Treatment sequences and drug costs from diagnosis to death in multiple myeloma.

Novel therapies for multiple myeloma (MM) have improved patient survival, but their high costs strain healthcare budgets. End-of-life phases of treatment are generally the most expensive, however, these high costs may be less justifiable in the context of a less pronounced clinical benefit. To manage drug expenses effectively, detailed information on end-of-life drug administration and costs are crucial. In this retrospective study, we analysed treatment sequences and drug costs from 96 MM patients in the Netherlands who died between January 2017 and July 2019. Patients received up to 16 lines of therapy (median overall survival: 56.5 months), with average lifetime costs of €209 871 (€3111/month; range: €3942-€776 185) for anti-MM drugs. About 85% of patients received anti-MM treatment in the last 3 months before death, incurring costs of €20 761 (range: €70-€50 122; 10% of total). Half of the patients received anti-MM treatment in the last 14 days, mainly fully oral regimens (66%). End-of-life treatment costs are substantial despite limited survival benefits. The use of expensive treatment options is expected to increase costs further. These data serve as a reference point for future cost studies, and further research is needed to identify factors predicting the efficacy and clinical benefit of continuing end-of-life therapy.

Evidence against the Human Metapneumovirus G, SH, and M2-2 Proteins as Bona Fide Interferon Antagonists.

The production of type I interferon (IFN) is the hallmark of the innate immune response. Most, if not all, mammalian viruses have a way to circumvent this response. Fundamental knowledge on viral evasion of innate immune responses may facilitate the design of novel antiviral therapies. To investigate how human metapneumovirus (HMPV) interacts with the innate immune response, recombinant viruses lacking G, short hydrophobic (SH), or M2-2 protein expression were assessed for IFN induction in A549 cells. HMPV lacking G or SH protein expression induced similarly low levels of IFN, compared to the wild-type virus, whereas HMPV lacking M2-2 expression induced significantly more IFN than the wild-type virus. However, sequence analysis of the genomes of M2-2 mutant viruses revealed large numbers of mutations throughout the genome. Over 70% of these nucleotide substitutions were A-to-G and T-to-C mutations, consistent with the properties of the adenosine deaminase acting on RNA (ADAR) protein family. Knockdown of ADAR1 by CRISPR interference confirmed the role of ADAR1 in the editing of M2-2 deletion mutant virus genomes. More importantly, Northern blot analyses revealed the presence of defective interfering RNAs (DIs) in M2-2 mutant viruses and not in the wild-type virus or G and SH deletion mutant viruses. DIs are known to be potent inducers of the IFN response. The presence of DIs in M2-2 mutant virus stocks and hypermutated virus genomes interfere with studies on HMPV and the innate immune response and should be addressed in future studies. IMPORTANCE Understanding the interaction between viruses and the innate immune response is one of the barriers to the design of antiviral therapies. Here, we investigated the role of the G, SH, and M2-2 proteins of HMPV as type I IFN antagonists. In contrast to other studies, no IFN-antagonistic functions could be observed for the G and SH proteins. HMPV with a deletion of the M2-2 protein did induce type I IFN production upon infection of airway epithelial cells. However, during generation of virus stocks, these viruses rapidly accumulated DIs, which are strong activators of the type I IFN response. Additionally, the genomes of these viruses were hypermutated, which was prevented by generating stocks in ADAR knockdown cells, confirming a role for ADAR in hypermutation of HMPV genomes or DIs. These data indicate that a role of the HMPV M2-2 protein as a bona fide IFN antagonist remains elusive.

Carfilzomib for relapsed and refractory multiple myeloma.

Although the prognosis of multiple myeloma (MM) patients has dramatically improved during recent years, virtually all patients eventually develop relapsed refractory disease. Several new therapeutics have been developed in the last few years, including carfilzomib, a second-generation proteasome inhibitor (PI) that has been approved by the US Food and Drug Administration (FDA) in the setting of relapsed and/or refractory MM, as a single agent with or without dexamethasone, and in combination with lenalidomide in 2012 and 2015, respectively. Other promising combinations with carfilzomib are being investigated. Carfilzomib has shown superiority over the first-generation PI bortezomib on both efficacy and toxicity. In particular, profoundly lower incidence in polyneuropathy compared to bortezomib has been described. However, carfilzomib has a different toxicity profile, with more cardiovascular adverse events. Therefore, caution should be taken with the use of carfilzomib for elderly and cardiovascularly compromised patients. The once-weekly administration of carfilzomib, recently approved by the FDA in combination with dexamethasone, will lead to a lower burden for the patient and caregivers compared to the twice-weekly schemes that were routinely used until recently. This review has a focus on clinical trial data that has led to drug approval, as well as new promising combination studies, and provides advice for treating physicians who are now prescribing this drug to patients.

The relationship between phenazone (antipyrine) metabolite formation and theophylline metabolism in healthy and frail elderly women.

The influence of aging on the metabolism of phenazone (antipyrine), and the relationship between the formation of 3 phenazone metabolites and the metabolic clearance of theophylline in healthy and frail elderly women, were examined. Whereas the elimination half-life did not change, clearance of phenazone decreased by about 50% with age in healthy women receiving phenazone without theophylline. However, the summation of the urinary recovery of phenazone and the measured metabolites, expressed as percentage of the phenazone dose, was lower in the healthy elderly (37 +/- 9% vs 74 +/- 15%). In both healthy and frail females the clearance of formation of 4-hydroxy-phenazone and the metabolic clearance of theophylline correlated strongly (r = 0.93 and 0.90, respectively). In non-healthy elderly females, strong correlations were also observed between the other metabolic pathways of phenazone and the metabolic clearance of theophylline. Coadministration of theophylline in the elderly increased the percentage of the phenazone dose excreted as the measured metabolites. A considerably higher interindividual variability in the disposition of phenazone and theophylline was observed in the frail elderly women. This high degree of variability in drug metabolism may be one of the explanations for the problems often occurring after drug prescription in the elderly.

Bioavailability of inorganic arsenic from bog ore-containing soil in the dog.

In some parts of The Netherlands, bog ore-containing soils predominate, which have natural arsenic levels that exceed, by a factor of 10, existing standards for maximum allowable levels of inorganic arsenic in soil. These standards are based on the assumption that in humans the bioavailability of arsenic from ingested soil is equal to that from an aqueous solution. In view of the regulatory problem that the arsenic levels of these soils present, we questioned the validity of this assumption. To obtain a more realistic estimate, the bioavailability of inorganic arsenic from soil in a suitable animal model was studied. In this report, a study performed in six dogs in a two-way cross-over design is presented. The dogs received orally, in random order, arsenic both as an intravenous solution and as arsenic-containing soil. During a 120-hr period after administration urine was collected in 24-hr fractions. Levels of arsenic were determined using a method of wet digestion, isolation and complexation of arsine, followed by molecule absorption spectrometry. Within 120 hr after intravenous administration, 88 +/- 16% of the dose was excreted renally. After oral administration of arsenic-containing soil, only 7.0 +/- 1.5% was excreted renally. From the urinary excretion data for these two routes of administration, the calculated bioavailability of inorganic arsenic from soil was 8.3 +/- 2.0%. The results from this study demonstrate the need to reconsider the present risk assessment for arsenic in soil.

Comparison of five incubation systems for rat liver slices using functional and viability parameters.

Precision-cut liver slices are presently used for various research objects, e.g. to study metabolism, transport, and toxicity of xenobiotics. Various incubation systems are presently employed, but a systematic comparison between these incubation systems with respect to preservation of slice function has not been performed yet. Therefore, we started a comparative study to evaluate five of these systems: the shaken flask (an Erlenmeyer in a shaking water bath), the stirred-well (24-well culture plate equipped with grids and magnetic stirrers), rocker platform (6-well culture plate with Netwell insert rocked on a platform), the roller system (dynamic organ culture rolled on an insert in a glass vial), and the 6-well shaker (6-well culture plate in a shaking water bath). The liver slices were incubated in these incubation systems for 0.5, 1.5, and 24.5 h and subsequently subjected to viability and metabolic function tests. The viability of the incubated liver slices was evaluated by: potassium content, MTT assay, energy charge, histomorphology, and LDH leakage. Their metabolic functions were studied by determination of the metabolism of lidocaine, testosterone, and antipyrine. Up to 1.5 h of incubation all five incubation systems gave similar results with respect to viability and metabolic function of the liver slices. However, after 24 h, the shaken flask, the rocker platform, and the 6-well shaker incubation systems appeared to be superior to the stirred well and the roller incubation systems.

Mathematical descriptions of accelerated transformation of 1,3-dichloropropene in soil; a microbiological assessment.

The rate of transformation of the soil fumigant (Z)-and (E)-1,3-dichloropropene in moist soil layers was measured at incubation temperatures of 5 degrees C, 10 degrees C and 20 degrees C. 'DD95' was added to four characterized soil layers, in amounts corresponding to realistic field contents after fumigation. Rapid transformation immediately after application was observed in layers with low initial contents (30-300 micrograms/kg dm) and could well be described with a first-order rate model. Incubation at higher doses (5-15 mg/kg dm respectively) showed distinctly different transformation pathways. Degradation curves could well be computed using a microbiological interspective competition (MIC) model for moist soil. The transformation rate is inversely correlated to microorganism population size and growth. Transformation curves described by MIC are characterized by a lag-time, a period of accelerated transformation and a period of decreasing transformation rates. At low temperatures, DT50 values of more than 20 days could be observed. First-order rate computations did not exceed 8 days. The use of different mathematical discriptions for various soil layers and soil temperatures permits simulation of DD95-transformation by microorganisms in the soil profile throughout the growing season.

Primary and metastatic liver cancer.

OBJECTIVES: To review liver physiology, the disease process, diagnostic tests, and current treatment options for primary and metastatic liver cancer. DATA SOURCES: Research studies, review articles, and textbooks relating to liver cancer. CONCLUSIONS: Surgical resection offers the best available treatment modality, but only a small percentage of patients are eligible. However, combined treatment of radiation therapy and chemotherapy (systemic and intra-arterial), as well as chemoembolization, cryosurgery, and transplantation, offers hope of palliation, conversion of unresectable to resectable disease, and prolonged survival. IMPLICATIONS FOR NURSING PRACTICE: Understanding and knowledge of the disease process and treatment modalities for primary and metastatic liver cancer will assist the oncology nurse in educating patients and families during their diagnostic and treatment phases.

Current regulatory (draft) guidance on chiral medicinal products: Canada, EEC, Japan, United States.

The rapid development of stereospecific analytical, synthetic, and preparative methods has profoundly changed the prospects for development and application of chiral medicinal products. This has induced regulatory agencies, e.g., in Canada, the EEC, Japan, and the United States, to prepare guidance on this subject. The present draft documents are discussed, with emphasis on the two most important cases: (1) New racemates: How many extra requirements are justified? (2) Development of a single enantiomer from an approved racemate: how few are acceptable? At the moment the opportunities for early harmonisation are favourable and the formulation of one international guidance document seems feasible.

Metabolism of simultaneously administered antipyrine and theophylline in male BN/BiRij rats before and after induction with 3-methylcholanthrene.

In order to study the metabolic activities of different P-450 enzymes in male Brown Norway rats, formation rates of antipyrine (AP) metabolites and theophylline (TH) metabolic clearance were determined. Brown Norway rats are often used in studies concerning the influence of age on liver function. Experiments were performed after simultaneous iv administration of the two compounds with and without 3-methylcholanthrene (3-MC) pretreatment. Pharmacokinetic data of both AP and TH were significantly influenced by 3-MC pretreatment. Metabolic clearance of AP increased from 6.8 +/- 1.0 (mean +/- SD, N = 23) to 18.4 +/- 7.9 (N = 10) ml.min-1.kg-1, whereas the metabolic clearance of TH increased from 1.9 +/- 0.6 to 20.0 +/- 5.1 ml.min-1.kg-1. Elimination half-life in plasma decreased from 77 +/- 10 to 33 +/- 9 min for AP and from 171 +/- 36 to 25 +/- 7 min for TH, respectively. Urinary recovery as the metabolites 3-hydroxymethylantipyrine, 4-hydroxyantipyrine, and norantipyrine accounted for approximately 36% of the administered dose in the control situation, and for approximately 21% after 3-MC pretreatment. 3-MC pretreatment strongly reduced the formation of 3-hydroxymethylantipyrine, but increased the formation rate of 4-hydroxyantipyrine and norantipyrine. Weak correlations were found between the clearances of formation of the AP metabolites and the metabolic clearance (CLm) of TH in the control rats. This may be caused by a large contribution of constitutive P-450 enzymes in the formation of AP metabolites and/or the metabolic clearance of TH in Brown Norway rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved clean-up procedure for the high-performance liquid chromatographic assay of bupivacaine enantiomers in human plasma and ultrafiltrate in the nanogram per milliliter range.

A clean-up procedure to obtain a minimal detectable concentration of 5-10 ng bupivacaine enantiomer per milliliter human plasma is described. The procedure consists of precipitation of plasma proteins using acetonitrile, followed by solid-phase extraction using a cyano column. The eluate is then made alkaline, and bupivacaine is extracted using n-hexane. After evaporation of n-hexane, the residue is redissolved in the eluent used for HPLC analysis. The HPLC method has been described previously. The minimal detectable concentrations using this method are ca. 8 and 10 ng/ml for R-(+)- and S-(-)-bupivacaine, respectively. For both enantiomers, r2 is > 0.995 over the range of 9.5-760 ng/ml enantiomer.

Sulphation and glucuronidation of xamoterol in the dog: dose dependence and site of sulphation.

1. Xamoterol has been administered both intravenously and orally over a 100-fold dose range to male beagle dogs. 2. Over the dose range examined, sulphation was not saturable, with the proportion of the dose excreted as the sulphate conjugate remaining constant. 3. Extensive first-pass sulphation of an oral dose of xamoterol occurred in the intestine with approximately 50% of sulphation occurring during absorption. 4. The intestine is not a major site of sulphation for circulating xamoterol. 5. The liver is not believed to play an important role in the first-pass sulphation of xamoterol.

Pharmacokinetics of xamoterol glucuronidation in the rat in vivo and in liver perfusion.

Xamoterol has a phenolic hydroxyl group at which both sulphation and glucuronidation may occur. In the rat in vivo it is almost exclusively glucuronidated. In bile the glucuronide conjugate is the only metabolite of xamoterol. In urine equal amounts of the glucuronide conjugate and unchanged xamoterol are present, together with a small amount of the sulphate conjugate (approx. 1% of the dose). The t1/2 of excretion of the glucuronide in bile was the same as the t1/2 for excretion of unchanged xamoterol in urine. The t1/2 for urinary excretion of the glucuronide conjugate was longer than that for its biliary excretion. In the isolated perfused rat liver glucuronidation was also the almost exclusive metabolic pathway. The extraction ratio of xamoterol by the liver was approx. 0.15. Since xamoterol is a very water-soluble compound, and is almost exclusively glucuronidated in the rat, it is an excellent model substrate for investigations on the pharmacokinetics of glucuronidation in the rat in vivo and in isolated perfused organs.

High-performance liquid chromatographic assay of mepivacaine enantiomers in human plasma in the nanogram per milliliter range.

A method enabling quantification of R-(-)- and S-(+)-mepivacaine in human plasma in the low nanogram per milliliter range is described. The procedure involves extraction from plasma with diethyl ether, centrifugation, back-extraction into an acidified aqueous solution, washing with a mixture of pentane and isoamylalcohol, alkalinisation, followed by extraction with a mixture of n-pentane and isoamylalcohol. After evaporation of the organic phase, the residue is redissolved in the mobile phase used for the HPLC analysis, which consists of a 6.8:93.2 (v/v) isopropanol-sodium hydrogenphosphate buffer solution with the pH adjusted to 6.8 using phosphoric acid. The HPLC method has been described previously. Separation of the enantiomers is achieved with an alpha 1-AGP column and the UV detection wavelength is 210 nm. The minimal detectable concentration is ca. 3 ng/ml and the lower limit of quantification is 5 ng/ml for each enantiomer. For both enantiomers r is > 0.9995 over the plasma enantiomeric concentration range of 10.5-1053 ng/ml.

The influence of aging on the metabolism of simultaneously administered hexobarbital enantiomers and antipyrine before and after phenobarbital induction in male rats: a longitudinal study.

The influence of aging on the metabolism of antipyrine (AP) and hexobarbital enantiomers (R-HB and S-HB) with and without phenobarbital (PB) induction was investigated in a longitudinal study in rats aged 6, 12, 24 and 30 months. The metabolic clearances of AP (Clm AP), R-HB (Clm R-HB) and S-HB (Clm S-HB) were used as indicators for P450 enzyme activities in vivo. This also included the assessment of the clearances of formation of three AP metabolites, 3-hydroxymethylantipyrine (Cl-->HMA), 4-hydroxyantipyrine (Cl-->OHA) and norantipyrine (Cl-->NORA). Aging appeared to have little influence on the pharmacokinetics of the model compounds. By contrast, the influence of PB pretreatment on Clm AP changed dramatically with aging. The extent of induction decreased from 4.5-fold at 6 months to 1.7-fold at 30 months. Aging influenced the clearances of formation of the three metabolites differentially. Clm S-HB was about six times higher than Clm R-HB without induction. After PB induction, S-HB did not reach detectable levels in plasma at 6, 12 and 24 months. At 30 months, PB pretreatment resulted in a significantly decreased Clm S-HB when compared with the uninduced state. The extent of induction of R-HB metabolism had decreased strongly at 24 and 30 months. The present results clearly indicate that in the aged rat, the P450 enzyme system is much less sensitive to PB induction.

Itraconazole pulse therapy is effective in the treatment of Majocchi's granuloma: a clinical and pharmacokinetic evaluation and implications for possible effectiveness in tinea capitis.

Majocchi's granuloma is a folliculitic and perifolliculitic dermatophyte infection of the dermis, a site that is not generally colonized by fungi in immunocompetent individuals. Topical agents are usually ineffective therapeutically because of the deep location of the infection. The objective of this study was to determine the effectiveness of oral itraconazole. We also examined the pharmacokinetics of the drug in scalp hair during pulse therapy. This information would then be useful in determining the efficacy of itraconazole administered by means of intermittent pulse dosing in the treatment of tinea capitis. Seven patients (age range 25-75 years) were treated up to three times with itraconazole pulse therapy, 200 mg twice daily for 1 week, with 2 weeks off between pulses. Samples of scalp hair and plasma were also obtained to determine the pharmacokinetics of the drug at these two sites. All seven patients responded to therapy, clinical and mycological cure being achieved after one pulse (one patient), two pulses (three patients), or three pulses (three patients, each with toenail onychomycosis); none relapsed over a 6-18-month follow-up period. In all six patients who received two or more pulses of itraconazole, almost complete cure was observed before the second pulse, with full resolution within 2 weeks of its completion. Itraconazole was also detected in the hair after 1 week, and at concentrations 2.6-fold and 3.4-fold higher, respectively, after the second and third pulses. After the discontinuation of therapy, itraconazole was then detectable in the hair for 9 months, at least in a female patient who did not have her hair cut. Two pulses of oral itraconazole therapy thus appear to be effective in the treatment of Majocchi's granuloma, and it is possible that one pulse may be sufficient in some patients. These data suggest that itraconazole pulse therapy should be effective in the treatment of tinea capitis.

Bioavailability and disposition of 3H-solanine in rat and hamster.

1. The toxicokinetics of [3H]-alpha-solanine after oral (p.o.) and intravenous (i.v.) administration in rat and hamster were studied, in order to decide which is the most appropriate model in risk assessment studies. The i.v. dose was 54 micrograms/kg; the oral dose was 170 micrograms/kg. 2. After i.v. administration, the toxicokinetics of total radioactivity in blood were comparable in rat and hamster. However, the clearance of total radioactivity from plasma was more effective in rat than in hamster. The half-lives of distribution and of the terminal phase of unchanged alpha-solanine were not different between rat and hamster, whereas the systemic and metabolic clearance were, respectively, about 1.6 and 2.7 times higher in rat than in hamster. The clearance of unchanged alpha-solanine is more effective than of total radioactivity. 3. After p.o. administration in rat and hamster, the mean bioavailability of total radioactivity is about 29 and 57%, respectively. The bioavailability of unchanged alpha-solanine is only 1.6 and 3.2%, respectively, when compared with i.v. administration. 4. T1/2el of alpha-solanine after p.o. administration was in rats a factor of four and in hamsters a factor of two shorter than after i.v. administration. A strong retention of radioactivity was seen in the hamsters after p.o. administration; only 40% of the dose was excreted within 7 days versus 90% in rat. 5. Based on these and toxicological data from literature, it was decided that the hamster is a more appropriate model in (sub)-chronic toxicity studies with alpha-solanine than the rat.