Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer''s disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development.     

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.     

Acute renal failure in a neonate due to pelviureteric candidal bezoars successfully treated with long-term systemic fluconazole

Systemic candidiasis with renal involvement is a rare but well-recognized complication during intensive care treatment in very-low-birth-weight infants. We report a term neonate who developed anuria associated with bilateral bezoar formation in the renal pelvis and candidemia. The treatment consisted of placement of a nephrostomy tube in the left kidney, short-term irrigation with amphotericin B and iv, and later, oral administration of fluconazole.     

Pelvic ultrasound findings in different forms of sexual precocity

Recently produced reference curves for various ultrasound dimensions were used to retrospectively assess 67 pelvic ultrasound scans carried out at the initial presentation in girls with sexual precocity. At presentation the group with precocious puberty had significantly increased uterine lengths and ovarian volumes compared with the normal population, and a significantly increased fundal–cervical ratio. Ovarian volume was also significantly increased in thelarche and thelarche variant. The fundal–cervical ratio was significantly increased in thelarche variant. There was considerable overlap between individuals with sexual precocity and normal subjects. The ultrasound findings that best discriminated early or precocious puberty from other forms of sexual precocity were the presence of a midline endometrial echo, and a uterine length above the 97th centile for age. An entirely normal pelvic ultrasound at presentation did not rule out the possibility of precocious puberty.     

Immunity to hepatitis B, poliomyelitis and measles in fully vaccinated Aboriginal and Torres Strait Island children

Objective: To determine the immunity to hepatitis B, poliomyelitis and measles in fully vaccinated Aboriginal and Torres Strait Island children in north Queensland.
Methodology: A cross-sectional survey of immunity in a sample of children; 101 fully vaccinated Aboriginal and Torres Strait Island children, with a median age of 24.5 months, from 10 communities in North Queensland participated in this study. The main outcome measures were the prevalence of adequate antibody levels against hepatitis B, poliomyelitis and measles.
Results: Only 54% (95% Cl 44–63%) of the children had adequate immunity (10 m iu/mL) to hepatitis B, and one child had been infected despite vaccination. Although all the children (95% Cl 96–100%) had adequate immunity (i.e. neutralizing antibodies at a dilution of 1:8) to poliovirus 2, only 93% (95% Cl 86–96%) and 60% (95% Cl 50–69%) had adequate immunity to polioviruses 1 and 3, respectively. Nearly all (96%; 95% Cl 90–98%) of the children had adequate immunity (i.e. detectable IgG antibody) to measles.
Conclusions: Although a relatively low proportion of the children had adequate antibody levels against hepatitis B the clinical significance of this observation is uncertain. Further studies are needed to determine whether fully vaccinated Torres Strait Island children have been adequately protected and whether they require a booster dose of hepatitis B vaccine. A substantial proportion of fully vaccinated Aboriginal and Torres Strait Island children are inadequately protected against poliomyelitis, and therefore any such child with acute flaccid paralysis should be investigated fully for poliomyelitis. Vaccinated Aboriginal and Torres Strait Island children are well protected against measles, as are other Australian children.     

Assessing primary care content: four conditions common in community health center practice

Under managed care, community health center (CHC) care patterns will be increasingly subject to outside scrutiny. This article discusses results of medical records reviews assessing quality of care at CHCs for acute otitis media, diabetes, asthma, and hypertension. As a group, these safety net providers meet or exceed prevailing practice across other health care settings; however, there is substantial variation among sites. Regression analyses indicate that the individual CHC used by a patient is the most consistent determinant of whether a patient receives recommended care. Drawing on these results, the article explores approaches for improving care and discusses the implications for performance measurement among CHCs and other safety net providers.     

INTESTINAL AGANGLIONOSIS IN THE SMITH-LEMLI-OPITZ SYNDROME

ABSTRACT. Two unrelated cases with clinical and autopsy findings of the Smith-Lemli-Opitz syndrome are described. Narrowing of the terminal ileum and congenital intestinal aganglionosis was found in both. This is a rare association and the importance of microscopic examination of the intestine in cases of the Smith-Lemli-Opitz syndrome is emphasized.     

Mechanical failure of the American Medical Systems Ultrex inflatable penile prosthesis: before and after 1993 structural modification

PURPOSE: The 700 Ultrex (American Medical Systems, Minnetonka, Minnesota) is the only penile prosthesis capable of length and girth expansion. Early experience with the 700 Ultrex showed an increased mechanical failure rate compared with the 700CX, mostly secondary to cylinder failure. In 1993 the Ultrex cylinders were modified. We examined the performance of the Ultrex device before and after modification. MATERIALS AND METHODS: We compared our results with the Ultrex prosthesis before (group 1) and after (group 2) the 1993 modification. We implanted 239 devices from October 1989 to December 1999. A total of 26 patients have died. Followup was obtained on the results of 137 of the remaining 213 implants (64%), including 85 pre-modification devices in 85 patients and 52 post-modification devices in 51, via a mailed questionnaire, telephone survey or chart review. The questionnaire and survey included a 5-point satisfaction scale. Groups 1 and 2 were compared in regard to 3 end points, namely cylinder, mechanical and overall failure. RESULTS: Followup was less than 1 to 136 months (median 92, 25th to 75th percentiles 43 to 108) in group 1 and less than 1 to 92 months (median 46, 25th to 75th percentiles 21 to 75) in group 2. The 5-year Kaplan-Meier estimates of overall, mechanical and cylinder survival in groups 1 and 2 were 64.7%, 70.7% and 80.2%, and 77.7% (p = 0.23), 93.7% (p = 0.017) and 96.2% (p = 0.008), respectively. Overall satisfaction was similarly high in groups 1 and 2 (mean 3.9 and 4 points). CONCLUSIONS: On long-term followup the 1993 modification of the Ultrex cylinders appears to have significantly decreased the propensity of cylinder failure of the pre-modification device.