Work overload is related to increased risk of error during chemotherapy preparation.

PURPOSE: Chemotherapy preparation units face peaks in activity leading to high workloads and increased stress. The present study evaluated the impact of work overloads on the safety and accuracy of manual preparations. METHOD: Simulating overwork, operators were asked to produce increasing numbers of syringes (8, 16, and 24), with markers (phenylephrine or lidocaine), within 1 h, in an isolator, under aseptic conditions. Results were analyzed using qualitative and quantitative criteria. Concentration deviations of < 5%, 5%-10%, 10%-30%, and >30% from the expected concentration were considered as accurate, weakly accurate, inaccurate, and wrong concentrations, respectively. RESULTS: Twenty-one pharmacy technicians and pharmacists carried out 63 preparation sessions (n = 1007 syringes). A statistically significant decrease in the manufacturing time for one syringe was observed when workload increased (p < 0.0001). Thirty-nine preparation errors were recorded: 30 wrong concentrations (deviation > 30%), 6 mislabeling, 2 wrong diluents, and 1 wrong drug. There was no statistically significant difference in the mean concentration accuracy of final preparations across the three workloads. The overall error rate increased with the number of preparations made in 1 h: 1.8% for 8 preparations, 2.7% for 16 preparations, and 5.4% for 24 preparations (p < 0.05). CONCLUSION: Although pharmacy technicians and pharmacists were able to increase production speeds with no effect on mean concentration accuracy under stressful conditions, there were greater probability errors being made. These results should encourage actions to spread workloads out over the day to avoid peaks in activity.

Preparation of phenylephrine 3-O-sulfate as the major in vivo metabolite of phenylephrine to facilitate its pharmacokinetic and metabolism studies.

INTRODUCTION: The in vivo disposition and metabolism of phenylephrine have not been establishedby previous analytical methods and there is a lack of available standards for quantitating the metabolites. METHODS: We pursued and compared the preparation of sulfation metabolites of phenylephrine and its ethyl analog etilefrine via chemical and bio-synthesis. RESULTS: Both sulfates were obtained in higher yield and purity through chemical syntheses compared to biosynthesis. DISCUSSION: A facile method for the production of phenylephrine 3-O-sulfate and etilefrine 3-O-sulfate was established. These compounds will be useful in the development of analytical assays for studying the pharmacokinetics of phenylephrine and its main route of metabolism in the presence of formulation changes and pharmacogenetic variation.

Study to Probe Subsistence of Host-Guest Inclusion Complexes of α and ß-Cyclodextrins with Biologically Potent Drugs for Safety Regulatory Dischargement.

Host-guest interaction of two significant drugs, phenylephrine hydrochloride and synephrine with α and ß-cyclodextrins were studied systematically. Initially two simple but reliable physicochemical techniques namely conductance and surface tension were employed to find out saturation concentration for the inclusion and its stoichiometry. The obtained 1:1 stoichiometry was further confirmed by two spectrometric methods, UV-Vis study and spectrofluorimetry. Significant shifts in IR stretching frequency also support the inclusion process. Relative stabilities of the inclusion complexes were established by the association constants obtained from UV-Vis spectroscopic measurements, program based mathematical calculation of conductivity data. Calculations of the thermodynamic parameters dictates thermodynamic feasibility of the inclusion process. Spectrofluorometric measurement scaffolds the UV-Vis spectroscopic measurement validating stability of the ICs once again. Mass spectroscopic measurement gives the molecular ion peaks corresponding to the inclusion complex of 1:1 molar ratio of host and guest molecules. The mechanism of inclusion was drawn by 1H-NMR and 2D ROESY spectroscopic analysis. Surface texture of the inclusion complexes was studied by SEM. Finally, the cytotoxic activities of the inclusion complexes were analyzed and found, Cell viability also balances for non-toxic behavior of the ICs. Moreover, all the studies reveal the formation of inclusion complexes of two ephedra free, alternatively emerging drugs (after their banned product having ephedra) SNP, PEH with α and ß-CD which enriches the drug delivery system with their regulatory release without any chemical modification.

Preparation and in vitro characterization of thermosensitive and mucoadhesive hydrogels for nasal delivery of phenylephrine hydrochloride.

The aim of the present work was to develop a nasal delivery system of phenylephrine hydrochloride (PE) in spray form to make prolonged remedy of nasal congestion. The formulations contain the thermosensitive hydrogel, i.e., Poloxamer 407 (P407) and Poloxamer 188 (P188) mixtures, and mucoadhesives, i.e., ε-polylysine (ε-PL) and low molecular weight sodium hyaluronate (MW 11,000Da). The in vitro characterizations of formulations including rheology studies, texture profiles and in vitro mucoadhesion potential were investigated after gelation temperatures measurements. The results showed that the concentration of P407 or P188 had significant influence on gelation temperature and texture profiles. The addition of mucoadhesives, though lowered the gel strength of formulations, increased interaction with mucin. After screening, two formulations (i.e., 1.0% PE/0.5% ε-PL/17% P407/0.5% P188 or Formulation A; and 1.0% PE/0.5% HA/17% P407/0.8% P188 or Formulation B) presenting suitable gelation temperatures (∼32°C) were used for further studies on in vitro release behaviors and mucosa ciliotoxicity. Both formulations showed sustained release of PE for up to 8h and similar toxicity to saline, the negative control. Thus, the thermosensitive and mucoadhesive PE-containing hydrogels are promising to achieve prolonged decongestion in nasal cavity.

[Synthesis of BODIPY-FL-labeled phenylephrine and the determination of its biological activity].

OBJECTIVE: To synthesize BODIPY-FL-labeled phenylephrine (BODIPY-FL-PE) and determine its biological activity. METHODS: Condensation of BODIPY-FL (green fluorescence dye) and phenylephrine (alpha1-adrenoceptor agonist) was performed by adding dicyclohexylcarbodiimide (DCC) in the presence of absolute tetrahydrofuran(THF). The reaction occurred in absolutely oxygen and water condition at room temperature. The crude product was separated and purified by thin-layer chromatography (TLC). The structure of BODIPY-FL-PE was characterized by TLC and mass spectrometry (MS). Its pharmabiological activity was determined by Western blot. RESULTS: BODIPY-FL-PE,the target molecule, was synthesized and its structure was identified by using ultra-violet spectrometry (UV) and MS. The result of Western blot indicated that alpha1-adrenoceptor (alpha1-AR) induced ERK phosphorylation was confirmed in both BODIPY-FL-PE and PE treated groups. CONCLUSION: The synthesized BODIPY-FL-PE has pharmacological activity that could activate alpha1-AR. Visualization of AR behaviors could be achieved by tracing the trajectories of BODIPY-FL-PE labeled AR. It might be a promising tool for investigating dynamic behaviors of AR in living cells.

Synthesis and preliminary evaluation of [11C]-(-)-phenylephrine as a functional heart neuronal PET agent.

The in vivo behavior of (-)-[11C]phenylephrine (PHEN) is compared with the structurally similar but monoamine oxidase (MAO)-resistant analog (-)-[11C]-m-hydroxyephedrine (HED), which is an established heart neuronal marker. The chiral synthesis of PHEN has been achieved by direct methylation of (-)-m-octopamine with either 11CH3I or CF3SO311CH3. These synthetic methods produced PHEN with a specific activity ranging from 500-1000 Ci/mmol, in a radiochemical yield of > 50% (EOS) and with an enantiomeric purity of 94-96%. Biodistribution studies indicate the initial uptake of PHEN in rat heart is approximately half that of HED. Following PHEN injection, radioactivity egresses from the rat heart rapidly, with 50% washout occurring from 5 to 60 min. HED washout over this interval was less than 20%. The heart neuronal selectivity determined by desipramine blockade of the amine neuronal transporter was 75-77% compared to 92-95% for HED. Ring-labeled (-)-[3H]phenylephrine gave tissue-to-blood concentration ratios and heart clearance times very similar to PHEN. Rats pretreated with the MAO A inhibitor clorgyline showed higher levels of activity in the heart at 15 and 60 min. Tandem PET studies with PHEN and HED in the closed-chest dog provided excellent heart images with both tracers.

Photolabile "caged" adrenergic receptor agonists and related model compounds.

The synthesis and photochemical characterization of caged derivatives of the adrenergic receptor agonists phenylephrine, epinephrine and isoproterenol are described. These compounds were prepared using 2-nitrobenzyl or substituted 2-nitrobenzyl photolabile protecting groups, and were designed to allow agonist concentration jumps to be made during pharmacological/physiological experiments. The advantage of this approach over conventional methods for changing the concentrations of agonists near receptors in mechanistic studies is the exquisite spatial and temporal resolution afforded by the use of light. Flash photolysis experiments revealed that photorelease is more than two orders of magnitude faster when the 2-nitrobenzyl group is attached to the beta-amino group rather than one of the phenolic oxygens of the catecholamine. For the caged phenylephrine derivatives, for example, the rate constants of release from the N-linked and O-linked derivatives are 1.8 x 10(4) s-1 and 1.1 x 10(2) s-1 respectively. However, the quantum yields of photorelease from the N-linked and O-linked derivatives are similar. In addition, several model compounds were prepared to allow examination of the effects of substituents on the aromatic ring and benzylic carbon (of the 2-nitrobenzyl moiety) on the rates and efficiencies of photorelease. These studies revealed that, although substituents had little effect on the rates of photorelease from the N-linked caged derivatives, electron-donating groups on the 2-nitrobenzyl ring increased the quantum yield of release by approximately fourfold, from 0.10 to 0.40. A summary of the studies completed to evaluate the biological properties of the caged adrenergic receptor agonists is also presented.

"Caged" phenylephrine: development and application to probe the mechanism of alpha-receptor-mediated vasoconstriction.

A "caged" analogue of the alpha-adrenergic receptor agonist phenylephrine (PE) was prepared by exploiting the 2-nitrobenzyl protecting group and using a synthetic procedure developed to permit preferential derivatization at the amino group. On isolated adult rat mesenteric arterioles, caged-PE had no measurable effects at concentrations up to 100 microM; 0.5-ms light flashes in the presence of caged-PE, however, produced marked and dose-dependent vasoconstriction. Flash-induced vasoconstrictions were blocked by the alpha-receptor antagonist phentolamine and were unaffected by the beta-receptor antagonist propranolol, indicating that the light-induced responses reflect the selective activation of alpha-adrenergic receptors. After a single flash, a large transient decrease in vessel diameter was recorded, and in most vessels, this was followed by a smaller, sustained constriction. The sustained component of the contraction was selectively eliminated when Ca2+ was removed from the bath, which suggests that different mechanisms underlie the transient and the sustained responses to PE. The responses to single flashes of varying intensities occurred with a mean latency of 460 ms, which is consistent with the intermediacy of several steps between alpha-receptor activation and contraction. We anticipate that it will be possible to extend this approach to develop caged analogues of other neurotransmitters for mechanistic and kinetic studies.

Rapid release of an alpha-adrenergic receptor ligand from photolabile analogues.

A series of 2-nitrobenzyl derivatives of the alpha 1-selective adrenergic agonist, L-phenylephrine [(R)-N-[2-(3-hydroxyphenyl)-2-hydroxyethyl]-N-methylammonium chloride], have been synthesized and characterized for the purpose of developing biologically inert compounds that can be rapidly converted to L-phenylephrine by near-UV irradiation. The compounds, derivatized on the phenolic oxygen, were O-(1-(2-nitrophenyl)ethyl)phenylephrine (I), O-(2-nitrobenzyl)phenylephrine (II), O-(4,5-dimethoxy-2-nitrobenzyl)phenylephrine (III), and O-(alpha-carboxyl-2-nitrobenzyl)phenylephrine (IV). All four compounds photolyzed to free phenylephrine following a brief exposure to 300-350-nm light or 347-nm laser light with steady-state quantum yields ranging from 0.05 to 0.28. The rates of phenylephrine formation on photolysis were estimated from the decay rates of aci-nitro intermediates detected by absorbance between 380 and 500 nm. Compound IV displayed the highest quantum yield (0.28) and most rapid photolysis rate (1980 s-1) measured under near physiological conditions, pH 7.0, 22 degrees C. Biological properties of the compounds were examined in smooth muscle from rat caudal artery. Laser pulse photolysis of IV at 347 nm initiated a maximal contraction in Krebs buffer, pH 7.1, 25 degrees C, that mimicked the response to 50 microM phenylephrine but was faster in onset. Photoinitiated contractions were characterized by a delay of 0.93 +/- 0.09 s followed by a rising phase with a 10-90% rise time of 3.56 +/- 0.17 s (n = 7). Responses were fully blocked by the alpha 1-selective antagonist prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenylephrine derivatives as leukotriene D4 antagonists.

Two series of phenylephrine derivatives were prepared and tested as inhibitors of leukotriene D4 (LTD4) induced and ovalbumin-induced bronchospasm in the guinea pig. The most potent compound of the urea series, (R)-N,N-diethyl-N-[2-hydroxy-2-[3-(2-quinolinylmethoxy)phenyl]ethyl]-N- methylurea (3, Wy-47,120), was orally active with ED50's of 56 mg/kg vs. LTD4 and 55 mg/kg vs. ovalbumin. When tested as an antagonist of LTD4-induced contraction of isolated guinea pig tracheal strips, 3 was a competitive inhibitor with a p kappa B value of 5.22. In the second series, (R)-3-methyl-5-[3-(2-quinolinylmethoxy)phenyl]-2-oxazolidinone (26, Wy-47,674) had oral ED50's of 36 mg/kg against LTD4 and 95 mg/kg against ovalbumin. Compound 26 selectively antagonized contractile responses of guinea pig trachea evoked by LTD4 (p kappa B = 6.09). In the cat coronary artery, 3 dilated the preparation and blocked the coronary constrictor effect of LTD4. Compound 3 (0.13 mg/kg, iv) also preserved myocardial integrity in rats 48 h after coronary artery ligation. When tested in the rat alcohol-induced gastric lesion model, 3 and 26 manifested a dose-dependent mucosal protection against ethanol.

Synthesis and adrenergic activity of ring-fluorinated phenylephrines.

2-Fluoro-, 4-fluoro-, and 6-fluorophenylephrine (6-FPE) were synthesized from the corresponding fluorinated 3-hydroxybenzaldehydes. New routes to 2-fluoro- and 6-fluoro-3-hydroxybenzaldehydes were developed based on regioselective lithiation of 2- and 4-[(dimethyl-tert-butylsilyl)oxy]fluorobenzene ortho to fluorine. As with norepinephrine and isoproterenol analogues, the adrenergic properties of phenylephrine were markedly altered by ring fluorination. The order of potency of the fluoro analogues as alpha 1-adrenergic agonists in the stimulation of contraction of aortic strips and of phosphatidylinositol turnover and potentiation of cyclic AMP accumulation in guinea pig synaptoneurosomes was 6-FPE greater than PE greater than 4-FPE greater than 2-FPE. The same pattern was observed for the displacement of radioligands specific for alpha 1- and alpha 2-adrenergic receptors on brain membranes. The order of potency for the displacement of [3H]dihydroalprenolol, a beta-specific adrenergic ligand from brain membranes, was 2-FPE greater than 4-FPE = PE much greater than 6-FPE. 6-FPE was much more selective for alpha-adrenergic receptors compared to beta-receptors than was phenylephrine. A rationale for the observed fluorine-induced alterations in potency and selectivity of the FPEs for alpha- and beta-adrenergic systems is presented based on fluorine-induced conformations due to electrostatic repulsion of fluorine and the benzyl hydroxyl group.

Improving the ocular absorption of phenylephrine.

An oxazolidine prodrug of phenylephrine and the base form of phenylephrine were synthesized, suspended in sesame oil, and tested for mydriatic activity against phenylephrine HCl. The HCl salt was formulated as a viscous aqueous solution and as a sesame oil suspension. A dosing volume of 10 microliter was instilled into rabbit eyes and the pupillary diameter was measured over time. A 0.045 M prodrug suspension was judged equal in mydriatic activity to a 0.45 M viscous solution of phenylephrine HCl with the exception that the time of maximum response occurred 60 min earlier with the prodrug. When phenylephrine base was suspended in sesame oil at 0.045, 0.12, and 0.45 M, the mydriatic activity was also greater than equimolar suspensions of phenylephrine HCl. The pH of tear fluids was also measured over time and found to rise 1.1, 0.70, and 0.30 pH units for 0.45, 0.12, and 0.045 M suspensions of the base form but remain unchanged when phenylephrine HCl was instilled in the rabbit eye. The greater activity associated with the base form of phenylephrine was judged a result of the change in pH to favour the absorption of phenylephrine. This latter approach should be applicable to either weak acids or weak bases with pKa values outside of the normal pH range (7-8) of the tears and in concentrations greater than 0.045 M suspended in a non-aqueous vehicle.

Synthesis and activity of (R)-(-)-m-trimethylacetoxy-alpha-[(methylamino)methyl]benzyl alcohol hydrochloride: a prodrug form of (R)-(-)-phenylephrine.

Optically pure (R)-(-)-m-trimethylacetoxy-alpha-[(methylamino)methyl]benzyl alcohol hydrochloride was synthesized by the following sequence: (R)-(-)-phenylephrine was condensed with acetone in the presence of calcium carbide to give an oxazolidine derivative and then treated with thallous ethoxide in ether followed by trimethylacetyl chloride to yield the phenolic ester. Finally, the oxazolidine ring was cleaved by one equivalent of hydrogen chloride in ethanol. Condensation of phenylephrine with benzaldehyde, with or without solvents, gave either 1,1,2-trimethyl-4,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline or a mixture of side-chain oxazolidine and the tetrahydroisoquinoline. Condensation of epinephrine with opianic acid in pyridine also gave a tetrahydroisoquinoline only. When applied on rabbit eyes, the prodrug (R)-(-)-m-trimethylacetoxy-alpha[(methylamino)methyl]benzyl alcohol hydrochloride exhibited an unexpected, three times higher mydriatic activity than the corresponding racemic prodrug and was 15 times more active than the parent, (R)-(-)-phenylephrine.