Insulin glulisine, a new rapid-acting insulin analogue, displays a rapid time-action profile in obese non-diabetic subjects.

AIMS/HYPOTHESIS: This study compared the pharmacokinetics and pharmacodynamics of insulin glulisine, insulin lispro, and regular human insulin in obese subjects. METHODS: In this single-dose, randomized, double-blind, crossover euglycaemic clamp study, 18 non-diabetic subjects (mean body mass index [BMI] 34.7 kg . m (-2)) were randomized to receive subcutaneous injections of each insulin (0.3 U . kg (-1)) in pre-determined sequences. RESULTS: Insulin glulisine and insulin lispro had more rapid-acting profiles than regular human insulin. Fractional glucose infusion rate (GIR)-area under curves (AUC) of the GIR curve and maximum GIR were greater for insulin glulisine and insulin lispro versus regular human insulin. Total glucose disposal was slightly greater with insulin glulisine than with regular human insulin, and was comparable to insulin lispro, although it decreased with increasing insulin resistance (HOMA index) with all insulins. Time to 20 % (early glucose disposal) and 80 % (bulk of activity) of total GIR-AUC were shorter for insulin glulisine and insulin lispro versus regular human insulin. This was corroborated by more rapid and shorter residing pharmacokinetic profiles of insulin glulisine and insulin lispro versus regular human insulin, evidenced by shorter times to 20 % of total INS-AUC, INS-C (max) (INS-t (max)), and mean residence time. Moreover, time to 20 % of total GIR-AUC demonstrated a less rapid-acting profile for insulin lispro versus insulin glulisine, which was consistent with the slightly less rapid pharmacokinetic profile of insulin lispro. There was no significant correlation between BMI or subcutaneous fat thickness and pharmacokinetic or pharmacodynamic profiles for insulin glulisine, unlike insulin lispro and regular human insulin. CONCLUSIONS/INTERPRETATION: Insulin glulisine and insulin lispro demonstrated substantially more rapid time-action profiles than regular human insulin in obese non-diabetic subjects, which prevailed with insulin glulisine irrespective of BMI and subcutaneous fat thickness.

A comparison of the steady-state pharmacokinetics and pharmacodynamics of a novel rapid-acting insulin analog, insulin glulisine, and regular human insulin in healthy volunteers using the euglycemic clamp technique.

Insulin glulisine is a new rapid-acting insulin analog. The aim of this study was to assess the glucodynamic efficacy of insulin glulisine compared with regular human insulin (RHI) using a manual euglycemic clamp technique. Steady-state pharmacokinetics of insulin glulisine, and its cardiac safety (ECG) and tolerability after intravenous administration, were also determined. This was a single center, randomized, open-label, two-way crossover study in healthy male subjects (n = 16). At the treatment visits subjects received an intravenous infusion of the study drug at a rate of 0.8 mU kg (-1) . min (-1) for 2 hours. Individual baseline glucose concentrations were targeted for euglycaemia and maintained with a manual adjusted 20 % glucose solution over the clamp period of a maximum 6 hours. A glulisine-specific antibody was used to quantify glulisine concentrations by radioimmunoassay, while a non-specific insulin antibody and C-peptide based correction for endogenous insulin was used to estimate exogenous human insulin (RHI). At steady state (90 - 120 min), insulin glulisine and RHI had equivalent glucose utilization (GIR-AUC (SS), 209 [corrected] mg . kg (-1) for glulisine, 214 [corrected] mg . kg (-1) for RHI) and infusion rates (GIR (SS), 7.0 and 7.2 [corrected] mg . kg (-1) . [corrected] min (-1) . kg (-1)). Both insulins also presented equal total glucose disposal (GIR-AUC (0 - clamp end), 995 and 1050 [corrected] mg . kg (-1)) and onset of activity within 20 min. Insulin glulisine and RHI showed parallel time concentration profiles with similar distribution and elimination, but the different antibodies employed for radioimmunoassay impeded a quantitative comparison. There were no noteworthy individual or within-group changes in cardiac repolarisation parameters measured by 12-lead ECG during insulin glulisine infusion. In conclusion, insulin glulisine and RHI show similar distribution and elimination profiles and equivalent glucodynamic efficacy on a molar, unit-per-unit basis.

Biotransformation of insulin glargine after subcutaneous injection in healthy subjects.

OBJECTIVE: It is important to establish pharmacokinetic or pharmacodynamic differences between novel insulin analogues and human insulin. This study examined the primary metabolic degradation products of insulin glargine (LANTUS) in humans. DESIGN: In this single dose, open-label study, insulin glargine was administered subcutaneously at a dose of 0.6 IU/kg; placebo was administered to one control subject. PATIENTS: Four healthy male subjects, plus one control subject, aged 18-50 years were enrolled in this study. MEASUREMENTS: Following insulin glargine administration, blood glucose levels were clamped at the subjects' fasting concentration for 6 h and the amount of 20% glucose infused to maintain this baseline concentration was recorded. Metabolite profiling was performed in plasma and injection site tissue using HPLC and radioimmunoassay (RIA). Pharmacokinetics were evaluated by RIA of serum and plasma immunoreactive insulin levels. The primary pharmacodynamic measure was the glucose infusion rate (GIR). Safety was evaluated by measuring blood glucose concentrations during the clamp and adverse events were observed by the investigator or reported by the subject. RESULTS: Metabolic profiling revealed a clear pattern: insulin glargine is metabolised by sequential cleavage at the carboxy terminus of the B chain, to yield products M1 and M2, which are both structurally similar to human insulin. These degradation products are present both at the injection site and in plasma. CONCLUSION: Thus, during treatment with a subcutaneous injection of insulin glargine, metabolic degradation is likely to be initiated at the injection site and continued within the circulatory system.

Extraskeletal myxoid chondrosarcoma of the falx.

Intracranial cartilaginous tumors are unusual lesions, of which myxoid chondrosarcoma is the rarest. We describe this tumor arising from the falx in a 28-year-old woman treated at recurrence with a second operation and a radiation implant. The behavior of classic chondrosarcoma and mesenchymal chondrosarcoma is also reviewed.

Long-term survival in patients with malignant astrocytoma.

From 1978 to 1988, 314 patients with malignant astrocytoma were treated by our neuro-oncology team. Twenty-five patients were excluded from further analysis because of a lack of adequate follow-up, the brain-stem location of the tumor, or an age of less than 18 years. Of the 289 remaining patients in the valid study group, 213 had Grade IV tumors (73.7%) and 76 had Grade III tumors; 167 patients were male (57.8%) and 112 were female, and 89 were less than 40 years of age (30.8%). There were 58 long-term survivors (> 36 mo) in the series (20%). Long-term survivors were much more likely to be less than 40 years of age (x = 41.8; P < 0.005), to have undergone repeated surgery (x = 17.3; P < 0.005), to have received more than 60 Gy of radiation (x = 11.6; P < 0.005), to have Grade III tumors (x = 10.6; P < 0.005), and to have received nitrosoureas (x = 6.09; P < 0.02). Neither sex nor blood type were significantly associated with long-term survival. Patients undergoing repeated surgery were more likely to be less than 40 years of age (x = 5.72; P < 0.02), but neither sex nor histological findings was associated with repeated surgery. For the series as a whole, the observed 5-year survival rate was 6%. We conclude that an aggressive multidisciplinary approach can produce sizable numbers of long-term survivors in malignant astrocytoma patients with favorable prognostic factors.

Equipotency of insulin glargine and regular human insulin on glucose disposal in healthy subjects following intravenous infusion.

The absolute glucose disposal of insulin glargine (Lantus) was compared to that of regular human insulin in healthy subjects (n=20) using the euglycaemic clamp technique in a single-dose, double-blind, randomized, two-way crossover design. Subjects received 30-minute intravenous infusions of insulin glargine (0.1 IU/kg) or human insulin (0.1 IU/kg) and a 20% glucose solution infused at a variable rate to maintain euglycaemia at the subject's baseline glucose level. At equal baseline blood glucose levels (4.42 mmol/l [range, 4.00-5.16 mmol/l] and 4.42 mmol/l [range, 4.01-4.94 mmol/l], respectively), the area under the glucose infusion rate (GIR) time curves from 0-6 hours (AUC(0-6h)) was within the bioequivalence range (insulin glargine, 663.92 mg/kg; human insulin, 734.85 mg/kg). Both the time to maximum GIR and the suppression of serum C-peptide were similar with insulin glargine and human insulin. The resulting maximum serum insulin concentrations (Cmax) were 151.16 microIU/ml and 202.23 microIU/ml, and the time to Cmax (Tmax) was 30 minutes (the duration of the infusion). The observed differences in the Cmax (the mean value for insulin glargine was about 25% lower than that of human insulin) could be explained by lower cross-reactivity of insulin glargine in the human insulin radioimmunoassay. The employed intravenous route, though definitely not the intended clinical use of insulin glargine, provided the clinical evidence in healthy subjects that on a molar basis insulin glargine is equipotent to regular human insulin regarding glucose disposal.

Muti or ritual murder.

Ritual or muti murders are a form of human sacrifice practised by some African tribes. The murder is carried out after body parts are removed while the victim is still alive. This case report describes the methods of identification of a young child who was murdered by a traditional healer (isangoma) in Cape Town, and the practice of the traditional healer.

Neuropeptides in macula utriculi and macula sacculi of guinea pig labyrinth. An immunohistochemical study.

The neuropeptides Substance P, beta-Endorphin, Prolactin, Cholecystokinin, and Glucagon were investigated by means of Sternbergers PAP technique in the neuroepithelium of the Maculae utriculi and sacculi of the labyrinth of newborn guinea pigs. This brief report will show the localization of some neuropeptides in the neuroepithelium of the Maculae utriculi and sacculi. We could not find information about similar studies on this topic in the literature. In connection with investigations of the sensory apparatus of the inner ear we have recently presented neuropeptides evidence for the presence of certain peptides in the Ggl. spirale and the hair cells of the organ of Corti. With this paper we continue to report on neuropeptides in the labyrinth of the juvenile guinea pig as revealed by immunohistochemistry (Nowak et al., in press).

Multiple intracerebral arteriovenous malformations: report of three cases and review of the literature.

Multiple intracerebral arteriovenous malformations are thought to be exceedingly rare lesions and have usually been reported as single cases. During the past 2 years, we have treated three patients with multiple cerebral arteriovenous malformations, representing 3.2% of a consecutive series of 95 arteriovenous malformation patients seen since 1976. Details on 17 other cases are available in the literature and are summarized here. The incidence of multiple arteriovenous malformations in major series ranges from 0.3% to 3.2%; the average incidence is 1.9% based on 21 cases encountered in a total population of 1102 arteriovenous malformation patients. Patients with multiple arteriovenous malformations often have other vascular anomalies of the brain or soft tissues, but the clinical mode of presentation, age, sex, and anatomical distribution of the lesions are the same as those of patients with single arteriovenous malformations. The use of four-vessel angiography in combination with magnetic resonance imaging may result in a higher detection rate for such cases.

Identification of a suicide victim by facial reconstruction.

Facial reconstruction is used in an attempt to identify an individual by a three dimensional representation of the facial features using the skull as the foundation after metrical and non-metrical analysis to determine age, race and gender. The skeletonized remains of a female who was reported missing six years previously were recovered from the summit of Table Mountain in Cape Town. Some personal possessions were also recovered, one of which was a shark tooth pendant which the victim's parents recognized. Although there were distinctive dental features, the antemortem dental records had been lost during the initial investigation which therefore precluded identification by this means. However, positive identification was required and facial reconstruction on the skull was undertaken which the parents duly identified. The method used for facial reconstruction is described.

Antibodies to Epstein-Barr virus in nasopharyngeal carcinoma, tonsillar carcinoma and control groups.

In the sera of 17 patients with nasopharyngeal carcinoma (NPC) and of 19 patients with tonsillar carcinoma (TC) the titres of IgA, IgG and IgM antibodies to EBV VCA (viral capsid antigen) and of IgG antibodies to EBV EA (early antigen) were determined by the indirect immunofluorescence (IF) method. Significant difference was observed in the frequency of IgA antibodies to EBV VCA and IgG antibodies to EBV EA between NPC patients and controls. There was also a significant difference between the frequency of IgM antibody to EBV VCA and EBV EA antibody titres in TC patients and controls. The geometric mean titre (GMT) of IgG antibodies to EBV VCA was significantly higher in the NPC and TC patients as compared to controls.

[Employees without pension arrangements]. / Werknemers zonder pensioenvoorziening.

Old age pensions in modern western industrial countries rest on three pillars: public, collective and individual-private arrangements. The flat-rate public system and the collective systems, domain of industrial relations, prevail in Holland. Since the early seventies the public old age pension (AOW) has been raised to the net minimum wage level. In the meantime the importance of the collective systems has been increasing. The pension levels of these systems are, however, not prescribed by law. In order to measure the present state of the collective systems the Dutch Chamber of Pensions has started a research project to investigate how many workers lack such an arrangement and why they lack it. The results of the project have recently been reported: in 1985 18% (650,000) of the workers (25-65 years) lacked an arrangement. The vast majority of them (87%) was found in the sector of services, especially the commercial services. A second research project has been started to find out the quality of the existing pension arrangements. The results of the two projects together are meant to answer the question whether or not some sort of collective pensions must be enforced by law. The improvement of collective pension schemes, however, should not lead automatically to decreasing public schemes. For most people the public pension system is the most important source of income.

Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique.

AIMS/HYPOTHESIS: This single-dose, double-blind, randomised, parallel-group study evaluated the reproducibility in systemic exposure and glucodynamic effect of insulin glargine, NPH insulin (NPH) and insulin ultralente (ultralente) using the manually adjusted euglycaemic clamp technique. METHODS: In total, 36 healthy volunteers received two consecutive s.c. injections (0.4 IU/kg) of glargine, NPH or ultralente with a wash-out period of 7 days between treatments. RESULTS: In healthy volunteers, glargine presented well-reproduced flat concentration profiles and no pronounced peaks in activity. NPH, by contrast, showed well-defined peaks in concentration and glucose disposal, while ultralente had highly variable profiles. Within-subject variability (ANOVA) for insulin exposure over 24 h was 15% for glargine and 19% for NPH, compared with 67% for ultralente (p<0.05, glargine and NPH vs ultralente). The 49% within-subject variability in total glucose disposal (glucose infusion rate [GIR]-AUC0-24 h) with ultralente was about twice as large as the 22% with NPH (p<0.05), but was intermediate with glargine at 31% (p=NS). By contrast, variability in the diurnal time-action profile (SD of diurnal day-to-day differences in GIR) for glargine was 30% (p<0.05) and 50% (p<0.05) less than with NPH and ultralente, respectively. No serious adverse events were reported. CONCLUSIONS/INTERPRETATION: Although representing insulins of different profiles, glargine and NPH showed a high and similar reproducibility of total absorption and glucodynamic effect, whereas ultralente proved to have poor reproducibility. However, while NPH yields peaks in concentration and activity, glargine shows flat and non-fluctuating profiles resulting in less variation in day-to-day 24-h activity.

[The management of pharyngeal cancer from the surgical viewpoint]. / Die Behandlung der Pharynxkarzinome aus chirurgischer Sicht.

From experiences in Rostock nasopharyngeal carcinomas are a domain of radiotherapy, whereas surgical measures can be used in lymph node metastases additionally. Carcinomas of the oropharynx need a balanced radiosurgical combination therapy, which has been done by sandwich-procedure in Rostock for 10 years. The value of an additional chemo- or immunotherapy needs further securing yet, as generally a prospective randomized study is suggested for all the country. Carcinomas of hypopharynx are treated in combination by operation of different dimension and after-irradiation.

[The importance of the vertebral venous plexus for the occurrence of haematogenous metastases in malignant diseases of the head and neck (author's transl)]. / Die Bedeutung des vertebralen Venenplexus für die hämatogene Metastasierung von Malignomen im Kopf-Hals-Bereich

The analysis of observation about the progress of 1136 malignant diseases of the epi- and mesopharynx and of the nasal cavity and sinuses from the ENT-Clinic of Jena showed in 16 to 18 per cent of the cases haematogenous metastases observed only in a third to a half in the lung. If the lung had been spared especially the axial skeleton and the liver had metastases. This finding was especially significant in cases of epipharyngeal carcinomas. The discussion about the causes of the frequent occurence of metastases in the axial skeleton led to the supposition, that an independent way of the spreading of haematogenous metastases via the vertebral venous system and the azygos veins could be possible.

[Problems of intracranial extension of malignant disease of the nose and sinuses (author's transl)]. / Probleme des Einbruchs der Malignome der Nase und ihrer Nebenhöhlen ins Schädelinnere

Out of 424 cancers of the nasal cavities or sinuses seen at the University E.N.T. Clinic Jena, 120 had penetrated into the anterior or middle cranial fossa. The commonest of these were tumours of the upper sinuses but a fifth of all antral tumours were also involved. The favourite site of intracranial breakthrough was studied in relation to the origin of the tumour and a particular liability of antral cancers to extend to the middle cranial fossa was noted. Critical analysis of the preoperative diagnostic features showed that the extent of the tumour relative to the base of the skull was often only demonstrated by a wide external surgical exposure. Operative and electrosurgical exenteration after Zange followed by radium application to the infiltrated dura resulted in over 17% of the operated patients surviving 5 years or more without recurrences. Irradiation alone was unsuccessful in all cases. In recent years resection of the tumour has been followed by excision of the infiltrated segment of the dura and the defect covered with fascia lata. First impressions and several examples are given.

[Crohn disease of the oral and pharyngeal cavities]. / Morbus Crohn der Mund- und Rachenhöhle.

Crohn's disease is very rarely found in the oral and pharyngeal cavity. The article reports on a female patient with Crohn's disease in the oral and pharyngeal cavity. The differences in the macroscopic findings due to the disease being localized in the oral and pharyngeal cavity are described. The clinical oral and pharyngeal lesions which suggest the presence of Crohn's disease.

Vertical saccades in brain stem disorders.

Mean peak velocity and accuracy of vertical saccades were measured in 15 patients with disorders in the brain stem and in 12 normal subjects. (1) In the normal group up-directed saccades were faster than down-directed and the velocity of the saccade was not dependent on the age of the subject. Up-saccades were faster whether electro-oculography or photo-electro-oculography were used. (2) In patients with brain stem disorders the velocity of vertical saccades did not significantly differ from the saccadic velocity in the normal group. This is in contrast to what was found in horizontal saccades, where a reduced velocity was characteristic.

Immunocytochemical detection of peptides in the guinea pig cochlea.

The cochleae of juvenile guinea pigs were investigated for the presence of several neuropeptides. Glucagon, insulin, CCK and beta-endorphin immunoreactive neurons and nerve fibers as well as hair cells were demonstrated by the peroxidase antiperoxidase technique. Small amounts of substance P were also found in different sites in the inner ear. In contrast, prolactin-like material could not be found at all. These findings have significance with regard to the putative role of neuropeptides in neuromodulation.