Photodynamic therapy and pain: A systematic review.

Photodynamic therapy (PDT) is an effective treatment for actinic keratoses and early skin cancers, and the only office procedure to control field cancerization. Procedure-associated pain limits widespread PDT use and by early termination of treatment can decrease overall therapeutic efficacy. Here we review and assess reported interventions on PDT-associated pain, in order to identify the most promising methods to manage treatment-associated pain and identify focus for future studies. Literature search was performed using MEDLINE, EMBASE, and the Cochrane Library by two independent reviewers to select publications that assessed and compared pain quantitatively during PDT treatment for actinic keratoses, basal cell carcinomas, and/or in situ squamous cell carcinomas. A total of 48 studies reporting on pain during PDT were identified and were comprised of two main categories of interventions: pain-controlling therapies and PDT parameter (photosensitizer or photo-irradiation) adjustments. Of these interventions: nerve block, subcutaneous infiltration anesthesia, cold analgesia, and transcutaneous electrical nerve stimulation, but not topical anesthetic gels, were associated with less PDT-related pain; 5-aminolevulinic acid (ALA) tended to be more painful than methyl-5-aminolevulinate (MAL); daylight PDT was less painful than conventional PDT; and lower irradiance delivery produced lower pain scores in general. There is no single crystalized protocol for management of PDT-related pain. Evidence suggests that continuous activation of low levels of PpIX with methods using lower irradiance and possibly shorter incubation times are associated with decreased pain without loss of PDT efficacy. Protocols to reduce pain should be standardized and large controlled trials are needed.

Overexpression of SIRT1 in rat skeletal muscle does not alter glucose induced insulin resistance.

SIRT1 is a NAD+-dependent deacetylase thought to regulate cellular metabolic pathways in response to alterations in nutrient flux. In the current study we investigated whether acute changes in SIRT1 expression affect markers of muscle mitochondrial content and also determined whether SIRT1 influenced muscle insulin resistance induced by acute glucose oversupply. In male Wistar rats either SIRT1 or a deacetylase inactive mutant form (H363Y) was electroprated into the tibialis cranialis (TC) muscle. The other leg was electroporated with an empty control vector. One week later, glucose was infused and hyperglycaemia was maintained at ~11mM. After 5 hours, 11mM glucose induced significant insulin resistance in skeletal muscle. Interestingly, overexpression of either SIRT1 or SIRT1 (H363Y) for 1 week did not change markers of mitochondrial content or function. SIRT1 or SIRT1 (H363Y) overexpression had no effect on the reduction in glucose uptake and glycogen synthesis in muscle in response to hyperglycemia. Therefore we conclude that acute increases in SIRT1 protein have little impact on mitochondrial content and that overexpressing SIRT1 does not prevent the development of insulin resistance during hyperglycaemia.

Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle.

Elevated mitochondrial reactive oxygen species have been suggested to play a causative role in some forms of muscle insulin resistance. However, the extent of their involvement in the development of diet-induced insulin resistance remains unclear. To investigate, manganese superoxide dismutase (MnSOD), a key mitochondrial-specific enzyme with antioxidant modality, was overexpressed, and the effect on in vivo muscle insulin resistance induced by a high-fat (HF) diet in rats was evaluated. Male Wistar rats were maintained on chow or HF diet. After 3 wk, in vivo electroporation (IVE) of MnSOD expression and empty vectors was undertaken in right and left tibialis cranialis (TC) muscles, respectively. After one more week, insulin action was evaluated using hyperinsulinemic euglycemic clamp, and tissues were subsequently analyzed for antioxidant enzyme capacity and markers of oxidative stress. MnSOD mRNA was overexpressed 4.5-fold, and protein levels were increased by 70%, with protein detected primarily in the mitochondrial fraction of muscle fibers. This was associated with elevated MnSOD and glutathione peroxidase activity, indicating that the overexpressed MnSOD was functionally active. The HF diet significantly reduced whole body and TC muscle insulin action, whereas overexpression of MnSOD in HF diet animals ameliorated this reduction in TC muscle glucose uptake by 50% (P < 0.05). Decreased protein carbonylation was seen in MnSOD overexpressing TC muscle in HF-treated animals (20% vs. contralateral control leg, P < 0.05), suggesting that this effect was mediated through an altered redox state. Thus interventions causing elevation of mitochondrial antioxidant activity may offer protection against diet-induced insulin resistance in skeletal muscle.

Muir-Torre syndrome: case report and review of the literature.

Muir-Torre syndrome (MTS), a subtype of Lynch syndrome II, presents as at least one internal malignancy associated with at least one sebaceous skin tumor. This autosomal-dominant genetic disorder is thought to arise from microsatellite instability. Although not all patients with sebaceous tumors have MTS, even a single biopsy-proven sebaceous adenoma may warrant evaluation for MTS. We report the case of a 76-year-old man with a marked family history of colon cancer; a personal history of colon cancer status post-partial resection of the colon; and multiple cutaneous neoplasms including sebaceous adenomas, sebaceous gland hyperplasia, and basal and squamous cell carcinomas. We review the literature describing MTS and highlight the important role of dermatologists and dermatopathologists in the potential early detection and initial diagnosis of this familial or hereditary colon cancer in patients presenting with cutaneous sebaceous adenomas. Correct diagnosis may be lifesaving in patients with MTS and their at-risk relatives who would benefit from earlier colonoscopy, tumor surveillance, and potential early cancer detection. Muir-Torre syndrome represents yet another dermatologic symptom of an internal disease.

PPARδ agonists have opposing effects on insulin resistance in high fat-fed rats and mice due to different metabolic responses in muscle.

BACKGROUND AND PURPOSE: The peroxisome proliferator-activated receptor (PPAR)δ has been considered a therapeutic target for diabetes and obesity through enhancement of fatty acid oxidation. The present study aimed to characterize the effects of PPARδ agonists during insulin resistance of the whole body, muscle and liver. EXPERIMENTAL APPROACH: Wistar rats and C57BL/J6 mice were fed a high fat diet (HF) and then treated with PPARδ agonists NNC61-5920 and GW501516. The effects on insulin resistance were evaluated by hyperinsulinaemic clamp or glucose tolerance tests combined with glucose tracers. KEY RESULTS: In HF rats, 3 weeks of treatment with NNC61-5920 reduced the glucose infusion rate (by 14%, P < 0.05) and glucose disposal into muscle (by 20-30%, P < 0.01) during hyperinsulinaemic clamp. Despite increased mRNA expression of carnitine palmitoyltransferase-1, pyruvate dehydrogenase kinase 4 and uncoupling protein 3 in muscle, plasma and muscle triglyceride levels were raised (P < 0.01). Similar metabolic effects were observed after extended treatment with NNC61-5920 and GW501516 to 6 weeks. However, HF mice treated with NNC61-5920 improved their plasma lipid profile, glucose tolerance and insulin action in muscle. In both HF rats and mice, NNC61-5920 treatment attenuated hepatic insulin resistance and decreased expression of stearoyl-CoA desaturase 1, fatty acid translocase protein CD36 and lipoprotein lipase in liver. CONCLUSIONS AND IMPLICATIONS: PPARδ agonists exacerbated insulin resistance in HF rats in contrast to their beneficial effects on metabolic syndrome in HF mice. These opposing metabolic consequences result from their different effects on lipid metabolism and insulin sensitivity in skeletal muscle of these two species.

Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery: a randomized, double-blind, placebo-controlled study.

UNLABELLED: In this randomized, double-blind, placebo-controlled, multicenter study we assessed the analgesic effect of etoricoxib (a new cyclooxygenase-2 inhibitor) in patients having had knee or hip replacement surgery. A total of 228 patients with moderate or severe pain were randomly allocated within 72 h after surgery to receive etoricoxib 120 mg, controlled-release naproxen sodium 1100 mg, or placebo (1:1:1) on day 1 followed by etoricoxib and placebo (1:2) on days 2 to 7. Patients reported pain scores, rescue (opioid-combination) medication use, and the response to study drug. On day 1, etoricoxib provided an analgesic effect superior to placebo and similar to controlled-release naproxen sodium as demonstrated by the total pain relief score over 8 h, the primary end-point; least-squares mean scores were 11.0, 11.5, and 5.6, respectively (P < 0.001 versus placebo). Similarly, a larger percentage of patients receiving etoricoxib and naproxen sodium than those receiving placebo reported good to excellent responses to study drug: 53%, 60%, and 26% respectively. On days 2-7, etoricoxib demonstrated a significant reduction of rescue medication use, 35% (P < 0.001 versus placebo). The clinical relevance of the decrease was confirmed by Patient's Global Evaluation (P < 0.05 versus placebo). Patients receiving etoricoxib also experienced significantly less "worst" and "average" pain than did those on placebo. Etoricoxib was generally well tolerated in this study; the incidence of adverse experiences was infrequent and similar across treatment groups. In summary, etoricoxib provided analgesia that was similar to controlled-release naproxen sodium on day 1 and superior to placebo with reduced supplemental opioid use over 7 days. IMPLICATIONS: In a postsurgery setting (knee and hip replacements), etoricoxib 120 mg provided analgesia superior to placebo and similar to controlled-release naproxen sodium 1100 mg. Patients receiving etoricoxib suffered less pain and took less opioid rescue medication compared with patients on placebo.

The analgesic effect of etoricoxib relative to that of cetaminophen analgesics: a randomized, controlled single-dose study in acute dental impaction pain.

BACKGROUND: To compare the analgesic effect of single doses of etoricoxib 120 mg, oxycodone/ acetaminophen 10 mg/650 mg and codeine/ acetaminophen 60 mg/600 mg in acute pain using the dental impaction model. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, patients reported pain intensity and pain relief (16 times) and global scores (twice) during a 24-h period. The primary endpoint was the overall analgesic effect, total pain relief over 6 h (TOPAR6). Other endpoints were patient global evaluation, time to onset (2-stopwatch method), duration of analgesic effect (median time to and amount of rescue medication use). Tolerability was evaluated by overall and opioid-related (nausea and vomiting) adverse experiences. RESULTS: 302 patients (mean age 23; 63% women; 63 % White) were randomized to etoricoxib 120 mg, oxycodone/acetaminophen 10 mg/650 mg, codeine/acetaminophen 60 mg/600 mg, and placebo (2:2:1:1). Etoricoxib demonstrated significantly greater overall analgesic efficacy (TOPAR6) (13.2 units) versus oxycodone/acetaminophen (10.2 units); and codeine/acetaminophen (6.0 units); p < 0.001 for all. All active treatments were superior to placebo. Median time to onset was significantly (p < 0.001) shorter for oxycodone/acetaminophen (20 min) and numerically but not significantly shorter (p = 0.259) for codeine/acetaminophen (26 min) compared with etoricoxib (40 min). Etoricoxib (24 h) had a significantly longer lasting analgesic effect than oxycodone/acetaminophen (5.3 h), codeine/acetaminophen (2.7 h), and placebo (1.7 h) (p < 0.001 for all). Etoricoxib patients experienced fewer clinical adverse experiences than patients on oxycodone/acetaminophen and codeine/acetaminophen, specifically, significantly (p < 0.05) fewer episodes of nausea. CONCLUSION: Etoricoxib 120 mg provided superior overall analgesic effect with a smaller percentage of patients experiencing nausea versus both oxycodone/acetaminophen 10 mg/650 mg and codeine/acetaminophen 60 mg/600 mg.