Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers.

OBJECTIVE: To assess the safety/tolerability and perform a preliminary efficacy evaluation of a multiple-dosing regimen of recombinant human vascular endothelial growth factor (VEGF165 or rhVEGF; telbermin) applied topically to chronic diabetic neuropathic foot ulcers. METHOD: Subjects with type 1 or 2 diabetes mellitus were randomised to receive either topical applied telbermin (72 microg/cm2) (n=29) or placebo (n=26) treatment to the foot ulcer surface in conjunction with standard ulcer care. Subjects received treatment every 48 hours (maximum three doses per week) for up to six weeks. Weekly 35mm photography, quantitative planimetry and physical examinations documented the ulcer appearance, surface area and stage. Safety endpoints included incidence of clinically significant hypotension, adverse events and ulcer infection. Exploratory efficacy endpoints included percentage reduction in total ulcer surface area, incidence of complete ulcer healing and time to complete ulcer healing. RESULTS: Incidence of adverse events was comparable in the two treatment groups. None of the adverse events were attributed to study drug, and no hypotension was observed as a result of telbermin treatment. Occurrence of infected study ulcers appeared to be balanced between the treatment groups. Positive trends suggestive of potential signals of biological activity were observed for incidence of complete ulcer healing (41.4% telbermin versus 26.9% placebo at day 43 [P=0.39]) and time to complete ulcer healing (25th percentile of 32.5 days telbermin versus 43.0 days placebo [log-rank P=0.13]). CONCLUSION: The topical application of telbermin 72 microg/cm2 three times a week for up to six weeks appeared to be well tolerated. Further studies are required to characterise the safety/efficacy of telbermin more completely.

Treatment of glucocorticoid-induced growth suppression with growth hormone. National Cooperative Growth Study.

Growth failure is common during long term treatment with glucocorticoids (GC) due to blunting of GH release, insulin-like growth factor I (IGF-I) bioactivity, and collagen synthesis. These effects could theoretically be reversed with GH therapy. The National Cooperative Growth Study database (n = 22,005) was searched for children meeting the following criteria: 1) pharmacological treatment with GC and GH for more than 12 months, 2) known type and dose of GC, and 3) height measurements for more than 12 months. A total of 83 patients were identified. Monitoring of glucose, insulin, IGF-I, IGF-binding protein-3, type 1 procollagen, osteocalcin, and glycosylated hemoglobin levels was performed in a subset of patients. Stimulated endogenous GH levels were less than 10 microg/L in 51% of patients and less than 7 microg/L in 37% of patients. The mean GC dose, expressed as prednisone equivalents, was 0.5 +/- 0.6 mg/kg day. Baseline evaluation revealed extreme short stature (mean height SD score = -3.7 +/- 1.2), delayed skeletal maturation (mean delay, 3.1 yr), and slowed growth rates (mean, 3.0 +/- 2.5 cm/yr). After 12 months of GH therapy (mean dose, 0.29 mg/kg x weeks), mean growth rate increased to 6.3 +/- 2.6 cm/yr, and height SD score improved by 0.21 +/- 0.4 (P < 0.01). During the second year of GH therapy (n = 44), the mean growth rate was 6.3 +/- 2.0 cm/yr. Prednisone equivalent dose and growth response to GH therapy were negatively correlated (r = -0.264; P < 0.05). Plasma concentrations of IGF-I, IGF-binding protein-3, procollagen, osteocalcin, and glycosylated hemoglobin increased with GH therapy, whereas glucose and insulin levels did not change. The following conclusions were reached. The growth-suppressing effects of GC are counterbalanced by GH therapy; the mean response is a doubling of baseline growth rate. Responsiveness to GH is negatively correlated with GC dose. Glycosylated hemoglobin levels increased slightly, but glucose and insulin levels were not altered by GH therapy.

Effect of donor age on outcome of kidney transplantation. A two-year analysis of transplants reported to the United Network for Organ Sharing Registry.

The shortage of cadaveric donors coupled with a rapidly growing number of potential recipients has resulted in an increased use of older donors. In 1992, 10.7% of all cadaveric kidney transplants were from donors above the age of 55 compared with 5.4% in 1988. The present investigation serves as a follow-up of a prior study of the effect of donor age on outcome with a 2-year analysis of more than 30,000 cadaveric kidney transplants performed in the United States between October 1, 1987, and December 31, 1991, that were reported to the United Network for Organ Sharing. There was no difference between the graft survival at 1 and 2 years comparing donors aged 56-65 versus 65 and older, but the older donors (aged 56 and greater) had a 1- and 2-year graft survival that was approximately 10% and 14% less than that for recipients from the ideal age group of donors (16-45 years). There was no practical adverse interaction between donor age and recipient age, gender, diabetic status, peak PRA (panel reactive antibody activity) level of mismatch, cold ischemia time, or recipient race on outcome. The kidneys from older donors had poorer graft survival than the kidneys from younger donors when transplanted into recipients of repeat transplants, though the impact of repeat transplant and donor age on graft survival are independent of one another. These data suggest that kidneys from donors over the age of 55 overall have reduced functional reserve, which has an adverse effect on long-term function. Thus, attempts should be made to better estimate functional reserve among the older age group, but age alone should not be the sole factor for exclusion of a potential donor. The use of older donors appears to present an increased but acceptable risk of graft loss 2 years after transplant.

Response to growth hormone in attention deficit hyperactivity disorder: effects of methylphenidate and pemoline therapy.

OBJECTIVE: To determine whether treatment of attention deficit hyperactivity disorder (ADHD) with methylphenidate hydrochloride or pemoline diminishes the response to growth hormone (GH) therapy in patients with idiopathic GH deficiency (IGHD) or idiopathic short stature (ISS). METHODS: The National Cooperative Growth Study database was used to identify patients between 3 and 20 years of age with IGHD or ISS and those within these groups who were treated with methylphenidate or pemoline for ADHD. Their growth in response to GH treatment (change in height standard deviation score [SDS]) was compared with that of patients with IGHD or ISS who were not treated for ADHD, by using a stepwise multiple regression analysis. RESULTS: In the IGHD cohort, there were 184 patients who were being treated for ADHD and 2313 who were not. In the ISS cohort there were 117 patients who were being treated for ADHD and 1283 who were not. There was a higher percentage of males being treated for ADHD in both cohorts. In the IGHD cohort, the change in height SDS was positively associated with the number of years of GH treatment, parents' heights, body mass index, and GH injection schedule, and was negatively associated with height SDS at the initiation of GH therapy, age, and maximum stimulated GH level. The use of methylphenidate or pemoline had a negative effect on the change in height SDS, but the magnitude of the effect was small. Similar effects were noted in the ISS cohort, but body mass index and the use of methylphenidate or pemoline had no effect on the change in height SDS. CONCLUSIONS: Concurrent ADHD therapy is associated with a slight decrease in the change in height SDS during GH treatment in patients with IGHD but not in those with ISS. Even in IGHD, the magnitude of the effect is small and should not deter the use of such concurrent therapy.

Patients who die awaiting heart transplantation.

In the United States, heart donor availability has increasingly failed to keep pace with rising demand. Transplant data were obtained from the United Network for Organ Sharing for 1988, 1989, and 1990 and by survey of 50 heart transplantation centers, which performed 1932 transplantations between 1983 and 1989. According to the United Network for Organ Sharing, 512 patients on the waiting list died in 1988; 527, in 1989; 650, in 1990, and if present trends continue more than 800 will have died in 1991. Similar numbers of patients were inactivated or removed from the list each year. Only 49% of patients (1647 of 3390) on the heart transplant waiting list at some time in 1988 underwent the procedure in that year. For 1989 the figure fell to 42% (1630 of 3915 patients). Survey data revealed a threefold increase in the ratio of the number of patients who died/number of patients who underwent transplantation from 0.07 in 1983 to 0.21 in 1989 and in the ratio (number of patients who died+number of patients who were removed from the list)/number of patients who underwent transplantation from 0.12 in 1983 to 0.38 in 1989. The major causes of death among waiting patients were congestive heart failure (46%) and arrhythmia (29%). From 1983 to 1989, 55% (134 of 243) of those patients with documented urgency status died in the intensive care unit; 45% (109 of 243) died elsewhere. Waiting time for patients dying in the intensive care unit rose from 10.7 days in 1985 to 50.3 days in 1989; patients dying out of the intensive care unit waited 103.7 days in 1985 and 85.6 days in 1989. In conclusion, the number and proportion of potential recipients who die awaiting heart transplantation is increasing every year. Congestive heart failure and arrhythmia are the major causes of death, and similar numbers of patients die in and out of the intensive care unit.

When perfectly HLA-matched kidneys are refused for transplant: implications for a national cooperative sharing system.

BACKGROUND: The transplant community attempts to maximize overall renal graft survival rates through nationwide sharing of perfectly-matched cadaveric kidneys. Although the number of such transplants is determined annually, the number available but not transplanted has never been assessed. There has also been no verification of the widespread claim that kidneys transplanted as paybacks for perfect matches are inferior. STUDY DESIGN: From records of the United Network for Organ Sharing, a complete accounting of six-antigen-matched kidney disposition was obtained, including a frequency distribution of reasons for refusal given when kidneys were refused for matched patients. Actuarial graft survival (GS) rates for matched, payback, and other cadaveric renal transplants were determined. RESULTS: Of the six-antigen-matched kidneys available, 97 percent were transplanted; 71 percent of those were accepted for matched patients. The two-year GS rate for matched patients was 84 percent, significantly higher than that for kidneys available for matched patients but transplanted into other patients (71.3 percent) and that for all other cadaveric kidneys (75.5 percent). Most reasons for refusal were related to donor quality. Kidneys refused for such reasons showed a 67.7 percent two-year GS rate in nonmatched patients and the highest rates of acute and chronic rejection and primary failure. The two-year GS rate for kidneys accepted as paybacks for matched kidneys (75.7 percent) was equivalent to that for all non-matched cadaveric kidneys (75.5 percent). CONCLUSIONS: If all normal-quality grafts refused for perfectly matched patients during 1990 through 1992 had been accepted for those patients, the number of transplants with typically superior survival rates could have increased by 25 percent, from 1,365 to 1,704. The payback requirement of the United Network for Organ Sharing does not seem to reduce the overall benefits of sharing perfectly matched kidneys nationwide.

Effects of intraperitoneal carbon monoxide on fixed-ratio and screen-test performance in the mouse.

The behavioral effects of carbon monoxide (CO) administered via IP injection were investigated in the mouse. Mice were trained to lever press under a fixed-ratio (FR) 100 schedule of water reinforcement. Thirty-min test sessions were conducted either immediately or 30 min following IP injections of air (100 ml/kg) or CO (7.5, 15, 30, 50 or 100 ml/kg). CO produced a decrease in rates of responding which was exhibited earlier and lasted longer with increasing doses. Motor performance was also measured with the inverted-screen test following the same doses of CO at either 5, 15, 30, 60, 120 min or 24 hr post-injection. Performance was affected in a dose- and time-dependent fashion. Peak carboxyhemoglobin (COHb) levels were observed at 15 or 30 min and were 20%, 32%, 42%, 51% and 60% for 7.5, 15, 30, 50 and 100 ml/kg CO, respectively. COHb saturation alone was not always a good predictor of behavioral effects since both level and duration of exposure contributed to behavioral impairment. The results also show that the IP route can be used to study the toxicity of CO.

Growth hormone treatment of children with myelomeningocele.

From the National Cooperative Growth Study database 106 patients (53 boys) with myelomeningocele who were treated with recombinant human growth hormone (GH) at 56 centers were identified. Eighty-one patients (41 boys) were prepubertal at enrollment. The mean pretreatment growth rate (GR) in these prepubertal patients was 4.5 +/- 3.7 cm/yr, and the mean height SD score was -4.0 +/- 1.2. The maximal stimulated GH level was less than 10 micrograms/L in 71% of these patients and less than 7 micrograms/L in 49%. The mean chronologic age was 6.5 +/- 2.9 years, and the mean height age was 3.7 +/- 1.7 years. After GH treatment the year 1 GR in those who remained prepubertal was 8.5 +/- 3.3 cm/yr, a significant increase over baseline (p < 0.01). This increase was sustained through year 4 and remained significant through year 3 (p < 0.01). The height SD score showed sustained significant improvement through year 4, to -2.2 +/- 1.4 (p < 0.001). The GR and SD score for stature improve with GH treatment in children with myelomeningocele.

Glucocorticoid-induced glycogen increases in extensor digitorum longus and soleus grafts in the rat.

The purpose of the present study was to compare dexamethasone-induced glycogen increases in normal EDL and SOL muscles with that in free muscle grafts. Glycogen in mature EDL and SOL grafts in the rat equalled control concentrations irrespective of whether the graft was a nerve-intact (NI), nerve-crushed (NC), reimplanted, or cross-transplanted graft. The grafts also possessed the glycogen-regulatory mechanisms to respond to the glucocorticoid dexamethasone (DEX), which increases muscle glycogen. The increase in glycogen induced by DEX in the EDL and SOL grafts resembled that of the EDL and SOL muscles, respectively, whether the grafted muscle was originally an EDL or SOL. DEX induced an approximate twofold increase in glycogen concentration in control muscles and nerve-intact SOL grafts, and a smaller but significant increase in all other free grafts. Nerve crushing prior to grafting resulted in no significant change in muscle weight, glycogen concentration, or DEX-induced glycogen increase in these grafts. The data suggest that skeletal muscle grafts are qualitatively similar to normal muscles in terms of metabolic responsiveness to hormones. Leaving the nerve intact during grafting quantitatively enhances the graft's hormonal sensitivity but the technique of nerve crushing prior to grafting has no such effect.

Exercise or overloading: effect on skeletal muscle grafts of rats.

The effects of increased usage on regenerated muscle grafts was studied in rats. Soleus muscles were grafted orthotopically, either without neuromuscular anastomoses (standard grafts), or with their original nerves undamaged (nerve-intact grafts). The rats were either run on a treadmill or their soleus grafts were overloaded by extirpation of approximately 50% of the gastrocnemius muscles. Twitch and tetanic contractions, glycogen concentration, and histological features of the grafts were evaluated 60 days after grafting. The results showed that exercise enhanced glycogen levels in nerve-intact grafts as in normal muscle. Overloading had no effect on glycogen. The nonexercised standard grafts had the lowest values for the mechanical parameters studied. However, this was apparently due to the smaller degree of innervation rather than from the lack of exercise. Within the population of nerve-intact grafts, neither exercise nor overloading significantly improved the twitch and tetanic tensions. It is concluded that exercise, but not overloading, is likely to have positive effects on muscle graft metabolism.

Linear growth in response to growth hormone treatment in children with short stature associated with intrauterine growth retardation: the National Cooperative Growth Study experience.

Short stature commonly follows intrauterine growth retardation (IUGR). Most patients are not growth hormone (GH)-deficient, but GH therapy has been used in IUGR. Early studies found a heterogeneous increase in initial growth rate that could not be maintained. Results of more recent studies with higher doses are more encouraging but do not establish whether final height is increased. Data from a large number of patients in the National Cooperative Growth Study were reviewed to evaluate the response to GH treatment in patients with IUGR-associated short stature. Two hundred seventy such patients were identified and were categorized as those with unclassified IUGR and those with Russell-Silver syndrome/primordial short stature (RSS/PSS). Patients were treated with standard doses of recombinant human GH (approximately 0.3 mg/kg per week) and were assessed periodically for up to 4 years. The height SD score at baseline in patients with unclassified IUGR was -3.49 +/- 1.16, and their relative height improved with each year of therapy. Patients who completed 4 years of treatment reached a height SD score of -1.32 +/- 0.79. Results were similar in patients with RSS/PSS; their baseline height SD score was -3.83 +/- 1.05 and improved to -2.10 +/- 0.99 by year 4. Despite these encouraging results, no change occurred in predicted adult heights. Furthermore the number of patients who remained in treatment for 4 years decreased substantially, thus limiting the interpretation of the data. These data suggest that a beneficial response to GH occurs in some patients with IUGR-associated short stature and that little difference exists in the responses in patients with RSS/PSS compared with those in patients with unclassified IUGR.

Overview of the National Cooperative Growth Study substudy of serial growth hormone measurements.

For the National Cooperative Growth Study II substudy, data on spontaneous growth hormone (GH) secretion were collected from 5106 children with short stature. Of these, 2123 with complete 12-hour samples were subsequently enrolled in the NCGS. Compared with NCGS enrollees who were not in the NCGS II substudy, these children were significantly older (11.3 +/- 3.3 years vs 9.9 +/- 4.2 years), had a higher maximum reported GH level (13.3 +/- 10.5 micrograms/L vs 9.2 +/- 8.7 micrograms/L), and were more likely to be male (71% vs 62%) and pubertal (27.3% vs 21.9%) (p<0.001) for all). Height deficit, bone age delay, and pretreatment growth rates were similar. Children who were classified as having GH deficiency on the basis of their response to standard pharmacologic tests had lower spontaneous GH secretion than those who were classified as having idiopathic short stature, but considerable overlap was seen between the two groups on all indexes of spontaneous GH secretion. This finding suggests that the investigators were using serial sampling studies in examining children with short stature who were not growing well but had "normal" GH responses to standard pharmacologic testing.