Stability of four commercial products delivered by mail order.

The purpose of this study was to investigate the stability of four commercial tablets commonly shipped via mail-order delivery. The products were: enalapril maleate 10-mg tablets, digoxin 0.25-mg tablets, clorazepate dipotassium 7.5 mg-tablets, and pyridostigmine bromide 60-mg tablets. The stability studies were conducted at 50 deg C, and tablets were exposed for three, seven and 14 days to that temperature. The results demonstrated that all tablets studied were stable in these conditions for their exposure time. Therefore, it appears that all the tablets remained stable and could be used with confidence in mail-order delivery provided the original product packaging is not compromised.

Accuracy in prescriptions compounded by pharmacy students.

Most compounded prescriptions are not analyzed to determine the accuracy of the employed instruments and procedures. The assumption is that the compounded prescription will be +/- 5% the labeled claim. Two classes of School of Pharmcacy students who received repeated instruction and supervision on proper compounding techniques and procedures were assessed to determine their accuracy of compounding a diphenhydramine hydrochloride prescription. After two attempts, only 62% to 68% of the students could compound the prescription within +/- 5% the labeled claim; but 84% to 96% could attain an accuracy of +/- 10%. The results suggest that an accuracy of +/- 10% labeled claim is the least variation a pharmacist can expect when extemporaneously compounding prescriptions.

Transdermal nicotine replacement in pregnancy: maternal pharmacokinetics and fetal effects.

OBJECTIVE: Our purpose was to measure any short-term effects that the transdermal nicotine replacement system may have in pregnancy and to verify salivary nicotine and cotinine levels during patch placement. STUDY DESIGN: After customary smoking cessation efforts had failed, six prenatal patients between 28 and 37 weeks' gestation who smoked between one and two packs per day were enrolled in this prospective study. The patients were admitted to the General Clinical Research Center for a period of 21 hours. During hospitalization we performed maternal and fetal assessments including vital signs, biophysical profile and electronic fetal monitoring, amniotic fluid index, and umbilical artery Doppler examinations. Salivary samples for cotinine and nicotine levels were collected at standard intervals. RESULTS: There were no measurable differences in fetal or maternal well-being. During patch use salivary nicotine levels increased as expected, to a mean value of 19.0 +/- 13.5 micrograms/L at 480 minutes. Salivary cotinine concentrations remained low (approximately 50 micrograms/L) and varied little during the 480-minute period that the patch was worn. Overall, patients were satisfied with the transdermal patches. CONCLUSION: There were no adverse maternal or fetal effects from the transdermal nicotine replacement system over the 6-hour period. Salivary nicotine concentrations were consistent with those seen in nonpregnant adults. Surprisingly, salivary cotinine concentrations were much lower than those seen in smoking nonpregnant adults.

Influence of moderate haemodilution with fluosol or normal saline on carbaryl disposition in Sprague-Dawley rats.

In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations. The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg-1 haemodilution with Fluosol or normal saline (0.9% NaCl). Volumes of distribution were significantly reduced after saline haemodilution for 72 h but only at 48 h after Fluosol haemodilution. Fluosol and saline haemodilution had little influence on carbaryl total body clearance (CL). These results indicate that both hepatic and non-hepatic clearance pathways were not influenced by the haemodiluents or the haemodilution procedure.

Atropine overdosage with a suppository formulation containing atropine sulfate.

A reformulation of ergotamine tartrate and caffeine (Cafergot) suppositories was prescribed for a 55-year-old woman who suffered from severe attacks of migraine. The patient developed toxic effects similar to atropine poisoning soon after the first dose. Since each suppository contained a very small amount of atropine sulfate (0.25 mg), it was possible that a miscalculation occurred during compounding, resulting in atropine overdose. Therefore, a simple, sensitive and accurate analytical methold was developed for the quantitation of atropine sulfate in the suppositories and the samples were examined. It was found that the suppositories dispensed contained 25 mg of atropine sulfate each instead of 0.25 mg. This incident demonstrates how important and vital it is for the pharmacist to be vigilant in all aspects of compounding prescriptions.

The Effects of Amine-Carboxyborane Related Derivatives on UMR-106 Bone Metabolism.

The amine-carboxyboranes and related derivatives have been shown to be potent anti-inflammatory and anti-osteoporosis agents. Their action in part appears to be mediated by the modulation of cytokines, e.g. TNFalpha or IL-1. Previous studies have demonstrated that LPS induced macrophages release of TNFalpha maximally at 60 to 90 min. and IL-1 from 5 to 8 hr. The amine-carboxyboranes reduced significantly the release of these cytokines but also blocked TNFalpha high affinity binding to UMR-106 receptor at 90 min. at 10 muM, and IL-1 high affinity binding at 5 hr. at 12.5 muM. In addition, the agents suppressed IL-8 binding to CHO K1 high affinity receptor at 24 hr. at 50 muM and IL-2 binding to HuT-8 receptors at 25 muM at 90 min. and 5 hr. Correlation of metabolic events associated with osteoporosis showed that at 90 min., when TNFalpha receptor binding was reduced by the agents, calcium uptake into UMR-106 cells was reduced at 10 muM as well as the acid and alkaline phosphatases, and the prostaglandin cyclo-oxygenase activities and adhesion of leukocytes and macrophages to UMR-106 cell monolayers. At 5hr. when the agents reduced IL-1 binding to UMR-106 receptors, calcitonin and 1,25-dihydrovitamin D(3) binding was reduced by the agents as was acid and alkaline phosphatase, and 5'-lipoxygenase activities and white blood cell adhesion. At this time calcium uptake and proline incorporation was increased significantly by the agents. At later times e.g. 18-48 hr. calcium uptake was still increased, and NAG activity was inhibited in the presence of the agents. These effects may be related more to the inhibition of other cytokine receptor binding, e.g. IL-8. Thus, many of the observed metabolic effects of amine-carboxyboranes as antiosteoporosis agents can be correlated with their inhibition of cytokine high affinity binding to target cell receptors.

The pharmacological activities of the metabolites of N-[(trimethylamineboryl)-carbonyl]-L-phenylalanine methyl ester.

The metabolites of N-[(trimethylamineboryl)-carbonyl]-L-phenylalanine methyl ester 1 proved to be active in a number of pharmacological screens where the parent had previously demonstrated potent activity. The proposed metabolites demonstrated significant activity as cytotoxic, hypolipidemic, and anti-inflammatory agents. In cytotoxicity screens several of the proposed metabolites afforded better activity than the parent compound against the growth of suspended and solid tumor cell lines. Evaluation of in vivo hypolipidemic activity demonstrated that the proposed metabolites of 1 were only moderately active and were generally less effective than the parent compound. Interestingly, L-phenylalanine methyl ester hydrochloride 3, which contains no boron atom, demonstrated equivalent hypolipidemic activity as the parent at 8 mg/kg/day in CF(1) male mice. As anti-inflammatory agents the proposed metabolites demonstrated variable capacities to reduce foot pad inflammation. These compounds were similarly effective as the parent 1 at blocking local pain and were generally better than the parent at protecting CF(1) male mice from LPS induced sepsis.

The disposition, tissue distribution, and cellular transport of N-[[(trimethylamino)boryl]carbonyl]-L-phenylalanine methyl ester in CF1 mice.

The disposition and tissue distribution of 14C-labeled N-[[(trimethylamino)boryl]carbonyl]-L-phenylalanine methyl esther (1) determined in CF1 mice following i.v., p.o., and i.p. administration. Compound 1 was found to undergo rapid and extensive metabolism, and the majority of the radioactivity was found in the skin and carcass regardless of the route of administration. Approximately 55% of the radioactivity was recovered in urine and feces after 78 h; however, excretion via these routes was not complete. Degradation of compound 1 occurred at the amide bond at low pH (0.8) but at the ester bond a physiological pH. This difference in degradation was reflected in elevation of the blood radioactivity levels after p.o. administration compared to i.p. and i.v. administration.

The Relationship Between Cytokine Regulation and Anti-Inflammatory Action of Amine-Carboxyborane in L929 Fibroblasts and IC-21 Macrophages.

The amine-carboxyboranes anti-inflammatory agents were shown to block TNF alpha release at 90 min. and IL-1 release at 5 hr. from macrophages. The agenst competed with L929 fibroblasts high affinity receptors for endogenous cytokines which regulate the inflammation process. Blocking the TNFalpha receptor at 90 min. by the agents from 10 to 50 muMu, resulted in lysosomal hydrolytic enzyme inhibition and lowering of prostaglandin synthesis as well as reductions in calcitonin high affinity receptor binding and calcium influx into the cells. IL-1 receptors when blocked by the agents at 5 hr. resulted in a reduction of NAG activity and leukotriene synthesis. An elevation of proline incorporation into collagen occurred at 90 min. and 24 hr. in the presence of the agents.

The effect of moderate hemodilution with Fluosol on cytochrome P4502D6 activity in the rat.

Desmethylimipramine (desipramine, DMI) is predominantly 2-hydroxylated to 2-hydroxydesipramine, and the remainder is N-demethylated to didesmethylimipramine (DDMI) in both rats and man. DMI 2-hydroxylation is mediated by the same cytochrome P-450 isoenzyme (P4502D6) in rats and man. Fluosol hemodilution has previously been shown to influence the activity of P4502B1 and P4502B2, the cytochrome P-450 isoenzymes induced by phenobarbital in rats. In this study, DMI was used as a model substrate to investigate the influence of moderate Fluosol hemodilution on P4502D6 activity in rats. DMI total body clearance was not influenced by Fluosol hemodilution. This was an anticipated outcome since phenobarbital had a negligible effect on DMI metabolism, and Fluosol and phenobarbital affect the same isoenzymes. DMI Vdss was increased at 0.5 hour after hemodilution, but decreased from 24-72 hours. The decreased Vdss is most likely due to increased concentrations of alpha-1-acid-glycoprotein. Thus, Fluosol hemodilution is not expected to influence the hepatic P4502D6 activity in man. However, Fluosol may have marked influences on the apparent volumes of distribution of basic drugs that bind to alpha-1-acid-glycoprotein.

Hypolipidaemic activity in rodents of boron analogs of phosphonoacetates and cyanoborane adducts of dialkyl aminomethylphosphonates.

Boron analogues of phosphonoacetates proved to be potent hypolipidaemic agents in rodents, lowering both serum cholesterol and triglyceride levels. (C2H5O)3PBH2COOCH3 proved to be the most effective agent in mice, lowering serum cholesterol 46% and serum triglycerides 54% after 16 days. (C2H5O)3PBH2COOH and Na+H+(C2H5O)2(-O)PBH2COO- caused greater than a 40% reduction in lipids. The cyanoborane adducts of aminomethylphosphonates were generally less effective; (C6H5O)2P(O)CH2NH2BH2CN was the most effective, lowering serum cholesterol 32% and serum triglycerides 43% after 16 days. The phosphonoacetates appeared to lower lipid concentrations by several mechanisms. First, they lowered the de novo synthesis of cholesterol and triglycerides in the liver. Second, they accelerated the excretion of lipids into the bile and faeces. Thirdly, they modulated LDL and HDL-cholesterol contents in a manner which suggests they reduced the deposition of lipids in peripheral tissues, and accelerated the movement of cholesterol from tissues (e.g. plaques) to the liver for excretion into the bile.

The effect of moderate haemodilution with Fluosol-DA or Hespan on the nonmicrosomal acetylation of sulphadimidine in the rat.

The effects of Fluosol-DA (Fluosol) and Hespan haemodilution on the nonmicrosomal acetylation of sulphadimidine were studied in male rats. Fluosol increased the acetylsulphadimidine percent excreted in urine, the metabolic formation rate constant (kf), and the formation clearance (CLF) for 72 h after haemodilution without any significant changes in the sulphadimidine apparent volume of distribution (Vd) or total body clearance (CL). Hespan haemodilution increased the acetylsulphadimidine percent excreted in urine only at 48 h while significantly decreasing the sulphadimidine clearance, urinary excretion rate constant (ku), and renal clearance (CLR) for 72 h. The enhanced N-acetyltransferase activity after Fluosol haemodilution may have therapeutic consequences for concomitantly given drugs metabolized by this enzyme.

Acute effects of moderate Fluosol-DA hemodilution on hepatic microsomal and nonmicrosomal metabolism in rats.

Fluosol has been shown to alter the disposition of several drugs immediately after its administration. Investigations in this laboratory established that the disposition of several drug markers requiring the hepatic microsomal cytochrome P-450 isoenzymes was time dependent for 72 hours. It was an additional purpose of the research to determine if the nonmicrosomal sulfation and acetylation pathways were also influenced by Fluosol hemodilution in a time dependent manner. Rats were moderately hemodiluted with Fluosol and received an intravenous dose of a drug marker 24, 48, or 72 hours after hemodilution. The formation clearance (ClF) of specific metabolites was used as the pharmacokinetic measure of a specific enzymatic activity. 3-Hydroxymethyl antipyrine ClF (phenobarbital inducible microsomal cytochrome P-450 isoenzymes) increased 300% only at 48 hours. Acetylsulfamethazine ClF (nonmicrosomal acetylation) increased 287% and 162% at 24 and 48 hours, respectively. Acetaminophen sulfate ClF (nonmicrosomal sulfation) decreased 30% only at 48 hours. Substantial evidence shows that cytochrome P-450 content is induced at 72 hours and remains induced for an unprecedented length of time by the PFCs in Fluosol. Therefore, it was unexpected that 3-hydroxymethyl antipyrine ClF was not increased at 72 hours. Several possible explanations are discussed for the unexpected findings.

Disposition of an antineoplastic sesquiterpene lactone, [3H]-plenolin, in BDF1 mice.

The pharmacokinetics of a radiolabelled analog of helenalin, [3H]-plenolin ([3H]-11,13-dihydrohelenalin), was determined in BDF1 mice following intravenous, intraperitoneal, and oral administration. A two-compartment pharmacokinetic model predicted that the maximum terminal (beta) half-life of [3H]-plenolin was 57.3 hours. Urinary excretion accounted for 40.3% to 64.4% of the administered radioactivity, while fecal excretion accounted for 9.3% to 39.7%. The fecal excretion data also suggested that [3H]-plenolin was secreted in the bile. Following intraperitoneal administration of [3H]-plenolin, no radioactivity was sequestered in the major organs. However, radioactivity was sustained in the carcass and skin for 24 days. [3H]-Plenolin was rapidly taken up by murine tumor cells and human fibroblasts. The drug did not significantly associate with DNA, RNA, or protein of P388 leukemia or human fibroblast cells.

Disposition of the hypolipidaemic agent, 6-amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid, in Sprague-Dawley rats.

The disposition of [2-14C]6-amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid has been determined in rats following intravenous and oral administration. A two-compartment pharmacokinetic model fitted to the blood and urinary data predicted its maximum terminal (beta) half-life to be 38 h. Urinary and faecal excretion accounted for approximately 30 and 8% of the administered radioactivity, respectively. The parent compound accounted for 88% of the urine radioactivity after oral administration. In a tissue distribution study, the largest percentages of radioactivity were found in the skin and carcass; by 24 h, all other organs contained less than 1% of the administered radioactivity. The drug was highly water soluble, not extensively bound to plasma proteins, nor taken up by red blood cells. The drug uptake by human fibroblasts or rat aorta cells appeared to be by passive diffusion.

Plasma volumes, blood volumes, and plasma protein concentrations after moderate haemodilution with fluosol-DA or normal saline in the rat.

Plasma volumes, blood volumes, and plasma total protein, albumin, and bilirubin concentrations have been determined in rats for 72 h following 20 or 40 mL kg-1 haemodilution with Fluosol-DA or 0.9% NaCl. Haemodilution with 20 mL kg-1 of either haemodiluent had no influence on the measured values. Plasma and blood volumes did not change after Fluosol-DA haemodilution at 40 mL kg-1, but albumin and bilirubin concentrations were decreased for 72 h. Only bilirubin concentrations were decreased for 72 h following haemodilution with 40 mL kg-1 of 0.9% NaCl. It was concluded that changes in a drug's plasma protein binding, and not the plasma or blood volume, are responsible for the reported alterations in a drug's apparent volume of distribution after haemodilution.

Influence of the method of fluosol-DA administration on antipyrine metabolism in the rat.

Antipyrine disposition has been determined in the rat following administration of Fluosol-DA by an intravenous infusion without blood removal or a haemodilution procedure, and compared with data from sham haemodiluted rats (blood removed and returned) and control rats which only received antipyrine. Antipyrine total body and renal clearance and the formation clearance of two of its metabolites were affected differently at 48 h by the pretreatments. The haemodilution procedure enhanced, the sham haemodilution reduced, and the intravenous infusion had no effect on the phenobarbitone inducible cytochrome P450 isoenzyme activity.

The effect of Fluosol-DA and Hespan haemodilution on S-warfarin elimination in the rat.

Fluosol and Hespan haemodilution in rats did not change S-warfarin elimination within 72 h although previous studies had indicated that Fluosol haemodilution caused an increased cytochrome P450b and P450e activity at 48 h. This study showed that the increased activity at that time was specific for those isoenzymes.

The in-situ absorption of antipyrine as a measure of intestinal blood flow in Fluosol-DA haemodiluted rats.

The effect of moderate Fluosol-DA haemodilution on intestinal blood flow has been investigated in the rat. Antipyrine in-situ intestinal absorption is blood flow limited, and did not alter 0.5, 24, 48, or 72 h after haemodilution with 40 mL kg-1 Fluosol. Thus the intestinal blood flow rate is maintained as part of the physiological response to ensure adequate perfusion of the vital organ.

Evaluation of cytochrome P-450 mediated metabolism of antipyrine in the rat at different extents of fluosol-DA hemodilution.

Two reports of antipyrine disposition in rats after hemodilution with 20, 40, or 80 ml/kg of Fluosol-DA are evaluated to determine if the extent of hemodilution influenced cytochrome P-450 mediated antipyrine metabolism. Alterations in antipyrine clearance (Cl) and 3-hydroxymethylantipyrine (3OHME) formation clearance (ClF) show that the extent of Fluosol hemodilution influences both the time and pattern of change in cytochrome P-450 isoenzyme activity. Alterations in antipyrine Vd had no consistent pattern with different extents of hemodilution.