Ocular Pharmacokinetics and Pharmacodynamics of Phenylephrine and Phenylephrine Oxazolidine in Rabbit Eyes

The aqueous humor concentration of phenylephrine and its corresponding mydriatic response were measured over time in New Zealand albino rabbit eyes following a 10-µl topical instillation of a phenylephrine HC1 viscous solution (10%) or a phenylephrine oxazolidine (prodrug) suspension in sesame oil (1 and 10%). The bioavailability of a 1% prodrug suspension in the rabbit eye (AUC of aqueous humor concentration vs time) was 30% lower than that of a 10% phenylephrine solution (P < 0.1) with the exception that the peak time occurred 34 min earlier with the prodrug. A 10% prodrug suspension increased the aqueous humor bioavailability approximately eightfold but improved the mydriatic activity (AUC of mydriasis vs time) only fourfold. The pharmacokinetic parameters, apparent absorption, and elimination rate constants, of phenylephrine and the prodrug were determined from aqueous humor concentration–time and mydriasis–time profiles. The study showed that the kinetic parameters of phenylephrine estimated from its mydriasis profile do not accurately reflect the kinetics of drug distribution in the iris. These parameters also varied with the instillation of phenylephrine solution or prodrug suspensions. A mydriatic tolerance of the pupil response was apparent after the topical instillation of phenylephrine solution. The mydriatic tolerance may be due to the decrease in receptor number in the iris dilator muscle.     

Ocular absorption and disposition of phenylephrine and phenylephrine oxazolidine

The ocular bioavailability of phenylephrine oxazolidine (PO), a prodrug intended for rapid corneal penetration, was micronized and suspended in sesame oil (1 and 10 per cent) and compared in bioavailability to phenylephrine HC1 (PE) dissolved (10 per cent) in a buffered (pH 5.75), viscous (30 centipoise) vehicle. Cornea and aqueous humor of New Zealand rabbits were measured over time following 10 microliter instillation to the eye. Based upon AUC measurements, corneal and aqueous humor levels were approximately 6 and 8 times greater for 10 per cent PO versus 10 per cent PE, respectively. In addition, the ocular pharmacokinetic values were determined for PE applied in a constant concentration (1 per cent) to the cornea over 180 min to anesthetized rabbits. Cornea and aqueous humor were measured for drug content over time. Using moment analysis and an initial slope method, the absorption rate constant, ka, the steady state volume of distribution in the eye, Vss, and ocular clearance, Qe, were calculated. Values obtained for PE were 4.15 x 10(-5) min-1, 0.423 ml and 14.6 microliter min-1, respectively. The half-life for drug elimination ranged from 63-83 min depending on the tissue or route of administration.     

The novel depot of buprenorphine propionate has a long‐acting effect on physical dependence on morphine

Buprenorphine is a promising drug for the treatment of physical dependence on opioids. The aim of the present study was to evaluate the efficacy and duration of action of a novel depot form of a buprenorphine prodrug, buprenorphine propionate, on physical dependence on morphine. Following intramuscular injection in morphine‐dependent mice, the efficacy and duration of action of buprenorphine propionate in sesame oil were evaluated. Two other dosage forms of buprenorphine were used as controls. Intramuscular injection of buprenorphine HCl (0.1 µmol/kg in saline) attenuated the severity of morphine dependence (P<0.05) with a 9‐h duration of action. However, a further increase in dose up to 60‐fold could not further increase its duration of action. On the other hand, buprenorphine base and propionate when prepared in sesame oil produced longer durations of action than did buprenorphine HCl in saline under an equimolar basis of 6 µmol/kg (P<0.05, for each comparison). Among dosage forms, buprenorphine propionate in sesame oil produced the longest duration of action, 11.3‐fold longer than that of buprenorphine HCl in saline and 2‐fold longer than buprenorphine base in oil. In conclusion, the novel depot of buprenorphine propionate produced a dose‐related long‐acting effect on physical dependence on morphine in mice. Drug Dev. Res. 67:462–469, 2006. © 2006 Wiley‐Liss, Inc.     

Consensual pupillary responses to mydriatic and miotic drugs.

1. Three experiments were conducted to examine whether mydriatic or miotic drugs instilled into one eye have any effect on the diameter of the pupil of the untreated fellow eye, in healthy volunteers. 2. In Experiment 1, the effects of four subjects, using photography in an illuminated room to assess pupil diameter. The drug evoked a dose-dependent mydriasis in the index eye which was accompanied by a simultaneous dose-dependent miosis in the fellow eye. 3. In Experiment 2, the same method was used to assess pupil diameter as in Experiment 1. The effects of mydriatic (methoxamine and tyramine) and of miotic (pilocarpine) drugs instilled into the fellow eye, were studied on the sizes of pupillary responses to the same drugs instilled into the index eye. The presence of a mydriatic drug in the fellow eye resulted in a decrease in the size of the mydriatic responses in the index eye. 4. In Experiment 3, the effects of three concentrations of phenylephrine hydrochloride (0.15-0.60 M) and of three concentrations of pilocarpine hydrochloride (0.002-0.008 M), were studied in darkness using an infra-red binocular television pupillometer, in seven subjects. Phenylephrine evoked dose-dependent mydriasis and pilocarpine evoked dose-dependent miosis. The pupillary responses of the index eye were not accompanied by any changes in the diameter of the pupil of the fellow eye. 5. It is concluded that drug-induced mydriasis in the index eye is accompanied by a consensual miosis in the fellow eye.(ABSTRACT TRUNCATED AT 250 WORDS)     

On the mechanism of drug release from oil suspensions in vitro using local anesthetics as model drug compounds

The objective of this study was to gain insight into factors influencing the drug release kinetics from oil suspensions. The in vitro drug release from suspensions was investigated at pH 7.4 using the local anesthetics, bupivacaine and ropivacaine, as model drug compounds. Two dialysis membrane-based in vitro release models differing with respect to stirring of the donor compartment were employed to study the release characteristics of oil suspensions comprising the free base or the corresponding drug hydrochloride salt. In the rotating dialysis cell model identical release profiles from aqueous and oil suspensions of the base form were obtained for both ropivacaine and bupivacaine. From the steady state fluxes, drug concentrations in the aqueous donor compartment were found to be in agreement with drug solubilities at pH 7.4. Also relatively fast transformation of a sesame oil suspension of the oil insoluble ropivacaine hydrochloride salt into an aqueous suspension of ropivacaine base was observed. Collectively, these observations indicate a lability of the oil film surrounding the solid particles eventually caused by rotation of the donor cell. In the Float A Lyzer^® model, which operates at much less intensive stirring, significantly slower release rates from aqueous and oil suspensions of ropivacaine base were obtained. In the latter model, ropivacaine was released faster from oil suspensions containing the hydrochloride salt than from the corresponding oil suspensions of the free base form. These findings suggest that the oil film surrounding the particles also is instable in the absence of significant shear forces.     

Novel site-specific chemical delivery system as a potential mydriatic agent: formation of phenylephrine in the iris-ciliary body from phenylephrone chemical delivery systems

The objective of this study was to test the three novel ester derivatives of phenylephrone (isovaleryl, phenylacetyl, and pivalyl esters) as potential site-specific chemical delivery systems. The mydriatic effect and ocular distribution/metabolism of these compounds were studied by topical application to the eyes of normal rabbits. It was assumed that a reduction-hydrolysis sequence could produce the active phenylephrine in the iris-ciliary body tissues. All the derivatives showed a more pronounced mydriatic effect than that of phenylephrine, whereas phenylephrone was completely devoid of any mydriatic activity. Phenylacetyl ester was the most potent drug, with short duration of action, and showed maximum activity in the presence of 0.01% benzalkonium chloride without causing any visible irritation to the rabbit eye. Administration of the novel compounds to the eyes of the rabbits showed no traces of phenylephrine in the systemic circulation, contrary to topical administration of phenylephrine. Phenylephrone was detected in different compartments of the eye, whereas phenylephrine was present only in the iris-ciliary body tissues following administration of phenylacetyl ester. The conversion of phenylephrone esters to the active drug, phenylephrine, and thus their subsequent activity was dependent on the physicochemical characteristics of the drugs. The results suggest the potential use of phenylacetyl ester as a potent short-term mydriatic agent without systemic side effects.     

In vitro and in vivo evaluation of the metabolism and pharmacokinetics of sebacoyl dinalbuphine.

A diester prodrug of nalbuphine, sebacoyl dinalbuphine (SDN), and its long-acting formulation are currently being developed to prolong the duration of nalbuphine. A comparative in vitro hydrolysis study was conducted for SDN in rat, rabbit, dog, and human blood. Both SDN and nalbuphine in blood or plasma were measured by high-performance liquid chromatography. The hydrolysis rates of SDN in blood were ranked as follows: rat > rabbit > human > dog. The rapid formation of nalbuphine in the blood accounted for almost 100% of the prodrug, which supported the contention that nalbuphine is the major metabolite after SDN hydrolysis. The hydrolysis profiles of SDN were similar both in plasma and in red blood cells when compared in the blood. In vitro release results of SDN long-acting formulation showed that the rate-limited step of SDN hydrolysis to nalbuphine in blood is the penetration of SDN from oil into the blood. After intravenous administration of SDN in sesame oil into rats, nalbuphine quickly appeared in plasma and, thereafter, exhibited monoexponential decay. Pharmaceutical dosage forms affecting the drug disposition kinetics were demonstrated after intravenous administration. The AUC of nalbuphine was significantly higher and clearance was significantly lower, without changes in the t(1/2) of nalbuphine after intravenous dosing of SDN in sesame oil when compared with that of intravenous dosing with nalbuphine HCl in rats. Overall, these results suggest that SDN fulfilled the original pro-soft drug design in which the prodrug can rapidly metabolize to nalbuphine, and no other unexpected compounds were apparent in the blood.     

Studies on the Mechanism of Absorption of Depot Neuroleptics: Fluphenazine Decanoate in Sesame oil

Purpose. The purpose of the present study was to investigate the pharmacokinetic characteristics of fluphenazine (FLU) and its decanoate (FLU-D) after intravenous and intramuscular administration to dogs. Methods. A group of four beagle dogs was used in all intravenous and intramuscular experiments, with washout periods of no less than three months between doses. Results. After intravenous FLU-D, the pharmacokinetics of the prodrug (mean ± SD) were as follows: Clearance (CL) 42.9 ± 6.3 L/h; terminal half-life (t_1/2) 3.5 ± 0.8 h; volume of distribution (Vd) 216 ± 61 L. The fractional availability of FLU was 1.0 ± 0.2. After intravenous FLU, the volume of distribution of FLU (51 ± 17.8 L) was some 4 fold less than that of the prodrug. Simulations (Stella II) suggested that the rate limiting step was slow formation of FLU from the prodrug in the tissue compartment. After intramuscular FLU-D in sesame oil, the apparent t_1/2 of FLU was 9.7 ± 2.0 days whereas after intramuscular FLU base in sesame oil, the apparent t_1/2 was only 7.7 ± 3.4 h showing that the absorption of FLU itself from the intramuscular site and proximal lymph nodes is relatively rapid. Conclusions. The rate limiting step after intramuscular FLU-D appeared to be the slow partitioning of the prodrug out of the sesame oil at the injection site and in proximal lymph nodes.     

The local vasoconstriction of infant’s skin following instillation of mydriatic eye drops

Background  

Systemic absorption of eye drops is known to occur via the nasal mucosa, cornea, and conjunctiva. Diffusion of eye drops through the skin is previously unrecognized. Here, two cases are presented in which we observed skin pallor around the eyes after instillation of phenylephrine 2.5% drops. Case 1 A 32-week gestational age premature infant had mydriatic eye drops instilled as part of retinopathy of prematurity screening. Case 2 A term newborn dysmorphic infant underwent fundus examination to rule out ocular pathology. In both cases, discoloration of periorbital skin was observed 45 min following administration of drops.     

pH‐dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2‐bis(methylsulfonyl)‐1‐(2‐chloroethyl)hydrazine prodrugs

Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short‐lived chloroethylating agent with anticancer activity. The short half‐life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl‐based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) They are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species. Previous speculations as to the therapeutic superiority of laromustine have focused upon the inhibition of enzymes by carbamoylation. We have investigated the therapeutic interactions of analogs with segregated chloroethylating and carbamoylating activities (singly and in combination) in the in vivo murine L1210 leukemia model. The combined treatment with chloroethylating and carbamoylating prodrugs failed to result in any synergism and produced a reduction in the therapeutic efficacy compared to the chloroethylating prodrug alone. Evidence supporting an alternative explanation for the superior tumor selectivity of laromustine is presented that is centered upon the high pH sensitivity of its base catalyzed activation, and the more alkaline intracellular pH values commonly found within tumor cells.     

Bioavailability of phenytoin from oil suspension and emulsion in dogs

Phenytoin as a sesame oil suspension or emulsion was administered orally to beagle dogs to study improvement of its bioavailability. The absorption of phenytoin by the digestive tract was better when it was given as a sesame oil suspension or emulsion than as a powder. With the dose amount of sesame oil and water fixed, the absorption of phenytoin from the emulsion was greater than that from the oil suspension, although the difference was not significant. Therefore, the absorption of phenytoin was not affected significantly by emulsifying the sesame oil. Its absorption corresponded not to the amount of water given with the dose amount of sesame oil fixed, but to the dose amount of sesame oil with the dose amount of water fixed, reaching maximum when the ratio of sesame oil to water was 1:3. Study of the influence of the type of oil in the emulsion on the absorption by the digestive tract showed that absorption was best with cod-liver oil, followed by sesame oil, and then oleic acid.     

Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH

No HeadingPurpose. To evaluate the effect of pH on solubility and dissolution rates of a model weak base, haloperidol, and two different salt forms, hydrochloride and mesylate.Methods. pH-solubility profiles were determined by using haloperidol base, haloperidol hydrochloride, and haloperidol mesylate as starting materials; concentrated or diluted HCl or NaOH solutions were added to aqueous suspensions of solids to adjust pH to desired values. Intrinsic dissolution rates were determined using intrinsic dissolution apparatus under various pH-stat conditions. Further, approximation of diffusion layer pH was estimated from that of 10% w/w slurries of drug substances in dissolution media, which were used to correlate with intrinsic dissolution rates of haloperidol and its salt forms under different pHs.Results. pH-solubility profiles of haloperidol base and its HCl salt were similar, while when the mesylate salt was used as starting material, it exhibited a higher solubility between pH 2 and 5. The higher solubility of the mesylate salt at pH 2–5 is attributed to its higher solubility product (K_sp) than that of the hydrochloride salt. The pH-solubility profiles indicated a pH_max (pH of maximum solubility) of 5, indicating that the free base would exist as the solid phase above this pH and a salt would be formed below this pH. Below pH 1.5, all solubilities were comparable due to a conversion of haloperidol base or the mesylate salt to the HCl salt form when HCl was used as the acidifying agent. These were confirmed by monitoring the solid phase by differential scanning calorimeter. When their dissolution rates are tested, dissolution rates of the mesylate salt were much higher than those of the free base or the HCl salt, except at very low pH (<2). Dissolution rates of free base and HCl salt also differed from each other, where that of HCl salt exhibits higher dissolution rates at higher pHs. A direct correlation of dissolution rate with solubility at diffusion layer pH at the surface of dissolving solid was established for haloperidol, its hydrochloride, and mesylate salts.Conclusions. Using pH-solubility and pH-dissolution rate interrelationships, it has been established that diffusion layer pH could be used to explain the observed rank order in dissolution rates for different salt forms. A non-hydrochloride salt, such as a mesylate salt, may provide advantages over a hydrochloride salt due to its high solubility and lack of common ion effect unless at very low pH.     

Studies on the Fate of Vegetable Oil after Intramuscular Injection into Experimental Animals

Abstract The fate of sesame oil and Viscoleo was studied in dogs after single intramuscular injection into the thigh of ¹⁴C-labelled oil (0.5 ml/kg). Parts of Viscoleo was absorbed as liquid oil to the regional lymph nodes occasionally to such an extent that small oil droplets were drained from the iliac lymph nodes into the lymph of the thoracic duct causing pulmonary oil microembolisation. Sesame oil was also absorbed to the regional lymph nodes after single injection but in no case to such an extent that pulmonary oil microembolism occurred. In dogs which received unlabelled sesame oil (0.45 and 1.0 ml/kg) or Viscoleo (0.45 ml/kg) intramuscularly once a week for six months and finally an injection of ¹⁴C-labelled oil, pulmonary oil microembolism was seen in all three groups and most markedly after the higher sesame oil dose. The iliac lymph nodes in both sesame oil dose groups were highly enlarged and appeared cystic due to presence of oil. The lungs from the dogs receiving Viscoleo were seat of small mononuclear interstitial cell infiltrations sometimes present in the vicinity of oil microemboli. In the sesame oil groups oil was additionally found extravascularly in the lung interstities together with accumulation of macrophages and leucocytes and focal hemosiderosis in the lungs occurred on the highest dose level. In the sesame oil groups of dogs pulmonary oil microembolism was found microscopically in a higher number than that seen on autoradiograms. The embolisation obtained at one injection may thus not disappear before the next injection. Except for presence of very few oil microemboli and small focal areas with interstitial oil deposits the lungs were normal in dogs examined three months after six month chronic weekly injection of sesame oil. Small oil deposits were still present at the injection site and in the iliac lymph nodes of these dogs, but the lymphoid tissue of the nodes had partly recovered. Pulmonary oil microembolism was also seen microscopically in rabbits after intramuscular injection of sesame oil or Viscoleo three times a week for two weeks, and also in rats after injection of sesame oil three times a week for five weeks. The content of radioactivity in the heart, kidneys, liver and lungs were generally low and the liver had the highest content (up to 1.32% of dose). The content in the lungs was not increased by presence of Viscoleo microemboli whereas sesame oil microembolisation significantly raised the amount of radioactivity in the lungs. The amounts of radioactivity at the injection site of dogs were reduced to half of the injected dose two days after injection of ¹⁴C-Viscoleo and five weeks after injection of ¹⁴C-sesame oil. In rats receiving an intramuscular injection (0.5 ml) into the thigh of ¹⁴C-Viscoleo or ¹⁴C-sesame oil the amounts of radioactivity at the injection site disappeared exponentially with time, and half of the dose had disappeared one week after injection of ¹⁴C-Viscoleo and 9 weeks after injection of ¹⁴C-sesame oil. The acute intravenous toxicity of sesame oil and Viscoleo was estimated in rabbits by determination of the LD50 dose which for sesame oil was 0.74 ml/kg and for Viscoleo 0.84 ml/kg. In the lungs of rabbits receiving 0.5 ml/kg of sesame oil or Viscoleo intravenously, numerous focal haemorrhages were present in the sesame oil group. Four weeks after the injection oil microembolisation was still pronounced in lungs from the sesame oil group while only few emboli were found in lungs from the Viscoleo group two weeks after the injection, In addition sesame oil was found extravascularly in the lung interstities with cellular infiltrate. Thus the pulmonary Viscoleo microemboli disappeared considerably faster than the sesame oil microemboli. In conclusion the present studies have revealed that chronic intramuscular injection of large volumes of two different oily drug vehicles may cause pulmonary oil microembolisation after lymphatic absorption as liquid oil. This occurred in spite of markedly different absorption rates of oil from the injection site. Toxicological implications of the present experiments with intramuscular injections of oil were related to the injection site, the regional lymph nodes and the lungs. Consequently the present finding demonstrate that the regional lymph nodes and the lungs may be the organs of interest in future studies on the relations to the human clinic. If pulmonary oil microembolisation should occur in patients receiving large volumes of oil the pathological sequelae may according to the present findings in animals be without importance.     

Capsules with prolonged action. II. Capsule filling by a gelation process

A new formulation for manufacturing sustained-release soft gelatin capsules was investigated. It consists of a gel solid formed by ethylcellulose and sesame oil and 20 to 35% polyethylene glycol 400 for the enhancement of drug release. Citric acid triethylester (Citroflex-2) makes it possible to combine sesame oil with polyethylene glycol. By recording the rheological behavior at various temperatures, the thixotropic properties of the mixture that leads to the gel-forming process were ascertained. The ideal temperature for filling into soft gelatin capsules can also be determined by this method. The release profile of codeine dissolved or suspended in the mixture shows the typical matrix-type release. In contrast, a high amount of theophylline suspended in the carrier system yields an erodible matrix with an almost-constant release rate.     

Novel depots of buprenorphine have a long-acting effect for the management of physical dependence to morphine

Buprenorphine is a promising new pharmacotherapy for the management of physical dependence to opioids. The aim of the study was to evaluate the duration of action of several novel depots of buprenorphine in the treatment of physical dependence to morphine in mice. Following intramuscular injection, the duration of action of several novel oil-based depots of buprenorphine base in morphine-dependent mice were evaluated. The traditional dosage form of buprenorphine hydrochloride in saline was used as control. We found that the depot of buprenorphine base in sesame oil produced a dose-related long-lasting effect. On an equimolar basis of 6 micromol kg(-1), its effect was 5.7-fold longer than that of buprenorphine hydrochloride in saline. When prepared in several other oleaginous vehicles (castor oil, cottonseed oil, peanut oil and soybean oil), buprenorphine base also produced a long-lasting effect, which was similar to buprenorphine base in sesame oil. In conclusion, buprenorphine base, when prepared in oleaginous vehicles and injected intramuscularly in mice, produced a long-lasting effect on physical dependence to morphine.     

Fenylefrineoogdruppels 2,5% en 5%

Data on the use, the mydriatic activity and the systemic adverse effects of phenylephrine eyedrops are reviewed in order to ascertain whether mydriatic concentrations lower than 10% should be included in theFormulary of Dutch Pharmacists (FNA). From the available data it is deduced that 2,5% and 5% may be useful mydriatic concentrations, whereupon their mode of preparation is discussed.Samenvatting Teneinde na te gaan of mydriatische fenylefrineconcentraties lager dan 10% in het Formularium der Nederlandse Apotherkers (Fna) kunnen worden opgenomen, zijn gegevens over het gebruik, de mydriatische effectiviteit en de systemische bijwerkingen van fenylefrineoogdruppels verzameld. Uit de beschikbare gegevens wordt afgeleid dat 2,5% en 5% bruikbare mydriatische concentraties kunnen zijn, waarna de bereidingswijze van deze concentraties wordt besproken.     

Miotic effect and irritation potential of pilocarpine prodrug incorporated into a submicron emulsion vehicle.

Pilocarpine prodrug, O,O'-dipivaloyl(1,2-ethylene) bispilocarpic acid diester, was introduced to a submicron emulsion vehicle in a dose equivalent to 0.5% pilocarpine base, and the formulation was studied in albino rabbits using miotic assay. Compared with pilocarpine HCl 0.5% solution delayed and prolonged miosis was observed after application of the prodrug emulsion. AUC(0-6 h) values for the prodrug emulsion and pilocarpine solution were 9252+/-1345 and 6845+/-1967%xmin, respectively. The prodrug was also administered twice daily for 5 days in the form of aqueous solution or submicron emulsion in order to study ocular irritation. Irritation potential of the prodrug was significantly reduced when submicron emulsion was used as a vehicle. Copyright     

Modified β-Cyclodextrin (SBE7-β-CyD) with Viscous Vehicle Improves the Ocular Delivery and Tolerability of Pilocarpine Prodrug in Rabbits

The complexation of pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, with various β-cyclodextrin (β-CyD) derivatives was studied by the phase solubility method. The effects of coadministered sulphobutyl ether β-CyD (SBE7-β-CyD) with and without poly(vinyl alcohol) (PVA) on the miotic response and eye irritation of the prodrug were investigated in pigmented rabbits. The pilocarpine prodrug formed 1:1 inclusion complexes with variably substituted sulphobutyl ether derivatives of β-CyD (SBE4-β-CyD and SBE7-β-CyD), and 1:1 and 1:2 complexes with hydroxypropyl-β-CyD (HP-β-CyD) at pH 7:4. Coadministered SBE7-β-CyD eliminated the eye irritation due to the pilocarpine prodrug, but also decreased the miotic response. Ocular absorption of the prodrug was improved by increasing the viscosity of prodrug/SBE7-β-CyD solution with PVA without inducing any eye irritation. Eye irritation due to viscous prodrug/SBE7-β-CyD solutions was comparable with isotonic NaCl solution. We conclude that administration of pilocarpine prodrug in viscous SBE7-β-CyD solution decreases substantially eye irritation while ocular absorption is not affected.     

Enhancement of transdermal apomorphine delivery with a diester prodrug strategy

Diester prodrugs of apomorphine, diacetyl apomorphine (DAA), and diisobutyryl apomorphine (DIA) were synthesized, and their partition coefficients, capacity factor (log K′), enzymatic hydrolysis, and in vitro permeation across nude mouse skin were characterized. The lipophilicity of the diesters was between that of apomorphine HCl and the apomorphine base. The prodrugs were chemically stable, but enzymatically unstable in esterase medium, skin homogenate, and human plasma. DAA showed a faster hydrolysis in plasma compared to DIA. Total fluxes (nmol/cm²/h) of the parent drug and prodrug were significantly greater after topical treatment with the diesters in aqueous solutions (water, 30% polyethylene glycol in water, and 30% glycerol in water) compared to treatment with HCl and base forms of apomorphine. DIA flux from deionized water was 51 nmol/cm²/h, which exceeded the flux of apomorphine HCl by 10-fold. The extent of parent drug regeneration after topical application ranged 51-88% and 34-61% for DAA and DIA, respectively, depending on the vehicles selected. Permeation measurements using intact and stratum corneum-stripped skins demonstrated that the viable epidermis/dermis was an important barrier to prodrug permeation. Nano-sized lipid emulsions were also used as carriers for apomorphine and its prodrugs. Diester prodrugs exhibited superior skin permeation compared to the parent drug when formulated into the emulsions. DAA and DIA fluxes from lipid emulsions were 11- and 3-fold higher than that of apomorphine HCl. The results in the present work suggest the feasibility of diester prodrugs for the transdermal delivery of apomorphine.     

Potentiation of the hyporeactivity induced by in vivo endothelial injury in the rat carotid artery by chronic treatment with fish oil.

1. The present study investigates whether or not chronic feeding of rats with a diet enriched in fish oil affects the reactivity of balloon-injured carotid arteries. The left carotid arteries were injured in vivo by the repeated passage of a balloon catheter. Both the right (control artery) and the left carotid arteries were excised 24 h after the injury, and suspended in organ chambers for the measurement of changes in isometric tension in the presence of indomethacin. 2. Phenylephrine evoked similar concentration-contraction curves in the right (control) carotid arteries without endothelium from control and fish oil-fed rats. Balloon injury decreased the contractility of carotid arteries to phenylephrine in both types of rats and the pEC50 for phenylephrine was significantly decreased in balloon-injured arteries from control rats compared to those obtained in arteries from fish oil-fed rats (pEC50 7.59 +/- 0.1 and 7.28 +/- 0.06, respectively) while maximal contractions were similar (1.93 +/- 0.15 g and 1.79 +/- 0.12 g, respectively). 3. The treatment of control right carotid arteries without endothelium with either NG-nitro-L-arginine (an inhibitor of nitric oxide synthase) or superoxide dismutase (which protects nitric oxide from degradation) did not affect significantly the contractions to phenylephrine in either group. In these preparations, methylene blue (an inhibitor of soluble guanylate cyclase) decreased slightly but significantly maximal contractions to phenylephrine in both groups. The treatment of balloon-injured carotid arteries with NG-nitro-L-arginine or methylene blue partly restored contractions to phenylephrine in arteries from both types of rat.(ABSTRACT TRUNCATED AT 250 WORDS)