Developing and paying for medicines for orphan indications in oncology: utilitarian regulation vs equitable care?

Despite 'orphan drug' legislation, bringing new medicines for rare diseases to market and securing funding for their provision is sometimes both costly and problematic, even in the case of medicines for very rare 'ultra orphan' oncological indications. In this paper difficulties surrounding the introduction of a new treatment for osteosarcoma exemplify the challenges that innovators can face. The implications of current policy debate on 'value-based' medicines pricing in Europe, North America and elsewhere are also explored in the context of sustaining research into and facilitating cancer patient access to medicines for low-prevalence indications. Tensions exist between utilitarian strategies aimed at optimising the welfare of the majority in the society and minority-interest-focused approaches to equitable care provision. Current regulatory and pricing strategies should be revisited with the objective of facilitating fair and timely drug supply to patients without sacrificing safety or overall affordability. Failures effectively to tackle the problems considered here could undermine public interests in developing better therapies for cancer patients.

Defective angiogenesis in mice lacking endoglin.

Endoglin is a transforming growth factor-beta (TGF-beta) binding protein expressed on the surface of endothelial cells. Loss-of-function mutations in the human endoglin gene ENG cause hereditary hemorrhagic telangiectasia (HHT1), a disease characterized by vascular malformations. Here it is shown that by gestational day 11.5, mice lacking endoglin die from defective vascular development. However, in contrast to mice lacking TGF-beta, vasculogenesis was unaffected. Loss of endoglin caused poor vascular smooth muscle development and arrested endothelial remodeling. These results demonstrate that endoglin is essential for angiogenesis and suggest a pathogenic mechanism for HHT1.

Novel arterial pathology in mice and humans hemizygous for elastin.

Obstructive vascular disease is an important health problem in the industrialized world. Through a series of molecular genetic studies, we demonstrated that loss-of-function mutations in one elastin allele cause an inherited obstructive arterial disease, supravalvular aortic stenosis (SVAS). To define the mechanism of elastin's effect, we generated mice hemizygous for the elastin gene (ELN +/-). Although ELN mRNA and protein were reduced by 50% in ELN +/- mice, arterial compliance at physiologic pressures was nearly normal. This discrepancy was explained by a paradoxical increase of 35% in the number of elastic lamellae and smooth muscle in ELN +/- arteries. Examination of humans with ELN hemizygosity revealed a 2. 5-fold increase in elastic lamellae and smooth muscle. Thus, ELN hemizygosity in mice and humans induces a compensatory increase in the number of rings of elastic lamellae and smooth muscle during arterial development. Humans are exquisitely sensitive to reduced ELN expression, developing profound arterial thickening and markedly increased risk of obstructive vascular disease.

Feral goats in Australia: A study on the quality and nutritive value of their meat.

The purpose of this study was to determine the quality of fresh and cooked meat, and the nutritive value of this meat from 62 male Australian feral goats. The goats were slaughtered at 5, 10, 20, 30, 40, 50, 60 and 70kg liveweights. Half of the goats were castrated and half were left as intact animals. The quality profiles of meat (e.g. pH, colour, pigment concentrations, cooking loss, shear force value and eating quality of cooked meat) from both castrated and intact feral goats started to decrease when animals were slaughtered at heavier liveweights (e.g. above 40kg). The nutritive value of the meat (chemical compositions, fatty acids and total cholesterol concentrations) changed when animals were castrated and had heavier slaughter weights. Overall, we recommend that 40kg liveweight is the heaviest slaughter weight, since the quality characteristics of meat will be lower when feral goats were slaughtered above 40kg liveweight.

Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314.

Following documented evidence of the synergism of 5-fluorouracil (5-FU) and radiation therapy and an additive effect with mitomycin and irradiation, pilot studies have demonstrated the potential for definitive radiation therapy in the management of squamous cell and basaloid carcinomas of the anal canal, allowing sphincter preservation. Our study explored the long-term effectiveness of combined therapy at this disease site and examined the feasibility of a Radiation Therapy Oncology Group study involving concomitant radiation therapy and chemotherapy. Between 1983 and 1987, 79 assessable patients with any primary tumor stage of anal canal carcinoma were treated by external-beam irradiation combined with mitomycin given by bolus iv injection and 5-FU given by continuous infusion. Radiation was delivered to the perineum and pelvis to a total dose of 4,080 cGy in 4.5-5 weeks. The inguinal nodal areas received 4,080 cGy, calculated at a 3-cm depth in the center of the nodal area. A 96-hour infusion of 5-FU was started on days 2 and 28 of the irradiation at a dose of 1,000 mg/m2 over 24 hours, and a bolus injection of mitomycin was administered on day 2 at a dose of 10 mg/m2. The overall survival rates are 97% at 1 year and 73% at 3 years. Patients with lesions less than 3 cm in diameter and those treated strictly according to the protocol did significantly better than those with larger lesions and those whose treatment did not comply with the protocol. The interim outcome of the study demonstrates that this combined therapy is effective for patients with anal cancer and allows preservation of the sphincter and of sexual function.

Enzymatic and chemical analyses of pig platelet membrane subfractions isolated by zonal centrifugation.

1. A mixed membrane fraction prepared from pig platelets was subfractionated, using the "B 14" zonal rotor, into two distinct subpopulations of membrane vesicles, each associated with a different phosphodiesterase activity. 2. The lighter subfraction (MI) was enriched 7-8 fold with bis-(p-nitrophenyl) phosphate phosphodiesterase activity and the denser subfraction (MII) showed a similar degree of enrichment of 5'dTMP-p-nitrophenyl ester phosphodiesterase activity. 3. Assays for other enzyme activities revealed slight enrichement (approx. 2 fold) of acid phosphatase, 3'-dTMP-p-nitrophenyl ester phosphodiesterase and beta-glucuronidase activities in MI, and beta-galactosidase in MII. Cyclic AMP phosphodiesterase, lactate dehydrogenase and N-acetyl-beta-glucosaminidase showed negligible activity in both MI and MII, and succinate dehydrogenase activity could not be detected in either subfraction. 4. Chemical analyses of the membrane subfractions demonstrated that MI contained approx. twice as much cholesterol, phospholipid, sialic acid and hexosamine per unit weight of protein than MII. These results are consistent with our previously reported observations from surface-labelling experiments, which indicated that MI was derived principally from the platelet surface-exposed membranes and that MII was probably intracellular in origin. 5. Analysis of the membrane polypeptides by sodium dodecyl sulphate-polyacrylamide gel electrophoresis revealed the presence of 12-15 components, in each subfraction, in the mol. wt. range 12000-200000, including a prominent band of approx. mol. wt. 46000, which has beeen identified to be actin. Qualitative as well as possible quantitative differences were apparent in that MII contained three components in addition to those present in MI. 6. Analysis of the periodate-Schiff staining components by sodium dodecyl sulphate-polyacrylamide gel electrophoresis demonstrated the presence of 4 major glycoproteins in both subfractions with apparent mol. wt. ranging from approx. 95000 to 150000; in addition two minor components were also present. Further, a very fast-migrating band, which did not stain with Coomassie blue, was observed in both MI and MII and probably represents lipid material.

Bis-(4-methylumbelliferyl) phosphate as a substrate for the surface membrane-associated phosphodiesterase activity of pig platelets.

It was found that the newly-available compound, bis-(4-methylumbelliferyl) phosphate, could be used as a substrate for the pig platelet surface membrane-associated phosphodiesterase activity, usually assayed with bis-(p-nitrophenyl) phosphate. This enzyme activity is distinct from the phosphodiesterase activity towards 5'-dTMP-P-nitrophenyl ester, which is probably associated with intracellular membrane structures in platelets. Consequently, the use of the 4-methylumbelliferyl derivative as substrate for the phosphodiesterase activity provides a sensitive, fluorimetric assay for this marker enzyme of the platelet surface membrane.

Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors.

A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.

Application of macromolecular additives to reduce the hydrolytic degradation of polyurethanes by lysosomal enzymes.

Of the various polymers used in medical devices, polyurethanes have been relatively successful because of their acceptable mechanical and biological properties. However, over the past decade, increasing concerns have arisen in relation to long-term biostability of polyurethanes when exposed to the harsh environment of the human body. Lysosomal enzymes released from inflammatory cells have been proposed to be important mediators in the degradation of biomedical polyurethanes. In order to increase the biostability of polyurethanes to lysosomal enzymes, a series of surface-modifying macromolecules (SMMs) were synthesized in this work and then combined into a base polyurethane to reduce the material's susceptibility to hydrolysis. X-ray photoelectron spectroscopy (XPS) studies showed that the SMMs were enriched within the upper 10 nm of the surface. In vitro biodegradation test results indicated that the degradation of a polyester-urea-urethane could be inhibited by the new SMM surface. It was also found that different SMM formulations provided varying degrees of inhibition against the biodegradation of the polyester-urea-urethane. Certain formulations of the SMMs were shown to be physically incompatible with the polyurethane and distorted surface morphology to the extent that biodegradation was enhanced.

Screening test for complement activation by counterimmunoelectrophoresis.

This report describes the use of counterimmunoelectrophoresis (CIE) as a method of detecting activation of the complement system. With this technic small amounts of C3 split products (C3c/d) can be detected in plasma samples by specific precipitation with antiserum in less than two hours. The CIE technic is a highly sensitive, rapid method for detecting activation of the complement system in the presence of normal concentrations of C3 measured hemolytically or by radial immunodiffusion (RID) in human disease. A clinical investigation was carried out in 40 patients with systemic rheumatic diseases and 116 normal healthy individuals. The following observations were made: (1) plasmas and sera from normal individuals had normal total complement hemolytic activity (CH50), hemolytic active C4 (C4H50) and C3 (C3H50); (2) in 30% of the serum samples it was possible to identify the presence of C3 split products, in contrast to only 2.5% of the plasma samples obtained simultaneously; (3) in the specimens from patients who had rheumatic disease activity, C3 split products were identified by CIE in all cases except one in the presence of normal C3 protein measured by RID.

The effects of insulin on vasoconstrictor responses in pithed rats.

Pressor responses to spinal sympathetic outflow and selected vasoactive agents were examined in control and diabetic Wistar-Kyoto pithed rats. Diabetes was induced by intravenous injection of alloxan (50 mg/kg). One week after the diabetogen, some of the rats were treated with one daily subcutaneous injection of Lente insulin (2 U/100 Gm) for five weeks. All rats were pithed at six weeks after alloxan. Vasoconstrictor responses to spinal sympathetic outflow, serotonin, norepinephrine, tyramine, and angiotensin were reduced in diabetic rats as compared to their age-matched controls. Administration of insulin caused only partial normalization of these responses. Nondiabetic rats given insulin exhibited vascular responsiveness similar to the treated diabetic group of animals. Blood pressures and heart rates were also found to be similar between the insulin-treated groups and significantly less than control. The finding that insulin does not produce complete normalization of vasoconstrictor responsiveness in diabetic rats may be relevant to the reduced blood pressure observed following insulin treatment.

Involvement of central GABA receptors in the regulation of blood pressure and heart rate of anesthetized cats.

Intracerebroventricular (i.c.c.) injections of muscimol (0.03-3 microgram/kg) and GABA (30-1000 microgram/kg) caused dose-related reductions in blood pressure and heart rate of anesthetized cats whereas glycine (30-3000 microgram/kg) was much less effective. I.v. administration of muscimol or GABA had little or no effect. Renal sympathetic nerve discharge was also reduced by central GABA receptor stimulation. The effects of both muscimol and GABA were reversed by either picrotoxin or bicuculline administered intravenously. The results suggest an important role for GABA receptors in the central regulation of blood pressure and heart rate.

Reduction in blood pressure, sympathetic nerve discharge and centrally evoked pressor responses by methysergide in anesthetized cats.

Methysergide (1 and 3 mg/kg i.v.) caused dose-dependent reductions in blood pressure and heart rate of anesthetized cats. In addition, sympathetic nerve discharges of the postganglionic renal nerve were also markedly reduced by the same doses of drug. Pressor responses to electrical stimulation of the diencephalon were inhibited by 3 mg/kg but not 1 mg/kg of methysergide. These results suggest that methysergide acts to decrease blood pressure by a centrally mediated reduction in sympathetic nervous outflow and, at higher doses, can additionally prevent pressor changes caused by electrical activation of suprabulbar central structures. These results are in agreement with previous reports that methysergide has little or no peripheral effects on the cardiovascular system.

Two phases of contractile response in rat isolated vas deferens and their regulation by adenosine and alpha-receptors.

Contractions to transmural electrical stimulation and exogenous norepinephrine were recorded in isolated longitudinal segments of rat vas deferens. Electrical stimulation for 30 s produced a biphasic contraction in the vas deferens consisting of a rapid, transient response (Phase I), followed by a slowly developing, sustained contraction (Phase II). N6-Cyclohexyladenosine (CHA), a selective adenosine1 (A1)-receptor agonist, attenuated in a concentration-dependent manner the Phase I contractile response, while having little effect on the Phase II response. In contrast, 2-(phenylamino)adenosine (CV-1808), a selective adenosine2 (A2)-receptor agonist had little effect on either contractile phase. CHA did not inhibit the contraction to exogenous norepinephrine, suggesting that A1-receptors were located at a presynaptic site. The relatively selective alpha 2-receptor agonist clonidine produced the same pattern of contractile inhibition as CHA. The inhibitory effect of CHA on the Phase I contractile response in the vas deferens could be antagonized by the selective A1-receptor antagonist 8-cyclopentyltheophylline, while the selective alpha 2-receptor antagonist idazoxan preferentially antagonized the inhibitory effect of clonidine on the Phase I response. Both the Phase I and Phase II contractile responses were reduced by the selective alpha 1-adrenoceptor antagonist prazosin and the ATP analog alpha, beta-methylene adenosine triphosphate (alpha, beta-methylene ATP), suggesting that norepinephrine and ATP are coreleased as neurotransmitters for both responses. The results of the present study demonstrate that in the rat vas deferens the presynaptic inhibitory effects of adenosine is mediated by the A1-receptor subtype, and that both A1- and alpha 2-receptor agonists exert a selective inhibitory effect on the Phase I contractile response to electrical stimulation.

Finding the common bond: stereoacuity and the other hyperacuities.

Hyperacuity thresholds for disparity, motion displacement and relative width (widths less than 10 min arc) were measured as a function of the separation between test and reference targets for separations ranging from 18-288 min arc. All three thresholds were similar in magnitude, and showed a nearly identical rise with increasing separation. Nevertheless, eccentricity, not separation, is the variable limiting all of these thresholds. This point is underscored by the fact that relative width judgments, made by comparing the narrow widths separating two pairs of lines (test and reference widths), are equally good without the reference pair. The most precise foveal judgments of stereo and motion do require a visible reference target because the observer cannot otherwise distinguish between oculomotor "jitter" and target-driven changes in disparity or motion. At eccentricities greater than 2 deg, stereo and motion thresholds for a single unreferenced line (150 msec duration) were equal to the referenced thresholds, presumably because the oculomotor noise is less than the positional uncertainty associated with these peripheral loci.

OKN, perceptual and VEP direction biases in strabismus.

The present study quantified nasalward/temporalward biases in monocular optokinetic nystagmus (MOKN) and perceived velocity in patients with either early onset esotropia, late onset esotropia and in normals. MOKN was measured with low spatial frequency, small-field gratings drifting at 9.4 degrees/s. MOKN bias was quantified as the ratio of nasalward slow-phase velocity divided by the sum of temporalward and nasalward slow-phase velocities (N/(N + T)). Observers also rated the perceived velocity of gratings moving in nasalward and temporalward directions (3 or 9.4 degrees/s) using a two interval forced choice task. MOKN and perceived velocity biases were correlated negatively in both early onset and late onset groups in the perceptual task--nasalward moving targets were rated as slower than temporalward targets, but in the MOKN task, slow-phase gain was higher for nasalward than for temporalward targets. Oscillatory-motion, visual evoked potentials (VEPs), were recorded in response to 1 c/deg gratings undergoing apparent motion at 10 Hz in a subset of the observers. VEP direction biases were quantified by calculating the ratio of first harmonic response amplitudes to the sum of first and second harmonic amplitudes. Significant correlations were found between the direction biases obtained on all three measures. Perceived velocity and MOKN bias measures were also correlated negatively. Patients with early onset esotropia (infantile esotropia) had larger biases than late onset esotropes or normals on each measure and the biases were more frequently bilateral in the early onset patients. The pattern of result is consistent with early critical periods for the mechanism(s) underlying MOKN, perceived velocity and cortical responsiveness. A single site model for all three asymmetries is unlikely, at least in simple form, because of the negative correlation between MOKN and perceived velocity biases and because of the differences in relative magnitude between the perceptual and MOKN biases.

Stereo matching precedes dichoptic masking.

Stereo matching can intervene to prevent dichoptic masking. In a dichoptic masking paradigm we measured the contrast threshold for a bar target, presented to one eye, as a function of the contrast of an identical masking bar, presented at retinal correspondence in the other eye. Confirming previous studies of dichoptic masking with sinusoidal gratings, the test bar thresholds rose proportionally with increasing masking contrast. This threshold elevation was almost nullified when an extra bar was presented to the eye seeing the test stimulus. Release from masking occurred when the disparity between the masking bar and extra bar was < 20 min arc over a range of contrast levels (8-45%), and for bars containing either broad spatial frequency spectra or bars with only high spatial frequencies (peak = 12 c/deg). The latter result rules out an explanation for the release from masking based on contrast discrimination in low spatial frequency channels. The extra bar was effective in releasing the test bar from masking as long as the extra bar's contrast was greater than about one-fifth the contrast of the mask, a result that suggests that there is a contrast threshold for stereo matching. We interpret our findings to indicate that a stage of stereo matching occurs prior to the neural site limiting dichoptic contrast discrimination.

Is stereopsis effective in breaking camouflage for moving targets?

It has been suggested that breaking camouflage is one of the major functions of stereopsis (Julesz, 1971). In this study, we found that stereopsis is less effective in breaking camouflage for moving targets than for static ones. Observers were asked to detect a single dot moving on a straight trajectory amidst identical noise dots in random motion. In the three-dimensional (3D) condition, the noise dots filled a cylindrical volume 5.7 cm in height and diameter; the trajectory signal dot moved on an oblique 3D trajectory through the center of the cylinder. In the two-dimensional (2D) control condition, observers viewed one half-image of the 3D cylinder binocularly. Surprisingly, trajectory detection in the 3D condition was only slightly better than in the 2D condition. Stereoscopic tuning for motion detection was also measured with a novel target configuration in which the random motion noise was presented in two depth planes that straddled the fixation plane where the trajectory target was presented. As the disparity between the noise planes and the fixation plane was increased, trajectory detection improved, reaching a peak between 6 and 12 arcmin, and then declining to the 2D level at larger disparities, where the noise became diplopic. Similar tuning measurements were made for detecting a static pattern, a string of five aligned dots presented in the fixation plane between two planes of static noise dots. Adding disparity to the noise planes produced a far greater improvement in static detection than in motion detection, for a comparable range of disparities (1.5-12 arcmin). We speculate that the temporal characteristics of the stereo system are not well suited for responding to moving targets, with the result that stereo does not greatly enhance motion detection in noise.

Measurements of viscosity and permeability of two phase miscible fluid flow in rock cores.

This paper describes the application of 1H magnetic resonance imaging (MRI) to the measurement of fluid viscosity and rock core plug permeability during two phase miscible displacements in certain rock types. The core plug permeability was determined by monitoring glycerol solutions displacing D2O. Simple physical principles were used to calculate the core permeability from the measured displacement angle for a set of Lochaline sandstone core plugs. In a further experiment the viscosity of polyacrylamide solution 1500 ppm was determined in the core plug. The permeability and viscosity results compared well to conventional core analysis methods.