Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid)-paclitaxel conjugate

Despite an intensive search, few water-soluble paclitaxel derivatives have been shown to have a therapeutic index superior to paclitaxel itself. We now report a water-soluble poly(L-glutamic acid)-paclitaxel conjugate (PG-TXL) that produces striking antitumor effects with diminished toxicity. A single i.v. injection of PG-TXL at its maximum tolerated dose (defined as that dose that produces a maximum 12-15% body weight loss within 2 weeks after a single i.v. injection) equivalent to 60 mg of paclitaxel/kg and at even a lower dose equivalent to 40 mg of paclitaxel/kg resulted in the disappearance of an established implanted 13762F mammary adenocarcinoma (mean size, 2000 mm3) in rats. (An equivalent dose of PG-TXL is the amount of conjugate that contains the stated amount of paclitaxel.) Similarly, mice bearing syngeneic OCA-1 ovarian carcinoma (mean size, 500 mm3) were tumor-free within 2 weeks after a single i.v. injection of the conjugate at a dose equivalent to 160 mg of paclitaxel/kg. The conjugate has little if any intrinsic tubulin polymerization activity in vitro and is >20 times less potent in supporting the growth of a paclitaxel-dependent CHO mutant cell line. PG-TXL has a prolonged half-life in plasma and greater uptake in tumor as compared with paclitaxel. Furthermore, only a small amount of total radioactivity from PG-[3H]TXL was recovered as free [3H]paclitaxel in either the plasma or the tumor tissue within 144 h after drug injection. Histological studies of tumor tissues obtained from mice treated with PG-TXL show fewer apoptotic cells but more extensive tumor necrosis as compared with paclitaxel treatment. These data suggest that in addition to its role as a carrier for selective delivery of paclitaxel to the tumor, PG-TXL exerts distinct pharmacological actions of its own that may contribute to its remarkable antitumor efficacy.     

Antitumour activity of mitoxantrone-loaded chitosan microspheres against Ehrlich ascites carcinoma

Glutaraldehyde cross-linked chitosan microspheres containing the antineoplastic agent mitoxantrone were prepared and the antitumour activity was evaluated against Ehrlich ascites carcinoma in mice by intraperitoneal injections. The tumour inhibitory effect was followed by monitoring animal survival time and change in body weight for a period of 60 days. While the mean survival time of animals which received 2 mg and 1 mg of free mitoxantrone intraperitoneally was 2.1 and 4.6 days, respectively, animals which received 2 mg mitoxantrone via microspheres showed a mean survival time of 50 days. Five out of 8 animals treated using microspheres lived beyond 60 days. The percentage ratio mean survival time of the treated group divided by the mean survival time of the untreated group for animals treated using mitoxantrone-loaded chitosan microspheres containing 2 mg of the drug was 290 compared with 12.2 for those which received 2 mg of the free drug. The antitumour effect of mitoxantrone-loaded microspheres against Ehrlich ascites carcinoma was much higher than that of doxorubicin-loaded microspheres reported by previous workers. Our data demonstrate the potential of mitoxantrone-loaded chitosan microspheres for sustained drug delivery to minimize drug toxicity and maximize therapeutic efficacy.     

Cardiac arrhythmias in chronic obstructive pulmonary disease

This study was designed to assess a local drug delivery system of an anticancer agent, doxorubicin (DOX), using fibrin glue (Beriplast P) as a drug carrier. In vitro release of DOX from the fibrin glue was examined by a dialysis method in the presence and absence of sodium alginate. The in vitro mean dissolution times of DOX with solution, fibrin glue, and fibrin glue containing sodium alginate were 3.7 h, 8.7 h, and 81 h, respectively, indicating a sustained release of DOX from fibrin glue, especially in the presence of sodium alginate. Fibrin glue containing 6 mg of DOX and 2.5 mg of sodium alginate was applied on the surface of an AH60C tumor at the back of rats. DOX concentrations in the tumor extracellular fluid were monitored by a microdialysis method. Local application of DOX using fibrin glue containing sodium alginate to the tumor resulted in extremely higher concentrations in the tumor extracellular fluid than those in plasma (AUC ratio > 800), indicating an advantage of the site-specific delivery of DOX using fibrin glue with sodium alginate. The tumor volumes were inversely correlated with tumor extracellular fluid-to-plasma AUC ratios (r = 0.882), suggesting the relevance of tumor size in the drug efflux from tumor to blood. In conclusion, the site-specific delivery of DOX using fibrin glue with sodium alginate to the tumor was demonstrated to be advantageous with regard to the extent and duration of drug concentrations in the tumor extracellular fluid, as assessed by a microdialysis technique.     

Enhanced oral absorption and decreased elimination of paclitaxel in mice cotreated with cyclosporin A

Recent experiments in mice have demonstrated that the systemic exposure to p.o. administered paclitaxel is significantly enhanced with coadministration of the P-glycoprotein blocker SDZ PSC 833 (J. van Asperen et al, Br. J. Cancer, 76: 1181-1183, 1997). To facilitate further research on the feasibility of a clinically effective oral formulation of paclitaxel, it is important to know whether cotreatment with a commonly applied and commercially available P-glycoprotein blocker, e.g., cyclosporin A, has a similar effect. Here, we present a detailed study about the effects of cyclosporin A on the pharmacokinetics of p.o. and i.v. administered paclitaxel. Female FVB mice received a combined treatment of 5 or 10 mg/kg paclitaxel (either i.v. or p.o.) plus 0, 10, or 50 mg/kg cyclosporin A (p.o.). The plasma concentrations of paclitaxel were determined at several time points after drug administration using high-performance liquid chromatography. Calculated relative to the area under the plasma concentration-time curve of i.v. administered paclitaxel in mice treated without cyclosporin A, the oral bioavailability of paclitaxel increased from 9.3% up to 67% with coadministration of cyclosporin A. The bioavailability in mice cotreated with 10 or 50 mg/kg cyclosporin A appeared to be similar. The effect of cyclosporin A on the systemic exposure to p.o. administered paclitaxel was the result of both a significantly decreased clearance and an increased uptake. A histological examination revealed that the enhanced absorption was not caused by gastrointestinal toxicity. We conclude that cyclosporin A and SDZ PSC 833 are equally effective in increasing the systemic exposure to p.o. administered paclitaxel. These data are promising for the development of a clinically useful oral formulation of this cytostatic drug and indicate that cyclosporin A is a suitable agent for further research of this concept.     

Programmed diffusional release rate from encapsulated cosolvent system

The programmed diffusional release rate of an active agent through a rate-controlling membrane from a cosolvent system is discussed. At initial conditions, the drug is present below saturation in solution in a solvent mixture, enclosed by the rate-controlling membrane; the solvent is composed of the main solvent and a consolvent, which increases the drug solubility in the main solvent. During operation, the active agent and cosolvent diffuse from the capsule at a rate controlled by the membrane. Equations were derived describing the release rate of the active agent as a function of the permeability of the cosolvent and agent, the capsule dimensions, and the system's initial conditions. A great variety of release rate profiles can be programmed from declining to increasing delivery rate patterns as a function of time. Experimental data are presented for the drug progesterone in solution in cyclohexane with methyl, heptyl, or cetyl alcohol as the cosolvent in a polyethylene capsule. The theory qualitatively predicts the theory qualitatively predicts the experimental results.     

Intratumoral chemotherapy with a sustained-release drug delivery system inhibits growth of human pancreatic cancer xenografts

This study provides the first evidence that treatment of human pancreatic adenocarcinoma is markedly improved by the intratumoral administration of chemotherapeutic agents in a novel drug delivery system. The effect of chemotherapeutic agents delivered in a sustained-release, protein-based, injectable gel was evaluated on the growth of human pancreatic adenocarcinoma cell line, BxPC-3. In vitro chemosensitivity of BxPC-3 cells exposed for 24 or 72 h to fluorouracil (0.01-5 mM), cisplatin or doxorubicin (0.1-50 microM) and floxuridine, vinblastine, mitomycin or paclitaxel (1.0-100 microM) was compared with that of untreated cells. In vitro chemosensitivity was also studied with fluorouracil and mitomycin in the poorly differentiated PANC-1, human pancreatic cancer cell line. Survival was determined after 7-10 days. All drugs decreased cell growth in a dose-dependent fashion. The efficacy of fluorouracil, cisplatin and doxorubicin increased with prolonged exposure, rendering these drugs most appropriate for a sustained-release preparation. For in vivo studies, athymic nude mice bearing BxPC-3 xenografts were treated either with fluorouracil, cisplatin or doxorubicin in the therapeutic injectable gel containing epinephrine or with vehicle alone administered intratumorally on days 1 and 4. After 28 days, the mice were sacrificed and tumors dissected and weighed. Tumors in mice treated with the injectable gel decreased in size by 72-79% compared with tumors in untreated controls and tumors treated with vehicle alone. Intratumoral injection of drug solution and intraperitoneal injection of drug in the injectable gel did not change tumor size compared with controls. In a drug-retention study, mice were injected intratumorally with [3H]fluorouracil either in the injectable gel or in solution. Sustained radioactivity was observed in tumors injected with the gel, and, conversely, greater radioactivity was detected in the liver and kidneys in mice receiving the radiolabeled solution. These results suggest that the therapeutic injectable gel chemotherapy, when given intratumorally, may improve tumor response with less systemic toxicity in comparison with conventional systemic chemotherapy.     

The Preterm Prediction Study: recurrence risk of spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network

Our study was designed to evaluate the pharmacokinetics, tissue distribution, toxicity and therapeutic efficacy of liposome-encapsulated paclitaxel (LET) in comparison to conventional paclitaxel. In normal mice, LET was much less toxic than the conventional drug. A dose of 32.5 mg/kg of conventional paclitaxel administered i.v. on three consecutive days produced 100% mortality by day three, while liposomal paclitaxel exhibited no mortality. The control group which received Diluent 12 (Chremophor EL and ethanol; 1:1 v/v), a vehicle used in conventional paclitaxel, 30% mortality was observed at this dosage level. In murine ascitic L1210 leukemia model, liposomal paclitaxel and conventional paclitaxel showed comparable antitumor activity. The pharmacokinetics of conventional paclitaxel and LET was studied in mice at dose levels of 5 mg/kg and 20 mg/kg. After intravenous administration of conventional paclitaxel at a dose of 5 mg/kg, the area under the plasma-concentration-time curve (AUC) was 2-fold lower and, the elimination half-life was 2-times shorter compared to LET. At a dose of 20 mg/kg, the terminal half-lives were comparable, however, conventional paclitaxel displayed non-linear pharmacokinetics with disproportionate increase in AUC. At the two dose levels studied, LET demonstrated linear kinetics. Tissue distribution of paclitaxel after administration of LET showed levels 10-fold higher in spleen and 3.5-fold higher in liver as compared to conventional paclitaxel. The significant decrease in toxicity shown by LET, coupled with an increase in plasma AUC and half-life indicates that LET may be a viable alternative to the therapeutic use of the conventional preparation of paclitaxel.     

Circadian rhythm in susceptibility of mice to the anti-tumor drug carboplatin

The platinum-containing compounds has become a major chemical agent in the treatment of cancer. A circadian rhythm in the susceptibility of rodents and human being to cisplatin has been demonstrated, the maximal tolerance being found in the animal's active phase. Carboplatin is a second generation analog. Two studies were performed on mice with carboplatin under 12:12 light dark cycle to study its chronotoxicity and chronoeffectiveness. In study I, single intraperitoneal injection of 192mg/kg (LD50) carboplatin was given to four groups of mice at four different circadian stage. It was found that at 50% the overall mortality of mice, there was a mortality difference of 28% for mice receiving the drug at 9 a.m. to 71% for mice receiving drug at 9 p.m. It demonstrated that carboplatin was better tolerated in the animal's early sleep phase. In study II, S180 tumor-bearing mice were treated with 50mg/kg of carboplatin. The longest mean survival time and the lowest marrow toxicity occurred in the group which received the drug at the beginning of the sleep phase. It showed that the susceptibility of mice to carboplatin is circadian stage dependent. These data clearly demonstrate that, by timing the administration of drugs according to body rhythms, such as the host susceptibility-resistance rhythm to a drug, one can gain a therapeutic advantage over an approach which ignores such rhythms.     

Comparative antitumor efficacy of docetaxel and paclitaxel in nude mice bearing human tumor xenografts that overexpress the multidrug resistance protein (MRP)

BACKGROUND: Multidrug resistance has been associated with expression of the multidrug resistance protein (MRP). Recently, MRP-expression has been detected in human tumor samples of patients with breast cancer and non-small-cell lung cancer. Since taxoids are the most active drugs in the treatment of both tumor entities, the antitumor efficacies of paclitaxel and docetaxel were compared in nude mice bearing human tumor xenografts that express MRP. MATERIALS AND METHODS: Athymic nude mice (nu/nu) bearing tumor xenografts of parental human sarcoma HT1080 or MRP-expressing HT1080/DR4 cells (as confirmed by Northern blot analysis) were treated with the maximum tolerated doses (MTD) of doxorubicin ([Dx] 10 mg/kg i.v. push), paclitaxel ([PC] 50 mg/kg three-hour i.v. infusion), or docetaxel ([DC] 40 mg/kg three-hour i.v. infusion). In vitro, the activity of doxorubicin, paclitaxel and docetaxel was evaluated by the sulphorhodamine B (SRB) assay using the pyridine analogue PAK-104P (5 microM), a potent inhibitor of MRP-function. RESULTS: At their MTDs both taxoids showed significant activity against MRP-negative HT1080 xenografts with response rates of 80% (40% CR) for PC and 100% (60% CR) for DC. In contrast, DC was significantly more active than PC in nude mice bearing doxorubicin resistant MRP-expressing HT1080/DR4 tumor xenografts (overall response rates: 100% (60% CR) for DC; 10% (0% CR) for PC; 0% for Dx). Since treatment of mice with the MTD of PC or DC yielded similar overall toxicity (maximum weight loss for HT1080: PC 8.6 +/- 2.2%; DC 7.5 +/- 2.2% and for HT1080/DR4: PC 11.6 +/- 3.0%; DC 7.6 +/- 1.8%, respectively), these results demonstrate the increase in the therapeutic index for docetaxel against MRP-expressing tumors. In vitro, HT1080/DR4 cells were 270-fold, 6.4-fold and 2.8-fold more resistant than parental cells to doxorubicin, PC and DC, respectively. Pyridine analogue PAK-104P completely restored drug sensitivity to PC and DC, while no effect of PAK-104P on parental HT1080 cells was observed. CONCLUSIONS: Both taxoids, when given at their MTDs, showed significant efficacy against parental HT1080 tumor xenografts. However, docetaxel at its MTD was significantly more active against MRP-expressing tumor xenografts than paclitaxel. Furthermore, in vitro resistance of HT1080/DR4 cells was higher for PC (6.4-fold) than for DC (2.8-fold). Since PAK-104P completely restored sensitivity to both taxoids, the observed resistance appears to be related to MRP. These data suggest, that docetaxel is not as readily transported by MRP as paclitaxel leading to an increased therapeutic ratio in MRP-expressing tumors in vivo. Therefore, docetaxel may have therapeutic advantages in the clinical treatment of MRP-expressing tumors.     

Indirect computed tomography lymphography of subdiaphragmatic lymph nodes using iodinated nanoparticles in normal dogs

RATIONALE AND OBJECTIVES: We evaluated the imaging characteristics of an iodinated particulate contrast agent for indirect computed tomography (CT) lymphography of normal subdiaphragmatic lymph nodes in dogs. METHODS: Four milliliters of a 15% (wt/vol) iodinated nanoparticle suspension was injected into the gastric, colonic, rectal, or cervical submucosa, loose paraprostatic fascia, or metatarsal subcutaneous tissues in 10 healthy beagles. Endoscopic, CT, or ultrasound guidance was used when necessary to facilitate contrast agent delivery. CT and radiographic images were obtained prior to contrast administration and at 4 hr, 24 hr, and 7 days postcontrast injection. Postmortem examinations were then conducted. RESULTS: CT images showed enhancement of regional lymph nodes draining the various injection sites. The mean attenuation of opacified nodes was 678 +/- 463 Hounsfield units 24 hr after injection and remained elevated 7 days later. Lymph node opacification on CT images correlated well with the node location observed on postmortem examinations. CONCLUSION: Subdiaphragmatic lymph nodes can be effectively opacified using an iodinated nanoparticle contrast agent for indirect CT lymphography.     

Maximal aerobic velocity measured by the 5-min running field test on two different fitness level groups

PURPOSE: A scleral plug made of biodegradable polymer implanted at the pars plana was evaluated to determine its ability to control the intravitreal release of ganciclovir. METHODS: Scleral plugs containing 25% ganciclovir were prepared with poly(lactic-glycolic acid) (molecular weight, 121 kDa). The release of ganciclovir was evaluated in vitro by spectrophotometry. In vivo intravitreal ganciclovir concentrations were measured by high performance liquid chromatography following plug implantation in pigmented rabbits. The biocompatibility of the device was determined by indirect ophthalmoscopy, electroretinography, and light and electron microscopy. RESULTS: The in vitro study showed that the plug released ganciclovir throughout a 10-week period. The in vivo study demonstrated that the plugs maintained the drug concentration in the vitreous in a therapeutic range adequate to treat cytomegalovirus (CMV) retinitis for 12 weeks. No significant retinal toxicity was observed. CONCLUSIONS: This study demonstrated that this drug delivery system can potentially be useful to treat CMV retinitis.     

In vivo characteristics of injectable poly(DL-lactic acid) microspheres for long-acting drug delivery

Poly(DL-lactic acid) (PLA) microspheres containing testosterone (T) were prepared by the solvent evaporation process to evaluate their physical properties such as size distribution, shape, drug content, in vivo controlled drug release, pharmacological influences on the prostate gland in castrated rats, and histopathological findings of tissues surrounding the implants. The in vivo release of T from PLA microspheres containing 30 mg of drug obtained with chloroform was continued over a 6-week period. This effect is attributed to high dispersibility of T in the device when obtained with chloroform. Both serum drug levels and prostate gland weight recovery suggested the effects of a long-acting drug delivery system. The histopathological findings showed that the devices used were completely degraded 10 weeks after injection.     

Greater antitumor efficacy of paclitaxel administered before epirubicin in a mouse mammary carcinoma

Combined treatment with paclitaxel and anthracyclines is increasingly being tested in clinical practice. Epirubicin is in general administered before paclitaxel. We have investigated, using a murine mammary adenocarcinoma, whether the efficacy and toxicity of this combination is influenced by treatment sequence, different time intervals and dose intensity. The tumor was transplanted into the right hind foot of C3D2F1 female mice. Paclitaxel was administered i.p. in doses ranging from 15 mg/kg to 75 mg/kg and epirubicin (i.p. or i.v.) in doses from 9 mg/kg to 30 mg/kg. The hepatic and peritoneal toxicity observed with epirubicin administration increased in combined treatments (stronger with i.p. than i.v. epirubicin administrations) and was dose-dependent. When paclitaxel and epirubicin were administered simultaneously or paclitaxel was given 24 h before epirubicin, the same tumor growth delays were obtained in all groups. A smaller effect was observed when paclitaxel was administered 24 h after epirubicin. Increasing the epirubicin or paclitaxel dose led to higher tumor growth delays but also an increased toxicity. In conclusion, in this experimental model, the administration of 45 mg/kg paclitaxel before 15 mg/kg epirubicin was very effective and the increased toxicity can be limited by introducing an interval of 24 h between drug administrations. These results should be considered when designing clinical trials.     

Long acting methadone

Tablets were prepared using pan-coating, congealing, plasticization with organic solvents and direct compression methods. The tablets were evaluated using the official dissolution test, and an analysis of the active ingredient was accomplished by employing gas-liquid chromatography. The formulation and dissolution characteristics of sustained release tablets, employing the matrix concept to regulate drug release, were studied. Particle size distribution of plastic material influenced the release rates from porous inert matrices, and it was found that incomplete drug release occurred from these preparations. Three-layer slowly-eroding sustained release tablets, using a swellable gum (carbomer) were formulated; by adjusting the proportion of the gum quantitative release of the drug was attained. Approximation of linearity for drug release-time relationship was achieved from three-layer slowly-eroding tablets containing different concentrations of drug in the middle and outer layers. Administration of the above tablets, containing 30 mg of methadone, produced analgesia in male albino rats for approximately 60 h, without undesirable effects.     

Contrast-agent gas bodies enhance hemolysis induced by lithotripter shock waves and high-intensity focused ultrasound in whole blood

Fresh canine whole blood was exposed in 1.3-mL disposable pipette bulbs with or without added Albunex contrast agent to lithotripter shock waves (rate: 2 Hz; mean pressure amplitude: 14.8 MPa) or 1.28-MHz high-intensity focused ultrasound up to a mean pressure amplitude of 17.8 MPa. Significant shock-wave-induced hemolysis up to about 10% was detected after 500 or more shock waves without added agent, after 200 with 1% added agent and after 100 with 10% added contrast agent. Hemolysis was increased somewhat with added contrast agent, but this enhancement was not statistically significant. For ultrasound exposure, significant hemolysis approaching 100% was detected for 100-ms continuous exposure at 17.8 MPa without added gas bodies. Addition of 1% contrast agent enhanced the hemolysis by reducing the apparent threshold to 10 MPa. Burst mode exposure with a 100-ms total on-time (20 microseconds, 100 microseconds and 1-ms bursts) also yielded hemolysis enhancement with added contrast agent, with results similar to the 100-ms continuous exposure. The added gas bodies appear to lower cavitation thresholds by serving as cavitation nuclei in the blood.     

Cathepsin B-sensitive dipeptide prodrugs. 2. Models of anticancer drugs paclitaxel (Taxol), mitomycin C and doxorubicin

Substrates containing doxorubicin (DOX), paclitaxel (taxol), and mitomycin C (MMC) attached to the cathepsin B-sensitive dipeptide Phe-Lys via a self-immolative spacer were prepared as model compounds for internalizing anticancer immunoconjugates. Cathepsin B-mediated release rates of free drug, rat liver lysosomal susceptibility and human plasma stability were measured for each.     

NLCQ-1, a novel hypoxic cytotoxin: potentiation of melphalan, cisDDP and cyclophosphamide in vivo

PURPOSE: To investigate in vivo interactions between the recently developed bioreductive agent 4-[3-(2-nitroimidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1) and the chemotherapeutic agents melphalan (L-PAM), cis-platin (cisDDP) and cyclophosphamide (CPM). METHODS AND MATERIALS: EMT6 and FSaIIC tumor cells were inoculated (subcutaneously) into the leg(s) of female Balb/c and male C3H mice, respectively. Treatment was initiated at 10 mm (EMT6) and 5 mm (FSaIIC) mean tumor diameter. The in vivo-in vitro and tumor regrowth assays were used, respectively, as endpoints. Bone marrow toxicity studies were also performed when the in vivo-in vitro assay was used. Drugs were given by i.p. injection. Tumors were excised 18-h after chemotherapeutic drug administration (Balb/c mice) or measured daily until three times their original size (C3H mice). The optimum administration schedule for potentiation between NLCQ-1 and each chemotherapeutic drug, as well as dose modification factors (DMF) at the optimum time, were determined with the in vivo-in vitro assay. When the tumor regrowth assay was used, each chemotherapeutic agent was given either as a single dose or as a split dose over two consecutive days at the optimum administration time after a 10 mg/kg NLCQ-1 i.p. injection. RESULTS: NLCQ-1 (at 0.33 times MTD), strongly potentiated the antitumor effect of L-PAM, cisDDP and CPM without concurrent enhancement in bone marrow toxicity. Potentiation was strictly schedule dependent and the optimum effect (1.5 to 2 logs killing beyond additivity) was observed when NLCQ-1 was given 60-, 45-, and 110-min before L-PAM, cisDDP, and CPM, respectively. The DMF values at 30% survival were 2.5, 1.9, and 3.8 for L-PAM, cisDDP, and CPM, respectively. DMF values for bone marrow toxicity at 50% survival were ca. 1 for all chemotherapeutic drugs. Pretreatment with NLCQ-1 resulted in 4-12 days extra delay in the regrowth of FSaIIC tumors. CONCLUSIONS: These results support the clinical investigation of NLCQ-1 as a chemosensitizer.     

Absorption of the anxiolytic pazinaclone in animals as a criterion for species selection for toxicity studies

In rats, mice, hamsters, and guinea pigs given a 5 mg/kg oral dose of pazinaclone (CAS 103255-66-9), unchanged drug concentration in plasma was highest in mice (AUC; 90 ng.h/ml), followed in decreasing order by guinea pigs (AUC; 41 ng.h/ml), hamsters (AUC; 18 ng.h/ml), and rats (AUC; 17 ng.h/ml). In terms of plasma drug concentrations and toxicological background data, there was no better alternative rodents than mice and rats for the toxicity studies. Among rabbits, dogs, and monkeys, the dogs had the highest plasma drug concentrations: AUCs of pazinaclone in dogs and monkeys were 1035 and 458 ng. h/ml, respectively (drug concentration in rabbit plasma was very low). Of the two polymorphs, forms 1 and 2 with particle size of < or = 5 microns, the oral absorption of form 2 in rats was more efficient than that of form 1 at 1000 mg/kg: AUCs of pazinaclone after dosing of form 1 and 2 were 489 and 965 ng.h/ml, respectively. However, form 1 was selected for the toxicity studies because of the poor physico-chemical properties of forms 2. Form 3 was not included in this study, because this form was relatively unstable and contained relatively large amount of impurities. The absorption of pazinaclone in dogs was improved by decreasing its particle size: AUCs of pazinaclone after dosing of the drug having particle size of 5.5, 20.8, and 79.3 microns were 1361, 822, and 297 ng.h/ml, respectively. Since large-scale preparation of bulk pazinaclone with a particle size of 5 microns or smaller was not feasible, the drug having a particle size of about 20 microns was used in the toxicity studies. The absorption of pazinaclone was more extensive when the drug was given to fed animals as suspension. Thus, the toxicity studies were performed using form I of pazinaclone with a particle size of about 20 microns primarily in rats, mice, and dogs.     

Direct suppression of Stat1 function during adenoviral infection

The phenomenon of enhanced backscatter from myocardial contrast agents was studied using two examples, a robust thicker-walled, intra-arterial agent (AIP 201) and a smaller thinner-walled, intravenous agent (Quantison). Both agents are composed of albumin-encapsulated microbubbles. Samples of the agents were inserted into an in vitro phantom and insonated under different scanning regimes. Upon insonation, Quantison exhibited a pronounced increase in mean backscatter at medium and low concentrations, which decreased dramatically with increasing number of frames of insonation. At high concentrations, no dramatic decrease or increase in mean backscatter was observed over the period of the experiment. AIP 201 exhibited an overall decrease in mean backscatter with increasing number of frames of insonation. These results suggest that the difference in size and wall thickness of the contrast microcapsules can significantly affect the behaviour of the contrast agents in an ultrasound field.     

Effect of ultrasound on the release of micro-encapsulated drugs

Although ultrasound is used extensively in medical therapies and diagnostics, it has been recognized only recently as a method for external controlled diversity of drugs. In this paper, firstly, a literature review on drug delivery and the combination with ultrasound is given. Then an experiment is described on measuring the release of a model drug (hexabrix) under ultrasound irradiation, from a polymer carrier.