Phenylpropanolamine (PPA), a synthetic sympathomimetic amine, is widely used as a nasal decongestant and as an appetite suppressant. Much controversy exists regarding the efficacy of the drug as an anorectic agent, the related adverse reactions caused by the relatively high doses required for appetite suppression and the potential of this drug for abuse. Whilst numerous studies have been carried out to assess the central and cardiovascular safety of PPA and many investigations have been performed to evaluate efficacy in terms of weight loss in humans, there is a relative paucity of information regarding the effects of PPA on appetite and food intake. A pilot trial was conducted to determine the feasiblility of a multidimensional approach to evaluate the safety and efficacy of PPA as ananorectic agent in humans. Eight normotensive caucasian women who were overweight participated in a randomised double-blind cross-over comparison of PPA (75 mg) and placebo and were dosed to steady-state on a 12-hour fixed-dose schedule for a period of eleven weeks. Aspects of efficacy evaluated included the effects of PPA on hunger, appetite and satiety,salivation, macro-nutrient food intake and body weight. Standardised scales were used to quantitatively assess the possible subjective mood and behavioural reinforcing effects of PPA. Supine systolic and diastolic blood pressures were monitored continually throughout the trial. In addition, peak and trough blood samp1es were taken to monitor serum concentrations of PPA reached at steady-state and patient compliance with the dosing schedule. An adaptation of a published reverse-phase high performance liquid chromatographic (HPLC) assay for PPA in serum using U.V. detection at 210 nm is presented. A significant decrease in body weight, salivation, total food intake and carbohydrate consumption was demonstrated following PPA administration. Phenylpropanolamine produced significant decrements in subjective reports of hunger and appetite, whilst apparently having little effect on satiety. No significant changes were observed for blood pressures and PPA did not produce significant mood alterations or behavioural reinforcing effects. The study demonstrates the feasibility of using this muti-faceted approach, with certain design modifications, to evaluate the overall safety and efficacy of PPA as an appetite suppressant.

Phenylephrine hydrochloride is a potent adrenergic agent and β-receptor sympathomimetic drug, used in its optically active form (Pandey et al., 2003; Pandey et al., 2006). As an α1-adrenergic receptor agonist, phenylephrine hydrochloride is used ocularly as a decongestant for uveitis and as an agent to dilate the pupil (Lang, 1995). High intraocular doses have been reported to cause tachycardia, hypertension, and headache. These side effects are caused by large amounts of the drop draining into the nasal cavity. Eye drops that contain phenylephrine hydrochloride have proven to have low intra-ocular bioavailability because of a short contact time with the eyes which reduces the amount of drug reaching the site of action. Formulations of phenylephrine hydrochloride eye drops have varying shelf-lives of approximately two to four years. The aim of this study was to formulate and manufacture an eye drop product containing phenylephrine hydrochloride. Important characteristics that were targeted were increased ocular absorption by increasing the viscosity of the product and reduced degradation of phenylephrine hydrochloride. A variety of phenylephrine hydrochloride formulations were manufactured on a laboratory scale using hydroxypropyl methylcellulose (HPMC), glycerol, and sodium carboxy methylcellulose as viscosity modifying agents (VMA). The concentration of phenylephrine hydrochloride was ten percent. Ten millimeters of each formulation was made in triplicate. The quantity in each was evaluated using a previously validated high performance (pressure) liquid chromatography method. Physicochemical properties including pH and colour were also evaluated. Stability was assessed using real time and accelerated stability conditions in accordance with the International Conference on Harmonization (ICH) guidelines. Formulations containing hydroxypropyl methylcellulose (HPMC) as the viscosity modifying agents proved to be stable under all storage conditions when compared with formulations containing other viscosity modifying agents (VMA). However, sodium citrate dihydrate; sodium metabisulphite and EDTA also stabilized the formulations to a certain extent Changes in the appearance and colour of products containing glycerol under accelerated storage conditions were observed. The sodium carboxy methylcellulose (SCMC) containing formulation was found to be physically and chemically stable in two conditions, namely 30 °C/65 percent RH and 25 °C/60 percent RH. The formulations containing hydroxypropyl methylcellulose along with an antioxidant showed to be most stable as it remained aesthetically pleasing did not change colour and did not have a reduction in phenylephrine hydrochloride concentrations. This meant that phenylephrine hydrochloride did not degrade while the viscosity modifying agents remained stable. Rheological tests showed differences in the viscosities of the formulations as glycerol had increased in viscosity over time while HMPC and SCMC displayed relative similarities. The formulations were compared to a marketed eye drop containing polyvinyl alcohol as a VMA. After rheological analysis the formulation containing HPMC displayed better viscosity than the product with polyvinyl alcohol. The preservatives in the formulations were active against the microbial organisms use to challenged them.

Phenylpropanolamine (PPA), a synthetic sympathomimetic amine structurally related to ephedrine has been widely used over t he past 40 years as a nasal decongestant and appetite suppressant. It has been the focus of much controversy concerning the efficacy of the drug in its use as an anorectic agent, and due to the side effects caused by the higher doses of PPA required for appetite suppression. Although extensively used, there is little information concerning the determination of PPA in biological fluids and on the pharmacokinetics of this drug. An adaptation of a published high-performance liquid chromatographic (HPLC) assay for PPA in serum and urine using U.V. detection at 210 nm is presented. PPA was separated in the reversed phase mode. The method has a limit of sensitivity of 5.0 ng/mL and 10.0 ng/mL in serum and urine respectively. Serum concentration data following a single 25 mg dose of phenylpropanolamine in human volunteers demonstrate the application of the analytical method for bioavailability and pharmacokinetic studies. After the administration of 25 mg, 50 mg or 100 mg PPA.HCl solutions to 5 human volunteers, a dose proportionality study demonstrated that PPA appears to exhibit linear kinetics. Linear one body compartment kinetics were assumed and the wagner-Nelson method used to transform in vivo serum data to absorption plots. The serum data were fitted to a model using nonlinear regression techniques to characterize the pharmacokinetic processes of PPA. The absorption of phenylpropanolamine appears to be discontinuous and the drug seems to favour a two body compartment model. The pharmacokinetic parameters obtained from a steady state study using multiple dosing of PPA.HCl solutions compared with those found from previous studies after the administration of sustained-release formulations. A plasma protein binding study using equilibrium dialysis demonstrated that PPA is not highly protein bound in the blood.

Phenylpropanolamine (PPA), a sympathomimetic amine, has been widely used over the past 40 years as a decongestant and, in much larger dosages, as an appetite suppressant. Considerable interest has recently been shown in this drug due to its increasing popularity as an over-the-counter anorectic agent. Much controversy exists concerning the unfavourable side-effects of PPA resulting from the higher doses required for appetite suppression and the potential of this drug for abuse. A literature search revealed a paucity of information concerning the determination of PPA in biological fluids and, most noticeably, on the pharmacokinetics of this drug. An original method for determining PPA in serum and urine using high performance liquid chromatography (HPLC) which has increased sensitivity over other published HPLC methods is presented here. The simplicity of the extraction from biological fluids and subsequent determination by HPLC, enables concentrations of PPA to be monitored after a single dose of the drug. This method is therefore readily applicable to bioavailability and pharmacokinetic studies. The dissolution profiles of 4 sustained-release formulations of PPA were determined in a modified USP rotating paddle apparatus and the samples analysed using HPLC. A mathematical equation was applied to these data which are expressed in terms of dissolution parameters. Oral test dosage forms and solutions of PPA were investigated in bioavailability trials using the developed HPLC method to analyse the urine and serum samples. Linear one body compartment kinetics were assumed and the WagnerNelson method used to transform in vivo serum data to absorption plots which were then fitted to the well known Weibull equation. In order to more appropriately characterize the kinetic processes of absorption, distribution and elimination, a more complex model was utilized which involved numerical integration of a series of differential equations. The data were fitted to these models using nonlinear regression techniques. The pharmacokinetics of PPA are shown to exhibit some evidence of nonlinearity. The absorption of the drug appears to be di scontinuous and PPA seems to favour a two body compartment model.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.