Drug discovery and development in the age of molecular medicine.

Drug discovery might be better termed drug invention. Discoveries take place globally, and many arise from academia and research institutes. The job of the biotechnology and pharmaceutical industry is to identify those that stand the greatest chance of being turned into medicines to improve health-in other words, to invent a practical outcome on the basis of discovery. In this commentary we identify some of the areas in which molecular medicine has had the greatest impact and continues to change the invention of medicines.

Sterilization of contaminated bone-tendon autografts using 10% povidone-iodine solution.

This study evaluates methods of sterilizing contaminated bone-tendon autografts using 10% povidone-iodine solution. Sterile grafts were prepared from human cadavers. Grafts were immersed in a suspension of either Staphylococcus aureus or Pseudomonas aeruginosa, and three sets of sterilization experiments were performed in 10% povidone-iodine for 30 minutes: one each with S. aureus and P. aeruginosa by static soaking and a third with S. aureus by serial washing with agitation. Of grafts inoculated with S. aureus, six of six grew the test organism after soaking at room temperature, as did five of six after soaking at 36 degrees C and also eight of nine after washing with agitation. Of grafts inoculated with P. aeruginosa, five of six grew the test strain after soaking at room temperature, as did six of six after soaking at 36 degrees C. Thirty minutes of exposure to aqueous 10% povidone-iodine does not adequately sterilize an inoculated graft.

Identification and characterisation of a functional peroxidoxin from Leishmania major.

Leishmania spp. encounter damaging oxygen metabolites from endogenous metabolic processes as well as from exogenous sources, such as inside the gut of the sandfly vector and within host macrophages. The recently described peroxidoxin protein family form part of a novel pathway for metabolising hydrogen peroxide that, in trypanosomatids, links peroxide reduction to NADPH oxidation via trypanothione. Here we report the cloning and characterisation of the Leishmania major peroxidoxin gene, tryparedoxin peroxidase (TryP). TryP is a multi-copy gene arranged in a complex tandem array located on the size polymorphic homologues of chromosome 15. Northern analysis showed that TryP expresses a single 1.6 kb mRNA throughout promastigote development. TryP encodes a 22-kDa protein with two conserved cysteine-containing domains that defines it as a 2-Cys peroxidoxin. Purified recombinant TryP protein catabolised hydrogen peroxide in the presence of the tryparedoxin homologue from Crithidia fasciculata (Cf-TryX), trypanothione, trypanothione reductase and NADPH. The demonstration that L. major utilises a three-protein peroxidase system confirms that this is a mechanism of protection against oxidative damage in this parasite.

Returning to work after heart transplantation.

The purpose of this study was to determine what factors influence a patient's return to work after heart transplantation. Two hundred fifty patients who had undergone heart transplantation were surveyed at seven regional centers in the United States (five of which were Medicare-certified). Of these patients, 45% were employed, 36% were unemployed, 13% were medically disabled, and 6% had retired. A stepwise discriminant analysis resulted in the selection of six variables that helped differentiate those patients who did and those who did not return to work after the transplantation. The factors associated with a patient's return to work included (1) self report of being physically able to work, (2) no loss of health insurance, (3) longer length of time after transplantation, (4) education level of more than 12 years, (5) no loss of disability income, and (6) shorter length of disability before heart transplantation. This information could accurately profile 91% of the patients who were employed, 69% of the patients who were unemployed, and 80% for the entire group. The implication of this study is that social rehabilitation is not synonymous with the medical results of heart transplantation. More attention to social rehabilitation is required if heart transplant recipients are to enjoy a better quality of life and become fully productive members of the community.

Social rehabilitation and return to work after cardiac transplantation--a multicenter survey.

As the medical results of heart transplantation steadily improve, the social rehabilitation of patients, in particular, their ability to return to some form of employment, is becoming increasingly important. Two-hundred fifty patients were therefore surveyed at 7 heart transplant centers (5 of which were Medicare certified) from different geographic regions in the U.S.A. Over all, 45% were employed, 36% were unemployed, 13% were medically disabled, and 6% were retired. Of those employed, 87% had returned to their previous employment, and only 13% had secured new employment. Of the unemployed, 16% had made job applications, and no fewer than 63% had no current plan to seek employment. Factors found to negatively influence a return to work included the following: (1) length of medical disability prior to transplantation; (2) a patient's self-perception of being physically unable to work; and (3) the potential loss of health insurance and/or disability income. At 2 centers, where there was a definite policy of not supporting a patient's claim for medical disability in the absence of an absolute indication, there were significantly increased numbers who (1) secured new employment and (2) planned to seek employment. More serious attention must be paid to aspects of employment if heart transplant recipients are to become fully productive members of the community.

Relation between plasma beta-endorphin and the ventilatory response to hypercapnia in humans.

1. Endogenous opioids have been implicated in the control of breathing in neonates, but their role in ventilatory control in adults remains unclear. 2. We studied the relationship between circulating immunoreactive beta-endorphin and the ventilatory and mouth occlusion pressure responses to hypercapnia in 12 healthy male subjects. In addition, we examined the effect of repetitive hypercapnia on plasma beta-endorphin and cortisol levels. 3. A weak but significant negative relationship between the ventilatory response to hypercapnia and basal plasma beta-endorphin levels was observed (r = -0.35, P less than 0.01). A similar negative relationship was noted between mouth occlusion pressure response to hypercapnia and basal plasma beta-endorphin levels (r = -0.36, P less than 0.01). 4. Repetitive hypercapnia prevented the fall in plasma cortisol that occurred under control conditions (P less than 0.02) but had no effect on plasma beta-endorphin. 5. We conclude that plasma beta-endorphin may play a role in the central chemical control of breathing in man.

Stress reduction with heart transplant patients and their families: a multidisciplinary approach.

Stress reduction is an important part of the treatment plan for heart transplant patients at Loyola University Medical Center, Maywood, Illinois. This individualized stress reduction program is offered to both patient and family members through the complementary efforts of the social work and occupational therapy departments. The objectives of this program are to educate the participants in a variety of coping and stress reducing techniques to help prepare them for the multitude of stressors encountered during the entire transplant experience. Patients and family members have positively responded to this program, both verbally and in practice.