Relationship between the administration of nicardipine hydrochloride and the development of delirium in patients on mechanical ventilation.

A history of hypertension is a known risk factor for delirium in patients in intensive care units, but the effect of antihypertensive agents on delirium development is unclear. Nicardipine, a calcium channel blocker, is widely used in ICU as a treatment agent for hypertensive emergency. This study investigated the relationship between the administration of nicardipine hydrochloride and delirium development in patients under mechanical ventilation. We conducted a medical chart review of 103 patients, who were divided into two groups according to the use of nicardipine hydrochloride. The prevalence of delirium was compared with respect to factors such as age, sex, laboratory data, and medical history, by multivariate analysis. 21 patients (20.4 %) were treated with nicardipine hydrochloride in 103 patients. The treatment and non-treatment groups differed significantly in age (72 vs. 65 years) and history of high blood pressure (57% vs. 11%). Multivariate analysis revealed that patients in the treatment group developed delirium significantly less often than those in the non-treatment group (19% vs. 48%). These results suggested that treatment of high blood pressure with nicardipine hydrochloride is a possible method for preventing the development of delirium.

Trends in incidence and mortality of tuberculosis in Japan: a population-based study, 1997-2016.

Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (-6.2% and -5.4%, respectively) and women (-5.7% and -4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035.

Poor applicability of estimation method for adults to calculate unbound serum concentrations of valproic acid in epileptic neonates and infants.

OBJECTIVE: To characterize the relationship between total and unbound concentrations of valproic acid (VPA) in epileptic neonates and infants, the clinical examination records of those patients archived via therapeutic drug monitoring (TDM) activities were retrospectively analyzed. METHODS: The screening encompassed 249 records of 114 epileptic patients aged 0-19 years old, who were treated with VPA monotherapy and whose total and unbound VPA concentrations were determined. These data were divided into groups according to the patients' age. In each group, the relationship between total and unbound VPA concentrations was compared to a reference profile, and the deviation from the reference was evaluated. The reference profile was calculated using the Langmuir equation, in which two parameters Kd and Bm were set to 7.8 and 130 microg/mL, respectively, according to our previous findings. RESULTS: The relationship between total and unbound VPA concentrations of patients of 0 years old considerably deviated from the reference, and their unbound VPA concentrations were generally higher compared to the corresponding reference values. It is suggested that the large deviation is related to the fact that the serum albumin concentrations of patients younger than 1 year old tend to be lower than those of patients in other age groups. CONCLUSION: Since the relationship between the VPA concentrations of epileptic neonates and infants is noticeably different from the reference, the unbound serum VPA concentrations of these patients are not adequately estimated using the same method as that for grown-ups. The unbound VPA concentrations of neonates and infants should be explicitly determined via TDM activities.

Relationship between oral mucositis and high-dose methotrexate therapy in pediatric acute lymphoblastic leukemia.

OBJECTIVE: Oral mucositis is a major toxicity in the high-dose methotrexate (HD-MTX) treatment for children with acute lymphoblastic leukemia (ALL). The first aim of this study was to evaluate the relationship between the MTX serum concentration and occurrence of oral mucositis in pediatric ALL patients. The second aim was to clarify the relationship between MTX exposure and epidermal keratinocyte cell injury using an in vitro study. METHODS: 49 patients were treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-HR02 protocol. This protocol involves HD-MTX treatment (3 g/m2 for 24-h i.v. infusion). The MTX serum concentrations were measured by a fluorescence polarization immunoassay. The relationship between oral mucositis and MTX serum concentrations 48 and 72 h after administration was determined. The cell toxicity of MTX for human epidermal keratinocytes was analyzed by using a cell viability assay (WST-1 assay). In addition, pharmacokinetic evaluation for clearance, AUC extrapolated from 48 h to infinity (AUC48h-inf) and elimination half-life (t1/2b) were done using the 1-compartmental models. RESULTS: Oral mucositis occurred in 24 patients (49.0%), in whom 20 patients (83.3% in oral mucositis group) showed WHO severity Grade 1 or 2. Only 4 patients (16.7% in oral mucositis group) showed Grade 3 severity. 22 patients (44.9%) had oral mucositis in the group with a concentration under 10-6 M 48 h after MTX administration. There was no significant deference among the cell viabilities in the concentrations of 10-6 M, 10-5 M and 10-4 M 48 h after the MTX exposure. However, the cell viability obtained 24 h after the MTX exposure was significantly different from the respective cell viability 48, 72 and 96 h after the MTX exposure. In the group with oral mucositis, the clearance decreased significantly (p = 0.042), and the t1/2b (p = 0.025) and AUC48h- yen (p = 0.025) increased significantly compared with the non-symptom group. CONCLUSIONS: It seems that there is no significant relationship between the serum MTX concentration and oral mucositis. This in vitro study has demonstrated that the cell injury was related to the duration of MTX exposure rather than a high MTX concentration.

Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children.

OBJECTIVE: To establish a regression equation to properly estimate the unbound serum concentration of valproic acid (VPA) from its total serum concentration; the relationship between total and unbound serum VPA concentrations was retrospectively characterized. METHODS: Data were obtained from the clinical examination records that were routinely archived during therapeutic drug monitoring. The screening encompassed 342 records of 108 paediatric patients whose total and unbound VPA concentrations had been determined. The relationship between total and unbound VPA concentrations was characterized according to the Langmuir equation by taking account of inter-individual variability with the nonmem program. RESULTS: The total VPA concentration (C(t)) in the screened patients ranged from 5.5 to 179.8 microg/mL, and the unbound VPA concentration (C(f)) increased in a non-linear manner as the total VPA concentration increased. Taking account of the effects of antiepileptics concurrently administered, the VPA dissociation constant (K(d)) and maximum binding site concentration (B(m)) were 7.8 +/- 0.7 and 130 +/- 4.5 microg/mL respectively, for the regression equation, C(t) = C(f) + B(m) x C(f)/(K(d) + C(f)). An alteration in the unbound concentration was seen in patients who were treated with the combination of VPA and ethosuximide and in those who received two additional antiepileptics. CONCLUSIONS: A regression equation for estimation of the unbound VPA concentration, based on total VPA concentration collected during routine therapeutic drug monitoring was established. Use of two additional antiepileptics and ethosuximide treatment was considered as potential factors affecting unbound VPA concentration.

Involvement of de novo ceramide synthesis in radiocontrast-induced renal tubular cell injury.

We reported previously that various radiocontrast media cause apoptosis in porcine proximal tubular (LLC-PK(1)) cells, in which reduction in B-cell lymphoma (Bcl)-2 expression and caspase-3 activation are implicated. In the present study, we investigated a role for ceramide in radiocontrast media-induced apoptosis in renal tubular cells. LLC-PK(1) cells were exposed to radiocontrast media for 30 min, followed by incubation for 24 h in normal medium. Cell viability was assessed by 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, while apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling stain. Immunofluorescent stains were performed using antibodies against phosphorylated Akt (pAkt) and cAMP response element binding protein (CREB) (pCREB), and ceramide. The mRNA expression and protein content of Bcl-2 were determined by reverse transcriptase-polymerase chain reaction and enzyme immunoassay, respectively. In vivo model of contrast-induced renal injury was induced in mice with unilateral renal occlusion. The cell injury induced by the nonionic radiocontrast medium ioversol was reversed by inhibiting de novo ceramide synthesis with fumonisin B(1) (FB(1)) and L-cycloserine, but not by suppressing sphingomyelin breakdown with D609. FB(1) reversed ioversol-induced decrease in the immunoreactivities of pAkt and pCREB, reduction in Bcl-2 expression and caspase-3 activation. Like ioversol, C2 ceramide and the Akt inhibitor Src homology-6 induced apoptosis by reducing pAkt and pCREB-like immunoreactivities, lowering Bcl-2 expression and enhancing caspase-3 activity. Indeed, various radiocontrast media, excluding iodixanol which showed the least nephrotoxicity, enhanced ceramide-like immunoreactivity. The role for de novo ceramide synthesis was also shown in the in vivo model of radiocontrast nephropathy. We demonstrated here for the first time that the enhancement of de novo ceramide synthesis contributes to radiocontrast nephropathy.

Delayed adverse reactions to iodinated radiographic contrast media after coronary angiography: a search for possible risk factors.

OBJECTIVE: The incidence of and risk factors for delayed adverse events (DAEs) that appear from 1 h to 7 days after injection of radiographic contrast media were investigated in patients who had undergone coronary angiography (CAG). METHODS: DAEs were monitored by questionnaire in 155 patients who received iomeprol. Isosorbide dinitrate was injected in every case. Risk factors for DAEs were analysed by a logistic regression model. RESULTS: Of 118 patients who returned questionnaires, 54 complained of DAEs, although no severe or fatal reactions occurred. Erythema, rash and nausea were frequent events. Female gender, total dose of isosorbide dinitrate <2 mg, and execution of acetylcholine provocation test were found to be the major risk factors, and the incidence of DAEs increased as the number of risk factors increased. CONCLUSION: Care should be taken when CAG is performed on female patients who undergo acetylcholine provocation tests and receive low-dose nitric oxide donor injections.

Application of dynamic laser scattering to the quality control of injectable drugs: polymer formation in ampicillin solution.

OBJECTIVE: To assess the usefulness of dynamic laser scattering for monitoring the stability of ampicillin after reconstitution from commercially available vials with respect to the polymer formation and potency. METHODS: Polymer formation and the remaining potency of the reconstituted ampicillin solution were estimated using dynamic laser scattering and high-performance liquid chromatography. RESULTS: The laser light-scattering submicron particle analyser was sufficiently sensitive for detecting both monomer and polymer aggregates with the average diameter of 1.1 +/- 0.2 and 7.3 +/- 1.7 nm, respectively, in the ampicillin solution. Polymer formation was dependent on both the storage temperature and the storage period, but it was detected, even when no precipitates were visible and when loss of potency was less than 10% of the initial value following storage at 4 or -15 degrees C. CONCLUSION: Submicron particle analysis using scanning electron microscopy, when used in combination with high-performance liquid chromatography, provides a useful method for studying polymer formation in antibiotic solutions and for the quality control of antibiotic injections during storage.

Particulate contamination of lyophilized amphotericin B preparation during reconstitution process.

OBJECTIVE: To investigate the effect of the reconstitution methods for the commercial amphotericin B preparation with respect to particulate contamination. METHODS: The particle counts in amphotericin B solutions reconstituted according to three different methods and amphotericin B fluids made with intravenous fluids after reconstitution were performed using a light extinction method. The particle contaminants were identified with X-ray emission spectrometry attached to a scanning electron microscope. RESULTS: Amphotericin B in a vial induced particle contamination during the reconstitution process, and the contamination was especially marked by shaking vigorously after injecting water into the vial. From the X-ray analysis, it appeared that the increased number of particles was derived from the amphotericin B-deoxycholate complex containing substances such as silicone released from the vial components. Amphotericin B fluid made with intravenous fluids after reconstitution also contained particles over the acceptable limits according to the Japanese or US pharmacopoeia. CONCLUSION: These findings suggest that reconstituted solutions should be filtered with membrane filters and diluted fluids with in-line filters.

Morphologic degeneration of human microvascular endothelial cells induced by iodinated contrast media.

RATIONALE AND OBJECTIVES: The purpose of this study was to characterize the adverse effects of iohexol and ioxaglate on human microvascular endothelial cells, which may result in phlebitis, pain, and thrombosis. MATERIALS AND METHODS: The degree of morphologic degeneration and of lactate dehydrogenase (LDH) efflux into the extracellular medium (as an index of cell viability) were determined in endothelial cell culture exposed for 10, 30, or 60 minutes to ioxaglate or iohexol (ionic and nonionic contrast media, respectively) at iodine concentrations of 100 or 150 mg/mL. RESULTS: Ioxaglate induced concentration- and time-dependent morphologic degeneration, including shrinkage and loss of the cell tip in 20%-80% of endothelial cells; iohexol did not. After 60 minutes of exposure, ioxaglate at the higher concentration (150 mg iodine per milliliter) significantly increased the LDH signal (ie, the percentage of LDH released), to 20%. CONCLUSION: The present findings demonstrate that ioxaglate but not iohexol causes morphologic degeneration of the microvascular endothelial cells. This direct cytotoxic action of ioxaglate probably causes endothelial cell dysfunction, closely associated with the occurrence of phlebitis, pain, and thrombosis.

Contrast medium-induced pulmonary vascular hyperpermeability is aggravated in a rat climacterium model.

UNLABELLED: Tominaga K, Kataoka Y, Sendo T, et al. Contrast medium-induced pulmonary vascular hyperpermeability is aggravated in a rat climacterium model. Invest Radiol 2001;36:131-135. RATIONALE AND OBJECTIVES: To test whether climacterium influences adverse pulmonary reactions to contrast media, the authors investigated the effect of ioxaglate on pulmonary vascular permeability in ovariectomized rats as a climacterium model. METHODS: From 7 days after surgery, ovariectomized rats were treated with estradiol valerate or vehicle once per week for 3 weeks. At 28 days after surgery, ioxaglate, an ionic contrast medium, was intravenously injected at 1.5 mL/min in rats. Pulmonary vascular permeability was evaluated by measuring the amount of Evans blue dye in the lung tissue. RESULTS: Ioxaglate dose-dependently increased pulmonary vascular permeability in sham-operated and ovariectomized rats. Ovariectomized rats showed a 2.6-fold increased aggravation of vascular permeability by ioxaglate 4 g I/kg compared with sham-operated rats. Estradiol valerate (0.2-5.0 mg/kg) dose-dependently blocked ioxaglate-increased vascular permeability in ovariectomized rats. CONCLUSIONS: These findings suggest that climacterium is included, at least in part, in the risk factors for contrast-induced adverse pulmonary reactions, and this risk is lowered by estrogen replacement therapy.

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.

Contrast medium-induced pulmonary edema is aggravated by silicone contamination in rats.

PURPOSE: To examine the effect of silicone contamination, which occurs in clinical settings during vial preparation with disposable syringes, on contrast medium-induced pulmonary edema in rats. MATERIALS AND METHODS: Ioxaglate, ioversol, and iohexol, silicone-containing physiologic saline solutions, and three silicone-containing contrast media were separately, intravenously injected at 1.5 mL/min in rats. Pulmonary edema was evaluated as changes in the relative lung weight and in the water, sodium, and potassium contents of the lung. RESULTS: Intravenous injection of ioxaglate induced marked pulmonary edema, even with a dose of only 4 g of iodine per kilogram of body weight. In contrast, ioversol and iohexol induced significant pulmonary edema only after the injection of large doses (6 g of iodine per kilogram; P < .05). The injection of 4 microL/mL silicone-containing physiologic saline at a dose of 18.75 mL/kg also produced marked pulmonary edema, whereas doses of 6.25 and 12.5 mL/kg showed no significant influence. The addition of an ineffective dose (12.5 mL of physiologic saline per kilogram of body weight) of silicone in contrast medium substantially aggravated the pulmonary edema induced by the contrast medium alone; this phenomenon was also confirmed with morphologic observation. CONCLUSION: Ionic contrast media are more toxic to the endothelial cells than are nonionic contrast media. Silicone contamination might be one of the causes of pulmonary edema after intravenous injection. However, caution must be exercised in extrapolating these results to humans.

High speed injection of radiographic contrast media induces severe particulate contamination.

In a study of exogenous particulate contamination during angiography, the effect of injection speed of four kinds of radiographic contrast media (RCM) was investigated. The particle count (> or = 10 microns) in all RCM increased in a speed-dependent manner and the increase was especially dramatic at 3 ml s-1. The extent of increase in particulate matter was higher for ioxaglate than for the other three RCM. As particulate matter is unwanted and unnecessary, to prevent the harmful effects in patients much attention should be paid to various factors generating particulate matters, such as characteristics of RCM and plastic syringe.

Quality evaluation of radiographic contrast media in large-volume prefilled syringes and vials.

RATIONALE AND OBJECTIVES: The authors compared the particle contaminations of radiographic contrast media packaged in large-volume prefilled syringes and vials. MATERIALS AND METHODS: Particle counting was performed for four contrast media packaged in large-volume prefilled syringes (iohexol, ioversol, ioversol for angiography, and ioxaglate) and three contrast media packaged in vials (iohexol, ioversol, and ioxaglate). X-ray emission spectrometry was performed to characterize the individual particles. The amount of silicone oil in the syringe was quantified with infrared spectrophotometry. RESULTS: The particle contamination in syringes containing ioversol was higher than that in syringes containing iohexol or ioxaglate. Particle contamination in the vials was relatively low, except with ioxaglate. X-ray emission spectrometry of the components of the syringe and vial showed that the source of particles was internal material released from the rubber stopper or inner surface. CONCLUSION: The particle counts for contrast media packaged in syringes and vials varied considerably among the different contrast media and were related to the amount of silicone oil on the inner surface and rubber piston of the syringe.

In-line filter occlusion during intravenous delivery of injectable menatetrenone (vitamin K2).

Filter occlusion during intravenous infusion of injectable menatetrenone in an electrolyte fluid was examined. The menatetrenone concentration and its emulsion droplet size were not changed by in-line filtration. However, particle counts in the admixed solution and examination of scanning electron micrographs of the surface of the filter membrane indicated that particle formation occurred immediately after the admixture of menatetrenone injection with Hicaliq No. 2, but not with 5% glucose injection. This may be due to the interaction of excess lecithin in the emulsion with the electrolyte. Filter occlusion also occurred with the admixture of menatetrenone-free emulsion and Hicaliq No. 2, but not with 5% glucose injection. These findings indicate that injectable menatetrenone should not be admixed with electrolyte fluids.

Vitamin K prodrugs: 2. water-soluble prodrugs of menahydroquinone-4 for systemic site-specific delivery.

PURPOSE: The hydrochloride salts of the N,N-dimethylglycine esters of menahydroquinone-4 (1-mono, 1; 4-mono, 2; and 1,4-bis, 3) were assessed in vivo as prodrug for the systemic site-specific delivery system of menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4, vitamin K2(20)). METHODS: The disposition of MK-4 and menaquinone-4 epoxide (MKO) following the intravenous administration of the prodrugs and MK-4 preparation solubilized with surfactant (H-MK-4) were studied in vitamin K cycle inhibited rats. The relative bioavailability of MKH after the administration of the prodrugs was assessed from the area under the plasma concentration of MKO vs. time curve (AUCMKO). The specific delivery of MKH to its active site (liver) and coagulation activity after the administration of selected prodrug 1 were then compared with those of H-MK-4 in warfarin poisoned rats. RESULTS: All compounds showed linear pharmacokinetics, and significant bioavailability of MKH was also observed following the administration of 1 (188%), 2 (87%) and 3 (135%). Prodrug 1 caused the following increases; AUCliver of MKO from 70.7 +/- 5.77 (H-MK-4) to 167 +/- 7.89 nmol.h/g, MRTliver of MKO, from 3.87 +/- 0.307 to 8.57 +/- 0.432 h. The liver accumulation of intrinsic 1 reached a maximum (88% of dose) by 0.25 h. The rapid and liver-selective uptake and liver esterase mediated MKH regeneration characteristics of 1 enhanced the delivery of MKH to its active site and the selective advantage was increased 5.7 fold. The coagulation activity was extended 1.9 fold by 1 administration. CONCLUSIONS: The results indicated that these highly water-soluble and liver-esterase hydrolyzable ester derivatives of MKH are potential candidates for parenteral prodrugs which can thus achieve the systemic site-specific delivery of MKH. Such effective and selective delivery of MKH to its active site can therefore lead to enhanced pharmacological efficacy and can also avoid the toxicity induced by the solubilizing agent used in the H-MK-4 preparation.

Quality evaluation of commercial lyophilized human growth hormone preparations.

The quality of three commercial injections (Genotropin, Humatrope and Norditropin) of lyophilized recombinant human growth hormone (r-hGH) was evaluated in tests by visual inspection, high-performance gel permeation chromatography, polyacrylamide gel electrophoresis, scanning electron microscopy and energy dispersion X-ray microanalysis. The influence of the reconstitution method on gel formation was examined as follows: rapid injection of the diluting solution into a vial against the wall, slow injection onto the surface of the content, and rapid injection onto the surface of the content. The degree of gel formation differed among reconstitution methods. Moreover, fibrous particulate matter in addition to degradation products of r-hGH were evident in all preparations. The quality of r-hGH injection differed among commercial products. Norditropin included the least particulate matter when examined immediately after reconstitution, but it was easily denatured after storage in solution. We advise medical specialists to reconstitute a preparation by the optimal method.

The evaluation of sizing accuracy of particle counters for parenteral drugs.

Our evaluation of electronic liquid-borne particle counter systems has shown that, for accurate measurement of particulate matter in injections, the half count values of voltage thresholds from the particle counter itself should be used in the calibration for the particle sizes being evaluated. The manual method which uses the half count values in the USP XXIII<788> was improved, and the validity of our calibration method was supported by the results based on the ratio test, at 10 microns to those obtained at 15 microns is between 1.5 and 3.5, as per the Seventh Supplement of USP XXII <788>. Additionally, computer-based systems with automated calibration routines which solve the approximate Gaussian distribution of calibration particles have advantages. For the proper determination of the sizing accuracy of a particle counter, criteria of the ratio test at 10 microns and 15 microns as per the Seventh Supplement of USP XXII <788> should be applied at all critical particle sizes.