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 pharmacokinetic models of clonidine-3H hydrochloride

A single topical instillation of clonidine-³H HCl solution (0.2%) was administered to the rabbit eye (30 μl) in order to study the drug's ocular pharmacokinetics. Seven different tissues and plasma were excised and assayed for drug over 180min. By 45–60 min pseudoequilibrium is reached for the cornea, iris/ciliary body, and aqueous humor. Thereafter, drug levels in these tissues decline in parallel. The data are fit separately to a physiological model and a classical diffusion model for which seven ocular tissue compartments and a plasma reservoir are constructed for each model. Clearance terms and distribution equilibrium coefficients are determined from the tissue level data and used as parameters in fitting the mass balance differential equations representing the physiological model. The model parameters can also be fit to a 0.4% single dose. In a separate experiment, a topical infusion technique was designed to provide a constant rate input to the cornea until an apparent steady state was reached in aqueous humor at 55 min. Aqueous humor levels were assayed for clonidine over the infusion and postinfusion periods. The physiological model parameters are fit to the topical infusion data and show good agreement between the predicted and experimental data. The classical model is too complex to fit the data to integrated exponential equations primarily because the method of residuals is inadequate in determining a sufficient set of initial estimates. This is overcome by dividing the eight-compartment model into seven fragmental models, each representing one to five compartments. A stepwise procedure is developed in which initial estimates are obtained for each separate fragmental model and refined. The refined parameter values can then be used as initial estimates for the complex model. Differential equations for the complex model are fit simultaneously to tissue levels representing each compartment. By observation, the classical model fit the data more closely than the physiological model. Statistical moment theory is also applied to the topical infusion data to determine ocular pharmacokinetic parameters for clonidine. The calculated values are: corneal absorption rate constantk _a , 0.00139 min^?1; aqueous humor elimination rate constantk ₁₀ , 0.0658min^?1; mean residence timeMRT _d , 35.6 min; apparent steadystate volume of distributionV _ss, 0.530 ml; and ocular clearanceQ _e , 14.9 =μl/min. The fraction absorbed from the single instillation is estimated as 0.0163.     

The contribution of treatment outcome research to the reform of children's mental health services: multisystemic therapy as an example

Service system reforms of the past decade have yielded innovations in type, accessibility, and cost of services provided for some children and families with serious problems, but few of the treatments delivered have been empirically evaluated. Rigorous tests of well-conceived treatments are needed to provide a solid foundation for continued reform. Multisystemic therapy has demonstrated efficacy in treating serious clinical problems in adolescents and their multineed families and is an example of the successful blending of rigorous treatment outcome research and service system innovation.     

Clinical Supervision in Effectiveness and Implementation Research

The role of clinical supervision in the larger‐scale implementation of effective mental health treatments has begun to attract attention in effectiveness research and implementation science. Clinical supervision approaches demonstrated to support the implementation of effective treatments could provide a fruitful basis for adaptation to the contours and implementation of other interventions. The adaptation of the Multisystemic Therapy supervision model to support the implementation of an innovative, experimental mental health service model called Links to Learning is described. An observational study provides the platform for consideration of the extent to which the Links supervision model was implemented as intended and of challenges to Links implementation illuminated by the supervision process. Implications are considered for research on supervision as a tool to effect the implementation and outcomes of effective treatment and service models in community practice contexts.     

Bilateral intravesical ureteral ligation Complication of Cooper''s ligament suspension

We report an unusual complication in a thirty-five-year-old woman in whom bilateral ligation of both intravesical ureters developed following a Cooper's ligament suspension for stress incontinence. The reason for the occurrence of this complication is described; prompt recognition early in the postoperative period and immediate intervention led to an excellent result.     

Effectiveness, transportability, and dissemination of interventions: what matters when?

The authors identify and define key aspects of the progression from research on the efficacy of a new intervention to its dissemination. They highlight the role of transportability questions that arise in that progression and illustrate key conceptual and design features that differentiate efficacy, effectiveness, and dissemination research. An ongoing study of the transportability of multisystemic therapy is used to illustrate independent and interdependent aspects of effectiveness, transportability, and dissemination studies. Variables relevant to the progression from treatment efficacy to dissemination include features of the intervention itself as well as variables pertaining to the practitioner, client, model of service delivery, organization, and service system. The authors provide examples of how some of these variables are relevant to the transportability of different types of interventions. They also discuss sample research questions, study designs, and challenges to be anticipated in the arena of transportability research.     

Pharmacokinetics of benzydamine

Benzydamine is a non-steroidal anti-inflammatory drug especially used topically for the treatment of primary or normoreactive types of inflammation. The pharmacokinetics of benzydamine are reported after both topical and systemic administration, and the available data are reviewed with particular reference to its topical use.     

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.     

INV(12) (p13q11) and dicentric chromosomes in a secondary leukaemia with basophilia

We report on a case of secondary myelodysplasia with basophilia. A karyotype showed 1) the involvement of 12p, which should be related to the basophilia and/or to previous drug exposure, and 2) the unexpected presence of three different dicentric chromosomes.