The effects of once-weekly teriparatide on hip structure and biomechanical properties assessed by CT.

SUMMARY: Once-weekly administration of 56.5 µg teriparatide improved cortical bone parameters and biomechanical parameters at the proximal femur by CT geometry analysis. INTRODUCTION: The aim of this study was to evaluate the effects of weekly administration of teriparatide [human PTH (1-34)] on bone geometry, volumetric bone mineral density (vBMD), and parameters of bone strength at the proximal femur which were longitudinally investigated using computed tomography (CT). METHODS: The subjects were a subgroup of a recent, randomly assigned, double-blind study (578 subjects) comparing the anti-fracture efficacy of a once-weekly subcutaneous injection of 56.5 µg teriparatide with placebo (TOWER trial). RESULTS: Sixty-six ambulatory postmenopausal women with osteoporosis were enrolled at 15 study sites having multi-detector row CT, and included women injected with teriparatide (n = 29, 74.2 ± 5.1 years) or with placebo (n = 37, 74.8 ± 5.3 years). CT data were obtained at baseline and follow-up scans were performed at 48 and 72 weeks. The data were analyzed to obtain cross-sectional densitometric, geometric, and biomechanical parameters including the section modulus (SM) and buckling ratio (BR) of the femoral neck, inter-trochanter, and femoral shaft. We found that once-weekly teriparatide increased cortical thickness/cross-sectional area (CSA) and total area, and improved biomechanical properties (i.e., decreasing BR) at the femoral neck and shaft. Teriparatide did not change the cortical perimeter. CONCLUSIONS: Our longitudinal analysis of proximal femur geometry by CT revealed that once-weekly administration of 56.5 µg teriparatide improved cortical bone parameters at the femoral neck and shaft and also improved biomechanical parameters.

Tacrolimus is effective for lupus nephritis patients with persistent proteinuria.

OBJECTIVES: To evaluate the safety and potential efficacy of tacrolimus for the treatment of patients with lupus nephritis and persistent proteinuria. METHODS: A total of 23 Japanese patients with lupus nephritis (21 females/2 males) were enrolled in this study. Patients were administered tacrolimus at a dose of 2-3 mg once daily after the evening meal for 6 months. The dose of tacrolimus was unchanged throughout the study period. Concomitant prednisolone therapy was unchanged or gradually tapered, while other immunosuppressants were stopped at the start of tacrolimus treatment. RESULTS: Tacrolimus was well tolerated, and none of the patients developed adverse drug reactions that required discontinuation of the study. Daily urinary protein loss, the U-prot/U-creat ratio, and serum albumin were significantly improved after 4 months, 3 months, and 1 month of treatment with tacrolimus (p<0.05), respectively, and the improvement persisted until 6 months. The serum complement hemolytic activity (CH50), complement C3 level, and CRP level were also significantly improved after treatment with tacrolimus (p<0.05). Improvement of the U-prot/U-creat ratio was most prominent for patients who were in WHO class IV. CONCLUSIONS: Tacrolimus is safe and effective as maintenance therapy for patients with lupus nephritis, at least for 6 months. A larger randomised, controlled trial over a longer period is needed to confirm these results.

Evaluation of inosin-5'-monophosphate dehydrogenase activity during maintenance therapy with tacrolimus.

OBJECTIVES: The aim of this study was to identify a target range for inosin-5'-monophosphate dehydrogenase (IMPDH) activity in maintenance therapy with tacrolimus (TCL), and to apply the measurement of IMPDH activity to the therapeutic drug monitoring for mycophenolate mofetil (MMF). METHODS: Eleven patients with renal transplants and 10 healthy volunteers were investigated. All patients were treated with a combination of TCL, steroid and MMF for 2 months after transplantation, and were in stable and good condition. IMPDH activity was determined indirectly by measuring xanthosine 5'-monophophate in cell lysates supplemented with IMP and beta-nicotine adenine dinucleotide using an high-performance liquid chromatography (HPLC) method. RESULTS: The within-run reproducibility of the assay was excellent, with relative standard deviation (RSD) values of 0.41-4.08%. The mean differences between the spiked concentrations of xanthosine 5'-monophophate and their real values (mean relative errors; MREs) were within a range of 2.66-8.89%, showing good accuracy. The interday RSD values were 1.51-6.12% and MREs ranged from 2.10% to 8.89%. Cell lysates showed a 5-6 nmol/L IC(50) mycophenolic acid (MPA) concentration. TCL, cyclosporine and prednisolone did not affect IMPDH activity. The peak MPA concentration was achieved at 1 h after dosing. IMPDH activity decreased to 75% and 67% at 1 and 2 h after dosing respectively. Therefore, the inhibition rates of MPA against IMPDH activity may be adequate at 25-40% in TCL maintenance therapy. CONCLUSION: Inosin-5'-monophosphate dehydrogenase activity in cell lysates could be reliably determined by HPLC. A 25-40% inhibition of IMPDH activity may be an appropriate range for preventing rejection with MPF but this requires further validation using larger studies with harder outcomes such as rejection episodes.

Estimation of the area under the curve for mycophenolic acid in adult renal transplant patients with concomitant tacrolimus using a limited sampling strategy.

OBJECTIVES: The aim of this study was to develop a limited sampling strategy (LSS) for monitoring the use of mycophenolic acid (MPA) in maintenance therapy with tacrolimus (TCL) in renal transplant patients. METHODS: Eighteen adult patients receiving a first transplant were investigated. All patients were treated with a combination of TCL, steroid and mycophenolate mofetil (MMF). Besides the predose trough concentration (C(0)), whole blood samples were taken for measurement of the MPA concentration at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 h for a 14-point 12-h pharmacokinetic (PK) profile. Using stepwise linear regression analysis, an abbreviated area under the concentration time curve (AUC) was calculated using all 14, and any combination of sampling points to give an estimating equation with up to three predictors. RESULTS: The equation derived from C(2), C(7) and C(12,) for AUC estimation: AUC = (2.05 x C(2)) + (8.51 xC(7)) + (2.29 x C(12)) + 4.24. was found to be optimal. Using this formula, there was an excellent correlation between the estimated 3-point AUC and AUC(0-12 h). To assess the agreement between the abbreviated methods and the full PK profile, we plotted the average AUC of the abbreviated estimates and the full PK profile. This Bland-Altman analysis indicated good agreement to within +/-2 SD and a prediction variability of 7.56 microg x h/mL. CONCLUSION: Our proposed three-sampling-point estimate of AUCs is clinically acceptable. However, the sampling times are inconvenient for outpatients, and is recommended only for monitoring MMF treatment of inpatients with suspected toxicity or at high risk of organ rejection.

Routine laparoscopic ultrasound can significantly reduce the need for selective intraoperative cholangiography during cholecystectomy.

BACKGROUND: The use of intraoperative cholangiography (IOC), routinely rather than selectively, during laparoscopic cholecystectomy (LC) is controversial. Recent findings have shown laparoscopic ultrasound (LUS) to be safe, quick, and effective not only for screening of the bile duct for stones, but also for evaluating the biliary anatomy. This study aimed to evaluate, on the basis of the LC outcome and the cost of LUS and IOC, whether and how much the routine use of LUS would be able to reduce the need for IOC. METHODS: During LC, LUS was used routinely to screen the bile duct for stones and to evaluate the biliary anatomy, whereas IOC was used selectively only when LUS was unsatisfactory or unsuccessful. RESULTS: For 193 (96.5%) of 200 patients, LUS was completed successfully, whereas IOC was needed for 7 patients (3.5%). Bile duct stones were identified in 20 patients (10%). For the detection of bile duct stones, LUS yielded 19 true-positive, 175 true-negative, 0 false-positive, and 1 false-negative results. It had a sensitivity of 95%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 99.4%. The postoperative complications included bile leaks from the liver bed in two patients and a retained bile duct stone in one patient. If IOC had been used selectively in a traditional manner on the basis of preoperative risk factors, IOC would have been needed for 77 patients (38.5%). The total cost of LUS plus IOC for the current 200 patients was 26,256 dollars. The total estimated cost of selective IOC, if it had been performed for the 77 patients, would have been 31,416 dollars. CONCLUSIONS: Routine LUS accurately diagnosed bile duct stones and significantly reduced the need for selective IOC from a potential 38.5% to an actual 3.5% without adversely affecting the outcome of the LC or increasing the overall cost. The routine use of LUS during LC is accurate and cost effective.

Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05.

BACKGROUND: National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 showed a benefit from leucovorin (LV)-modulated 5-fluorouracil (5-FU) adjuvant therapy (5-FU + LV) in patients with Dukes' stage B or C carcinoma of the colon. Preclinical and clinical phase I/II data suggested that interferon alfa-2a (IFN) enhanced the efficacy of 5-FU therapy. Accordingly, in NSABP protocol C-05, the addition of recombinant IFN to 5-FU + LV adjuvant therapy was evaluated. METHODS: Data are presented for 2176 patients with Dukes' stage B or C cancer entered onto protocol C-05 during the period from October 1991 through February 1994. Individuals with an Eastern Cooperative Oncology Group performance status of 0-2 (ranges from fully active to ambulatory and capable of self-care but unable to work), a life expectancy of at least 10 years, and curative resection were stratified by sex, disease stage, and number of involved lymph nodes and were randomly assigned to receive either 5-FU + LV or 5-FU + LV + IFN; the mean time on the study as of June 30, 1997, was 54 months. All statistical tests were two-sided. RESULTS: There was no statistically significant difference in either disease-free survival (5-FU + LV, 69%; 5-FU + LV + IFN, 70%) or overall survival (5-FU + LV, 80%; 5-FU + LV + IFN, 81%) at 4 years of follow-up. Toxic effects of grade 3 or higher were observed in 61.8% of subjects in the group treated with 5-FU + LV and in 72.1% of subjects in the group treated with 5-FU + LV + IFN; fewer patients in the latter group completed protocol-mandated 5-FU + LV therapy than in the former group (77.1% versus 88.5%). CONCLUSION: The addition of IFN to 5-FU + LV adjuvant therapy confers no statistically significant benefit, but it does increase toxicity.

Direct evidence for increased continuous histamine release in the striatum of conscious freely moving rats produced by middle cerebral artery occlusion.

Extracellular histamine in the stratum of conscious freely moving rats collected by intracerebral microdialysis 1 day after implantation of a U-shaped dialysis probe was measured by HPLC coupled with postcolumn o-phthalaldehyde derivatization fluorometry. The basal fractional histamine outputs were almost constant from 1 to 7 h after the start of perfusion (5.9-8.4 pg/30 min). Depolarization by perfusion with a high K+ (100 mM)-containing medium produced a significant (124%) increase and neuronal blockade by perfusion with a tetrodotoxin (1 microM)-containing medium resulted in a 68% reduction in the histamine output. The histamine output was markedly reduced by intraperitoneal injection of alpha-fluoromethylhistidine (100 mg/kg), an irreversible inhibitor of histidine decarboxylase, or (R)-alpha-methylhistamine (5 mg/kg), a potent and specific H3-receptor agonist. After middle cerebral artery (MCA) occlusion, the histamine output gradually increased, and reached four times the control value 8 h later. When rats were pretreated with metoprine (10 mg/kg), a histamine N-methyltransferase inhibitor, there was no significant difference in the histamine output between the MCA-occluded and the sham-operated groups during the first 3.5 h after the operation, but the histamine output gradually increased thereafter in the MCA-occluded group. In rats treated with alpha-fluoromethylhistidine, MCA occlusion failed to cause an increase in the histamine output. These results demonstrate that MCA occlusion induces a long-lasting increase in neuronal histamine release in the rat striatum.

Stereospecific accumulation of dihydromorphine and naltrexone by corpus striatal slices of morphine-dependent mice.

Stereospecific accumulation of [3H]dihydromorphine and [3H]naltrexone by striatal slices from morphine-dependent mice was examined in Krebs-Ringer bicarbonate medium. Striatal slices showed a saturable and stereospecific accumulation of both [3H]ligands. The accumulation constant of naltrexone, determined by Wilkinson's analysis, was significantly decreased in both morphine-dependent mice and dependent mice abruptly withdrawn for 6 hr. The maximal accumulation of naltrexone was not changed in withdrawn mice, but decreased in dependent mice. This could be due to the high concentration of residual morphine in the slices. There were no significant differences in the accumulation constant or maximal accumulation of dihydromorphine among the striatal slices from control, dependent and withdrawn mice. These data indicate that in morphine-dependent mice, there is an increased affinity of the opioid receptors for the narcotic antagonist, naltrexone but not for the agonist, dihydromorphine.

In vivo binding of naloxone to opioid receptors in morphine-dependent mice.

In vivo binding assay of opioid receptors for naloxone was tested in morphine-dependent mice. The content of naloxone in the brain (whole brain minus cerebellum) and cerebellum was determined as the total binding and non-specific binding, respectively, 20 min after the intravenous injection of [3H]-naloxone. Acute treatment with 8 mg/kg of morphine sulfate markedly enhanced the non-specific binding of naloxone. In contrast, withdrawal for 6 hr after 72 hr of implantation of morphine decreased the non-specific binding of naloxone. The Scatchard analysis of the specific binding revealed two binding sites. The apparent low affinity Kd values of both morphine-tolerant and morphine-withdrawn mice were significantly decreased when compared to their respective controls. The apparent high affinity Kd and the high and low Bmax values were not altered by the morphine dependent-tolerant state.

Noradrenergic involvement in catalepsy induced by delta 9-tetrahydrocannabinol.

In order to elucidate the role of the catecholaminergic system in the cataleptogenic effect of delta 9-tetrahydrocannabinol (THC), the effect of pretreatment with 6-hydroxydopamine (6-OHDA) or with desipramine and 6-OHDA and lesions of the locus coeruleus were investigated in rats. The cataleptogenic effect of THC was significantly reduced in rats treated with 6-OHDA and in rats with lesions of the locus coeruleus but not in rats treated with desipramine and 6-OHDA, as compared with control rats. On the contrary, the cataleptogenic effect of haloperidol was significantly reduced in rats treated with desipramine and 6-OHDA but not in rats treated with 6-OHDA or in rats with lesions of the locus coeruleus. These results indicate that noradrenergic neurons have an important role in the manifestation of catalepsy induced by THC, whereas dopaminergic neurons are important in catalepsy induced by haloperidol.

Nitric oxide protects against contrast media-increased pulmonary vascular permeability in rats.

RATIONALE AND OBJECTIVES: Nitric oxide (NO) regulation of endothelial function is involved in the development of acute lung injury. The role of NO in contrast media-induced increases in pulmonary vascular permeability was investigated in a rat model. METHODS: Nonionic (iohexol) and ionic (ioxaglate) contrast media were intravenously injected at 1.5 mL/min in rats. Pulmonary vascular permeability was evaluated by measuring the amount of Evans blue dye uptake as a quantitative marker of albumin extravasation in lung tissue. RESULTS: Intravenous injections of contrast media at doses of 4 and 6 g I/kg induced a dose-dependent increase in pulmonary vascular permeability. L-Arginine (an NO synthase substrate) and N(G)-nitro-L-arginine (L-NNA) (an NO synthase inhibitor) prevented and aggravated, respectively, the increase in pulmonary vascular permeability induced by the contrast medium. An aggravating action of L-NNA was confirmed by morphological and histological observations, this action being blocked by L-arginine (300 mg/kg) but not by D-arginine. Isosorbide dinitrate (1-20 mg/kg), an NO donor, had a dose-dependent protective effect on ioxaglate-increased vascular permeability. CONCLUSIONS: Our experimental findings suggest that contrast media at high doses produce pulmonary edema by inhibiting endothelial NO production, and nitrovasodilators protect against this adverse effect in rats.

Enhancement by alpha-fluoromethylhistidine of the thiopental sleep-prolonging action of delta 9-tetrahydrocannabinol.

The effect of alpha-fluoromethylhistidine (alpha-FMH), a specific inhibitor of histidine decarboxylase, on the potentiation of thiopental-induced sleep by delta 9-tetrahydrocannabinol (THC), which inhibits the histamine turnover in the brain, was examined in mice and rats. The sleeping time after injection of thiopental sodium (40 mg/kg, IV) was prolonged by THC (10 mg/kg, IP, 1 h before) to approximately twice the control value. alpha-FMH (50 mg/kg, IP) administered alone had no significant influence on the thiopental sleeping time. However, alpha-FMH given 1 or 3 h before THC treatment markedly enhanced the THC potentiation of thiopental-induced sleep. Such an enhancement by alpha-FMH was not observed when alpha-FMH was administered 15 h before THC treatment. The brain histamine level decreased by 60% during the first 4 h after alpha-FMH injection and remained low until 15 h after the treatment. The thiopental sleep-potentiating action of morphine, chlorpromazine and diazepam was not affected by pretreatment with alpha-FMH. The transient enhancing effect of alpha-FMH on the THC potentiation of thiopental-induced sleep suggests that the histaminergic system is one of the activating transmitter systems in the brain.

Safety and efficacy of radiofrequency thermal ablation in advanced liver tumors.

HYPOTHESIS: Radiofrequency thermal ablation (RFA) can be performed safely and effectively to control local disease in patients with advanced, unresectable liver tumors. DESIGN, SETTING, AND PATIENTS: Prospective study of 76 patients with unresectable liver tumors who underwent RFA at a private tertiary referral hospital. INTERVENTIONS: Ninety-nine RFA operations were performed to ablate 328 tumors. MAIN OUTCOME MEASURES: Complications and local recurrence. RESULTS: There was 1 death (1%), major complications occurred in 7 operations (7%), and minor complications occurred in 10 operations (10%). Local recurrence was identified in 30 tumors (9%) at a mean follow-up of 15 months. Size (P<.001), vascular invasion (P<.001), and total volume ablated (P<.001) were associated with recurrence but the number of tumors was not (P =.39). CONCLUSION: Radiofrequency thermal ablation provides local control of advanced liver tumors with low recurrence and acceptable morbidity.

The role of locus coeruleus in decapitation convulsions of rats.

The role of the central norepinephrine (NE) system, especially the locus coeruleus (LC), in the occurrence of decapitation convulsions was investigated in rats. Intraspinal injection of 6-hydroxydopamine (6-OHDA) caused a significant inhibition of decapitation convulsions as shown by prolongation of the latency and shortening of the convulsion's duration, as well as decreasing the NE content of the spinal cord to 35% of the control value without affecting the NE content of the various regions in the brain. Chemical lesion of the descending bundle from the LC by treatment with 6-OHDA significantly inhibited decapitation convulsions in a similar manner. Moreover, there was a decrease in the NE content of the spinal cord and hypothalamus to 24% and 47% of the control value, respectively. Bilateral electrolytic lesion of the LC also significantly inhibited decapitation convulsions and decreased the NE content of the cortex and spinal cord to 15% and 74% of the control value, respectively. However, lesions of the dorsal and ventral NE bundle by treatment with 6-OHDA, which caused a marked decrease in the NE content of the cortex and hypothalamus, respectively, did not affect the decapitation convulsion. Intraspinal injection of 5,6-dihydroxytryptamine resulted in a decrease in the 5-hydroxytryptamine content of the spinal cord only; moreover, it did not change the decapitation convulsion. These results suggest that coeruleospinal NE neurons play an important role in the occurrence of decapitation convulsions.

Involvement of opioid and non-opioid mechanisms in footshock-induced enhancement of brain histamine turnover in mice.

Naloxone (1-10 mg/kg, i.p.) dose-dependently inhibited the footshock-induced elevation in levels of tele-methylhistamine (t-MH), a predominant metabolite of brain histamine (HA), although this compound had no effect on the HA dynamics in the non-shocked control mice. Footshock significantly enhanced the HA depletion induced by alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. However, in mice treated with naloxone (5 mg/kg, i.p.) footshock did not significantly facilitate the alpha-fluoromethylhistidine-induced HA depletion. In mice which had been rendered morphine-tolerant following an s.c. implantation of a pellet containing 50 mg of morphine base 3 days before, footshock produced no significant elevation of the t-MH level. The treatment with alpha-methyl-p-tyrosine, p-chlorophenylalanine or atropine had no significant influence on the footshock-induced t-MH elevation. The t-MH elevation was the most marked in the midbrain. In the hypothalamus and pons-medulla oblongata, no significant change in the t-MH level was produced by footshock. These results suggest that footshock increases the HAergic activity in the mouse brain partly through activation of opioid-related mechanisms and that alterations in HA dynamics differ with region of the brain.

Regional distribution of histamine and tele-methylhistamine in the rat, mouse and guinea-pig brain.

Regional histamine (HA) and tele-methylhistamine (t-MH) contents were determined in the rat, mouse and guinea-pig brain. The highest HA and t-MH levels were found in the hypothalamus of all species. Fairly high t-MH levels were observed in the amygdala of all species and in the guinea-pig hippocampus. The t-MH/HA ratio was higher in the regions of the telencephalon than in the diencephalon and brainstem. The cerebellum and spinal cord showed extremely low t-MH/HA ratios. These results suggest higher histaminergic neuronal activities in the hypothalamus and some regions of the telencephalon than in other parts of the brain.

Decrease in histamine turnover in the brain of spontaneously hypertensive rats.

Histamine (HA) turnover rate in the brain of spontaneously hypertensive rats (SHR) was determined by the accumulation of telemethylhistamine after pargyline treatment. The values in these SHR were lower than in the Wistar Kyoto rats, particularly in the hypothalamus and brainstem. However, chronic treatment with L-histidine had no effect on the development of hypertension in the SHR. The functional significance of the decreased HA turnover in SHR is discussed in relation to the pathogenesis of hypertension.

Brain histamine turnover enhanced by footshock.

When footshock was given to mice at 15-s intervals for 30-120 min, there was a significant increase in the brain level of tele-methyl-histamine (t-MH), a predominant metabolite of brain histamine (HA). This footshock-induced elevation of the t-MH level also occurred in mice pretreated with pargyline but not in mice pretreated with metoprine. The footshock facilitated the HA depletion induced by a-fluoromethylhistidine. These results suggest that footshock increases the brain HA turnover.

Hyperdipsia induced by bilateral destruction of the locus coeruleus in rats.

Bilateral lesions in the locus coeruleus (LC) of rats induced a urinary disorder and hyperdipsia. Dilatation of the urinary bladder, urinary retention and hematuria with bleeding originating from the urinary bladder, occurred immediately after the lesioning and continued for 2-5 days. Water intake increased 4 days after the lesioning. This hyperdipsia persisted for at least 4 days and then gradually returned to the control level. Food intake decreased for the first 5 days, and then returned to the control level. Lesions in the ascending dorsal bundle (DB) originating from the LC also produced hyperdipsia, but not urinary disorder. Destruction of the ascending ventral vundle (VB) originating from the noradrenaline (NA) neurons in the medulla oblongata did not affect eating, drinking or urination. The LC- or DB-lesioning caused a significant reduction of NA in the whole forebrain except the hypothalamus, whereas VB-lesioning caused reduced NA in the hypothalamus. In LC-lesioned animals, no significant changes were observed in serum osmolarity, Na+, K+, albumin and glucose in serum, or in the excretion of urine in the water-loading test.

Repeated interferon-alpha administration inhibits dopaminergic neural activity in the mouse brain.

In vivo effects of single and repeated interferon-alpha administrations on the dynamics of noradrenaline, dopamine and 5-hydroxytryptamine were investigated in the mouse brain. Single interferon-alpha administration (15, 30 and 60 X 10(6) U/kg i.p.) had no significant effect on the levels of monoamines and their metabolites or monoamine turnover. When interferon-alpha (15 X 10(6) U/kg i.p.) was administered once a day for 5 days, however, both dopamine and 3,4-dihydroxyphenylacetic acid levels were significantly decreased and alpha-methyl-p-tyrosine-induced dopamine depletion was significantly suppressed. These results suggest that repeated interferon-alpha administration inhibits dopaminergic neural activity. This inhibitory action of interferon-alpha in dopamine neurons may be involved in adverse central effects, such as parkinsonism and depression with suicidal potential.