Inhibitors of catechol-O-methyltransferase sensitize mice to pain

BACKGROUND AND PURPOSE

Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson''s disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy. Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice.

EXPERIMENTAL APPROACH

We used single and repeated administration of a peripherally restricted, short-acting (nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor. We also tested CGP 28014, an indirect inhibitor of COMT enzyme. Effects of OR-486 on thermal nociception were also studied in COMT deficient mice. Effects on spinal pathways were assessed in rats given intrathecal nitecapone.

KEY RESULTS

After single administration, both nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration. These effects were still present after chronic treatment with COMT inhibitors for 5 days. Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation. CGP 28014 shortened paw flick latencies. OR-486 did not modify hot plate times in Comt gene deficient mice. Intrathecal nitecapone modified neither thermal nor mechanical nociception.

CONCLUSIONS AND IMPLICATIONS

Pro-nociceptive effects of COMT inhibitors were confirmed. The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord. COMT protein was required for these actions.     

Dengue vaccine: The current status

Dengue fever is a re-emerging public health problem with two-fifths of the world population being at risk of infection. Since there are no antiviral drugs available against the dengue virus, and vector control programmes have been largely unsuccessful in preventing outbreaks, vaccination seems to be the most viable option for preventing infection. An ideal dengue vaccine should provide long lasting immunity against all four serotypes of the virus. The envelope protein of the virus plays a key role in vaccine development. The present day candidate vaccines includes a live attenuated tetravalent vaccine, intertypic chimaeric vaccines based on live attenuated dengue virus vectors, chimaeric vaccines based on the live attenuated Yellow Fever 17D vector and recombinant vaccines which include vaccines based on flavivirus and non-flavivirus vectors. Tetravalent live attenuated vaccines, intertypic chimaeric vaccines and chimaeric vaccines are being tested in human trials. Recombinant DNA vaccines based on flavivirus and non-flavivirus vectors are being tested in animal trials. Recent studies have shown that the tetravalent formulations may elicit an unbalanced immune response. Research is continuing to find means of obtaining a balanced response to all antigens in the tetravalent formulations.     

A 52‐week extension study of switching from gemigliptin vs sitagliptin to gemigliptin only as add‐on therapy for patients with type 2 diabetes who are inadequately controlled with metformin alone

We investigated the long‐term efficacy and safety of gemigliptin and the efficacy and safety of gemigliptin treatment after once‐daily treatment with sitagliptin 100 mg, in patients with type 2 diabetes. This was a 28‐week extension of a 24‐week, randomized, double‐blind, parallel study of gemigliptin or sitagliptin added to ongoing metformin therapy. After randomization to sitagliptin 100 mg qd (S), gemigliptin 25 mg bid (G1) or gemigliptin 50 mg qd (G2) and after completing 24 weeks of treatment, 118 patients switched from gemigliptin 25 mg bid to 50 mg qd (G1/G2), 111 patients continued gemigliptin 50 mg qd (G2/G2) and 106 patients switched from sitagliptin 100 mg qd to gemigliptin 50 mg qd (S/G2). All 3 treatments reduced glycated haemoglobin (HbA1c) (S/G2,?0.99% [95% CI ?1.25%, ?0.73%]; G1/G2, ?1.11% [95% CI ?1.33%, ?0.89%]; G2/G2, ?1.06% [95% CI ?1.28%, ?0.85%]). The percentage of patients achieving HbA1c < 6.5% was 27.6% in the G1/G2 group at both Week 24 and Week 52, and ranged from 27.3% to 32.7% in the G2/G2 group (difference in proportions, 5% [95% CI ?6%, 17%]), while it increased from 6.8% to 27.3% from Week 24 to Week 52 in the S/G2 group (difference in proportions, 20% [95% CI 7%, 34%]). Addition of gemigliptin 50 mg qd to metformin was shown to be efficacious for 52 weeks. Switching from sitagliptin 100 mg to gemigliptin 50 mg showed consistent glyacemic control over the previous treatment.     

Correlation of Intra Vascular Cannula Insertion Technique and Ward Practices with Local Site Infection

Background

Peripheral intravascular cannulas are indispensable in modern day medical care. These cannulas, if not inserted properly, predispose a patient to various morbidities. The present study was carried out to assess the incidence of intravascular cannula associated infections and correlate it with cannula insertion techniques and ward practices.

Methods

The study was carried out in the wards of a tertiary care hospital. The study was divided into two phases, each phase comprising of 50 patients. In phase 1, cannula insertion was carried out after normal ward cleaning practices. In phase 2, cleaning of the site was done by standard surgical cleaning procedure. The cannula samples after removal were cultured and local signs of thrombophlebitis looked for at the site of insertion. Thrombophlebitis was considered a surrogate marker of local infection in the vessel wall.

Result

The relative risk of acquiring thrombophlebitis increased by 2.18 times (applying univariate analysis) by existing methods as compared to the standard method.

Conclusion

Use of standard cleaning protocol had a significant effect on decreasing the incidence of cannula associated infections and cannula related morbidity.Key Words: Intravascular cannula, Peripheral vein thrombophlebitis, Cannula associated infections     

Toxicity of Low-Dose Intermittent Isotretinoin in Recalcitrant Acne

Background

Isotretinoin, an oral retinoid, has been utilized to achieve long term remissions in cases of recalcitrant acne. In the conventional dosage schedule, the use of oral isotretinoin has been limited by the occurrence of biochemical abnormalities such as hypertriglyceridaemia and impaired liver function tests and radiological changes consistent with diffuse idiopathic skeletal hyperostosis. Low-dose intermittent regimen of oral isotretinoin has been evolved as a cost effective alternative to the conventional dosage regimen in cases of acne. This study addresses the issue of adverse effects of low-dose intermittent isotretinoin and the safety of this regimen.

Methods

A total of 60 cases of recalcitrant acne were included in the study. Baseline haematological, biochemical and radiological investigations were carried out. Low-dose intermittent isotretinoin was instituted in a dose of 0.5 mg/kg/day for one week in every four weeks for six months. The investigations were repeated at the end of six months therapy.

Result

High triglyceride levels occurred in 5% of cases whereas impaired liver function tests and skeletal hyperostosis of the spine were not observed in any case after low-dose intermittent isotretinoin.

Conclusion

The low-dose intermittent regimen in cases of acne may be utilized to limit the systemic toxicity of oral isotretinoin.Key Words: Recalcitrant acne, Isotretinoin, Low-dose intermittent regimen     

Twenty year review of histopathological findings in enucleated/eviscerated eyes

BACKGROUND/AIMS: To evaluate the need for routine histopathological analysis of enucleated/eviscerated eyes and changes in indications for eye removal. METHODS: Retrospective review of all enucleation/evisceration histopathology reports over 20 years. Clinical history was correlated with pathological findings. Two 10 year periods (1984-93, 1994-2003) were compared to detect changes in indications for eye removal. RESULTS: In total, 285 histopathology results were traced from 1984 to 2003; 161 and 124 were evisceration and enucleation specimens, respectively. Glaucoma, malignant melanoma, trauma, and retinal detachment were the most frequent diagnoses 1984-1993. Ocular trauma was the most frequent diagnosis 1994-2003, followed by phthisis bulbi and endophthalmitis. Three cases were diagnosed as metastatic carcinoma; all were suspected preoperatively. A fourth case was a diagnostic surprise: adenocarcinoma found in an eye removed for pain and phthisis. Comparison of two 10 year periods showed a decrease in the number of enucleations/eviscerations, perhaps reflecting a decrease in the number of specimens sent. A preference for eviscerations was evident over the 20 years. CONCLUSION: The number of eyes removed and histologically analysed decreased in the period 1994 to 2003, perhaps because of better treatment options, allowing globe preservation. There was a significant shift in the diagnosis in the two time periods, and a preference for evisceration in both. Only one diagnostic surprise was discovered (0.35%). This study does not support the need to send all globes/contents for histopathological examination. However, because of the one unexpected finding, it is recommended where the examination is incomplete or the history of visual loss is unclear.