Plasma Level-time Curve Research Articles

The preparation of Cistanche phenylethanoid glycosides liquid proliposomes: Optimized formulation, characterization and proliposome dripping pills in vitro and in vivo evaluation

Water-soluble Cistanche phenylethanoid glycosides (CPhGs) have poor permeability and low bioavailability. However, liposomes can improve the permeability of such drugs and their poor stability, and proliposomes have been used to overcome these problems. Based on this, Cistanche phenylethanoid glycoside liquid proliposomes (CPhGsP) and dripping(?) pills were prepared and optimized using response surface methodology. The properties of CPhGsP were evaluated in terms of their encapsulation efficiency, particle size, zeta potential, and morphology. The results obtained showed that the optimal formulation was drug/soybean phospholipid/poloxamer-188/sodium deoxycholate/propylene glycol 1:22.38:3.52:0.84:80 (w/w/w/w/v). This resulted in an encapsulation efficiency, particle size, and zeta potential of hydrated proliposomes with phosphate buffer solution (pH7.4) of 51.97%, 671.7nm, and −25.49mV, respectively. Stability testing of CPhGsP and CPhGs ordinary liposomes was carried out for 3months at 4±2°C, 25±2°C, 40±2°C, 75±5% RH. The results obtained showed that the stability of the proliposomes was better than that of ordinary liposomes at the same temperature, while a lower temperature of 4°C is ideal for storage. Cistanche phenylethanoid glycoside liquid proliposomes dripping pills (CPhGsPD) are efficiently released in gastrointestinal solution as shown by in vitro release experiments and the structure of the liposomes does not destroy the proliposome dripping pills by hydration. In vivo experiments showed that the areas under the plasma level-time curves and peak concentrations of CPhGsPD and hydrated proliposomes were higher than those of CPhGs. Moreover, with CPhGsPD, the pharmacokinetic parameters were similar to those with hydrated proliposomes. These results showed that CPhGsPD offer a good way to improve the oral delivery of CPhGs.

Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects

To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased C max (25% ∼ 64%), increased area under the plasma level-time curves (30~76%), increased area under the time infinity (43% ∼ 80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.

Sex Difference in Formation of Propofol Metabolites: A Replication Study

Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men - an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I-II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose- and weight-adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4-hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4-hydroxypropofol-1-O-β-D-glucuronide (Q1G) and 4-hydroxypropofol-4-O-β-D-glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p=0.03), Q1G (2.9 times, p<0.001), Q4G (2.4 times, p<0.01) and OHP (4.6 times, p=0.01) were found in women (n=53) than in men (n=45) after intravenous infusion of propofol using target-controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women - a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients.

Liquid Proliposomes of Nimodipine Drug Delivery System: Preparation, Characterization, and Pharmacokinetics

To investigate the possibility of liquid proliposomes being carriers for oral delivery, nimodipine liquid proliposomes-based soft capsules (NPSC) were prepared. Nimodipine proliposomes were characterized by transmission electron microscopy (TEM), conversion rate from proliposomes to liposomes, entrapment efficiency, particle size, and zeta potential. Accelerated stability testing of NPSC was carried out for 3 months at 40±2°C, 75±5% RH. The concentration of nimodipine in plasma of New Zealand rabbits of NPSC, nimodipine soft capsules, and hydrated liposomes was studied. Results showed that nimodipine proliposomes were automatically converted into liposomes when exposed to a water phase in 30 s. The average diameter was 378.6±26.5 nm in distilled water with entrapment efficiency (EE%) of 84.7±5.9%, while the average diameter was 316.9±34.6 nm in 0.1 M hydrochloric acid solution with EE% of 72.8±4.7%. Accelerated stability test showed that there was no change in drug content, particle size, and EE% except for a decrease in dissolution of nimodipine. In vivo experiments, areas under the plasma level-time curve of NPSC and nimodipine-hydrated liposomes increased 2.41 and 2.34 times more than that of nimodipine soft capsules, peak concentration increased 2.87 and 2.92 times, time of peak concentration from 0.75 to 2 and 1 h, respectively. Nimodipine-hydrated liposomes presented similar pharmacokinetic parameters compared with NPSC. Results suggested that NPSC offered a potential way to improve oral delivery of nimodipine.

A Comparative Study of the Pharmacokinetics of Conventional and Sustained-release Tablet Formulations of Aceclofenac in Healthy Male Subjects

Purpose: To examine the pharmacokinetics of a formulated aceclofenac sustained release tablet formulation and determine if it is bioequivalent to a commercial brand of aceclofenac immediate release tablet (Zerodol® 100 mg). Methods: Each of two groups of twelve fasting volunteers received either the reference standard (Zerodol 100 mg tablets) or the test formulation (200 mg aceclofenac) orally once, using a cross-over design with a one week wash-out period. Their blood samples were obtained at regular time intervals over 24 h and analyzed by high performance liquid chromatography (HPLC). Using the noncompartmental approach, plasma levels of aceclofenac were employed to compute their individual disposition kinetics, including peak plasma concentration (Cmax), peak time (Tmax), area under the plasma level-time curve (AUC 0-t), elimination rate constant (Kel) and elimination half life ( t1/2). Results: The Cmax values of 11043 ± 3073 ng/ml and 12301 ± 3000 ng /ml were attained in 2.58 ± 1.22h and 1.29 ± 0.75 h for the test and reference products, respectively, while AUCO-
was 45996 ± 10427 and 50253 ± 8283 ng.h/ml, respectively. At 90% confidence interval, the C max, AUC 0-t and AUC0-
values of the test preparation were 96.4 - 101.3, 100.2 -101.9 and 98.5 - 99.8%, respectively, of the values for the reference. The t1/2 values were found to be 4.50 ± 1.25 and 2.20 ± 2.59 h for the reference and test products. Conclusion: On the basis of the pharmacokinetic data, it can be said that the test aceclofenacsustained release formulation and the reference product were bioequivalent in some respects. However, the test formulation exhibited a longer elimination half-life (t1/2), thus demonstrating sustained release properties, unlike the reference.Keywords : Pharmacokinetics; Bioequivalence; Sustained release aceclofenac formulation.

Spray-dried doxorubicin-albumin microparticulate systems for treatment of multidrug resistant melanomas

As multidrug resistance continues to be a problem in cancer treatment, controlled release delivery systems, such as microspheres, may aid to give a slower release of anticancer drugs into drug resistant tumor cells. In this study doxorubicin microspheres microencapsulated in an albumin matrix were prepared via the spray-drying method and characterized for particle size, content analysis, and release studies. They were then evaluated in vitro using drug resistant murine melanoma tumor cells for uptake and efflux studies. Spray-drying produced a dispersed powder with a mean particle size of 4.91 ± 1.2 µm, 60% product yield, and encapsulation efficiency of 85% and a ζ potential range of 37 to −40 mV. Intracellular doxorubicin concentrations were higher in drug resistant tumor cells treated with microspheres as opposed to solution, and efflux of doxorubicin from the tumor cell was inhibited. Greater cytotoxic effects were seen in tumor cells treated with doxorubicin microspheres versus solution up to and after 3 days. In vivo pharmacokinetic studies conducted in male Sprague–Dawley rats, revealed a plasma-level time curve indicative of a two-compartment model, and showed prolonged half-life of doxorubicin, greater area under the plasma concentration time curve, and increased plasma concentrations of doxorubicin in rats at 8 and 24 h after administration of doxorubicin microspheres.

A Phase II Study of Cisplatin and Irinotecan as Induction Chemotherapy Followed by Accelerated Hyperfractionated Thoracic Radiotherapy with Daily Low-dose Carboplatin in Unresectable Stage III Non-small Cell Lung Cancer: JCOG 9510

It is important to find optimal regimens of cisplatin (CDDP)-based third-generation chemotherapy and radiotherapy for patients with unresectable Stage III non-small cell lung cancer (NSCLC). This Phase II study was designed to determine the toxicity and efficacy of two courses of chemotherapy (CDDP 80 mg/m(2) on day 1 and irinotecan 60 mg/m(2) on days 1 and 8) followed by accelerated hyperfractionated thoracic radiotherapy (60 Gy/40 fractions in 4 weeks) combined with daily carboplatin (CBDCA) administration. CBDCA was administered at a target area under the plasma level-time curve of 0.4 x (24 h creatinine clearance + 25), according to Calvert's formula. Twenty-six patients were enrolled in the study. The patients' median age was 63 years (range 40-74 years) and included 22 males and 4 females. Seven patients were Stage IIIA and 19 were Stage IIIB. Twenty had a performance status (PS) of 1 versus six with a PS of 0. There was one treatment-related death due to sepsis and pneumonia associated with Grade 4 neutropenia and diarrhea during chemotherapy. Grade 3 or 4 neutropenia and diarrhea were observed in 14 and 5 patients, respectively. Toxicity of the radiotherapy was mild. There were 0 complete response and 13 partial responses, giving a response rate of 50.0%. Median survival time and 2-year survival were 16.4 months and 21.5%, respectively. This study was designed with Simon's two-stage design, and the response rate did not meet the criteria to proceed to the second stage and the study was terminated early. This regimen might be inactive for patients with unresectable Stage III NSCLC.

Acute-phase Response Alters the Disposition Kinetics of Cefepime following Intravenous Administration to Rabbits

The effect of experimentally induced fever on the pharmacokinetics of cefepime administered intravenously at a dose of 75 mg/kg bw was studied in six healthy rabbits. The study was conducted in two consecutive phases, separated by a washout period of 2 weeks. Infection was induced by the intravenous inoculation of 5 x 10(8) cfu of Escherichia coli 24 h before the pharmacokinetic investigation was carried out. Serial blood samples for cefepime concentration determination were obtained for 48 h following drug administration. The concentrations of cefepime in the plasma were determined by a quantitative microbiological assay using an agar-gel diffusion method employing Bacillus subtilis ATCC 6633 as the test organism, with a level of detectability of approximately 0.10 microg/ml. Cefepime plasma concentrations versus time were evaluated by non-compartmental methods using WinNonLin. Cefepime was well tolerated and no serious adverse events were observed. Rectal temperature increased 1 degree C 24 h post injection in infected animals. Highly significant differences in the blood plasma concentrations of cefepime were observed between febrile and healthy animals at all the sampling times. This could explain the greater area under the plasma level-time curve of the drug in febrile compared with healthy animals. The results from pharmacokinetic calculations showed that both the distribution volume at steady state (V (dss)) and body clearance (CL(tot)) were affected in febrile as compared to healthy animals. The mean values of V (dss) and CL(tot) of cefepime in healthy rabbits were 1.168 L/kg and 0.303 L/kg/h, respectively. As compared with healthy animals, the mean estimates of V (dss) (0.917 L/kg) and CL(tot) (0.205 L/kg per h) of cefepime were significantly lower, whereas t (1/2lambda), MRT and AUMC were significantly higher in febrile rabbits. It is concluded that, although experimental infection had an effect on the disposition kinetics of cefepime in healthy and febrile rabbits, this was not sufficiently pronounced to require alteration of the dosage during disease.

Effects of Oils and Pharmaceutical Excipients on the Bioavailability of Ampicillin Orally Administered, Different Oily and Aqueous Suspensions in Rabbit

The in vivo bioavailability and in vitro drug-release studies of ampicillin trihydrate in different oily and aqueous suspensions have been investigated. In addition, partition, solubility, and rheological measurements have also been carried out. The in vivo experimental design was based on a 6 × 6 latin square using the rabbit as the test animal. The bioavailability of ampicillin was determined using the plasma levels, which were measured microbiologically. Results of the study showed that oily and sucrose-containing aqueous formulations enhanced the extent of ampicillin absorption, although not statistically significantly, but was close to the borderline of significance. Ampicillin appears to be absorbed at essentially the same rate from both aqueous and oily formulations. The latter showed plasma-level time curves with biphasic absorption and are likely to produce prolonged plasma concentrations of ampicillin because of the effects of enterohepatic recycling. Viscosity appears to play an insignificant role in the results obtained since the bioavailability parameters correlate poorly with the viscosity except Cmax. It is suggested that enhancement in the bioavailability of ampicillin is due to the decrease in the gut transit rate brought about by the oil which predominates and masks the other effects of viscosity and osmotic effects of sucrose. The existence of a correlation between the in vitro drug-release rate (t50%) and viscosity and the lack of a correlation between in vivo and in vitro parameters support the above suggestion and indicate that traditional dissolution rate tests, such as flask-stirrer method, are unsatisfactory as bioavailability indicators when applied to dosage forms that caused marked changes in physiological factors like GER and biliary excretion.

Improved oral bioavailability of artemisinin through inclusion complexation with β- and γ-cyclodextrins

The bioavailability of β- and γ-cyclodextrin artemisinin complexes was evaluated in comparison with a normal commercially available preparation, Artemisinin 250 ®. Twelve healthy male volunteers participated in the study conducted according to a three-way crossover design. The bioavailability was compared using the parameters, total area under the plasma level–time curve (AUC 0–∝), peak plasma concentration ( C max), and time to reach peak plasma concentration ( T max). A statistically significant difference was observed between the values of the complexes and Artemisinin 250 ® for the three parameters. However, no statistically significant difference was observed between the values of the β- and γ-cyclodextrin complexes. Moreover, the 90% confidence interval for the ratio of the AUC 0–∝ values of the β-cyclodextrin complex over those of Artemisinin 250 ® was estimated to be between 1.51–2.04, while that of C max was between 1.73–2.93. For the γ-cyclodextrin complex, the respective intervals were 1.30–1.76 and 1.43–2.43. These findings indicated that the β- and γ-cyclodextrin complexes had a much higher rate and extent of bioavailability compared to Artemisinin 250 ®. In addition, the absorption of artemisinin was observed to be poor and negligible when the preparations started to arrive in the colon. This could be attributed to poor dissolution of artemisinin in the semi-solid faecal matter in the lower part of the gastrointestinal tract.

Identification of functionally variant MDR1 alleles among European Americans and African Americans.

MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1 ) or a site-directed Ser893 mutation (MDR1*2 ) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy. The ARBs specifically block the interaction of angiotensin II at the AT1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development. The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect. The variation in the molecular structure of the ARBs results in differences in the binding affinity to the receptor and pharmacokinetic profiles. The differences observed in lipid solubility, absorption/distribution, plasma protein binding, bioavailability, biotransformation, plasma half-life, and systemic elimination influence the time of onset, duration of action, and efficacy of the ARBs. On the basis of the daily mg dose, the antihypertensive potency of the ARBs follows the sequence: candesartan cilexetil > telmisartan approximately = losartan > irbesartan approximately = valsartan > eprosartan. After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels = 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavailability, except for valsartan (a reduction of 40-50%) and eprosartan (increase). A limited dose-peak plasma levels/areas under the plasma level-time curve proportionality is observed for some of the ARBs. Most of these drugs have high plasma protein binding (95-100%); irbesartan has the lowest binding among the group (90%). The steady-state volumes of distribution vary from a low of 9 L (candesartan) to a high of 500 L (telmisartan). (ABSTRACT TRUNCATE

Comparative Bioavailability Study of Two Controlled-Release Pentoxifylline Tablet Preparations

The bioavailability of a generic preparation of pentoxifylline sustained-release (SR) tablet was evaluated in comparison with a proprietary product (Trental 400®). For the study, 12 healthy male volunteers participated; the study was conducted according to a randomized, two-way crossover design. The bioavailability was compared using the parameters total area under the plasma level-time curve AUC0−∞, peak plasma concentration Cmax, and time to reach peak plasma concentration Tmax. No statistically significant difference was observed between the values of the two products in all three parameters. The 90% confidence interval for the ratio of the logarithmic transformed AUC0−∞ values of the generic pentoxifylline over those of Trental 400 was found to lie between 0.83 and 1.00, while that of the parameter Cmax was between 0.91 and 1.29. In addition, elimination half-life t1/2 and apparent volume of distribution Vd were calculated. There was no statistically significant difference between the t1/2Vd values obtained from the data of the two preparations.

Contrasting Nutrient Effects on the Plasma Levels of an Amino Acid-Like Antiepileptic Agent from Jejunal Administration in Dogs

The absorption of gabapentin was investigated by monitoring drug plasma levels as a function of time following midjejunal administration in mongrel dogs. From previous work, dose-dependent absorption had been postulated to be a consequence of carrier-mediated transport and a paracellular pathway had been postulated to contribute to the passive absorption component in mammalian small intestine. The potential for amino acid inhibition of the carrier-mediated absorption component was investigated by drug coinfusion with leucine and phenylalanine. The potential for monosaccharide-enhanced increases in drug absorption was studied by drug coinfusion with D-glucose and 3-O-methylglucose. While lower drug plasma levels were observed with amino acid coinfusion versus controls in each of the dogs studied, mean area under the plasma level time curves (AUC) were not statistically significantly different (p ≤ 0.07). Monosaccharide coinfusion significantly increased gabapentin AUC over control studies (p≤0.014) and over coinfusion with L-system amino acids (p≤0.0025). Implications for the mechanisms of intestinal absorption of this amino acid-like antiepileptic drug in this canine model are discussed.

Colonic absorption of antiepileptic agents.

To evaluate a canine intestinal accessport model to study colonic absorption of drugs. The antiepileptic drugs phenytoin and gabapentin were chosen to study absorption of a lipophilic and hydrophilic compound, respectively. Drug plasma level-time plots were generated subsequent to small intestinal and colonic drug administration of both drugs. The poorly water-soluble phenytoin was administered in two doses to evaluate the impact of dissolution rate limits on colonic absorption. Maximal plasma concentration (Cmax) and area under the plasma level-time curve (AUC) were used to assess the relative contribution of colonic absorption to plasma levels. Whereas colonic gabapentin AUC and Cmax were only 0.25 and 0.15 of those seen after small intestinal administration, colonic phenytoin AUC and Cmax were one half and equivalent to, respectively, those observed for small intestinal administration. Furthermore, colonic administration of a higher phenytoin dose showed secondary maxima and continued increases in drug plasma levels with time. Colonic gabapentin absorption is poor compared with upper intestinal absorption, consistent with membrane transport rate limits to the absorption of this hydrophilic AED. Peak phenytoin plasma levels from colonic and small intestinal administration are comparable, indicating membrane transport does not limit absorption of this lipophilic agent. Continued plasma-level increases from higher phenytoin doses are consistent with dissolution-rate control of drug absorption in the colon. We suggest that colonic absorption provides a greater potential for toxicity from phenytoin overdose as a function of continued drug dissolution than for gabapentin overdose.

Concurrent daily carboplatin and accelerated hyperfractionated thoracic radiotherapy in locally advanced nonsmall cell lung cancer

Purpose : This study was designed to evaluate the feasibility and efficacy of accelerated hyperfractionated thoracic radiotherapy concurrently combined with daily carboplatin in patients with locally advanced, unresectable nonsmall cell lung cancer. Methods and Materials : Thirty-one patients with locally advanced nonsmall cell lung cancer were treated with continuous course, twice daily thoracic radiotherapy (1.5 Gy each) to a total of 60 Gy over 4 weeks. Carboplatin (25 mg/m2) i.v. was given immediately before each morning thoracic radiotherapy. Blood samples were taken to measure the blood free platinum pharmacokinetics on day 1. Results : All 31 patients completed the protocol treatment without delay. The median age was 73 years, and the majority had Stage IIIA (32%) or IIIB (48%) disease. Major acute toxicity (≥Grade 3) included 17 patients (55%) with leukopenia, 5 patients (16%) with thrombocytopenia, and 7 patients (23%) with esophagitis. One possible treatment-related death due to diffuse pneumonitis was observed. There were three complete responses (CRs) and 23 partial responses 9PRs) in the radiation field, for a response rate of 84%. The relapse pattern was predominantly loco-regional, and the median survival time was 9.8 months. The area under the plasma level-time curve (AUC) of free platinum correlated significantly ( r = −0.41, p = 0.01) with the surviving fraction of leukocytes, but not with the severity of the esophagitis. Responders had significantly ( p = 0.04 by Welch's t-test) higher AUCs than nonresponders. Conclusions : This combination therapy was feasible and efficacious against locally advanced nonsmall cell lung cancer. Although long-term local control still remains unsatisfactory, pharmacokinetic data are suggestive of a role for platinum in enhancing the radiation effect.

Pharmacokinetics and Comparative Bioavailability of Two Metoprolol Tablet Preparations

AbstractThe bioavailability of a generic preparation of metoprolol (Beatrolol®) was evaluated in comparison with a proprietary product (Betaloc®). Twelve healthy volunteers participated in the study conducted according to a two-way crossover desing. The bioavailability was compared using the parameters, total area under the plasma level-time curve (AUC0-00), peak plasma concentration (Cmax), and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the values of the two products in all three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic tranformed AUC0-00 values of Beatrolol over those of Betaloc was found to lie between 0.93 and 1.07, which is within the acceptable equivalence limit of 0.80-1.25. From the data obtained, it also appeared that a relatively high proportion of our volunteers were poor metabolizers of metoprolol. The mean elimination half-life (t1/2), was found to be relatively larger than those report...

塩酸モルヒネの経鼻吸収および脳内移行に及ぼすシクロデキストリン誘導体の影響

The extent of systemic availability of morphine after the nasal administration of morphine hydrochloride in solution was much greater than those when the opioid was given orally in solution and rectally in suppository in rats. The ratio of area under the plasma level-time curve of intact morphine to the main metabolite, morphine-3-glucuronide for the nasal administration was about twice those for the oral and rectal administrations and almost equivalent to that for the intravenous administration. Furthermore, higher levels of morphine in the cerebrospinal fluid were attained after the nasal administration compared with the oral and rectal routes. The nasal administration of morphine produced a dose-dependent analgesic response, as measured by the hot-plate method. The efficacy of morphine to block the hot-plate response increased in the order : oral < nasal < subcutaneous route. The scanning electron microscopic observations and membrane permeability studies using a transport marker, 6-carboxyfluorescein revealed that morphine neither induced noticeable changes in surface morphology of the nasal mucosa nor affected the nasal membrane permeability to the transport marker. Dimethyl-β-cyclodextrin significantly enhanced the rate of nasal absorption of morphine by facilitating the nasal epithelial permeability and consequently increased the entry of the opioid into the cerebrospinal fluid. In contrast, 2-hydroxypropyl-γ-cyclodextrin sustained the plasma levels of morphine, probably through the formation of a complex that was less permeable through membranes. The present results suggest that the nasal cavity is a potential route of administration for morphine to bypass first-pass metabolism and is able to deliver the opioid more effectively into the central nervous system. A proper use of the cyclodextrin derivatives in nasal morphine preparations may provide adequate analgesia for both acute and chronic pain states, thus offering an improvement in patient comfort.

Distribution, metabolism and tumoricidal activity of doxorubicin administered in sorbitan monostearate (Span 60) niosomes in the mouse.

Encapsulation of doxorubicin in niosomes was sought as a route to tumour targeting and improved tumoricidal through the alteration of doxorubicin pharmacokinetics and metabolism. Doxorubicin niosomes (10 mg kg-1 doxorubicin) prepared from sorbitan monostearate (Span 60), cholesterol and choleth-24 (a 24 oxyethylene cholesteryl ether) in the molar ratio 45:45:10 were administered intravenously to female NMRI mice bearing the MAC 15A subcutaneously implanted tumour. Plasma doxorubicin was fractionated by gel filtration and quantified by HPLC with fluorometric detection as niosome-associated doxorubicin and released doxorubicin. Tumoricidal activity of the formulation was assessed by the intravenous injection of 5 mg kg-1 and 10 mg kg-1 doxorubicin niosomes to male NMRI mice bearing a 6 day old MAC 15A tumour. At least 90% of the plasma doxorubicin was associated with the niosome fraction 4 h after dosing, and 50% was still associated after 24 h. The clearance of doxorubicin released from the niosomes was about 10 fold greater than the clearance of niosomal doxorubicin (176.5 mL h-1 and 16.2 mL h-1, respectively). The area under the plasma level-time curve increased 6 fold when doxorubicin was administered in niosomes, compared to doxorubicin solution (66.0 micrograms.h mL-1 and 10.3 micrograms. h mL-1, respectively). The area under the tumour level time curve was increased by over 50% by the administration of doxorubicin in niosomes when compared to the drug administered in solution (58.6 micrograms.h mL-1 and 34.3 micrograms.h mL-1, respectively). There was no statistically significant difference between levels of the drug in the heart when niosomal doxorubicin or doxorubicin solution were administered. Doxorubicin metabolites, namely doxorubicinol and the aglycones doxorubicinone, doxorubicinolone and 7-deoxydoxorubicinone, were found associated with the niosomes in the plasma, possibly due to their adsorption to the vesicle surface once formed outside the niosome. Overall metabolite levels in the liver were increased when doxorubicin niosomes were administered compared to the drug in solution. A 5 mg kg-1 injection of doxorubicin niosomes produced a terminal mean tumour weight that was similar to that obtained from animals administered 10 mg kg-1 doxorubicin solution. Modest tumour targeting was achieved by the delivery of doxorubicin in sorbitan monostearate niosomes, increasing the tumour to heart AUC0-24 ratio from 0.27 to 0.36 and a doubling of tumoricidal activity. The overall level of doxorubicin metabolites was also increased.

Pharmacokinetics of torasemide and its metabolites in end-stage renal disease.

The pharmacokinetics of torasemide, a new loop diuretic, as well as its active metabolites M1 and M3, and its inactive main metabolite, M5, were studied in 12 patients with end-stage renal failure during single i.v. (n = 6) or single oral (n = 6) dosing of 200 mg torasemide, and during chronic oral treatment for 9 days (n = 12). The elimination half-life (t1/2) of torasemide was unchanged in renal failure, whereas t1/2 of the torasemide metabolites M1, M3, and M5 were markedly prolonged. However t1/2 as well as the area under the plasma level time curve of torasemide and its metabolites were unchanged during chronic compared to acute administration. The results of this study suggest that despite the increased half-life of torasemide metabolites M1, M3 and M5 in end-stage renal failure patients, no accumulation of the parent drug torasemide and its metabolites during chronic dosing is demonstrable.