Disposition, bioavailability and clinical efficacy of orally administered acepromazine in the horse

The pharmacokinetics and pharmacological efficacy of orally (p.o.) administered acepromazine were studied and compared with the intravenous (i.v.) route of administration in a cross-over study using six horses. The oral kinetics of acepromazine can be described by a two-compartment open model with first-order absorption. The drug was rapidly absorbed after p.o. administration with a half-life of 0.84 h, tmax of 0.4 h and Cmax of 59 ng/ml. The elimination was slower after p.o. administration (half-life 6.04 h) than after i.v. injection (half-life 2.6 h). The bioavailability of the orally administered drug formulation was 55.1%. After p.o. administration of 0.5 mg/kg acepromazine, the parameters of the sedative effect were similar to those obtained after i.v. injection of 0.1 mg/kg. The effect of the drug on blood cell count and haemoglobin content was similar after both p.o. administration and injection, while the effects on the parameters of penile prolapse and on the mean arterial blood pressure were less pronounced after p.o. administration than after injection. After p.o. administration, no significant effects on haematocrit-level as well as on the heart and respiratory rates were observed, while these parameters were significantly affected after injection. It is concluded that the high initial plasma level of the drug after i.v. injection may play a role in producing adverse effects of acepromazine.     

Extravascular administration of factor IX: potential for replacement therapy of canine and human hemophilia B

Current therapy for hemophilia B requires large intravenous doses of factor IX (F.IX) given in the clinic or at home. Although home therapy is possible for many patients, it is often complicated by factors such as the lack of good venous access. Very little is known about extravascular routes for administering proteins like F.IX (57 kD) or other vitamin K-dependent procoagulant factors into the circulation. Questions about the absorption rate from extravascular administration as well as plasma recovery and bioavailability have arisen recently with the growing availability of highly purified procoagulant proteins and increased interest in gene therapy of hemophilia B. Therefore, a group of studies were undertaken to determine the absorption rate, plasma recovery, and bioavailability of high purity, human plasma-derived F.IX concentrates administered via extravascular routes in hemophilia B dogs and in one human hemophilia B subject. Five hemophilia B dogs were given human F.IX via either a subcutaneous (s.c.), intramuscular (i.m.), intraperitoneal (i.p.) or intravenous (i.v.) route. In a subsequent study, a single SC administration of human F.IX was compared to an identical i.v. dose of F.IX in the human hemophilia B subject. All extravascular routes of F.IX administration in both the canine and human gave lower levels of circulating plasma F.IX than the i.v. route, however all routes resulted in measurable F.IX activity. Of the extravascular routes, the i.m. injection in the canine resulted in a bioavailability of 82.8%, while the s.c. injection resulted in a bioavailability of 63.5%. F.IX reached the plasma compartment by all extravascular routes used, confirming that F.IX can be absorbed extravascularly. The duration of measurable F.IX activity following extravascular administration is prolonged beyond that typically seen with i.v. administration. These data show that significant levels of F.IX may be obtained via s.c. injection in canine and human hemophilia B subjects and further highlight the potential of extravascular routes of administration for future experimental and clinical uses of F.IX and other procoagulant proteins.     

Electrophysiology of atrial fibrillation and its prevention by coronary sinus pacing

OBJECTIVES: Prehospital providers are often unable to obtain intravenous (i.v.) access in cardiac arrest victims. While several drugs can be administered via the endotracheal (ET) route, serum drug levels are lower than those obtained with the i.v. route. The authors hypothesized that a 90-degree torso tilt after ET drug administration would increase drug levels. METHODS: A randomized, prospective, unblinded laboratory trial was conducted. Twenty-three mixed-breed domestic swine (20-25 kg) were sedated, anesthetized, instrumented, shocked into cardiac arrest, and randomized into three groups. Lidocaine was administered either i.v. (1.5 mg/kg), traditional ET (4.5 mg/kg), or ET followed by a 5-second 90-degree upright torso tilt (4.5 mg/kg). While standard CPR was performed, lidocaine levels were obtained at 0.5, 1, 2, 3, 4, and 5 minutes after administration. Repeated-measures ANOVA was used for data analysis (alpha = 0.05). RESULTS: Experimental ET compared with traditional ET administration produced significantly higher levels at all time points except 0.5 minutes. Comparing experimental ET with i.v. administration yielded significantly higher levels for the i.v. route at 0.5 and 1 minute and for the experimental ET route at 4 and 5 minutes. i.v. lidocaine administration resulted in significantly higher levels at 0.5, 1, and 2 minutes when compared with traditional ET administration. CONCLUSIONS: Endotracheal instillation of lidocaine followed by a 90-degree torso tilt resulted in better drug absorption, as evidenced by higher serum lidocaine levels, than did traditional recumbent ET delivery at all but the earliest time point and produced more sustained lidocaine levels than i.v. administration at 4 and 5 minutes. ET drug delivery followed by a 5-second 90-degree torso tilt and the mechanisms for this enhanced absorption warrant further investigation.     

Quantitative studies of the kinetics of 5-aminolaevulinic acid-induced fluorescence in bladder transitional cell carcinoma

Photodynamic therapy is a potential treatment for superficial bladder cancer that utilizes photosensitizer drugs, which are activated by light to cause tissue destruction. However, first-generation photosensitizers cause prolonged phototoxicity, have poor tumour specificity and can accumulate within detrusor muscle, resulting in permanent loss of bladder capacity following treatment. A newer drug, called 5-aminolaevulinic acid (ALA), generates a sensitizer called protoporphyrin IX (PpIX) in situ and has been shown, qualitatively, to be more tumour specific. The fluorescence kinetics of ALA-induced PpIX was investigated in patient biopsies of bladder tumour, normal urothelium and detrusor muscle, both in vitro after incubation of specimens in ALA-rich culture medium for various times and in vivo after instillation of intravesical ALA before endoscopic resection. The fluorescence in tumour tissue was twice that of normal urothelium in vitro and up to tenfold in vivo. There was little ALA-induced fluorescence in detrusor muscle, both in vitro and in vivo. Most importantly, no patients experienced phototoxicity or other adverse events following intravesical instillation of ALA.     

Experimental study on intraperitoneal sequential MTX/5-FU therapy for peritoneal seeding in comparison with intravenous administration

Sequential MTX/5-FU therapy (intravenous route) is powerful chemotherapy especially for poorly differentiated adenocarcinoma of the stomach and its peritoneal metastases. The authors had proposed the idea of intraperitoneal sequential MTX/5-FU chemotherapy for potential peritoneal metastases and micrometastases from advanced gastric carcinoma. This experimental study was planned to confirm this experimentally. Peritoneal seeding model of nude mice was made by the intraperitoneal inoculation of human gastric cancer cell line MKN-45. Control group (n = 5) had no treatment. The intraperitoneal (i.p.) group and intravenous (i.v.) group underwent the treatments on the 7th, 14th, and 21st day after cell implantation. Experimental chemotherapies consisted of intraperitoneal injection of MTX (15 mg/kg, 1.5 ml saline) and 5-FU (50 mg/kg, 1.0 ml saline) for i.p. group and intravenous injection of MTX (15 mg/kg, 0.2 ml saline) and 5-FU (50 mg/kg, 0.2 ml saline) for i.v. group. Interval time between MTX and 5-FU administration was 2 hours. On the 35th day after the cell implantation necropsies were performed. Counting of peritoneal metastatic nodules revealed the number of nodules of control group. (14.2 +/- 6.7) > i.v. group (5.3 +/- 4.1) > i.p. group (0.41 +/- 0.7) (p < 0.05). Weight of omental tumors showed Control group (0.246 +/- 0.136 g) > i.v. group (0.140 +/- 0.068 g) > i.p. group (0.051 +/- 0.017 g) (i.v.-i.p., p < 0.01). The mouse body weight decrease less in the i.p. group than in the i.v. group (p < 0.05) throughout this experiment. The results of this experiment demonstrated intraperitoneal sequential MTX/5-FU therapy was more effective than intravenous sequential MTX/5-FU therapy for potential peritoneal seeding and peritoneal micrometastases from the gastric cancer. Moreover, the side effect of intraperitoneal administration was milder than by the intravenous route.     

Dosimetric analysis of chimeric monoclonal antibody cMOv18 IgG in ovarian carcinoma patients after intraperitoneal and intravenous administration

In this study the potential of intraperitoneal (i.p.) and intravenous (i.v.) administration of chimeric iodine-131-labelled MOv18 IgG for radioimmunotherapy was determined. The dosimetry associated with both routes of administration of cMOv18 IgG was studied in patients. Eight patients suspected of having ovarian carcinoma received 150 MBq 131I-cMOv18 IgG i.p. Blood and urine were collected and serial gamma camera images were acquired. Another group of four patients received 7.5 MBq 131I-cMOv18 IgG i.v. For all patients, tissue biopsies were obtained at surgery. Activity in the blood after i.p. administration was described by a bi-exponential curve with a mean uptake and elimination half-life of 6.9+/-3.2 h and 160+/-45 h, respectively. For i.v. infusion the mean half-life for the elimination phase was 103+/-12 h. Cumulative excretion in the urine was 17%+/-3% ID and 21%+/-7% ID in 96 h for i.p. and i.v. administration, respectively. Scintigraphic images after i.p. administration showed accumulation in ovarian cancer lesions, while all other tissues showed decreasing activity with time. Tumour uptake determined in the ovarian cancer tissue specimens ranged from 3.4% to 12.3% ID/kg for i.p. administration and from 3.6% to 5.4% ID/kg for i.v. administration. Dosimetric analysis of the data indicated that 1.7-4.3 mGy/MBq and 1.7-2.2 mGy/MBq can be guided to solid or ascites cells after i.p. and i.v. administration, respectively. Assuming that an absorbed dose to the bone marrow of 2 Gy will be dose limiting, a total activity of 4.1 GBq 131I-cMOv18 IgG can be administered safely via the i.p. route and 3.5 GBq via the i.v. route. At this maximal tolerated dose, a maximum absorbed dose to 1-g tumours in the peritoneal cavity of 18 and 8 Gy can be reached after i.p. and i.v. administration, respectively. For the i. p. route of administration, dose estimates for the tumour are even higher when the electron dose of the peritoneal activity is also taken into account: total doses to the tumour of 30 Gy and 22 Gy will be absorbed at the tumour surface and at 0.2 mm depth, respectively. In conclusion, therapeutic tumour doses can be achieved with 131I-cMOv18 IgG in patients with intraperitoneal ovarian cancer lesions with no normal organ toxicity. The i.p. route of administration seems to be preferable to i.v. administration.     

Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption

The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy could be enhanced by means of intracarotid (i.c.) injection of sodium borocaptate (BSH) or boronophenylalanine (BPA) with or without blood-brain barrier disruption (BBB-D). For biodistribution studies, F98 glioma-bearing rats were injected i.v. or i.c. with either BSH (30 mg of boron/kg of body weight) or BPA (24 mg of boron/kg of body weight) with or without mannitol-induced, hyperosmotic BBB-D and killed 2.5 h later. The highest tumor boron concentrations for BSH and BPA were attained following i.c. injection with BBB-D (48.6 and 94.0 microg/g, respectively) compared to i.c. (30.8 and 42.7 microg/g) and i.v. injection (12.9 and 20.8 microg). Using the same doses of BSH and BPA, therapy experiments were initiated 14 days after intracerebral implantation of F98 glioma cells. Animals were irradiated 2.5 h after i.v. or i.c. administration of the capture agent with or without BBB-D using a collimated beam of thermal neutrons at the Brookhaven Medical Research Reactor. The median survival times of rats given BSH or BPA i.c. were 52 and 69 days, respectively, for rats with BBB-D; 39 and 48 days for rats without BBB-D; 33 and 37 days for i.v. injected rats; 29 days for irradiated controls; and 24 days for untreated controls. i.c. injection of either BSH or BPA resulted in highly significant enhancement (P = 0.01 and P = 0.0002, respectively) of survival times compared to i.v. injection, and this was further augmented by BBB-D (P = 0.02 and P = 0.04, respectively) compared to i.c. injection. Normal brain tissue tolerance studies were carried out with non-tumor-bearing rats, which were treated in the same way as tumor-bearing animals. One year after irradiation, the brains of these animals showed only minimal radiation-induced changes in the choroid plexus, but no differences were discernible between irradiated controls and those that had BBB-D followed by i.c. injection of either BSH or BPA. Our data clearly show that the route of administration, as well as BBB-D, can enhance the uptake of BSH and BPA, and, subsequently, the efficacy of boron neutron capture therapy.     

Effects of the K+ channel opener, ZD6169, on volume and PGE2-stimulated bladder activity in conscious rats

PURPOSE: To investigate the effects of the new K(ATP) channel opener, ZD6169, shown to have an in vivo selectivity for the bladder, on bladder activity in rats. MATERIALS AND METHODS: ZD6169 was given intra-arterially (i.a., 0.1 and 1 mg./kg.) or orally (3 mg./kg.) to conscious Sprague-Dawley rats undergoing continuous cystometry. Investigations were also performed before and after stimulation of bladder activity by intravesical prostaglandin (PG) E2. RESULTS: Intra-arterial ZD6169 increased residual volume, but caused no changes in other cystometric parameters. In rats receiving oral ZD6169, cystometric parameters were compared (every hour up to five hours) to those recorded in rats receiving oral vehicle. No differences were found, except in threshold pressure, which was significantly increased. Intravesical PGE2 20 microM increased micturition and basal pressures, and decreased bladder capacity and micturition volume. ZD6169 1 mg./kg., given i.a., reduced or completely prevented the activity induced by intravesical PGE2. Three hours after orally administered ZD6169 (3 mg./kg.), intravesical PGE2 20 microM had no effect. Three hours after oral administration of vehicle, the effects of PGE2 were attenuated, but still statistically significant. CONCLUSIONS: ZD6169, given i.a. or orally, increased threshold pressure, but had otherwise little effect on volume-induced micturition. However, the drug markedly reduced or prevented PGE2-induced bladder activity when given i.a.; it was also effective when given orally. If ZD6169 has inhibiting effects on bladder contraction in man without any cardiovascular actions, the drug may represent a novel, promising way of treating bladder overactivity.     

Pharmacokinetics of gentamicin following single-dose parenteral administration to goats

The disposition kinetics of parenterally administered gentamicin (5 mg kg-1) has been studied in Gaddi goats. The serum concentration-time profile was described by bi-exponential and mono-exponential equations following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration with elimination half-life values of 0.96 +/- 0.09, 2.37 +/- 0.47 and 3.56 +/- 0.39 h, respectively. The apparent volume of distribution following i.v. administration (Vdarea: 0.26 +/- 0.041 kg-1) reflected limited extracellular distribution of the drug. The bioavailability was higher following i.m. administration (96.3%) compared to s.c. (76.9%). In view of the significantly longer biological half-life and larger area under the curve values, the s.c. route may be preferred. It is concluded that a suitable and practical dosage recommendation for gentamicin in goats would be 3.35 mg kg-1 body weight given s.c. at 12 h intervals.     

Human microsporidiosis in the acquired immunodeficiency syndrome

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) for sensitization is a promising treatment for carcinoma in situ and diffuse premalignant changes of the bladder. We studied the biodistribution of PpIX in a range of tissues with oral and intravesical routes of administration of ALA and compared the photodynamic effects on bladder and skin. STUDY DESIGN/MATERIALS AND METHODS: Normal Wistar rats were given oral or intravesical ALA and PpIX levels in the liver, kidney, skin, and bladder measured by fluorescence microscopy on tissue sections. At the time of maximum PpIX levels, the bladder and skin on the back were illuminated with light at 630 nm and the PDT effects compared. RESULTS: PpIX fluorescence in the urothelium after 200 mg/kg given intravesically was comparable to that found after 100 mg/kg orally. The ratio of PpIX levels between the urothelium and the underlying muscle was the same for both routes of administration, although there appeared to be more selectivity of urothelial PDT necrosis after intravesical administration. Skin photosensitization was greater after oral ALA, the epidermal PpIX level being three times higher than after intravesical administration for comparable urothelial levels and the PDT effect being more marked. CONCLUSIONS: Intravesical instillation is preferable to oral administration of ALA for PDT ablation of the urothelium of the rat bladder without damage to the underlying tissue layers and for minimizing skin photosensitivity. The technique is now ready for clinical trials.     

Administration of Epoetin alfa. Case study of the anemic patient

Improving patient outcomes by achieving a stable Hct in the higher end of the target Hct range of 30% to 36% is the primary goal of anemia management and Epoetin alfa therapy. Recently, attention has been focused on the potential differences between subcutaneous (s.c.) and intravenous (i.v.) administration. Although some patients may require less Epoetin alfa when it is administered by the s.c. route, many patients require the same dose or more due to the significant heterogeneity in response. To ensure that therapeutic outcomes are maintained or improved, clinicians should evaluate both staff considerations and individual patient tolerance and response when determining the optimal route of administration.     

Intraarterial vs intravenous administration of antivenin for the treatment of Crotalidae atrox envenomation: a pilot study

OBJECTIVE: Standard therapy for significant snake envenomation includes antivenin. i.v. administration is currently the only recommended route. Intraarterial (i.a.) administration has potential advantages over i.v. that could improve outcome. To study this, the authors compared i.v. and i.a. antivenin administrations for the treatment of experimental snake envenomations. METHODS: 14 adult female swine were anesthetized and prepared with femoral artery and ear vein catheters, and baseline hoof, forearm, and thigh circumference and volume displacement measurements were taken. Crotalidae atrox venom was injected into the subcutaneous tissue of the hoof. The doses of venom were 4.75, 9.50, 19.00, 37.90, 47.30, 56.90, and 66.40 mg. Immediately following injection of venom, polyvalent antivenin (Crotalidae) (0.285 mg/10 mL saline) was infused over 30 minutes into the femoral artery (i.a. group) or ear vein (i.v. group). As a control, 10 mL of saline was infused into the ear vein (i.a. group) or femoral artery (i.v. group). Measurements were recorded up to 48 hours. Linear mixed-effect regression models were used for each measurement and to compare the i.a. and i.v. groups. RESULTS: Venom dose and time after administrations were associated with increased circumferences and increased volumes (p < 0.05). i.v. administration was associated with larger hoof (1.26 cm) and forearm (0.42 cm) sizes and volume displacement (21.71 mL) when compared with i.a. administration ( p < 0.05). CONCLUSION: i.a. antivenin results in a modest but significant decrease in tissue edema when compared with i.v..     

The effects of volume and speed of injection in peribulbar anaesthesia

Therapy of detrusor hyperactivity with anticholinergic agents often is followed by adverse drug reactions. Intravesical application may be an interesting alternative. A randomised, single-blind, placebo-controlled, mono-centre clinical trial was carried out in 84 patients with urgency or urge incontinence. Due to intravesical administration of oxybutynin (CAS 5633-20-5) (n = 21) and trospium chloride (CAS 10405-02-4) (n = 21), respectively, a significant increase in maximum bladder capacity and decrease of detrusor pressure accompanied by an increase of residual urine were found in comparison to placebo in urodynamical investigations. Improvement of uninhibited bladder contractions occurred leading to higher filling volume. Under verapamil (CAS 152-11-4) (n = 21) no marked changes in the efficacy variables were found compared with placebo. All patients completed the study and were assessed with regard to efficacy and safety. No adverse events or marked changes in the vital signs were reported. The immediate onset of effect and the lack of adverse drug reactions suggest that treatment with topical oxybutynin or trospium chloride is an effective alternative in patients with intolerable side effects when orally treated. In addition, intravesical administration may be indicated in patients with bladder spasms due to indwelling catheter or in order to increase bladder capacity before percutaneous cystostomy.     

Electromotive drug administration of lidocaine as an alternative anesthesia for transurethral surgery

PURPOSE: A multicenter study was undertaken to evaluate the safety, efficacy and cost of electromotive drug administration of intravesical lidocaine to produce bladder local anesthesia as an alternative to traditional methods of spinal or general anesthesia. MATERIALS AND METHODS: A total of 94 patients were enrolled in the study who had either a history of bladder tumor that required cold cup bladder biopsy with fulguration for possible recurrence as a comparison trial, a bladder tumor treated with transurethral resection/fulguration or benign prostatic hyperplasia/carcinoma treated with transurethral resection. Pain scores using a Verbal Rating Scale were recorded for each individual biopsy, fulguration and resection event. Data for direct and indirect costs were collected using a standardized form for each patient to capture the details of the procedure, including times, drugs and disposables for each patient. RESULTS: There was a significant reduction in pain for patients who received electromotive intravesical lidocaine compared to no anesthesia for biopsy (p<0.03). Similarly, electromotive intravesical lidocaine for bladder biopsy and transurethral bladder tumor resection/fulguration was associated with higher patient satisfaction compared to previous treatments (p<0.00002). In contrast, electromotive intravesical lidocaine was insufficient for 3 of 6 transurethral prostatic resections. The cost per patient was about $146 Cdn less with electromotive intravesical lidocaine than with conventional general/spinal anesthesia. CONCLUSIONS: Electromotive intravesical lidocaine may be a safe, effective and affordable form of anesthesia for the ambulatory care of patients requiring transurethral bladder biopsy, resection or fulguration with a potential for cost savings.     

Complications of intravesical oxybutynin chloride therapy in the pediatric myelomeningocele population

PURPOSE: We report our experience with the intravesical administration of oxybutynin chloride with particular focus on the incidence and characterization of untoward effects and inconvenience of therapy. MATERIALS AND METHODS: From 1990 to 1995, 23 children 5 to 11 years old with myelodysplasia were treated with intravesical oxybutynin chloride. Initial dose was 1.25 mg. in 5 cc sterile water instilled during routine catheterization 3 times daily, which was increased as tolerated and clinically indicated. Oral anticholinergic, antispasmodic and sympathomimetic medications were discontinued during therapy. We reviewed therapeutic indications, doses, frequency duration, reason for discontinuation and untoward effects. Patients/parents were surveyed for convenience of treatment as well as side effects and their timing with respect to drug administration and dose. RESULTS: In 15 patients (65%) treatment was discontinued and oral formulations were resumed or other therapy was required due to side effects, ineffectiveness or inconvenience. Seven patients had untoward effects, ranging from facial flushing and dizziness to agoraphobia and hyperactivity. Six patients discontinued therapy due to side effects after 1 day to 2 years (mode 1 month) at doses of 1.25 to 5 mg., including 5 who previously had side effects from oral oxybutynin chloride. Inconvenience of therapy was noted irrespective of the degree of independence of the child for performing intravesical therapy. CONCLUSIONS: Untoward effects and inconvenience are the most common reasons for discontinuing intravesical oxybutynin chloride therapy for neurogenic bladder dysfunction. Children who previously had side effects from oral oxybutynin chloride are more likely to have them during intravesical therapy.     

Toxicity management in patients receiving low-dose aldesleukin therapy

OBJECTIVE: To review the pathophysiology and subsequent treatment options for low-dose aldesleukin-induced toxicity when administered via intravenous bolus infusion, continuous intravenous infusion, or subcutaneous injection. BACKGROUND: The adverse events associated with high-dose aldesleukin therapy (600,000 IU per kg i.v. every 8 h for a maximum of 14 doses) are well documented in the literature; however, the adverse event profile of lower doses and alternative administration routes are less well described. An understanding of the adverse event profile associated with these alternative regimens can enhance management of toxicity. DATA SOURCES: English-language clinical studies, abstracts, and review articles pertaining to low-dose intravenous, continuous intravenous infusion, or subcutaneous injection of aldesleukin, as well as aldesleukin-induced adverse events. STUDY SELECTION AND DATA EXTRACTION: Relevant studies were selected that assist with understanding the pathophysiology, clinical management, diagnosis, and management of aldesleukin-induced adverse events. CONCLUSIONS: Aldesleukin therapy initiates a cytokine-mediated proinflammatory process resulting in a toxicity profile that is different from traditional nonbiologic chemotherapeutic agents. The frequency and severity of adverse events associated with aldesleukin administration are dependent upon dose, route, and administration schedule. In addition, most adverse reactions are self-limiting. Alleviation of aldesleukin-induced adverse effects can usually be achieved on an outpatient basis with agents such as antiemetics, antipyretics, and topical creams or lotions, as well as nonmedication interventions. Aggressive and proactive management of aldesleukin associated toxicities can help facilitate completion of therapy.     

Estimation of the effective amount entering the body for drugs subject to enterohepatic recirculations

A pharmacokinetic model is used to take into account multiple recirculations of drug occurring at various times after gall bladder emptying. If a dose D is initially administed, due to recirculation, an effective amount A* reaches the body. This value A* is expressed as a function of D and the model parameters, after oral administration or intravenous injection. Using areas under curves in two different situations, the reabsorption rate may be identified.     

The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent thymidylate synthase inhibitor ZD9331 in mice

ZD9331 is a novel, potent thymidylate synthase (TS) inhibitor which does not require polyglutamation by folylpolyglutamate synthetase (FPGS) for its activity. In contrast to Tomudex (ZD1694), ZD9331 may therefore be active against tumours with low FPGS activity. ZD9331 shows anti-tumour activity by both 24-h infusion and bolus administration in the murine thymidine kinase-deficient (TK -/-) lymphoma L5178Y. In view of the history of renal toxicity with some earlier TS inhibitors and the possible therapeutic use of bolus ZD9331, we have examined the effects of bolus ZD9331 dose and route of administration on plasma and kidney pharmacokinetics and renal function in mice. Renal function was assessed by measuring [14C]inulin clearance, and drug concentrations were assayed by reverse-phase high-performance liquid chromatography (HPLC). Renal function was unaffected by ZD9331 up to 150 mg kg(-1) either i.v. or i.p. However, at 200 mg kg(-1), glomerular filtration rate was significantly inhibited following i.v. but not i.p. administration. Pharmacokinetic studies showed that these effects were consistent with the markedly higher plasma drug concentrations occurring during early times following i.v. dosing, although the plasma drug profiles were otherwise similar for both routes. Kidney drug concentrations were slightly elevated in i.v.- versus i.p.-treated animals at the low dose (50 mg kg(-1)), with a correspondingly larger area under the curve. However, at the highest dose (200 mg kg(-1)), peak kidney drug concentrations were 20-fold higher following i.v. administration than after i.p., with marked kidney retention, resulting in a 50-fold greater kidney drug exposure for the i.v. versus the i.p. route. These data show that ZD9331 is non-nephrotoxic at active anti-tumour doses (50 mg kg(-1) i.p.) in mice, and only at very high bolus i.v. doses is there impaired renal function as a result of very high peak plasma concentrations. These adverse effects can be readily overcome by i.p. administration, indicating the likely need for short infusions in clinical settings.     

Superficial bladder cancer: decreasing the risk of recurrence

Bladder cancer appears to develop through two alternative pathways. Papillary bladder cancer, the most common pathway, has a less aggressive course and is frequently heralded by hematuria, whereas carcinoma in situ appears to be more aggressive and is more difficult to detect. Superficial bladder cancer has a high propensity for recurrence but a low rate of progression. Transurethral resection is frequently employed for both diagnosis and treatment. The risk of tumor recurrence is related to the number of tumors at presentation and the findings on the first follow-up cystoscopy. Even patients with a low risk of recurrence need periodic cystoscopic examinations. Patients with a higher risk of recurrence may benefit from adjuvant intravesical chemotherapy or immunotherapy. Bacillus Calmette-Guérin (BCG) appears to be the most effective drug for intravesical therapy but has the highest rate of side effects. It is the treatment of choice for carcinoma in situ. Newer treatment strategies include perioperative intravesical chemotherapy and chemoprevention.     

Enhanced delivery of boronophenylalanine for neutron capture therapy of brain tumors using the bradykinin analog Cereport (Receptor-Mediated Permeabilizer-7)

OBJECTIVE: Using the well-characterized F98 rat glioma model, the purpose of the present study was to determine whether the delivery of boronophenylalanine (BPA) could be enhanced by prior administration of the bradykinin analog Cereport (Alkermes, Inc., Cambridge, MA) (previously known as Receptor-Mediated Permeabilizer-7), which produces a transient, pharmacologically mediated opening of the blood-brain barrier. METHODS: Two series of experiments were performed in F98 glioma-bearing rats that had received either intracarotid (i.c.) or intravenous infusions of Cereport (at doses ranging from 1.5 to 7.5 microg/kg of body weight), followed by i.c. (or intravenous) injection of BPA (300 mg/kg of body weight). Animals were killed 0.5, 2.5, or 4 hours later, samples of blood, skin, muscle, and eye were obtained, brains were removed, and tumors were excised for boron determination by direct current plasma-atomic emission spectroscopy. RESULTS: Averaged over all time points, i.c. infusion of Cereport significantly enhanced tumor boron uptake (P = 0.0001), compared with the excipient (saline) control values. Tumor boron values were equivalent at 0.5 (36.0 microg/g) and 2.5 hours (38.5 microg/g) after i.c. administration of Cereport and BPA and then decreased by 33% (to 25.7 microg/g) at 4 hours. These tumor boron uptake values were significantly different (alpha = 0.05), compared with values measured at the corresponding times after i.c. administration of BPA without Cereport (22.6, 21.8, and 15.3 microg/g, respectively). Although no time-related effects were observed, i.c. administration of Cereport followed by intravenous administration of BPA also significantly enhanced (alpha = 0.05) tumor boron uptake at 0.5, 2.5, and 4 hours (27.4, 30.3, and 28.0 microg/g, respectively), compared with values obtained without Cereport (11.3, 13.4, and 15.2 microg/g, respectively). Boron levels in normal brain tissue from tumor-bearing and non-tumor-bearing cerebral hemispheres and in blood were not significantly different from those measured in saline-treated control animals. CONCLUSION: This study established that i.c. infusion of Cereport significantly increased delivery of BPA to F98 rat gliomas, and this could enhance the efficacy of boron neutron capture therapy of this tumor.