An exploration of modified monovision with diffractive bifocal contact lenses.

A group of eight presbyopic subjects wore in succession four types of correction. One of these (A) consisted of a conventional pair of diffractive bifocals in which equal amounts of light contributed to the distance and near images in both eyes. Two (B and C) were modified monovision corrections using non-standard diffractive bifocal lenses. The diffractive designs were such that in the dominant eye a greater fraction of light was sent into the distance image and less into the near image and in the non-dominant eye a greater fraction contributed to the near image. The last lens combination (D) was a conventional monovision arrangement, with a single-vision distance correction on the dominant eye and a single-vision near correction on the non-dominant eye. Monocular and binocular high-contrast acuity, contrast sensitivity and stereopsis were assessed at both distance and near with each of the four lens combinations. It was hoped that the modified monovision arrangements (B and C) might yield improved distance and near acuities in comparison with the standard diffractive bifocals (A) while still maintaining good stereopsis in comparison with the single-vision monovision combination (D) and thus allow wearers to achieve better all round visual performance. Although these expectations were at least partly fulfilled, the modest advantages offered by the diffractive modified monovision approach did not appear to compensate for the disadvantages of its greater complexity.

Relative performance of soft contact lenses having lathe-cut posterior surfaces with and without additional polishing.

After a preliminary investigation of the effects of tool feed rate and spindle speed on the surface roughness of unhydrated, lathe-cut polymacon surfaces, a laboratory and clinical comparison was made between lenses with identical parameters except that the lathe-cut posterior surface was left unpolished in the "test" lenses and was polished in the "control" lenses. The lenses had moulded anterior surfaces. Laboratory comparisons included surface roughness, lens power and its uniformity across the surface. Double-blind clinical trials over 4-hour (27 subjects) and 1-month (10 subjects) periods, involved one eye of each subject wearing a "test" lens and the other, a "control" lens. No clinically significant differences were found between the results for the test and control lenses. It is concluded that today's lathing technology makes a final polishing stage unnecessary.

Wavefront technology: past, present and future.

After outlining what is meant by wavefront aberration, the history of the field of wavefront technology is sketched and methods for measuring ocular wavefront aberration are briefly described. The variations in aberration of the normal eye with the individual and their pupil size, accommodation and age are summarised. Potential contact lens applications are outlined, including the design and on-eye performance of single-vision lenses, lenses for presbyopes and keratoconics, orthokeratology, tear film studies, and the design and performance of customised contact lenses intended to minimise residual lens-eye wavefront error.

In vitro assessment of oral lipid based formulations.

In recent years there has been an increase in interest in the utility of lipid based delivery systems, at least in part as a result of the effective development of lipid based products such as Sandimmun Neoral (cyclosporin), Norvir (ritonavir) and Fortovase (saquinavir). The development pathway for lipid based formulations, however, is still largely empirical, and in vitro models that are predictive of oral bioavailability enhancement are lacking. The use of modified dissolution media, reflecting the bile salt and phospholipid levels in the intestine, has met with some success in terms of the ability to predict the bioavailability of poorly water soluble drugs and the potential bioavailability enhancing effects of food. These approaches, however, do not have the flexibility or complexity to deal with the interactions inherent in the digestion, dispersion and solubilisation of a lipid based formulation and the coincident dissolution profile of a co-administered drug. In this review, the utility of modified dissolution media to predict the impact of food on the absorption of poorly water soluble, lipophilic drugs, is explored. These dissolution based systems are subsequently contrasted with the use of lipid digestion models which have found increasing application in assessment of the interaction of digestible dose forms with the gastrointestinal milieu.

Intestinal lymphatic drug transport: an update.

The trend towards identification of poorly water-soluble and highly lipophilic candidate drug molecules has led to an increase in interest in intestinal lymphatic drug transport. In this article we provide a brief background to the mechanism of access of drugs to the intestinal lymph and the role of lipid digestion and absorption in the stimulation of lymphatic transport. The ability of different lipid types to stimulate lymphatic drug transport, is addressed, concentrating specifically on the impact of the class, chain length and degree of unsaturation of co-administered lipids. Comment is also made as to the relevance of dosing different lipid volumes to the rat and the possible complications this may provide when trying to assess the likely extent of intestinal lymphatic transport. Recent studies are described in which the extent of lymphatic transport of a highly lipophilic antimalarial, halofantrine, was investigated after post-prandial administration to greyhound dogs. Finally the possible future directions for studies of intestinal lymphatic transport are discussed, including the use of cell culture models and genetically modified animals.

Animal models for the study of intestinal lymphatic drug transport.

Drug transport via the intestinal lymphatic system has been shown to contribute to the absorption of a number of orally administered highly lipophilic drugs. In order to investigate this phenomenon and assist in the development of improved oral formulations, the use of appropriate animal models is required. This paper reviews the use of various animal models for this purpose, and describes in detail the conscious rat and dog models used in our laboratory. The advantages and disadvantages of both small and large animal models are explored, as well as the factors which have been found to influence the outcome of intestinal lymphatic drug transport studies with these models.

Accommodation responses and ageing.

PURPOSE: To study the impact of age on accommodation dynamics. METHODS: Monocular accommodation responses were measured continuously using a modified Canon Auto Ref R1 infrared optometer. The stimulus was a single letter oscillating sinusoidally between 2.38 and 1.33 D providing a stimulus amplitude of 0.52 D, about a mean level of 1.86 D. Response characteristics were used to quantify gain and phase. Step responses were also recorded between these stimulus vergence levels for calibration purposes and to measure reaction and response times. Nineteen visually normal subjects 18 to 49 years of age participated, and 11 frequencies were used in the range 0.05 to 1.0 Hz. A key feature of the experimental design was to use a stimulus vergence range that lay within the amplitude of accommodation of all the observers. RESULTS: Accommodation gain reduced and phase lag increased with age, particularly at the higher frequencies used. No strongly significant change with age was found for reaction and response times or accommodation velocity, and results were similar for both far-to-near and near-to-far responses. Response amplitude for the step change in target vergence declined with age, and substantial differences were found between the measured and predicted (from reaction time) phase lags at 1.0 Hz as a function of age. Young observers showed a phase lag that was shorter than predicted, whereas older observers' measured phase lags were considerably larger than predicted. CONCLUSIONS: Results show that for a target oscillating sinusoidally in a predictable manner at a modest amplitude, the main ageing effects occur in phase lag, which is appreciably longer than predicted from reaction times in the older observers. The effects of ageing on gain were not as marked. Although responses to small step changes do reduce with age, there is no evidence of increased response times with ageing. In general, accommodation function in the middle-aged eye is quite robust despite a dwindling amplitude of accommodation. These results provide evidence of accommodative vigor in youth and a slowing of accommodation with ageing.

Prodrugs. Do they have advantages in clinical practice?

Prodrugs are pharmacologically inactive chemical derivatives of a drug molecule that require a transformation within the body in order to release the active drug. They are designed to overcome pharmaceutical and/or pharmacokinetically based problems associated with the parent drug molecule that would otherwise limit the clinical usefulness of the drug. The scientific rationale, based on clinical, pharmaceutical and chemical experience, for the design of various currently used prodrugs is presented in this review. The examples presented are by no means comprehensive, but are representative of the different ways in which the prodrug approach has been used to enhance the clinical efficacy of various drug molecules.

Absorption of danazol after administration to different sites of the gastrointestinal tract and the relationship to single- and double-peak phenomena in the plasma profiles.

The absorption of danazol (100 mg) after oral or intraintestinal administration to the proximal jejunum or proximal ileum has been studied in healthy female subjects. The extent of danazol absorption after administration as a solubilized glycerol mono-oleate emulsion formulation was approximately twofold and fourfold greater after oral dosing when compared with jejunal or ileal administration, respectively. Although not statistically significant in this study, the extent of absorption after jejunal administration was generally greater than after ileal administration. After oral dosing, qualitative assessment identified the presence of double peaks or major shouldering characteristics in 14 of the 16 individual danazol plasma concentration-time profiles, whereas only single peaks were present after intraintestinal administration. These data are consistent with the double peaking phenomena after oral administration of the emulsion formulation being stomach-related. The double peaking effect may be explained in terms of a probable combination of gastric emptying regulated absorption (due to the presence of the lipid in the emulsion formulation) and the dependence of danazol solubility on bile salt solubilization within the upper small intestine.

Effect of food and a monoglyceride emulsion formulation on danazol bioavailability.

The bioavailability of a single 100-mg dose of danazol delivered from the commercial formulation (hard gelatin capsule) and from an experimental lipid emulsion formulation of danazol was studied in 11 healthy female volunteers in both fed and fasted states. The emulsion formulation (fasted) increased bioavailability fourfold compared with the capsule (P = .0001); the difference, however, was not significant in the fed state. Food increased the bioavailability of the capsule formulation more than threefold over fasted administration (P = .0001). In a separate study of 12 female volunteers, single doses of the emulsion formulation of danazol administered with food demonstrated essentially dose-proportional pharmacokinetics over the dose range studied (50-200 mg). The authors conclude that factors that increase the extent of solubilization lead to significant enhancement in the bioavailability of danazol.

Variation in the diffusion and release of ribonuclease through and from esterified hyaluronic acid membranes: effect of changes in matrix characteristics.

50 h) were detected for the transport and release of a model protein (ribonuclease A) compared with that for the translucent region which showed no lag time. The results highlight the importance of carefully controlling matrix formation to ensure reproducible transport and release characteristics from polymer matrices.

Mechanisms controlling diffusion and release of model proteins through and from partially esterified hyaluronic acid membranes.

The effects of polymer percent esterification and protein molecular weight on the diffusion of two model proteins, deoxyribonuclease (DNase) and ribonuclease A (RNase A), through and from partially esterified hyaluronic acid membranes were compared. The permeability of the polymer membranes was inversely related to the degree of polymer esterification and the molecular weight of the protein. Transport rates of proteins through the membranes decreased dramatically over narrow ranges of polymer esterification. As expected, the apparent diffusivity of the larger protein in the polymer matrix was more sensitive to changes in membrane hydration than that of the smaller protein. These observations demonstrated the dependence of the mobility of large molecular weight proteins on polymer hydration and chain relaxation. The relationship between protein diffusion through and release from the modified hyaluronate matrices was also investigated using RNase A as a model. The release profiles from fully esterified membranes showed lag behavior and varied with protein load and hyaluronate hydrolysis rates, while release from less esterified membranes was rapid and independent of polymer esterification or hydrolysis. Potential applications of modified hyaluronate matrices in the controlled delivery of proteins are discussed.

Choice of spatial frequency for contrast sensitivity evaluation after corneal refractive surgery.

PURPOSE: To study the utility of measurements of contrast sensitivity at different spatial frequencies as an index of visual recovery following refractive surgery. METHODS: Contrast sensitivity at 1.5, 3, 6, 12, and 18 c/deg was measured with the Stereo Optical FACT chart in 20 patients after photorefractive keratectomy (PRK) using the Nidek EC-5000 excimer laser system, and in 18 patients following laser in situ keratomileusis (LASIK). Contrast sensitivity was measured preoperatively and 1, 3, 6, and 12 months after surgery. RESULTS: Results showed a statistically significant reduction (P<.01) in contrast sensitivity at all spatial frequencies in PRK patients during the first and third month, but contrast sensitivity recovered to preoperative values by 6 months after surgery (P>.1). In LASIK patients, decreased contrast sensitivity values 1 month after surgery were also obtained at all spatial frequencies. After 3 months, contrast sensitivity at 1.5 and 3 c/deg had recovered and did not differ significantly from preoperative values (P>.1), although contrast sensitivity at other frequencies remained reduced (P<.01). At 6 and 12 months, contrast sensitivity at all spatial frequencies did not differ from that obtained preoperatively (P>.1). CONCLUSIONS: Contrast sensitivity measurements at 6 and 12 c/deg appear to be most useful in the assessment of patients who have undergone laser refractive surgery because defocus and optical aberrations primarily affect the higher spatial frequencies.

The effect of pupil centration and diameter on ocular performance.

The variation in sphero-cylindrical refractive error with position in the human eye pupil is derived from the wavefront error of two subjects. The modulation transfer function is also calculated for 1, 2 and 3 mm pupils decentred 1 and 2 mm nasally and temporally. Whilst decentration causes relatively little difference in the M.T.F. at the smaller pupil size, it can produce marked degradation for the larger pupils which can be of significance in the experimental determination of contrast sensitivity or other visual functions.

Visual sensitivity to temporal change in focus and its relevance to the accommodation response.

Measurements were made of the ability of observers, whose accommodation had been paralysed, to detect the small changes in contrast resulting from sinusoidal, oscillatory changes in the dioptric focus of test objects, as a function of the mean position of focus. Variables studied included the form and wavelength composition of the test object, the diameter of the entrance pupil of the eye and the temporal frequency of the focus change. The dioptric amplitudes of the thresholds found (approximately 0.1 D) were comparable with the normally observed amplitudes of the microfluctuations of the accommodation system of the eye. A maximum for the threshold change of focus was found to occur about a mean position of focus corresponding to the nominal "best-focus". Two threshold minima occurred symmetrically on either side of this position of optimal mean focus; the positions of these minima depended on the spatial frequency content of the test object and the pupil diameter. The results are interpreted in terms of the corresponding through-focus changes in optical modulation transfer of the eye and data on the sensitivity of the visual system to spatial and temporal modulation. For sinusoidal grating test objects, it appears that the results can qualitatively be explained if it is assumed that the detectable focus change is such that the ratio of the modulation change in the retinal image, produced by the focus change, to the modulation at the mean position of focus is constant. Results for targets of broad spatial bandwidth suggest that sensitivity to focus change may be dominated by spatial frequency components approximately 5 c/deg. The implications of the data for the understanding of the accommodation control system are briefly considered.

Analytic approximation of the off-axis modulation transfer function of the eye.

Published experimental measurements of the ocular modulation transfer function (MTF) in the peripheral field are approximated by the expression T(f) = exp[-(f/fc)n], where T(f), f, fc, and n are modulation transfer, spatial frequency, spatial frequency constant and MTF index, respectively. It is shown that n (which describes the shape of the MTF) remains relatively constant at about 0.9 for field angles out to 40 deg but fc (which defines the spatial frequency scaling) declines steeply over this range, depending upon the pupil diameter and conditions of focus. The oblique astigmatism of the eye plays a major role in the off-axis changes in fc at field angles > or = 20 deg. The approximation may be useful in allowing the form of the degraded optical stimulus in studies of the peripheral retinal function to be evaluated.

Accommodation as a function of age and the linearity of the response dynamics.

The changes with age in the accommodation responses to dynamic stimuli can reveal useful information on the factors underlying presbyopia development. Analysis of the monocular accommodation responses of 19 normal observers (ages 18-49 years) to stimuli whose vergence varied sinusoidally with time at different temporal frequencies (peak-to-peak stimulus 1.33-2.38 D, at 0.05-1.00 Hz) showed that at all ages both the gain and phase of the response were essentially linear functions of the temporal frequency. Extrapolation of least-squares, regression line fits to the gain data for each subject gave the gain at zero frequency, G0, and the cut-off frequency, fc, at which the gain fell to zero. G0 reduced with age but fc remained essentially constant at about 1.7 Hz, up to at least the age of about 40. The magnitude of the response to step stimuli covering the same stimulus range was well correlated with the value of G0. The linear changes in phase lag with temporal frequency corresponded to simple time delays td. The time lag varied from close to zero for the youngest subjects to about 0.5 s for the subjects in their late forties. There was substantial variation between the responses of subjects of similar age: those subjects with high values of G0 also tended to have low values of td, both effects probably being due to the superior ability of some individuals to predict the sinusoidal changes in the accommodation stimulus. Comparison of theoretical step responses, derived by applying linear theory to the parameters obtained from the results for the sinusoidal stimuli, with the actual responses to unpredictable steps for the same subjects supports the view that prediction effects and other possible factors make linear theory inapplicable to this type of data. The results are discussed in the context of current ideas on the development of presbyopia: it is suggested that the constancy of fc with age is the result of the ciliary body maintaining its efficiency, whereas the fall in G0 and increase in td result from increases in lens rigidity.

The subjective sensitivity to small changes in the contrast of a suprathreshold grating.

Small periodic (0.25-40 Hz) changes in the contrast of suprathreshold, spatially sinusoidal (0.8-10.5 c/deg) grating test objects were generated on an oscilloscope screen. It was found that the minimum temporal modulation in spatial contrast which could be detected subjectively was approximately proportional to the mean contrast of the grating during the change, provided that the minimal spatial modulation of the grating was above threshold. The contrast increment threshold was dependent on both the grating spatial frequency and the temporal frequency of the modulation: for any fixed temporal frequency in the range 2-8 Hz it increased approximately linearly with spatial frequency; for fixed spatial frequency the threshold was minimal at temporal frequencies of a few Hz. The relevance of these results to the possible role of fast fluctuations in the control of accommodation response is considered.

Effect of pupil size on steady state accommodation.

Experiments are described in which monocular accommodation response/stimulus curves were measured with Snellen targets over the stimulus range from +1.0 to -5.0 D, using artificial pupils with diameters of 1.0, 1.5, 2.0, 2.5 and 3.0 mm and a constant retinal illuminance of 600 td. The results agree with those of earlier authors in showing a diminished response with smaller pupils. The slopes of the quasi-linear central portions of the response/stimulus curves are well described in terms of a geometrical optical approximation in which the accommodation system works to produce a retinal blur circle whose diameter is a linear function of the dioptric difference between the magnitudes of the stimulus and the accommodative resting state, this blur circle diameter being independent of the pupil diameter. Further consideration of diffractive effects suggests that contrast changes in the intermediate spatial frequency components (approximately 5 c/deg) of the retinal image may play a dominant role in guiding the response.