Future drugs for migraine

Migraine is a complex, neurovascular disorder in which genetic and environmental factors interact. At present, frontline therapies in the acute treatment of migraine include the use of non-steroidal anti-inflammatory drugs and triptans. Evidence indicates that calcitonin gene-related peptide (CGRP) plays a fundamental role in the mechanism of migraine. CGRP is a strong vasodilatatory neuropeptide that is released from activated trigeminal sensory nerves. The development of CGRP antagonists has also been driven by the fact that triptans are vasoconstrictive and cannot be safely used in patients with cardiovascular risk factors. Olcegepant (BIBN4096) is the first CGRP antagonist for the treatment of migraine that has been tested in clinical trials, but because of its poor oral bioavailability, only the intravenous formulation has been tested. The first oral non-peptide CGRP antagonist, telcagepant, has been shown recently to be highly effective in the treatment of migraine attacks. This development can be considered as the most important pharmacological breakthrough for migraine treatment since the introduction of sumatriptan in the early 1990s. These results are also of importance, since they support an interesting pathophysiological hypothesis of migraine. The pipeline of future compounds for the treatment of acute migraine headaches include TPRV1 antagonists, prostaglandin E receptor 4 (EP₄) receptor antagonists, serotonin 5HT1_F receptor agonists and nitric oxide synthase inhibitors. The immediate future of a preventative treatment for migraine headaches is well represented by botulinum toxin type-A, glutamate NMDA receptor antagonists, gap-junction blocker tonabersat and an angiotensin type 1 blocker candesartan.     

Studies on the haemostatic system in peripheral arterial disease 2. Variations in factor VIII components (FVIII:C ; FVIIIR:Ag ; FVIII:WF) before and after venous occlusion

Factor VIII coagulant activity (FVIII:C), ristocetin co-factor or Willebrand Factor activity (FVIII:WF) and antigen related to FVIII (FVIIIR:Ag) were measured in a group of patients with peripheral arterial disease (PAD) and in a comparable control group. No differences were recorded between patients and controls both in basal conditions and after a standardized venous occlusion (VO) test. VO induced a significant increase in all the FVIII components, comparable in the two groups, with only minor variations in the ratios between them, due to a relatively greater response of the two activities with regard to the protein (FVIIIR:Ag) concentration. FVIII:C was significantly correlated with FVIIIR:Ag and with FVIII:WF only in controls in basal conditions, while no correlation was found in PAD group, nor after VO in either group.

Patients with atherosclerosis obliterans seem therefore to have normal levels of FVIII components and to mantain a normal capacity of responding to VO stimulation. FVIII coagulant activity can be acquired in local blood, or, in alternative, FVIII complex can be released as a whole from vascular walls following venous stasis.     

A controlled multicenter study of adjunctive use of tetracycline periodontal fibers in mandibular class II furcations with persistent bleeding

Abstract. The aim of this randomized single-blind multicenter controlled clinical trial was to clinically evaluate the effectiveness of adjunctive local controlled drug delivery in the control of bleeding on probing in mandibular class II furcations during maintenance care. 127 patients presenting with a class II mandibular furcation with bleeding on probing were included in the study. They had been previously treated for periodontitis and were participating in supportive care programs in periodontal speciality practices. Treatments consisted of scaling and root planing with oral hygiene instructions (control) and scaling and root planing and oral hygiene combined with local controlled drug delivery with tetracycline fibers (test). The following outcomes were evaluated at baseline and 3 and 6 months after therapy at the furcation site: bleeding on controlled force probing (BOP), probing pocket depth (PD) and clinical attachment levels (CAL). Levels of oral hygiene and smoking status were also assessed. Both test and controls resulted in significant improvements of BOP and PD at 3 and 6 months. The test treatment, however, resulted in significantly better improvements: BOP decreased by 52% in the control group and by 70% in the test group at 3 months; at 6 months, however, the difference was no longer significant. The test treatment resulted in a 0.5 mm greater reduction of PD than the control at 3 months, the improvement was highly significant but its duration did not extend until the 6 months evaluation. No differences were observed in terms of changes in CAL. These data indicate that addition of tetracycline fibers to mechanical therapy alone resulted in improved control of periodontal parameters during periodontal maintenance of class II mandibular furcations. Short duration of the effect, however, requires further investigations to optimize conservative treatment of these challenging defects.     

No detrimental effect of fibrin glue on the regeneration of intrabony defects

Abstract. This controlled clinical trial evaluated the potential of fibrin glue as a biological carrier to locally deliver guided tissue regeneration (GTR) modulators. 2 controlateral, morphologically similar defects were selected in each of 11 patients and randomly assigned to the test (teflon membrane and fibrin glue) and the control treatment (teflon membrane alone). Outcomes were assessed at membrane removal as newly formed granulation tissue and at the 1-year follow-up in terms of changes in probing attachment level, probing pocket depth, recession of the gingival margin, probing bone levels and percentage of fill of the intrabony defects. Data confirmed that GTR treatment of deep intrabony defects results in clinically and statistically significant improvements of the clinical parameters. No significant differences, however, were evidenced between the test and the control treatments. It is suggested that, since fibrin glue did not show detrimental effects on GTR, it could be applied as a biological carrier for the delivery of GTR enhancers into the surgical wound.     

Risk of acute cerebrovascular events related to low oestrogen oral contraceptive treatment

To establish if an association exists between use of oral contraceptives (OC) and the occurrence of cerebral arterial thromboembolism, cerebral venous thrombosis and retinal vein/artery thrombosis, we identified all women aged 15-44 years resident in the province of Parma, Italy, who were hospitalized because of a documented cerebral or retinal thromboembolic event during the period 1989-1993. The numbers of users and nonusers of OC were estimated from drug sale data and demographic statistics for the province. There were 21 cases of cerebral arterial thromboembolism during the study period: 10 in OC users and 11 in nonusers, for an estimated incidence rate of 1.70 and 0.35 per 10,000 woman-years OC of use and nonuse, respectively (RR=4.8, 95% CI = 1.8-9.0). Eight cases of cerebral venous thrombosis were observed: 6 in OC users and 2 in nonusers (both in puerperium), for an incidence rate of 1.00 and 0.06 per 10,000 woman-years, respectively (RR=16.7, 95% CI = 3.3-81.4). Finally, 13 cases of retinal vein/artery thrombosis were found: 1 in OC users and 12 in nonusers, for an incidence rate of 0.17 and 0.37 per 10,000 woman-years, respectively (RR=0.46, 95% CI = 0.06-3.7). In our population study the use of low oestrogen OC was associated with an increased risk of cerebral venous thrombosis and ischemic stroke, but not of retinal vein/artery thrombosis.