The relevance of therapeutic drug monitoring in plasma and erythrocytes in anti-cancer drug treatment.

Therapeutic drug monitoring generally focuses on the plasma compartment only. Differentiation between the total plasma concentration and the free fraction (plasma water) has been described for a number of limited drugs. Besides the plasma compartment, blood has also a cellular fraction which has by far the largest theoretical surface and volume for drug transport. It is with anti-cancer drugs that major progress has been made in the study of partition between the largest cellular blood compartment, i.e., erythrocytes, and the plasma compartment. The aim of the present review is to detail the progress made in predicting what a drug does in the body, i.e., pharmacodynamics including toxicity and plasma and/or red blood cell concentration monitoring. Furthermore, techniques generally used in anti-cancer drug monitoring are highlighted. Data for complex Bayesian statistical approaches and population kinetics studies are beyond the scope of this review, since this is generally limited to the plasma compartment only.     

The value of MCA, CA 15-3, CEA and CA-125 for discrimination between metastatic breast cancer and adenocarcinoma of other primary sites

MCA, CA 15-3, CEA and CA 125 were determined in the serum of 49 patients with metastatic breast cancer and 38 patients with metastatic adenocarcinoma of other primary sites. By using the 99th percentile of the normal value distribution as the cut-off point, the positive predictive value (PV+) was found to be 85% (95% CI 76-94) for MCA, and 71% (95% CI 61-81) for CA 15-3. When receiver-operating-characteristic (ROC) curves were constructed, the PV+ for CA 15-3 was increased to 82% (95% CI 72-92), using 60 U ml-1 as the cut-off point. With the exception of two patients who had a slightly elevated MCA, MCA and CA 15-3 identified the same patients with breast cancer. By combining a positive MCA or CA 15-3 with a negative CEA and CA 125, further improvement of the PV+ could be achieved; 100% (95% CI 91-100). We conclude that MCA and CA 15-3 may play a useful role in discrimination between patients with metastatic breast cancer and those with adenocarcinoma of other primary sites.     

The ventral rib cage muscles in the dog: contractile properties and operating lengths

To have some insight into the mechanical interplay between the parasternal intercostal and triangularis sterni muscles during breathing, we have examined the isometric contractile properties of these two muscles in the dog. Using piezoelectric crystals, we have also measured the respiratory changes in muscle length in eight spontaneously breathing animals in the supine posture, and we have compared the in situ relaxation length (Lr) of these two muscles to their respective in vitro optimal force-producing length (Lo). The triangularis sterni and parasternal intercostals had similar isometric twitch, force-frequency, and length-tension characteristics. These two muscles, therefore, are intrinsically similar. In supine dogs, however, they operate on quite distinct segments of their length-tension curve. Whereas Lr for the parasternals corresponded to 117% Lo, Lr for the triangularis sterni was only 75% Lo. This suggests that the triangularis sterni in supine dogs operates on a poorly advantageous portion of its length-tension curve. However, shortening of the parasternals during inspiration causes considerable passive distension of the muscle. As a result, the triangularis sterni is much closer to its optimal length when it starts contracting in early expiration.     

Astroglial alterations in rat hippocampus during chronic lead exposure.

The present study was performed in order to follow the response of astroglial cells in the rat hippocampus to chronic low-level lead exposure. The experiments combined immunohistochemistry using anti-glial fibrillary acidic protein (GFAP) antibody and conventional transmission electron microscopy (EM). Chronic administration with drinking water [1 g% w/v (subclinical dose) of lead acetate dissolved in distilled water] was started through the mother's milk when pups were 7 days old. Following weaning, experimental offspring were treated for 3 months with the same concentration of adulterated water. The group of intoxicated animals and their controls were sacrificed by perfusion-fixation at 30, 60, and 90 days of exposure. After 60 days of lead treatment, staining of GFAP-positive cells demonstrated an astroglial transformation from the quiescent to the reactive state, characterized by an increase in GFAP. In control rats no changes in GFAP immunostaining were observed. The intensity of the astroglial response was enhanced after 90 days of lead intoxication, showing an increment of GFAP immunoreactivity. Quantification of these changes was made by computerized image analysis, confirming that the sectional areas of the astroglia in lead-exposed animals were larger than those in controls. These results are consistent with the ultrastructural alterations. Simultaneously with the increment in gliofilaments, intranuclear inclusions were seen in some astrocytes. The mechanisms by which lead affects astrocytes are unknown. Probably the astroglial changes induced by lead intoxication produce microenvironmental modifications that may disturb the neuronal function.     

Circulating adipocytokines in non-diabetic and Type 1 diabetic children: relationship to insulin therapy, glycaemic control and pubertal development.

AIM: To determine the influence of Type 1 diabetes mellitus on circulating adipocytokines in children. METHODS: The circulating concentrations of leptin, adiponectin, resistin and tumour necrosis factor (TNF)-alpha were measured in 91 children, aged 11.1 +/- 2.7 years, with Type 1 diabetes mellitus (T1DM). Ninety-one healthy children were selected as control subjects. RESULTS: Body mass index-adjusted leptin concentrations were higher in the pubertal diabetic children compared with the control children. There was a significant positive correlation between leptin and daily insulin dose in the diabetic group. Circulating adiponectin concentrations were higher in the prepubertal diabetic children and were positively associated with HbA(1c). Resistin concentrations were lower in the prepubertal non-diabetic subjects compared with the pubertal non-diabetic children, whose values were higher than those of the diabetic children. TNF-alpha concentrations were similar in non-diabetic and diabetic children. CONCLUSIONS: Circulating concentrations of adipocytokines are abnormal in Type 1 diabetic children, although the direction of change differs by cytokine. Pubertal development, in addition to insulin treatment and glycaemic control, also influences the concentrations.     

P6 Complaints of halitosis related to the oral cavity. A preliminary report of 700 consecutive patients

Patients with complaints of halitosis do seek treatment from physicians and dental practitioners, because of the fear that their halitosis may interfere with their social activities. Although the prevalence of halitosis has been reported to be as high as 50%, most physicians and dental practitioners are poorly informed about the causes and treatments of halitosis. In order to care for patients with complaints of halitosis a multidisciplinary team was established at the Erasmus Medical Centre, Rotterdam, The Netherlands. The team included a dental hygienist, an otorhinolaryngologist, and a dentist, who developed a special halitosis programme. One short press release regarding the establishment of the team, was provided to the national press-centre. In the out-patient clinic more than 700 patients were seen by the team. Using a structured questionnaire fed to a PC, patients answered questions regarding complaints about the oral cavity, the upper respiratory tract, the throat, their general health, their cleansing habits of the oral cavity, and prior experiences with general physicians, dental practitioners, and medical specialists. They underwent examinations of the extent of their halitosis, of the perioral and neck region, the oral cavity, the upper respiratory tract, and the upper digestive tract. Finally, the members of the team came to a joint diagnosis and a joint treatment plan for every individual patient. Of the first 700 consecutive patients around 90% had a natural dentition without removable partial dentures. More than 60% were diagnosed as having periodontal disease with pockets of 4 mm or more in the maxilla. This figure was more than 50% in the mandible. Around 95% had tongue coating.     

In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCl

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non-disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus. The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and t_d of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and t_d between 149 and 291 min. The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half-life t_1/2 (7.12 h), while apparent t_1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for C_max and AUC values, and no relationships could be established with the type of formulation. An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p <0.05). In a few cases the Wagner-Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the ‘Levy's plot’ (per cent released versus per cent absorbed) approach and provided further support for the correlation found.     

Effects of androgen treatment in impotent men with normal and low levels of free testosterone

The relation between sexual function and serum free testosterone (fT) levels, which represent the active fraction of circulating testosterone, was evaluated. Two groups of impotent male subjects with mild hypogonadism were treated with oral testosterone undecanoate (TU); these men presented with tT/luteinizing hormone (LH) ratio and tT levels at the lower limits of normal. The first group had serum fT below 6.6 ng/ml, considered the lower normal value, according to our laboratory method, whereas the second group had normal fT limits. Administration of TU improved sexual function only in impotent men with low fT levels, but not in subjects with normal fT levels, even though the tT levels and the tT/LH ratio of the two groups were not significantly different. The results of our study suggest the presence of a minimun serum fT threshold, lying near the lower normal range, which determines the male sexual function. Moreover, serum fT levels were a more sensitive index than tT for identifying impotent men who can be successfully treated with androgens.