From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

A survey of sentenced prisoners transferred to hospital for urgent psychiatric treatment over a three-year period in one region.

This study describes a survey of sentenced prisoners who were transferred to psychiatric hospitals in South Wales under 8.47 of the Mental Health Act of 1983 (England & Wales) over a three-year period. During this time there were 29 such transfers of 25 prisoners and all were male. Fifty per cent of these prisoners who became patients had a clinical diagnosis of schizophrenia, 13 per cent of recurrent depressive disorder, 4 per cent of a drug-induced psychosis, 4 per cent of hypomania and 6.6 per cent had some form of personality disorder. Forty-four per cent were returned to prison to complete their sentence once their mental disorder was treated.

The effect of mannitol on the oral bioavailability of cimetidine.

The aim of the study was to investigate whether mannitol at amounts relevant to pharmaceutical formulations would alter the oral bioavailability of cimetidine, a drug primarily absorbed from the small bowel. Seven healthy male subjects each received four formulations, a chewable tablet or a solution, containing 0.200 g of cimetidine and either 2.264 g of mannitol or sucrose, in a randomized four-way cross-over study. Frequent blood samples were taken over a 24 h period to allow a cimetidine plasma profile to be obtained for each formulation. Transit of the radiolabeled formulations was followed by gamma scintigraphy. Statistically significant reductions in the AUC0-24 and maximum plasma concentration values were observed with the mannitol dosage forms compared to the sucrose controls. The mean small intestinal transit times were shortened after administration of the mannitol solution and tablet; the transit time of the solution was significantly shorter with values 23% of those for the sucrose solution. The implication of the study findings is that excipients cannot always be regarded as "inert" substances that can be incorporated into a formulation without having any deleterious effect on the overall in vivo behaviour of the product.

Echo-planar magnetic resonance imaging to assess water volume in the distal small bowel.

PURPOSE: Assessment of fluid volumes and flow through the small intestine has in the past only been possible by means of invasive intubation studies on human volunteers. Intubation very likely disturbs gut motility and stimulates secretion. METHODS: The aim of this study was to utilise the new technique of echo-planar magnetic resonance imaging in order to non-invasively visualise the changing volume of water in the small intestinal lumen. 200 mls of test solution was ingested and water volume assessed using a multi-slice scanning technique on 3 separate days. The solutions were pure water, pure water plus 2.264 or 10 g of mannitol. These were taken on separate days by 8 healthy male volunteers. Regions of interest were constructed in the area of the lower pelvis excluding retroperitoneal structure. RESULTS: The water content of the lower small intestine did not change significantly over the 4 hours after the control solution. By contrast after both mannitol solutions there was an increase in the amount of water in the distal intestine as assessed by the area under the curve of the volume time profile (Control 51 ml.h (SD +/- 47); mannitol 2.264 g/200 ml 72 ml.h (SD +/- 57); 10 g/200 ml mannitol 115 ml.h (SD +/- 56)). Page's L Trend test showed that the trend for the volume to increase with increasing mannitol concentration to be statistically significant at the 1% level (L = 108). CONCLUSIONS: The study highlights the potential of echo-planar magnetic resonance imaging to visualise changes in gastrointestinal physiology in a noninvasive manner.

Male rape victims referred to a forensic psychiatric service.

A series of male victims of rape are presented who were identified following referral to a Forensic Psychiatric Service. In addition to being victims they were also offenders in their own right. The 22 male rape victims represent 12.5 per cent of male referrals to the service over a six-month period.

The effects of pharmaceutical excipients on small intestinal transit.

1. The effect of three iso-osmotic pharmaceutical excipient solutions on gastrointestinal transit were investigated in eight healthy male volunteers. Each subject received 200 ml radiolabelled purified water, or a 200 ml solution of sodium acid pyrophosphate ((SAPP) 1.1 g/200 ml), mannitol (2.264 g/200 ml) or sucrose (4.08 g/200 ml) in a four way cross over design. On each of the study days the volunteers also received five 6 mm diameter non-disintegrating tablets. Dual isotope gamma scintigraphy was used to assess the transit behaviour of the tablets and solutions. 2. There were no significant differences between the gastric emptying times of the four solution formulations. Rapid gastric emptying was observed in all cases (mean t 50% varied from 11-14 min). 3. Small intestinal transit (SIT) times for the SAPP and mannitol solutions were reduced by 39 and 34%, respectively, when compared with the control solution (purified water = 240 min; SAPP = 147 min; mannitol = 158 min). The 95% confidence limits for the mean differences in SIT time between the control and SAPP solutions was 39-94-149 min, and 40-82-124 min between the mannitol and the control. Intestinal transit for the sucrose solution was similar to that for the control solution (sucrose = 229 min). 4. There were no significant differences in the transit times of the non-disintegrating tablet preparations, when co-administered with each solution.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of different concentrations of mannitol in solution on small intestinal transit: implications for drug absorption.

The aim of the present study was to investigate the effect that different concentrations of mannitol have on small intestinal transit, and whether any observed effect was concentration dependent. Eight, healthy male subjects each received 200ml of radiolabelled purified water, or a 200ml solution of mannitol at three different concentrations; 0.755g/200ml, 1.509g/200ml and 2.264g/200ml, in a randomised, four way cross-over study. Transit of the radiolabelled solutions was followed by gamma scintigraphy. The study demonstrated no significant differences between the gastric emptying times of the four solutions. Rapid gastric emptying was observed in most cases. The mean small intestinal transit times for the 0.755g/200ml, 1.509g/200ml and 2.264g/200ml mannitol solutions was reduced by 11%, 23% and 34% respectively, when compared to the control solution. The intestinal transit data of the four solutions demonstrate that mannitol has a concentration dependent effect on small intestinal transit. Small concentrations of mannitol included in a pharmaceutical formulation could therefore lead to reduced uptake with any drug exclusively absorbed from the small intestine.

Managing resistant schizophrenia.

Approximately 25% of patients with schizophrenia remain actively psychotic despite treatment with conventional antipsychotic medication. Many of these patients become new long-stay patients or are frequent readmissions to psychiatric hospitals. This article reviews some of the causes of treatment resistance and the management of this group of patients.

Familial factors in going to medical school.

Attending medical school has long been known to be strongly familial. We set out to discover whether this tendency has been altered by recent procedures for selection of medical students. Preclinical medical students in the University of Wales College of Medicine, Cardiff and first-year zoology students completed a self-report questionnaire on the frequency of going to medical school among their first- and second-degree relatives. Thirteen per cent of the first degree relatives of the medical student proband group had attended medical school, compared with approximately 0.22% of the general population, giving a 'relative risk' of 61. Twenty-one per cent of the siblings over age 18 years of the medical student probands had been or were currently in a medical school, compared with 4% of the zoology student proband siblings. We conclude that going to medical school remains highly familial and this is probably largely determined by environmental/cultural and social factors. However, it is possible that genetic factors contribute in a non-specific way, e.g. via their influence on general intelligence.

Simulation of Mendelism revisited: the recessive gene for attending medical school.

Much of the recent confusion concerning studies of complex phenotypes such as neuropsychiatric disorders may derive from the inappropriate assumption of simple Mendelian transmission. This has sometimes led to unrealistic expectations regarding the potential benefits of linkage studies. To investigate how Mendelism may be simulated, we collected data on a common familial behavioral trait, attendance at medical school, among the relatives of 249 preclinical medical students. The "risk" of first-degree relatives going to medical school was approximately 61 times that of the general population. Complex segregation analysis carried out under a unified model provided strong evidence of vertical transmission. The results were compatible with transmission of a major effect, and a recessive model provided as satisfactory a fit as a general single-locus model. Moreover, a commonly applied test, allowing the transmission probability parameter (tau 2) to deviate from its Mendelian value, did not give a significant improvement of fit. Only a more general model where all three transmission probabilities (tau 1, tau 2, and tau 3) were unrestricted resulted in a significantly better fit than did the recessive model.

The use of rating scales to identify post-natal depression.

One hundred and forty-seven mothers were screened for major depression at six to eight weeks post-partum. Using predetermined cut-off points, the Edinburgh Postnatal Depression Scale and the Beck scale were compared in their abilities to identify the 15% of subjects who had major depression according to DSM-III criteria. The sensitivity of Edinburgh scale was 95% and its specificity 93%. The performance of the Beck scale was markedly inferior, with a sensitivity of 68% and specificity of 88%.

The use of strain gauges for radial stress measurement during tableting.

The influence of size, configuration and positioning of die wall strain gauges on the measurement of radially transmitted stress developed during tableting was investigated. Calibration of strain gauges attached to a cutaway die wall was achieved by compression of rubber-like materials in the die, Breon Polyblend 504 being more effective than red rubber for this purpose. Hysteresis of response observed when calibrating a thin-walled die was possible due to excessive distortion of the weakened die wall although the extent of this hysteresis varied with calibration material. The use of full bridge arrangements produced an increase in response when the compression site was moved away from the gauges. The opposite effect was seen when half bridge arrangements, using two active gauges, were used. The paradoxical effect observed when full bridge arrangements were used was shown to be due to straining of the compensating gauges. The dependence of die wall response on compact position was substantially reduced by the use of multiple gauges mounted along the die length and connected together to form a single gauge on each side of the die.