Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies.

BACKGROUND: We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics. METHODS: Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate. RESULTS: Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months). CONCLUSIONS: Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.

Cholesterol and glycemic effects of Niaspan in patients with type 2 diabetes.

STUDY OBJECTIVE: To determine the effect of Niaspan--a niacin preparation with both immediate- and extended-release characteristics--on lipid and glycemic control in patients with type 2 diabetes. DESIGN: Retrospective study SETTING: Private-practice endocrinology group. PATIENTS: Thirty-two patients (mean age 60 yrs; 72% men) with type 2 diabetes identified by a computerized text search. INTERVENTION: Patients received Niaspan 1000, 1500, or 2000 mg/day (median daily dosage 1000 mg). MEASUREMENTS AND MAIN RESULTS: Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, hemoglobin A1c, and transaminase levels were compared for each patient before and 6 months after initiation of Niaspan. Niaspan therapy was associated with a significant 34% increase in HDL (p=0.033), a significant 36% reduction of triglycerides (p=0.049), and no significant change in LDL (p=0.236) or total cholesterol (p=0.122). Mean hemoglobin A1c levels significantly decreased from baseline by 0.5 +/- 0.3% (p=0.032), even though dosages and treatment with antidiabetic agents remained constant. There were no significant changes in transaminase levels. Seven patients (21.9%) discontinued Niaspan; one of them experienced an increase in blood glucose while receiving the agent. CONCLUSION: For most patients with type 2 diabetes, Niaspan is a safe and effective therapy for dyslipidemia and does not exacerbate glycemic control.

Unlimited opportunities for environmental interventions with inner-city asthmatics.

The purpose of this study was to identify the asthmatics living in the Lower West Side (LWS) of Buffalo, New York, and then explore the relationship between urban asthmatic and nonasthmatic exposures to many common household aeroallergens. Eight hundred twenty-eight households were visited and 167 asthmatics and 161 nonasthmatics were identified for comparison. Specific self-reported household exposure prevalences were identified for environmental tobacco smoke, sources of molds, household pets, rats, cockroaches, and sources of dust. Sources of molds, pets, and cockroaches were more likely to be found in the homes of asthmatics compared to nonasthmatics (p < 0.05). Other aeroallergens studied, although highly prevalent, were not more likely to be found in either asthmatic or nonasthmatic homes.

Management of toenail onychomycosis.

The treatment of toenail onychomycosis is reviewed. Onychomycosis contributes to 40% of all nail disorders and appears to be increasing in frequency. Mycotic nail infections are usually caused by dermatophytes, yeasts, and nondermatophyte molds. Most cases of toenail onychomycosis are caused by dermatophytes. Mycotic nail infections do not always resolve spontaneously and may have a substantial impact on the patient's quality of life. Current treatment modalities for onychomycosis include surgery, topical antifungals, and oral antifungals. Surgery is generally not recommended as first-line therapy. Broad-spectrum topical and oral antifungal agents are the most frequently used treatments. Topical treatment is well tolerated but is usually not effective because of poor patient compliance and inadequate penetration of the nail. Oral antifungals are more successful but carry greater risks. Griseofulvin and ketoconazole have been oral antifungals traditionally used for onychomycosis, but these agents are associated with relatively low cure rates. Itraconazole and terbinafine are both safe and effective first-line agents, with reported overall cure rates of 50-90% for dermatophyte-related onychomycosis. Intermittent oral antifungal therapy may reduce the risk of systemic adverse effects and the cost of therapy; more study of this approach is needed. Oral antifungal agents offer patients with toenail onychomycosis greater likelihood of a cure than topical antifungals, but oral therapy carries greater risks and requires closer monitoring.

Stability of drug additives to peritoneal dialysate.

OBJECTIVE: The primary literature was reviewed to determine the stability of drug additives in peritoneal dialysis solutions. DATA SOURCES: A MEDLINE search and retrieval, covering the period 1981 to 1994, was undertaken to identify relevant original literature. Additional references were identified from citations within the original literature. Non-English literature was excluded unless an English abstract was provided. STUDY SELECTION: Forty-nine studies were identified. Of these, 24 were directly related to drug stability, 13 were related to the clinical use of the drug additives but included no stability data, and 12 examined other, nonstability aspects of in vitro activity of antibiotics, additives, or drug adsorption in peritoneal dialysis bags and tubing. DATA EXTRACTION: Data included concentrations of drug additives and dialysate solutions, duration and temperatures of storage conditions, types of assay, and whether they were stability-indicating. RESULTS: Stability was defined as the duration of time that the drug concentration remained at 90% or more of the original concentration. Stability was examined under a large variety of conditions. Thirty-one drugs were identified from 20 manuscripts as single-drug additives. Most beta-lactams were stable for 1-2 weeks in a refrigerator and for several days at room temperature. Aminoglycosides were stable for 1-2 days at room temperature. Glycopeptides were stable for several weeks refrigerated or at room temperature. Prolonged storage at room temperature resulted in instability of cefotaxime, ceftazidime, ceftriaxone, and miconazole. Eleven drugs were identified from seven manuscripts as drug combination studies and showed similar stability as single agents. Dialysate concentration appeared to have minimal effect on stability. CONCLUSIONS: Drug additives in peritoneal dialysate, singly or combined, should be avoided unless data are available to support their stability. Additives should be made as close as possible to the time of the exchange. Alternatively, additives should be stored refrigerated, then warmed prior to use. The practice of preparing numerous bags at one time should be avoided. Finally, stability data do not indicate sterile integrity of the dialysate.

Stability of ciprofloxacin injection in peritoneal dialysis solutions.

The stability of ciprofloxacin 25 mg/L in peritoneal dialysis solutions containing 1.5% and 4.25% dextrose after storage at 4 degrees C for two weeks, 25 degrees C for one week, or 37 degrees C for two days was evaluated. Ciprofloxacin 50 mg was added to 18 2-L bags of peritoneal dialysis solutions, nine containing 1.5% dextrose and nine containing 4.25% dextrose. Three bags of each dialysis solution were stored at 4 degrees C for 14 days, 25 degrees C for 7 days, and 37 degrees C for 2 days. Samples were drawn from each bag, and ciprofloxacin concentrations were measured by high-performance liquid chromatography. Stability was defined as less than 10% decrease from initial concentration. In the solution containing 1.5% dextrose, 87.2% of the ciprofloxacin remained after 14 days of storage at 4 degrees C, 93.4% remained after 7 days of storage at 25 degrees C, and 95.2% remained after 2 days of storage at 37 degrees C. In the solution containing 4.25% dextrose, 89.0% of the ciprofloxacin remained after 14 days of storage at 4 degrees C, 93.7% remained after 7 days of storage at 25 degrees C, and 97.8% remained after 2 days of storage at 37 degrees C. In peritoneal dialysis solutions containing 1.5% and 4.25% dextrose, ciprofloxacin was stable for seven days at 25 degrees C and for 48 hours at 37 degrees C. Ciprofloxacin concentrations after two weeks at 4 degrees C were below 90% of initial concentration.

Evaluation of patient-care interventions by Pharm.D. clerkship students.

A program is described in which Pharm.D. clerkship students provide pharmaceutical care by identifying drug-related problems, suggesting interventions to solve the problems, and documenting the patient's outcome. Four doctor of pharmacy degree students under the direct guidance of a clinical pharmacy preceptor suggested 231 patient-care interventions during their clinical rotations; 219 (94.8%) of the interventions were either fully or partially accepted by the prescriber. The most commonly solved drug-related problems were underdose (31.5%) and overdose (17.4%), followed by untreated indications (14.1%) and drug given without indication (13.7%). The remainder of the drug-related problems that the students solved were improper drug selection, failure to receive drug, adverse drug reactions, or drug interactions. All but 10 interventions were considered by preceptors to be significant contributions to patient care. The interventions were estimated to have decreased drug costs in 50.7% of the cases, increased drug costs in 23.7% of the cases, and not changed drug costs in 25.6% of the cases. Patient outcomes were documented by the students in 58.9% of cases; the desired goals of the accepted intervention were achieved in all documented cases. A preceptor-supervised intervention program was beneficial to Pharm.D. students and patients and was well received by prescribers.

Drug-use review program for concurrent histamine H2-receptor antagonist-sucralfate therapy.

The effect of drug-use review on concomitant histamine H2-receptor antagonist-sucralfate therapy at a 600-bed, university-affiliated Veterans Affairs medical center was studied. In an effort to curtail the concomitant use of H2-antagonist plus sucralfate therapy, the department of pharmacy, in conjunction with the gastroenterology service, developed and introduced criteria for the appropriate use of combination therapy. The extent of prescribing of concomitant histamine H2-receptor antagonist-sucralfate therapy before and after implementation of criteria-based guidelines and the appropriateness of current H2-receptor antagonist-sucralfate combination therapy, based on the guidelines, were assessed. The effectiveness of the intervention process was evaluated, and cost savings associated with intervention were calculated. After intervention, the number of treatment courses of histamine H2-receptor antagonist-sucralfate combination therapy decreased by 30%. However, of the 109 evaluable postintervention combination treatment courses, only one complied with both the indication and the duration of treatment criteria. This review of prescribing patterns and the implementation of criteria-based guidelines proved an effective means of reducing inappropriate combination therapy and resulted in annual cost savings of $25,000.

Radiolytic degradation scheme for 60Co-irradiated corticosteroids.

The cobalt 60 radiolytic degradation products have been identified in the following corticosteroids: cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone sodium succinate, isoflupredone acetate, methylprednisolone, methylprednisolone acetate, prednisolone, prednisolone acetate, and prednisone. Two major types of degradation processes have been identified: loss of the corticoid side chain on the D-ring to produce the C-17 ketone and conversion of the C-11 alcohol, if present, to the C-11 ketone. Minor degradation products derived from other changes affecting the side chain are also identified in several corticosteroids. These compounds are frequently associated in corticosteroids as process impurities or degradation compounds. No new radiolytic compounds unique to 60Co-irradiation have been found. The majority of corticosteroids have been shown to be stable to 60Co-irradiation. The rates of radiolytic degradation ranged from 0.2 to 1.4%/Mrad.

Improved high-pressure liquid chromatographic method for the analysis of erythromycin in solid dosage forms.

A stability-indicating high-pressure liquid chromatographic (HPLC) method for the assay of erythromycin in enteric film-coated tablets was developed. The method used a reversed-phase column at 70 degrees with a mobile phase of acetonitrile-methanol-0.2 M ammonium acetate-water (45:10:10:35) at pH 7.0. The column were evaluated for the analysis of erythromycin. The HPLC method was also applicable for the analysis of salts and esters of erythromycin. The linearity and precision of the HPLC assay method for erythromycin in the solid dosage form were examined by spiking erythromycin into a tablet placebo a 60-120% of the label. The recovery of erythromycin was 99.9% with a relative standard deviation of less than 1%. The correction factors to express the results of HPLC in terms of antimicrobial bioequivalency against Staphylococcus aureus TCC 6538P for erythromycins A, B, and C were determined to be 1.0, 0.92, and 0.48, respectively. Eight lots of tablets were assayed by the HPLC method, and the results, expressed in terms of erythromycin bioequivalency, showed no statistically significant difference from those of the microbiological assay method.

A new nontricyclic antidepressant agent. Synthesis and activity of N-[trans-2-(dimethylamino)cyclopentyl]-N-(3,4-dichlorophenyl)propanamide and related compounds.

A series of new nontricyclic antidepressant compounds was synthesized. A representative of this class is compound 6. Five structural parameters were investigated: ring size, cis/trans stereochemistry, amide substitution, aromatic substitution, and amine substitution. The pharmacological tests employed, indicative of antidepressant activity, were yohimbine potentiation test, oxotremorine antagonism test, and apomorphine potentiation test. Structure--activity relationship is discussed.