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1.  International models of investigator-initiated trials: implications for Japan 
Annals of Oncology  2012;23(12):3151-3155.
Academic/institutional investigator-initiated clinical trials benefit individuals and society by supplementing gaps in industry-sponsored clinical trials.
In May 2010, experts from Japan, the Republic of Korea, the UK, and the United States, met at a symposium in Tokyo, Japan, to discuss how policies related to the conduct of clinical trials, which have been shown to be effective, may be applied to other regions of the world.
In order to increase the availability of anticancer drugs world-wide, nations including Japan should examine the benefits of increasing the number of investigator-initiated clinical trials. These trials represent one of the most effective ways to translate basic scientific knowledge into clinical practice. These trials should be conducted under GCP guidelines and include Investigational New Drug application submissions with the ultimate goal of future drug approval.
To maximize the effectiveness of these trials, a policy to educate health care professionals, cancer patients and their families, and the public in general on the benefits of clinical trials should be strengthened. Finally, policies that expedite the clinical development of novel cancer drugs which have already been shown to be effective in other countries are needed in many nations including Japan to accelerate drug approval.
PMCID: PMC3501232  PMID: 22843420
academic/institutional investigator-initiated clinical trials; anticancer drugs; good clinical practice; health care policy; international clinical trials; patient advocates
2.  L-carnitine in cyclical vomiting syndrome 
PMCID: PMC1719739  PMID: 15557068
3.  Proceedings of a GOG Workshop on Intraperitoneal Therapy for Ovarian Cancer 
Gynecologic oncology  2006;103(3):783-792.
Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a third phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on Intraperitoneal Therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.
PMCID: PMC1987372  PMID: 17070570
4.  Follow up of fetal outcome in cases of maternal phenylketonuria in Northern Ireland 
Objective: To assess the outcome of 39 pregnancies in 20 mothers.
Results: Dietary control was established before conception in 17 pregnancies (44%). Five mothers with hyperphenylalaninaemia had 11 pregnancies. There were no congenital anomalies in this group, and all appear to be developing normally. Fifteen women with classical PKU had 28 pregnancies. One pregnancy ended in a first trimester miscarriage. Twelve out of 27 (44%) completed pregnancies produced babies with a congenital anomaly and/or developmental delay.
Conclusions: Most problems occurred when dietary control was not established until after the 2nd trimester. As the cohort of young women with treated PKU is growing steadily, maternal PKU is going to become an even greater cause for concern.
PMCID: PMC1721451  PMID: 12193524
5.  Effect of genotype on changes in intelligence quotient after dietary relaxation in phenylketonuria and hyperphenylalaninaemia 
Archives of Disease in Childhood  2000;82(3):216-221.
BACKGROUND—Associations between genotype and intellectual outcome in patients with phenylketonuria are complicated because intelligence is influenced by many variables, including environmental factors and other genetic determinants. Intellectual changes with age, both on and after relaxation of diet, vary within the patient population. This study aims to determine whether a significant association exists between genotype and change in intelligence after relaxation of diet.
METHODS—125 patients with hyperphenylalaninaemia and phenylketonuria whose diet was relaxed after 8 years of age. Verbal, performance, and full scale intelligence quotients at 8, 14, and 18 years were expressed as standard deviation scores (IQ-SDS), and genotype as predicted residual enzyme activity (PRA) of phenylalanine hydroxylase.
RESULTS—IQ-SDS at 8, 14, and 18 years were significantly below normal; no association was found between PRA and IQ-SDS. Significant reductions in verbal and full scale IQ-SDS occurred between 8and 14 years and 8 and 18 years. There was a significant association between PRA and the reduction in verbal, performance, and full scale IQ between these years. Multiple regression analysis of 18 year results, using 8 year results as covariates, supported the association between PRA and IQ-SDS; after adjustment for phenylalanine control, both up to and after the age of 8 years, the full scale IQ-SDS at 14 and 18 years was 0.15 higher for each 10% increase in PRA.
CONCLUSIONS—Genotype might be useful in predicting the likelihood of intellectual change in patients with hyperphenylalaninaemia and phenylketonuria whose diet is relaxed after the age of 8years.

PMCID: PMC1718236  PMID: 10685924
6.  An audit of therapeutic drug monitoring of anticonvulsants. 
The Ulster Medical Journal  1995;64(2):151-156.
An audit of therapeutic drug monitoring (TDM) of anticonvulsants was performed to assess both its use and misuse in the management of patients with epilepsy. Over a four week period all samples received for phenytoin, carbamazepine, sodium valproate and phenobarbitone assays were included in the audit. The aims were to establish the source of the specimens, the reasons for the requests and to ascertain what action, if any, would be taken when the result of the assay was provided. A total of 163 separate assays were performed over the four week period (43 phenytoin, 74 carbamazepine, 41 valproate, 5 phenobarbitone). Only 18.7% of all requests originated from the adult neurology department. The vast majority of tests had been ordered by junior medical staff (only 10% by consultants) and approximately 50% were 'routine' with no satisfactory clinical reason for the request offered. There was a tendency to manipulate prescribed doses on the basis of drug levels alone without taking the clinical picture into consideration. These results demonstrate a general ignorance, especially amongst junior medical staff, of the value of TDM of anticonvulsants, and reinforce the need for both an educative and interpretive service to be provided by the Chemical Pathology Department.
PMCID: PMC2448526  PMID: 8533181
7.  A comparison of acipimox and nicotinic acid in type 2b hyperlipidaemia. 
The side effect profiles and lipid lowering efficacy of nicotinic acid (1 g three times daily) and its analogue acipimox (250 mg three times daily) in type 2b hyperlipidaemia were compared in a double-blind placebo controlled study. In the nicotinic acid group (n = 7) at 12 weeks there were significant reductions (P less than 0.05) with respect to placebo (n = 9) in total cholesterol (median and range) 6.6 mmol l-1 (4.8-8.4) vs 8.8 mmol l-1 (7.5-9.5), triglyceride 1.4 mmol l-1 (0.5-4.6) vs 2.8 mmol l-1 (1.5-9.5) and apoprotein B 88.6 mg dl-1 (62.1-114) vs 121.9 mg dl-1 (88.0-170.7). In contrast there was no significant alteration in lipids in the acipimox group (n = 12). Nicotinic acid was associated with a high incidence of side effects, principally cutaneous flushing, while acipimox was well tolerated by all patients.
PMCID: PMC1381338  PMID: 1576071
8.  Magnesium status and digoxin toxicity. 
1. Eighty-one hospital patients receiving digoxin were separated into groups with and without digoxin toxicity using clinical criteria. Serum digoxin, sodium, potassium, calcium, creatinine, magnesium and monocyte magnesium concentrations were compared. 2. Subjects with digoxin toxicity had impaired colour vision (P less than 0.0001, Farnsworth-Munsell 100 hue test) and increased digoxin levels (1.89 (1.56-2.21) vs 1.34 (1.20-1.47) nmol l-1, P less than 0.01) (mean (95% confidence limits], though there was considerable overlap between two groups. 3. Subjects with digoxin toxicity had lower levels of serum magnesium (0.80 (0.76-0.84) vs 0.88 (0.85-0.91) mmol l-1, P less than 0.01) and monocyte magnesium (6.40 (5.65-7.16) vs 8.76 (7.81-9.71) mg g-1 DNA, P less than 0.01), but there were no significant differences in other biochemical parameters. A greater proportion of toxic subjects were receiving concomitant diuretic therapy (20/21 vs 37/60, P less than 0.05). 4. Magnesium deficiency was the most frequently identified significant electrolyte disturbance in relation to digoxin toxicity. In the presence of magnesium deficiency digoxin toxicity developed at relatively low serum digoxin concentrations.
PMCID: PMC1368552  PMID: 1768564
9.  Simvastatin in severe hypercholesterolaemia: a placebo controlled trial. 
The effect of simvastatin in 27 patients with severe primary hypercholesterolaemia was assessed by a double-blind placebo controlled parallel group trial. Total serum cholesterol, LDL-cholesterol and apoprotein B (ApoB) were significantly reduced by simvastatin 40 mg daily. Reductions in triglyceride and VLDL-cholesterol and an increase in HDL-cholesterol levels were only significant when calculated as a percentage of baseline, because of wide inter-individual variability. No changes in apoprotein A1, lipoprotein (a), fibrinogen, viscosity or blood pressure were observed. Leucocyte HMG-CoA reductase activity was unchanged after 4 weeks of active treatment but increased by 87% after 3 months (n = 21, P less than 0.05). No severe adverse effects or changes in CK or AST levels were noted. We conclude that simvastatin is effective in the treatment of severe and resistant hypercholesterolaemia, and well tolerated in the short term.
PMCID: PMC1368362  PMID: 2054273
10.  Functional differences between rat islets of ventral and dorsal pancreatic origin. 
Journal of Clinical Investigation  1982;69(2):405-413.
Do functional linkages between islet endocrine cells exist? The effect of differences in frequency and distribution of islet endocrine cells on B cell function was examined in islets from the ventral (ventral islets) and dorsal (dorsal islets) areas of the rat pancreas. Dorsal islets contained 10 times as much glucagon as ventral islets, whereas insulin and total protein contents were similar. Basal rates of insulin secretion and proinsulin biosynthesis were similar in the two types of islet, but, under conditions of glucose stimulation, both insulin secretion and proinsulin biosynthesis were significantly greater in the glucagon-rich dorsal islets. Similarly, glucose utilization rates an ATP levels were greater in dorsal islets. In contrast, the rates of processing of newly synthesized proinsulin were similar in ventral and dorsal islets. That the islet glucagon content may have affected B cell function is inferred from two independent findings. Firstly, basal and glucose-stimulated cyclic AMP contents of glucagon-rich dorsal islets were greater than those of ventral islets. Secondly, in the presence of excess exogenous glucagon (1 microgram/ml), the differences in glucose-induced insulin secretion and proinsulin biosynthesis rates between the two types of islets were eliminated. These results strongly suggest that changes in the relative proportions of the different islet endocrine cells exert marked effects on islet function. In particular, a greater A cell and glucagon content is associated with higher rates of glucose-induced insulin secretion and biosynthesis.
PMCID: PMC370990  PMID: 6173398
11.  Importance of preabsorptive insulin release on oral glucose tolerance: studies in pancreatic islet transplanted rats 
Gut  1980;21(11):1002-1009.
The role of preabsorptive (cephalic phase) insulin release in oral glucose tolerance was investigated using diabetic rats treated by intraportal transplantation of isogenic islets. This early neurally mediated phase of insulin release has been shown to be absent in such rats. When the body weight of transplanted rats was normalised, glucose tolerance tests (GTTs) were performed in the unstressed state using permanent cardiac catheters. Transplanted rats had a normalised intravenous GTT, whereas, as we have shown previously, their oral GTT remained clearly pathological. During both tests peripheral insulin levels were decreased compared with controls. While during intravenous GTT the onset of insulin release occurred as early in transplanted rats as in controls, during oral GTT there was a clear delay, probably because of the absence of the cephalic phase. Re-establishment of normal preabsorptive insulin levels was attempted by a small intravenous insulin injection during this period. This resulted in a transient increase in peripheral insulin levels, which, at two minutes after glucose ingestion, gave values similar to those found in controls at that time. This small insulin injection caused a marked improvement of the oral GTT which was most evident after exogenous insulin had disappeared from the blood. While the injection did not affect the 60 minute incremental insulin area, the glucose area was decreased by 50%, to a value not significantly different from that of control rats. The cephalic phase of insulin release appears, therefore, to be one important factor in the control of glycaemia during food intake. Its absence plays a major role in the pathological oral glucose tolerance of diabetic rats treated by intraportal islet transplantation.
PMCID: PMC1419285  PMID: 6778779
14.  Maturity onset diabetes mellitus: response to intensive dietary management. 
British Medical Journal  1975;3(5978):276-278.
Analysis of the first six months of intensive dietary management of 57 maturity onset diabetics showed that a large proportion of such patients could be satisfactorily controlled without the need of either oral hypoglycaemic agents or insulin. A dietitian's assessment of the patient's adherence to the prescribed diet allowed groups of good and poor dieters to be selected. Among the poor dieters the plasma insulin and triglyceride levels were significantly increased though plasma glucose levels were not significantly higher. Dietary adherence may thus be an prognostic risk factor in this group of diabetic patients.
PMCID: PMC1674182  PMID: 1148773

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