The Well-being Model: A New Drug Interaction Model for Positive and Negative Effects

Background: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account.

Methods: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs.

Results: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed.     

The influence of noradrenergic blockade on vasospasm and the quantity of cerebral dopamine ß-hydroxylase following subarachnoid haemorrhage in rabbits

BACKGROUND: The aim of this study of experimental subarachnoid haemorrhage (SAH) and exclusion of the sympathetic nervous system (SNS) in rabbits was to find out if changes in the central noradrenergic areas of the hypothalamus and brain stem could be ascertained, in parallel with measurement of the intensity of chronic cerebral vasospasm in the basilar arteries. METHODS: Histologic specimens were prepared by perfusion fixation on day 8 after the SAH. The spastic effect of experimentally induced SAH in New Zealand rabbits was investigated: firstly, using our previously developed method for measuring the corrugation coefficient (CC) of the vessel intima on precisely defined locations of the basilar artery (BA) with the aid of computer image analysis; and secondly, by immunohistochemical assessment of the concentration and localization of dopamine beta-hydroxylase (DBH), using anti-DBH, at precisely defined sites of the hypothalamus and brain stem of the same rabbit. RESULTS: The intima of the BA, assessed by CC, was significantly less corrugated and had significantly less DBH in group A (the control group without SAH and without additional interventions; mean CC = 1.192, P = 0.004; median DBH = 0.50, P = 0.044), in group C (SAH and alpha-blocker phenoxybenzamine; mean CC = 1.142, P = 0.000; median DBH = 0.75, P = 0.001), and in group D (SAH and cervical gangliectomy; mean CC = 1.210, P = 0.003; median DBH = 0.50, P = 0.002) compared with group B (rabbits with SAH and without medication). Group B showed a significantly more intensive accumulation of DBH (median DBH = 1.15) and, according to the CC (mean CC = 1.369), more intensive corrugation of the intima of BA than all other groups. The correlation between CC and DBH for all the rabbits (groups A, B, C and D together) was significantly positive (Spearman Rho = 0.470; p = 0.010). CONCLUSIONS: The results of this study demonstrated: firstly, an intensive excitatory influence of SAH on the quantity of DBH in central noradrenergic areas in the hypothalamus and brain stem; secondly, a very effective influence of peripheral and systemic sympathetic exclusion on lowering the quantity of central sympathetic DBH; thirdly, that the changes in the BA of individual rabbits occur simultaneously with corresponding changes in DBH-containing neurons, thus suggesting the likelihood of SNS involvement in the pathogenesis of post-SAH vasospasm in rabbits.     

Anti-MAG and anti-SGPG antibodies in neuropathy

We compared the binding of human antibodies from patients with neuropathy to the myelin-associated glycoprotein (MAG), to its cross-reactive glycolipid sulfoglucuronyl paragloboside (SGPG), and to sections of peripheral nerve. Titers were correlated with the clinical presentation and results of electrophysiological and pathological studies. Most patients had a predominantly sensory or sensorimotor demyelinating neuropathy and highly elevated antibodies to both MAG and SGPG, but 2 had highly elevated antibodies to MAG alone, and 1 to SGPG alone. Two patients had predominantly motor neuropathy and highly elevated antibodies to SGPG which reacted with MAG by Western blot but not by enzyme-linked immunosorbent assay. One patient had amyotrophic lateral sclerosis and antibodies to SGPG but not to MAG. These studies indicate that the neuropathic syndrome associated with anti-MAG or -SGPG antibodies are more heterogeneous than previously suspected, and that although most of the antibodies react with both MAG and SGPG, some may react with MAG or SGPG alone. © 1996 John Wiley & Sons, Inc.     

Novel Mutations Including Deletions of the Entire OFD1 Gene in 30 Families with Type 1 Orofaciodigital Syndrome: A Study of the Extensive Clinical Variability

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X‐linked condition with lethality in males. Mutations in OFD1 also cause X‐linked Joubert syndrome (JBTS10) and Simpson–Golabi–Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X‐inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.     

Tomaculous neuropathy in chromosome 1 Charcot-Marie-Tooth syndrome

We performed morphological and immunohistochemical studies on sural nerve biopsies from two members of a Charcot-Marie-Tooth type 1B family, in which a mutation of the P₀ gene on chromosome 1 had been found. Biopsies showed a tomaculous neuropathy with loss of myelinated fibers and frequent small onion bulbs. Immunofluorescence with antibodies to P₀ showed this protein to be present in tomaculous and non-tomaculous areas of the nyelin sheath. The severity of the myelin abnormalities suggests that in this family Charcot-marie-Tooth disease may result from a generalized disturbance of Schwann cells as a result of an abnormal P₀ protein.Supported by the Aaron Diamond Foundation and center grants from the MDA and from NINCDS to R.V. Lebo (NS25541) and N. Latov (NS11761). F.P. Thomas is a fellow of the Medical Research Council of Canada     

Antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold in two rat venous thrombosis models

The antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold (LK-732, LK-639 and LK-731) and their amidoxime prodrugs (LK-658, LK-633 and LK-730) was studied in comparison to argatroban and nadroparin in two rat models of venous thrombosis, induced either by complete stasis combined with hypercoagulability (model 1) or by partial stasis combined with vessel injury (model 2). In initial experiments LK-732 was established as the most promising antithrombotic of the LK inhibitors and as such was further tested. In model 1, intravenous bolus administration of LK-732 produced a dose-dependent inhibition of thrombus formation with an ID50 value of 1.3 mg/kg. This ID50 value was approximately four times higher than the ID50 value of argatroban (0.3 mg/kg; p=0.011). However, in model 2, LK-732 and argatroban decreased thrombus weight by 50% at similar ID50 values (3.8 mg/kg vs 3.0 mg/kg, respectively; p=0.726). The ex vivo anticoagulant effect of LK-732 was substantially weaker compared to argatroban at doses that produced comparable antithrombotic effects. After subcutaneous administration, in vivo thrombus weight reduction of LK inhibitors (10 mg/kg) ranged between 22 to 48%. However, their oral antithrombotic effect at a dose of 30 mg/kg was rather low. LK amidoxime prodrugs failed to produce a substantial antithrombotic effect after subcutaneous (10 mg/kg) as well as after oral administration (30 mg/kg). In conclusion, thrombin inhibitors built on the azaphenylalanine scaffold represent a new group of intravenously effective antithrombotics. However, optimisation of the oral antithrombotic effect of amidoxime prodrug LK-658 of the lead inhibitor LK-732 is required for justifying further development of these inhibitors.     

Hypoxic and pharmacological preconditioning preserves vasomotor response of porcine coronary artery

Vasomotor response of the coronary artery depends on both endothelial and smooth muscle cells. Response is altered by hypoxia-reoxygenation-induced damages. Hypoxic preconditioning and pharmacological preconditioning as well can prevent these alterations. We compared the effectiveness of both types of preconditioning against hypoxia-reoxygenation-induced changes in vasomotor response of the isolated artery. Porcine arterial rings (3-4 mm wide) were cut from the left anterior descending porcine coronary artery and placed in Krebs-Henseleit solution. In order to obtain control response of the arteries, we contracted arterial rings with 20 mM KCl before ("standard contraction") and after 60-min hypoxia and 30-min reoxygenation. In other groups, nitric oxide-synthase and cyclooxygenase were inhibited. Then, the rings were pre-contracted with U46619 and relaxed by cumulative addition of the substance P. Contractions and relaxations of non-preconditioned and hypoxically or pharmacologically preconditioned rings were compared. Hypoxic preconditioning was performed by two periods of 5-min hypoxia and 10-min reoxygenation. For pharmacological preconditioning, we used application of adenosine, adrenaline, acetylcholine and angiotensin II. Analysis was performed with one-way ANOVA, followed by Dunnett's Multiple Comparison Test. After hypoxia-reoxygenation, in non-preconditioned rings KCl-induced contractions were significantly increased compared to standard contraction. Relaxations of hypoxically and pharmacologically preconditioned rings (expressed as percentages of U46619-induced pre-contraction) were significantly decreased (p < 0.01) compared to hypoxic but not to normoxic rings. Hypoxic and pharmacological preconditioning may preserve contraction and endothelium-dependent relaxation of porcine coronary artery after long-lasting hypoxia-reoxygenation.     

Lethal injuries among the members of the 4th Guardian Brigade of Croatian Army during the 1991-1995 war

OBJECTIVE: We analyzed the causes of deaths among the members of the 4th Guardian Brigade (GB) of the Croatian Army during the war in Croatia from 1991 to 1995: the site of the lethal injuries, the type of wounds, and estimated the severity of injuries with lethal outcome according to the Abbreviated Injury Scale. METHODS: This was a retrospective study using the files and data obtained from 4th GB, Croatian Ministry of Defense, and Croatian Ministry of War Veterans. RESULTS: During the War in Croatia from 1991 to 1995, 182 members of 4th GB were killed. One hundred fifteen (63.2%) suffered lethal injuries caused by shell fragments, 47 (25.8%) soldiers had gunshot wounds, and 20 ( 11.0%) died in traffic accidents. Mean Abbreviated Injury Scale for killed soldiers was 7.61 +/- 1.27. CONCLUSION: During the war in Croatia, the leading causes of death were mines and explosions, and, in a minor proportion, gunshot wounds.