[Indications and use of stereolithographic skull reconstructions in oromaxillofacial surgery]. / Indikationen und Anwendung stereolithographischer Schädelrekonstruktionen in der Mund-, Kiefer- und Gesichtschirurgie.

Stereolithography (SLA), a rapid prototyping technique, was introduced in 1991 at the Clinic for Maxillofacial Surgery in Vienna and was adapted, in cooperation with the company Laserform, for our clinical requirements. As a refinement to physical models milled out of polyurethane, which had been used since 1989, this technique offered new applications for preoperative planning in craniomaxillofacial surgery. The proportions of these 3D models correspond 1:1 to the patients dimensions, with a possible accuracy of 0.25 mm. Since 1992 stereolithography has been used in 124 cases, primarily in traumatology, tumor surgery and in craniofacial surgery.

[Technique and applications of stereolithographic cranial models]. / Technik und Anwendungsmöglichkeiten der stereolithographischen Schädelmodellherstellung.

3-D-modelling of the skull is useful referring to improve diagnostics, for surgical planning and simulation of surgical procedure. Stereolithography is a constructive process producing a model by building it up layer by layer with plastic using an "ultraviolet" laser to catalyse the polymerization of a liquid plastic solution. This fast prototyping derives from using a new interface between a CT-Scanner and a SLA. By avoiding the tool path problems inherent in conventional computerdriven CNC milling machines we succeeded in producing closed cavities and even intraosseous course of vessels and nerves. The compact and smooth surface makes manual postprocessing unnecessary. By using a new software (interpolation +/- 0.25 mm) we could improve the accuracy. At our studies we found a maximum aberration of at least 0.25 mm.

Novel diazinone derivatives separate myofilament Ca2+ sensitization and phosphodiesterase III inhibitory effects in guinea pig myocardium.

The inotropic state of the myocardium can be enhanced via an increase in cell Ca2+ loading or in myofilament responsiveness to Ca2+. Although different pharmacological agents combine these properties, no presently available drug acts predominantly as a myofilament sensitizer in situ. We have investigated the effects and the mechanism of action of novel diazinone derivatives, EMD 54622, EMD 53998, and EMD 54650 (developed by E. Merck, Darmstadt), on guinea pig myocardial preparations. Force- and ATPase-pCa relations in skinned fibers show differing potencies of these agents on myofilament sensitization: EMD 54622 greater than EMD 53998 much greater than EMD 54650. This is in contrast to their relative potencies to inhibit isolated myocardial phosphodiesterase III: EMD 54650 greater than EMD 53998 greater than EMD 54622. In isolated hearts studied at constant coronary flow, each of the three diazinone derivatives had a positive inotropic effect. In enzymatically dissociated left ventricular myocytes loaded with the Ca2+ probe indo-1, the positive inotropic effect of EMD 54622 occurred with no change in the amplitude of the cytosolic [Ca2+] (Cai) transient. In contrast, both EMD 53998 and EMD 54650 enhanced Cai transient and twitch contraction amplitudes. Length-indo-1 fluorescence relations were analyzed to determine the effects of the three substances on myofilament responsiveness to Ca2+. EMD 54622 enhanced and EMD 54650 had no effect on myofilament responsiveness to Ca2+. Less uniform results were obtained with EMD 53998 (in two of five cells the myofilament responsiveness to Ca2+ was increased, whereas in three other cells it was unaltered). Our results indicate that structural changes in the diazinone molecule shift the mechanism of action for the positive inotropic effect of the diazinone derivatives in the intact cell from a predominant myofilament sensitization (EMD 54622) to an enhancement in cell Ca2+ loading and an augmentation in the Cai transient (EMD 54650).

The effect of etomoxir on insulin sensitivity in type 2 diabetic patients.

Oral application of 50 mg Etomoxir caused a significant rise (33.1%) of insulin-mediated glucose uptake. This was shown in a placebo-controlled, double-blind randomized study in 8 type 2 diabetic patients by using the euglycemic clamp technique. The mean metabolic clearance rate of glucose (MCR) was raised from 4.1 +/- 0.9 mg/(kg.min) to 5.4 +/- 1.2 mg/(kg.min) (x +/- SEM, P = 0.039). Plasma levels of free fatty acids (FFA), glucose counterregulatory hormones, lipids and C-peptide values during the clamps were not different after verum and placebo. We conclude that Etomoxir improves insulin sensitivity in type 2 diabetic patients.

Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus.

To determine the therapeutic effect of the carinitine palmitoyltransferase I (CPT-I) inhibitor, etomoxir, eight hospitalized obese non-insulin-dependent diabetes mellitus (NIDDM) patients were studied (body mass index [BMI], 28.7 +/- 1.3 kg/m2; age, 54 +/- 8 years [means +/- SE]) at baseline (placebo = t1), and after oral etomoxir (50 mg/d = t2, 100 mg = 3, 150 mg = t4, 200 mg = t5, placebo = t6). Fasting blood glucose (mmol/L), triglycerides (mmol/L), cholesterol (mmol/L), free fatty acids (mumol/L), beta-hydroxybutyrate (mumol/L), and alanine aminotransferase (GPT, U/L) were determined (t1 to t6), as were glucose utilization (M value; indirect calorimetry) and hepatic glucose production during a 10 mU/kg.min euglycemic clamp (t1 and t4). A dose-dependent decrease was induced by etomoxir in fasting blood glucose (t1 to t5: 9.5 +/- 0.7, 8.7 +/- 1.0, 8.3 +/- 1.1 [P v t1 less than .05], 7.8 +/- 0.9, [P v t1 less than .01], 7.9 +/- 1.1 [P v t1 less than .05]), which was reversible in t6 (9.9 +/- 1.1). Mean plasma lipids were reduced (t1 v t5) for triglycerides (-54%, P v t1 less than .01), cholesterol (-24%, P v t1 less than .05), and beta-hydroxybutyrate (-44%, P v t2 less than .01), while free fatty acids increased by 52% (P v t1 less than .05), as did GPT (t1: 17 +/- 3; t5: 32 +/- 7 U/L [P v t1 less than .01]).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of hypoglycaemic action of methylenecyclopropylglycine.

The effects of methylenecyclopropylglycine (MCPG), the lower homologue of hypoglycin A, on starved rats are described. Upon oral ingestion of MCPG (43 mg/kg), a 50% decrease in blood glucose compared with controls was observed after 4 h. The plasma concentrations of lactate and non-esterified fatty acids were substantially increased during this period. The activity of general acyl-CoA dehydrogenase from isolated rat liver mitochondria was not significantly changed. By contrast, the activity of 2-methyl-(branched-chain)-acyl-CoA dehydrogenase decreased by over 80%. The enzyme activity of enoyl-CoA hydratase (crotonase) from pig kidneys decreased by 80% on incubation with the hypothetically toxic metabolite of MCPG, methylenecyclopropylformyl-CoA. These results suggest that the inhibition spectrum of MCPG is quite different from that of hypoglycin A and that similar physiological effects might result from inhibition of different enzymes of beta-oxidation, e.g. hypoglycaemia and lacticacidemia. Accumulation of medium-chain acyl-CoA thioesters is probably at the origin of disturbances in pyruvate metabolism.

Antinociceptive effects of the 5-HT2 antagonist ritanserin in rats: evidence for an activation of descending monoaminergic pathways in the spinal cord.

The antinociceptive properties of the 5-HT2 antagonist ritanserin have been investigated in the writhing test using rats implanted with chronic lumbar catheters. The antinociceptive action of 15 mg/kg ritanserin applied subcutaneously (s.c.) was powerfully inhibited by the intrathecal (i.t.) application of ritanserin (50 nmol), methysergide (15 nmol), yohimbine (20 nmol), alpha-flupenthixol (20 nmol) or naloxone (15 nmol), but not atropine (30 nmol), at doses which themselves produced no change in nociceptive threshold. It is concluded that ritanserin acts supraspinally to activate pain-modulating descending serotonergic, noradrenergic, dopaminergic and possibly opioidergic pathways, while spinopetal cholinergic pathways do not seem to be involved. Hyperalgesic effects of s.c. ritanserin following the i.t. application of methysergide or yohimbine were interpreted in terms of the co-release of an excitatory transmitter, possibly substance P, from descending serotonergic and noradrenergic nerve fibres. The supraspinal mechanism by which ritanserin activates spinopetal pathways and its dependence on 5-HT2 receptors have not yet been established.

The effect of etomoxir on glucose turnover and recycling with [1-14C], [3-3H]-glucose tracer in pigs.

Infusion of etomoxir to 4 fasted pigs caused significant (48%) falls in blood glucose concentrations. To assess whether inhibition of hepatic glucose production or increase of peripheral glucose utilisation is causally associated, a primed infusion of [3-3H]-glucose and [1-14C]-glucose was used, and glucose turnover rates, recycling and metabolic clearance rate of glucose were determined. No effects of infusion of etomoxir on glucose turnover rates could be found. Recycling of glucose carbon was affected to a relatively small extent. The metabolic clearance rate, however, increased by 126% from 5.0 +/- 0.7 ml/kg x min in the control group to 11.3 +/- 3.5 ml/kg x min in the treated group (mean +/- SEM; P less than 0.05). We conclude that under fasting conditions an increase in glucose utilization plays a major part in the blood glucose lowering effect of etomoxir.

Decrease of fatty acid oxidation, ketogenesis and gluconeogenesis in isolated perfused rat liver by phenylalkyl oxirane carboxylate (B 807-27) due to inhibition of CPT I (EC 2.3.1.21).

Sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27 or POCA) inhibits ketogenesis from endogenous and exogenous long-chain fatty acids and 14CO2 production from [U-14 C]palmitate, but not from [U-14 C]palmitoylcarnitine or octanoate, and inhibits gluconeogenesis from lactate and pyruvate in perfused livers of starved rats. Inhibition of ketogenesis, 14CO2 production and gluconeogenesis was complete at concentrations of 10 mumol/l POCA, but onset was more rapid for inhibition of ketogenesis and CO2 production than for gluconeogenesis. Infusion of octanoate abolished inhibition of all three processes. Experiments with isolated rat liver mitochondria showed that carnitine palmitoyltransferase I (EC 2.3.1.21) is inhibited by POCA-CoA. The inhibitory process is dependent on time and concentration, and more pronounced in mitochondria from fed than from fasted rats. Concentrations required for 50% inhibition after 20 min preincubation with POCA-CoA are 0.02, 0.06 and 0.1 mumol/l in liver mitochondria from fed, 24-h-fasted and 48-h-fasted rats, respectively. The inhibitor appears to be tightly bound to the enzyme. The extent of inhibition of carnitine palmitoyltransferase I correlates well with the hypoglycaemic and hypoketonaemic effects of the compounds in fasted rats. We conclude that specific inhibition of the enzyme leads, due to inhibition of long-chain fatty acid utilization, to depressed ketogenesis and gluconeogenesis and, in consequence, to hypoglycaemic and hypoketonaemia in vivo under gluconeogenic and ketogenic conditions.

Synthesis and hypoglycemic activity of benzamidophenyl-alkanoic acid derivates: new inhibitors of gluconeogenesis.

A series of omega-[2-(N-alkylbenzamido)-phenyl]-alkanoic acids was synthesized and tested for its effects on blood glucose concentration in fasted rats and on gluconeogenesis from lactate and pyruvate in isolated perfused rat livers. The compounds led to a dose-dependent and reversible inhibition of gluconeogenesis, with 4-[2-(N-methyl-3-trifluoromethylbenzamido)-phenyl]-butanoic acid leading to a 50% inhibition at 0.02 mM. The compounds lowered blood glucose in fasted rats. No correlation between hypoglycemic effect and inhibition of gluconeogenesis could be detected, however.

Phenylalkyloxirane carboxylic acids, a new class of hypoglycaemic substances: hypoglycaemic and hypoketonaemic effects of sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) in fasted animals.

Phenylalkyloxirane carboxylic acids and esters are a new class of potent hypoglycaemic substances. Sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) produces a dose-dependent hypoglycaemic effect when administered orally or intravenously to several fasted laboratory animals, i.e. rats (with and without adrenalectomy), guinea pigs, dogs, streptozotocin-treated diabetic pigs and db/db-mice. In addition, the substances have a more pronounced lowering effect on ketone bodies in the blood than any other known substance. The minimal dose for lowering blood glucose significantly in rats is 15 mumol/kg. The corresponding dose for a significant lowering of ketone bodies in the blood is less than 2.4 mumol/kg. Hence, the substance B 807-27 is approximately five times more potent than tolbutamide and 30 times more potent than the biguanide buformin with respect to lowering blood glucose levels. B 807-27 differs from the sulphonylureas in that it fails to stimulate insulin secretion. In contrast to the biguanides, the substance decreases rather than increases blood lactate concentration and blocks both fatty acid oxidation and gluconeogenesis. The therapeutic usefulness of these compounds in diabetic man remains to be elucidated.

Synthesis and hypoglycemic activity of phenylalkyloxiranecarboxylic acid derivatives.

A series of new 2-(phenylalkyl)oxirane-2-carboxylic acids has been synthesized and studied for its effects on the concentration of blood glucose. Most of the compounds exhibit remarkable blood glucose lowering activities in fasted rats. Structure-activity studies reveal that substituents like Cl or CF3 on the phenyl ring and a chain length of three to five carbon atoms lead to the most effective substances. Among these compounds, ethyl 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate (36) exhibits the most favorable activity.

Role of polymorphs in inflammatory cartilage destruction in adjuvant arthritis of rats.

The inflammatory destruction of cartilage in rat adjuvant arthritis has been studied by histochemistry and autoradiography. Naphthol-AS-D-chloroacetate esterase has been used as a marker for polymorphs. The evidence presented here shows that polymorphs accumulate at the cartilage-pannus border and in areas of cartilage loss. These cells appear therefore to be of decisive importance for the destruction of cartilage. Proteoglycans were demonstrated by safranin-O staining: there is a loss of PG that is particularly prominent in zones where pannus had invaded cartilage. By means of 35S labelling of proteoglycans it was possible to show that pannus containing polymorphs can invade living cartilage.

[Pathogenesis of inflammatory cartilage destruction in adjuvant arthritis in the rat]. / Untersuchungen zur Pathogenese der entzündlichen Knorpelzerstörung bei der Adjuvansarthritis der Ratte.

By morphological studies on adjuvant arthritis of the rat the following questions were investigated: (1) the participation of polymorphonuclear granulocytes in inflammatory cartilage destruction, and (2) the ability of pannus tissue to invade living cartilage. Polymorphonuclears, identified by a histochemical technique, were observed in the pannus tissue beneath partial destructed cartilage. By means of 35S-autoradiography it was observed that in the neighbourhood of the invading pannus tissue chondrocytes usually retained the capacity to incorporate the radioactive material. From the observations it is concluded that (1) polymorphonuclears are important cells in inflammatory cartilage destruction, even in non-septic arthritis and that (2) pannus tissue may invade a cartilage with viable chondrocytes.

Incorporation of 3H-proline into hyaline articular cartilage. An autoradiographic study in rats with and without adjuvant-induced arthritis.

The incorporation of 3H-proline into the hyaline articular cartilage of rats with and without adjuvant-induced arthritis was investigated 1 h after the intravenous injection of radioactive proline. In the control animals, silver grains were present predominantly over the chondrocytes at all times; on the 28th day the intensity of labeling was notably reduced. In the animals with adjuvant disease reduced radioactivity was observed in the cartilage of the arthritic joints from the 14th experimental day onwards. At all times, however, silver grains occurred over the chondrocytes, including those in the pannus-covered cartilage and in cartilage sequesters. It is concluded from the investigations that the arthritic process accompanying the development of pannus reduces collagen synthesis and that the pannus tissue ingrows vital cartilage.

[The influence of mepiprazol on monoamine metabolism in the rat CNS: demonstration of reduced norepinephrine activity and simultaneously enhanced serotonin and dopamine activities (author's transl)]. / Der Einfluss von Mepiprazol auf den Monoaminstoffwechsel im ZNS der Ratte: Nachweis verminderter Noradrenalin-Aktivität unter gleichzeitig erhöhter Serotonin- und Dopamin-Aktivität

Biochemical studies of monamine turnover and neuronal reuptake indicate that mepiprazole, a novel psychotropic pyrazole derivative, decreases norepinephrine receptor activity and enhances serotonin and to a lower extent also dopamine activity in the rat CNS. It can be concluded that mepiprazole might be of value in the treatment of certain types of depression and might be helpful to alleviate side effects of L-dopa in the treatment of parkinsonism.