Pharmacy

BACKGROUND: Cytokine therapy is currently used as first-line treatment of metastatic renal cell carcinoma (mRCC). Until recently, treatments with proven efficacy after the failure of first-line cytokine therapy were not available. In recent clinical trials, sunitinib has been associated with good response rates in patients with mRCC.OBJECTIVE: The aim of this study was to analyze the cost-effectiveness of sunitinib as second-line therapy for cytokine-refractory mRCC compared with current routine clinical practice in Finland (ie, best supportive care [BSC], including palliative biochemotherapy).METHODS: A probabilistic decision-analytic model was developed to estimate the cost-effectiveness of sunitinib. Data were gathered from clinical trials, literature sources, and expert opinions, as well as from a local sample (n = 39) from 2 university hospitals in Finland. Clinical experts treating patients with mRCC in Finland provided the information on care practices of prescribing sunitinib. The analysis was conducted from the perspective of the health care payer in Finland.RESULTS: According to estimated incremental cost-effectiveness ratios (ICERs), 1 progression-free month gained cost euro4802 (2005 Euros); 1 life-year gained cost euro30,831; and 1 quality-adjusted life-year (QALY) gained cost euro43,698, compared with BSC, in the treatment of mRCC. The expected mean cost in BSC was euro5543. When parameter uncertainty was considered, the probability of sunitinib being the more cost-effective choice of treatment was ~70% at the willingness-to-pay level of euro45,000/QALY gained.CONCLUSIONS: Based on the results of this cost-effectiveness analysis, sunitinib is potentially cost-effective as a second-line treatment of mRCC compared with the treatment currently practiced in Finnish hospitals. The ICER (euro/QALY gained) obtained in the present study was less than the value considered suitable for novel oncology treatments.

Information on detailed treatment costs and the economic burden of renal cell carcinoma (RCC) is rare. The current study provides treatment costs and outcomes of patients with metastatic RCC (mRCC), as well as estimates of the future burden from the perspective of Finnish health care. These results offer a baseline against which the impact of emerging treatments may be evaluated.MATERIALS AND METHODS: Information on treatment modalities, survival, and the cost of treatment was retrospectively gathered from mRCC patients (n = 83) receiving first-line interferon-alpha (IFN). Predictions of the number of new cases, premature deaths, and productivity losses were made using local epidemiological data, which were projected to the future using population growth forecasts. The future costs of mRCC treatment and the budget impact of sunitinib were estimated through modeling.RESULTS: Patients survived 11.9 months (median; 95% CI 9.2-14.7) after initiation of active IFN treatment, accruing an average total treatment cost of 951 euros. Most of the treatment costs were due to hospitalization and active IFN treatment. The aging of the population leads to nearly a 2% increase in the absolute number of new diagnoses annually, while at the same time it results in declining productivity losses. The estimated five-year population cost of IFN-based treatment was 16M euros-26M euros. Adding sunitinib to the first-line treatment protocol increased this cost by 13M eruos-41M euros.CONCLUSIONS: Despite the limited number of patients, metastatic renal cell carcinoma places a considerable economic burden on Finnish society. Treatment costs are likely to increase substantially due to the adoption of new and more expensive medications, the aging population, and enhanced survival times.

Novel oxime derivatives (2, 3 and 5) of buparvaquone (1) and O-methyl-buparvaquone (4) were synthesized and their in vitro activities against Leishmania donovani, the causative agent of visceral leishmaniasis (VL), were determined. Buparvaquoneoxime (2) was also studied as a bioreversible prodrug structure of buparvaquone (1). Buparvaquone-oxime (2) released buparvaquone (1) in vitro when it was incubated with induced rat liver microsomes, which suggests that the oxime-structure is a useful prodrug template for developing novel prodrugs of buparvaquone and other hydroxynaphthoquinones. Moreover, the formation of NO 2 À , formed via oxidation of NO, was confirmed during the bioconversion. The release of NO from buparvaquone-oxime (2) may provide an additional therapeutic effect in the treatment of leishmaniasis. Buparvaquone-oxime (2) and buparvaquone-O-methyloxime (3) demonstrated moderate activity against amastigotes of the Leishmania species that causes VL. However, the studied oximes (2, 3) most probably did not release buparvaquone (1) and NO during the present in vitro experiment. Further in vivo studies are needed to verify the biological activity of buparvaquone-oximes in the treatment of leishmaniasis.

An efficient five-step synthetic route was developed for full N-substitution of chitosan with a quaternary betaine moiety. The developed synthetic procedure can also be controlled to produce chitosan N-betainates having lesser degrees of substitution. 6-O-Triphenylmethylchitosan, which is highly soluble in organic solvents, was used as an intermediate for N-acylation reactions. Intermediate products were characterized by 13 C CP/MAS NMR, FT-IR, and elemental analysis. The water-soluble quaternary chitosan N-betainates were thoroughly characterized by 1 H NMR and 13 C NMR and by 2D 1 H-1

Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueous solubility at low pH and/or its hydrophilic character at neutral pH. Various novel N -alkyl and N,Ndialkyl carbamate esters of entacapone were synthesized as possible prodrugs of entacapone in order to increase its aqueous solubility at an acidic pH and to increase its lipophilicity at neutral pH. Oral bioavailability of entacapone and selected carbamate esters were investigated in rats. Both N -alkyl and N,N -dialkyl carbamate esters were relatively stable against chemical hydrolysis at pH 7.4 (t 1/2 ϭ 14.9Ð 20.7 h), but hydrolyzed rapidly (t 1/2 ϭ 0.8Ð2.7 h) in human serum. However, in contrast to N -alkyl carbamates, N,N -dialkyl carbamates did not release entacapone in in vitro enzymatic hydrolysis (human serum) studies. N -Alkyl carbamates, 2a-c, showed increased aqueous solubility at pH 7.4, of which 2a and 2c also show increased aqueous solubility at pH 5.0, compared to entacapone. In addition to increased aqueous solubility, 2c showed increased lipophilicity at pH 7.4. However, two N -alkyl carbamates of entacapone did not increase the oral bioavailability of the parent drug in rats. Thus, it can be concluded that the relatively low lipophilicity of entacapone is not the cause of its low bioavailability.

A novel codrug, in which L-Dopa and entacapone are linked via a biodegradable carbamate spacer to form a single chemical entity, was synthesized and studied kinetically. This carbamate codrug provides adequate stability [t 1/2 ) 12.1 h (pH 1.2); 1.4 h (pH 5.0); 1.1 h (pH 7.4)] against chemical hydrolysis but rapidly hydrolyzes to L-Dopa and entacapone in liver homogenate (t 1/2 ) 7 min; pH 7.4) at 37°C. The therapeutical potential of this novel codrug is discussed.

Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successfull prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethylbuparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (e0.03 µg/mL) over a pH range of 3.0-7.4. Moreover, 4a and 4b maintained adequate lipophilicity as indicated by distribution coefficients (log D) between 0.5 and 3.0 over this pH range. Both 4a and 4b were also shown to be substrates for alkaline phosphatase in vitro and thus are promising bioreversible prodrugs for the improved topical and oral bioavailability of 1. Buparvaquone and its prodrugs showed nanomolar or lowmicromolar ED 50 activity values against species that cause cutaneous leishmaniasis, e.g., L. major, L. amazonensis, L. aethiopica, L. mexicana, and L. panamensis and also L. donovani, which is the causative agent of visceral leishmaniasis. From these results, the human skin permeation of the prodrugs 4a and 4b were studied in vitro. While no buparvaquone permeated across post mortem skin in vitro during 72 h of experiments, both prodrugs 4a and 4b permeated readily through the skin. In addition, 4b easily released the parent drug in human skin homogenate and, therefore, is a promising prodrug candidate to deliver buparvaquone through the skin for the treatment of cutaneous leishmaniasis.

The highly CB2 selective cannabinoid receptor inverse agonist, 7-methoxy-2-oxo-8-pentyloxy-1,2dihydroquinoline-3-carboxylic acid N-benzo dioxol-5-ylmethyl)amide (JTE-907; 9b), served as the lead compound for investigating the structure-activity relationships of its analogues and in the search for more potent and effective CB2 receptor inverse agonists. A series of aromatic amides of 7-methoxy-2-oxo-8pentyloxy-1,2-dihydroquinoline-3-carboxylic acid 6 was synthesized, and the CB2 receptor activities of the compounds were determined by a [ 35 S]GTP γ S-binding assay using membranes of CHO cells stably transfected with the human CB2 receptor. As a result, all the compounds were defined as full CB2 receptor inverse agonists, and additionally, except for two 3,4-dihydroxyphenylalkylamides, they were found to be equally potent as SR144528.

AbstractÐEntacapone was reacted with phosphorous oxychloride in dry pyridine to yield a phosphate ester. The phosphate promoiety increased aqueous solubility of the parent drug by more than 1700-and 20-fold at pH 1.2 and 7.4, respectively. The phosphate ester provides adequate stability (t 1/2 =2227 h; pH 7.4) towards chemical hydrolysis, and allowed for release of the parent drug via enzymatic hydrolysis in liver homogenate. #

Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme. Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain, inflammation, and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2. In the present study, a total of 34 novel compounds were designed, synthesized, characterized, and tested against FAAH and MAGL-like enzyme activity. Altogether, 16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC 50 ) between 28 and 380 nM. All the active compounds belong to the structural family of carbamates. Compounds 14 and 18 were found to be the most potent FAAH inhibitors, which may serve as lead structures for novel FAAH inhibitors.

A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl prodrugs. All of the prodrugs were more lipophilic than their parent molecules, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log Papp). However, their solubilities in aqueous solutions decreased markedly compared with the parent molecules. The prodrugs were stable toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The abilities of the selected naproxen acyloxyalkyl prodrugs to deliver naproxen through excised human skin were evaluated. Generally, the prodrugs showed similar dermal delivery as the parent drug through cadaver skin. In the present series of lipophilic prodrugs of naproxen, the prodrug with the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.

Purpose. To synthesize and evaluate various novel aminoacyloxyalkyl esters of naproxen (3a-i) and naproxenoxyalkyl diesters of glutamic and aspartic acids (3j-m) as potential dermal prodrugs of naproxen. Methods. The prodrugs 3a-m were synthesized, and their aqueous solubilities, lipophilicities and hydrolysis rates were determined in a buffered solution and in human serum. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. Results. The aminoacyloxyalkyl prodrugs showed higher aqueous solubilities and similar lipid solubilities, in terms of octanol-buffer partition coefficients (log Papp) at pH 5.0, when compared with naproxen. At pH 7.4 the prodrugs were significantly more lipophilic than naproxen. Prodrugs3a-i showed moderate chemical stability in aqueous solutions at pH 5.0 and were rapidly converted to naproxen in human serum (t1/2 = 4−19 min). The selected aminoacyloxyalkyl prodrugs possessed a higher flux across the skin than naproxen, with a maximum enhancement of 3-fold compared to naproxen. Prodrugs 3j-mshowed poor aqueous solubility and permeation across the skin. Conclusions. Combinations of adequate aqueous solubility and lipophilicity of naproxen aminoacyloxyalkyl prodrugs having fast rates of enzymatic hydrolysis resulted in improved dermal delivery of naproxen.

An efficient synthetic route was developed for the mild chloroacylation of chitosan with different chloroacyl chlorides. Full N-chloroacylation was obtained with this procedure without any O-acylation, and products having lower degrees of substitution can also be produced. Organo-soluble 6-O-triphenylmethylchitosan was used as a starting material for the acylation reactions. The resulting N-chloroacyl-6-O-triphenylmethylchitosan intermediates were also organo-soluble and characterized by FT-IR. N-Methylpiperazine moieties were attached to make end products that were sufficiently soluble for characterization by NMR and also to prove that the present intermediates could be used for further modifications. The end products were fully characterized by 1 H NMR, 13 C NMR, and 2D 1 H-13 C heteronuclear single-quantum correlation NMR spectroscopy. The degrees of substitution were determined by 1 H NMR. Molecular weight determination by GPC-LS displayed a significant degradation of the polymer. The weight-average molar masses (M w ) of the end products ranged from 29.6 to 49.4 kDa, when the M w of the starting material was 144.2 kDa.

Novel oxime derivatives (2, 3 and 5) of buparvaquone (1) and O-methyl-buparvaquone (4) were synthesized and their in vitro activities against Leishmania donovani, the causative agent of visceral leishmaniasis (VL), were determined. Buparvaquoneoxime (2) was also studied as a bioreversible prodrug structure of buparvaquone (1). Buparvaquone-oxime (2) released buparvaquone (1) in vitro when it was incubated with induced rat liver microsomes, which suggests that the oxime-structure is a useful prodrug template for developing novel prodrugs of buparvaquone and other hydroxynaphthoquinones. Moreover, the formation of NO 2 À , formed via oxidation of NO, was confirmed during the bioconversion. The release of NO from buparvaquone-oxime (2) may provide an additional therapeutic effect in the treatment of leishmaniasis. Buparvaquone-oxime (2) and buparvaquone-O-methyloxime (3) demonstrated moderate activity against amastigotes of the Leishmania species that causes VL. However, the studied oximes (2, 3) most probably did not release buparvaquone (1) and NO during the present in vitro experiment. Further in vivo studies are needed to verify the biological activity of buparvaquone-oximes in the treatment of leishmaniasis.

An efficient five-step synthetic route was developed for full N-substitution of chitosan with a quaternary betaine moiety. The developed synthetic procedure can also be controlled to produce chitosan N-betainates having lesser degrees of substitution. 6-O-Triphenylmethylchitosan, which is highly soluble in organic solvents, was used as an intermediate for N-acylation reactions. Intermediate products were characterized by 13 C CP/MAS NMR, FT-IR, and elemental analysis. The water-soluble quaternary chitosan N-betainates were thoroughly characterized by 1 H NMR and 13 C NMR and by 2D 1 H-1

Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueous solubility at low pH and/or its hydrophilic character at neutral pH. Various novel N -alkyl and N,Ndialkyl carbamate esters of entacapone were synthesized as possible prodrugs of entacapone in order to increase its aqueous solubility at an acidic pH and to increase its lipophilicity at neutral pH. Oral bioavailability of entacapone and selected carbamate esters were investigated in rats. Both N -alkyl and N,N -dialkyl carbamate esters were relatively stable against chemical hydrolysis at pH 7.4 (t 1/2 ϭ 14.9Ð 20.7 h), but hydrolyzed rapidly (t 1/2 ϭ 0.8Ð2.7 h) in human serum. However, in contrast to N -alkyl carbamates, N,N -dialkyl carbamates did not release entacapone in in vitro enzymatic hydrolysis (human serum) studies. N -Alkyl carbamates, 2a-c, showed increased aqueous solubility at pH 7.4, of which 2a and 2c also show increased aqueous solubility at pH 5.0, compared to entacapone. In addition to increased aqueous solubility, 2c showed increased lipophilicity at pH 7.4. However, two N -alkyl carbamates of entacapone did not increase the oral bioavailability of the parent drug in rats. Thus, it can be concluded that the relatively low lipophilicity of entacapone is not the cause of its low bioavailability.