An important aim of Phase 2 clinical trials is the firm determination of the doses and the dose regimes to be used both in later clinical trials and in clinical practice. Comparisons of findings made during clinical development and recommendations contained in the package leaflets of marketed preparations indicate that this objective is rarely achieved. The possible reasons for this difficulty are investigated by reviewing the methodology used in the so-called dose-finding trials performed during drug development. Since the terminology used in this context is frequently misleading, definitions are given and alternative approaches, referring to the direct and indirect methods of bioassay, are suggested. The practical use of these models depends on a number of medical and ethical considerations, on the indications for treatment and on the characteristics of the drug under investigation. Some examples are given, indicating that dose-response relationships can be determined more easily for efficacy, where endpoints more reliably fit commoner distributions, than for tolerability, where the responses frequently follow irregular patterns. This area deserves further investigation to improve the criteria for assessment and to develop adequate statistical methods.

Anti-Bacterial Agents↗

PubMedDate not supplied

Virulence properties of Escherichia coli strains in patients with chronic pyelonephritis.

In 50 Escherichia coli strains obtained from the bladder puncture urine of patients with chronic pyelonephritis, determinations of virulence properties were performed. All of the E. coli strains isolated from 26 acute episodes of pyelonephritis were found in the smooth form. 30% possessed K 1 antigen, 77% showed the ability to form hemolysin and 30% produced colicin V (aerobactin). Fimbriae (detected by mannose-resistant hemagglutination) were registered in 81%, and plasmids ranging between 50 and 70 Md were demonstrated in 70% of the bacteria. In contrast to this, only 70% of the E. coli strains isolated from 24 patients at an inactive stage of pyelonephritis were found in the smooth form; 10% of these encoded K 1 antigen, 20% hemolysin and 10% colicin V. Plasmids in the range 50 to 70 Md could be found in 30%. On the basis of multivariate analysis of variance and discriminant analysis, it was confirmed that uropathogenic strains possess several virulence properties, mannose-resistant hemagglutination being of particular importance.

Adult↗

PubMedDate not supplied

Pentosidine and N(epsilon)-(carboxymethyl)-lysine in Alzheimer's disease and vascular dementia.

Increasing evidence suggests an interaction of oxidative stress and the formation of advanced glycation end products (AGE) in the onset and progression of Alzheimer's disease. We studied levels of pentosidine and N(epsilon)-(carboxymethyl)-lysine (CML) in serum and cerebrospinal fluid (CSF) of 15 patients with probable Alzheimer's disease (AD), 20 patients with vascular dementia (VD), and 31 control subjects (14 matched for age, and 17 younger patients). AGE protein concentrations in CSF did not differ within controls when divided into two subgroups by age. We found significantly elevated levels of CML in CSF of AD patients and of pentosidine in CSF of patients suffering from vascular dementia when compared to controls. The concentrations of pentosidine and CML in serum apparently did not relate directly to CSF values, suggesting influence of extra-cerebral factors in serum samples. It is concluded that AGE proteins are differentially affected in these types of dementia, depending on the specific neuropathology. Furthermore, measurements of AGE products in vivo should rely on CSF rather than blood samples.

Aged↗

PubMedDate not supplied

[Results of cardiopulmonary resuscitation in children].

We retrospectively evaluated the outcome from cardiopulmonary resuscitation (CPR) in 149 children of all age groups. Only 7 children experienced ventricular fibrillation. 47 children (31.5%) died immediately. Further 47 children died within 24 hours of their arrest, 24 (16.1%) survived longer than 24 hours after CPR but not until discharge. Only 31 children (20.8%) survived to discharge, 5 with severe neurologic sequelae, attributable to the arrest or resuscitation efforts. Cardiopulmonary arrests in the Pediatric Intensive Care Unit carried the worst prognosis. Better results were obtained out-of-hospital, in the OR or on the pediatric floor. Long-term survival rate did not correlate with age, or type of administered catecholamine. None of the children receiving calcium survived. This large study confirms the poor outcome of CPR in children.

Calcium↗

PubMedDate not supplied

A pilot epidemiologic study of possible health effects associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin contaminations in Missouri.

In 1971, 2,3,7,8-tetrachlorodibenzodioxin (TCDD)-containing waste oils were sprayed for dust control on residential, recreational, and work areas in Missouri. In several of these areas, the magnitude and the extent of this environmental contamination were not known until late 1982 or 1983. In the first phase of the investigation, a group of persons considered to be at highest risk of exposure and an appropriate comparison group were selected from reviews of Health Effects Survey screening questionnaires. These persons received complete medical examinations and a series of laboratory tests focused on detecting presymptomatic effects in key target organ systems (i.e., hepatic, dermatologic, immunologic, and neurologic effects). Comparisons of these two groups did not produce any firm indications of increased disease prevalence directly related to the putative exposures; of significance is the fact that no cases of chloracne or porphyria cutanea tarda were seen. Nevertheless, no overall definitive conclusion should be based just on this initial pilot study. Insights were provided that are being examined in more refined epidemiologic studies using different designs and strategies--especially of larger, more homogeneous population groups in which exposure status can be better characterized--focused primarily on discerning any potential effects on the urinary tract, liver, neurological, and immune systems. Concurrently, research into the development of replicable laboratory analytical methods and reference ranges for measuring TCDD body burden are being pursued.

Adolescent↗

PubMedDate not supplied

Detection of elevated N epsilon-carboxymethyllysine levels in muscular tissue and in serum of patients with fibromyalgia.

OBJECTIVES: To compare levels of the advanced glycation end product (AGE) N(epsilon)-carboxymethyllysine (CML) present in the muscle tissue and in the serum of patients with fibromyalgia (FM) vs. healthy controls. METHODS: The serum levels of CML were measured in 41 patients with FM and 81 healthy controls. The presence of CML, nuclear factor kappa B (NF-kappaB), the AGE receptor (RAGE), collagen types I, II, VI, and CD68-positive monocytes/macrophages in muscle tissue of 14 patients with FM was investigated by immunohistochemistry. RESULTS: Patients with FM showed significantly increased serum levels of CML in comparison to healthy controls. The immunohistochemical investigation revealed a stronger staining for CML and NF-kappaB and more CD68-positive monocytes/macrophages in the muscle of FM patients. The collagens and CML were co-localized, suggesting that the AGE modifications were related to collagen. RAGE was absent in controls but a faint and patchy staining was seen in FM. CONCLUSIONS: In the interstitial connective tissue of fibromyalgic muscles we found a more intensive staining of the AGE CML, activated NF-kappaB, and also higher CML levels in the serum of these patients compared to the controls. RAGE was only present in FM muscle. AGE modification of proteins causes reduced solubility and high resistance to proteolytic digestion of the altered proteins (e.g. AGE-modified collagens). AGEs can stimulate different types of cells by activation of the transcription factor NF-kappaB, mediated by specific receptors of AGEs (e.g. RAGE) on the cell surface. Both mechanisms may contribute to the development, perpetuation, and spreading of pain characteristic in FM patients.

Adult↗

PubMedDate not supplied

Iothalamate ethyl ester as hepatolienographic agent.

In search of a hepatolienographic agent, the iothalamate ethyl ester particulate suspension was prepared with the average particle size of 1.5 mu in diameter. When mixed with plasma of different animal species, the physical properties of the particular suspension changed significantly. The nature of this difference is not understood but is probably related to protein-particle interaction in the different species. Doses of 550 mg iodine per kg body weight as a single intravenous infusion of the particulate suspension resulted in satisfactory opacification of liver and spleen in rats, followed by complete loss of radiopacity within three days. Larger doses resulted in the death of the rats within 12-14 hours. In general, the mice tolerated larger doses than rats, but there was very poor opacification of the liver, despite good opacification of spleen. Further work is being carried out to improve the suspension and to better understand the difference in behavior of the particulate suspension in different animal species.

Animals↗