) were compared with those induced by methamphetamine (10 mg/kg) in rats. On day 1, mazindol increased locomotor activity, which was enhanced by daily administrations. Stereotyped behaviors were also induced by mazindol, which became more marked following daily administrations. Methamphetamine markedly increased stereotyped behavior rather than locomotor activity on day 1, and the effects were not enhanced by daily administrations. The increased locomotor activity and stereotyped behaviors caused by mazindol and methamphetamine were markedly reduced by the dopamine receptor antagonist pimozide (0.1-0.4 mg/kg, ip) in a dose-dependent manner. These results suggest that repeated mazindol administration enhances locomotor-stimulant and stereotypy-producing effects, which are mediated by the central dopaminergic system.

Potentiation of L-dopa-induced behavioral excitement by histamine H1-receptor antagonists in mice.

Effects of histamine H1-receptor antagonists on L-dopa-induced behavioral excitement were examined in mice to confirm behaviorally the inhibition of dopamine uptake by these compounds. L-Dopa (100-300 mg/kg, s.c.) combined with pargyline hydrochloride (80 mg/kg, i.p.) caused a dose-dependent behavioral excitement. The marked excitement induced by L-dopa (300 mg/kg) plus pargyline was significantly inhibited by pimozide (0.1 - 1 mg/kg, s.c.), a selective dopamine antagonist. Tripelennamine (10 mg/kg, s.c.), d-chlorpheniramine (1 and 2 mg/kg, s.c.), homochlorcyclizine (2 and 5 mg/kg, s.c.), diphenhydramine (2 and 5 mg/kg, s.c.) and mepyramine (2 and 5 mg/kg, s.c.) each markedly enhanced the moderate behavioral excitement induced by L-dopa (150 mg/kg) plus pargyline. These findings are behavioral evidence for inhibition of dopamine uptake by H1 antagonists, which has been suggested by neurochemical studies.

[Peripheral plasma corticotropin-releasing hormone (CRH) in an aged patient with fasting hypoglycemia associated with an insufficient secretion of insulin: an implication of plasma CRH in glucose metabolism].

We present a 66-year-old man with morning fasting hypoglycemia from an unknown cause associated with markedly suppressed levels of insulin. In this patient we examined the diurnal changes of plasma corticotropin-releasing hormone (CRH). ACTH, cortisol, glucose, insulin and body temperature, and the correlations among them. We also discussed an implication of plasma CRH in glucose metabolism by taking these findings together with results from previous studies on plasma CRH in diabetic or hypoglycemic animals and human beings. In this case, the stress induced by severe spontaneous hypoglycemia in the morning fasting state increased CRH in plasma compared to the euglycemia state and simultaneously activated the hypothalamic-pituitary-adrenal system as well as the sympathetic nervous system remarkably. The daily intravenous infusion of glucose brought the fasting hypoglycemia to normal and hypothermia to normothermia in the morning, and improved no or blunt responsiveness of insulin to glucose. On the 50th day of therapy, the i.v. infusion of glucose quickly produced moderate hyperglycemia and an increase in plasma insulin, and inhibited secretions of CRH, ACTH and cortisol. The source of plasma CRH remains obscure. However, the positive correlations of plasma CRH with both plasma ACTH and cortisol and several lines of evidence indicate that CRH in peripheral plasma is derived from both the hypothalamus and extrahypothalamic peripheral tissue and that during stressed conditions, in particular, the CRH increase in plasma is derived mainly from the paraventricular nucleus of the hypothalamus. The role of CRH not only in the systemic circulation but also in the endocrine pancreases for glucose metabolism remains to be clarified.