Does perfusion matter? Preoperative prediction of incisional hernia development.

PURPOSE: Incisional hernias complicate 12-15% of general surgery cases with higher rates reported after laparotomy for aortoiliac occlusive disease (10-17%) and aneurysmal disease (17-38%). We hypothesize that inadequate perfusion of the abdominal wall promotes future hernia development. METHODS: Thirty-eight patients undergoing midline laparotomy or thoracoabdominal approach for aortic disease with at least 2 years of follow-up were included in the study. Preoperative imaging was reviewed to assess vessel patency, contributing to the abdominal wall perfusion. Patency of the superior epigastric artery was determined at the T10 level, the inferior epigastric artery at the L4 level, and the deep circumflex iliac artery at the anterior superior iliac spine. Lumbar arteries were considered patent if they were seen branching from the aorta. Clinic notes and hospital medical records were reviewed to evaluate the hernia development post-procedure. RESULTS: Thirteen patients (34%) developed an incisional hernia. Absent flow from bilateral superior epigastric arteries or absent flow from ipsilateral superior and inferior epigastric arteries was found to be predictive of hernia development (P = 0.013, 0.011, respectively). There was no association identified with perfusion from the lumbar or deep circumflex iliac arteries. CONCLUSIONS: Absent patency of the abdominal wall vasculature is a novel risk factor for incisional hernia development in the setting of aortic disease. Preoperative assessment of perfusion may convey the risk of hernia development and may be a tool to guide measures such as prophylactic mesh placement to reduce the future risk of incisional hernia.

Randomized trial of nutrition education added to internet-based information and exercise at the work place for weight loss in a racially diverse population of overweight women.

OBJECTIVE: Obesity in the United States is highly prevalent, approaching 60% for black women. We investigated whether nutrition education sessions at the work place added to internet-based wellness information and exercise resources would facilitate weight and fat mass loss in a racially diverse population of overweight female employees. METHODS: A total of 199 (average body mass index 33.9±6.3 kg m(-2)) nondiabetic women (57% black) at our institution were randomized to a 6-month program of either internet-based wellness information (WI) combined with dietitian-led nutrition education group sessions (GS) weekly for 3 months and then monthly with shift in emphasis to weight loss maintenance (n=99) or to WI alone (n=100). All were given access to exercise rooms convenient to their work site. Fat mass was measured by dual-energy X-ray absorptiometry. RESULTS: WI+GS subjects lost more weight than WI subjects at 3 months (-2.2±2.8 vs -1.0±3.0 kg, P>0.001). Weight (-2.7±3.9 vs -2.0±3.9 kg) and fat mass (-2.2±3.1 vs -1.7±3.7 kg) loss at 6 months was significant for WI+GS and WI groups (both P<0.001), but without significant difference between groups (both P>0.10); 27% of the WI+GS group achieved 5% loss of initial weight as did 18% of the WI group (P=0.180). Blacks and whites similarly completed the study (67 vs 74%, P=0.303), lost weight (-1.8±3.4 vs -3.3±5.2 kg, P=0.255) and fat mass (-1.6±2.7 vs -2.5±4.3 kg, P=0.532), and achieved 5% loss of initial weight (21 vs 32%, P=0.189), irrespective of group assignment. CONCLUSION: Overweight women provided with internet-based wellness information and exercise resources at the work site lost weight and fat mass, with similar achievement by black and white women. Additional weight loss benefit of nutrition education sessions, apparent at 3 months, was lost by 6 months and may require special emphasis on subjects who fail to achieve weight loss goals to show continued value.

Pain measurement: Visual Analogue Scale (VAS) and Verbal Rating Scale (VRS) in clinical trials with OTC analgesics in headache.

AIM: The aim was to assess the performance of the Visual Analogue Scale (VAS) in patients recruited in a clinical trial with over the counter analgesics in headache. METHODS: The Thomapyrin Study showed the significant superiority of the fixed combination of acetylsalicylic acid + paracetamol + caffeine over the combination without caffeine, the single preparations, and placebo in the treatment of headache. Patients enrolled into the study were trained in the handling of the VAS by naming categories of a 6-point Verbal Rating Scale (VRS). These data were used to evaluate the level of order consistency between the VAS and VRS, to deduce cut-off points for rescaling the continuous VAS into a discrete ordinal scale using the receiver operating characteristic methodology, and to assess the test-retest performance. RESULTS: Approximately 75% of the patients recorded the pain intensity on the VAS in the same order as given on the VRS. However, in 12.6% of patients, the German terms 'leicht' (mild) and 'mäßig' (moderate) were mixed up regarding their order on the VAS. Substantial overlapping of the frequency distributions of the VAS assessment were found for the VRS categories mild and moderate pain as well as severe and very severe pain. Grouping of the VAS assessments into a discrete ordinal scale necessitated a non-equidistant rescaling based on the categories of the VRS. By means of analysis of the receiver operating characteristic curves, the following cut-off points were determined on a 100 mm VAS: no pain 0-2 mm, mild pain 2-17 mm, moderate pain 17-47 mm, severe pain 47-77 mm, very severe pain 77-96 mm, most severe pain imaginable 96-100 mm. Repeated assessment up to several months after the first assessment demonstrated a test-retest agreement on the VAS in 61.0-91.4% of the patients, depending on the VRS category. CONCLUSIONS: This study shows that the VRS categories cannot be presented in an equidistant manner on the VAS, and that contrary to previous assumptions, the pain intensity descriptors are less clear and can have different meanings in different languages. Therefore, both in the 3rd edition of the International Headache Classification (ICHD-III) and in the guidelines for clinical trials of patients with headache illnesses, rather than a 4-grade VRS, a 6-grade or higher level VRS or a VAS should be recommended, with correspondingly broadly defined anchor points.

The efficacy and tolerability of a fixed combination of acetylsalicylic acid, paracetamol, and caffeine in patients with severe headache: a post-hoc subgroup analysis from a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study.

BACKGROUND: We investigated efficacy and tolerability of two tablets of the fixed combination of 250 mg acetylsalicylic acid (ASA) + 200 mg paracetamol + 50 mg caffeine (Thomapyrin) in comparison to two tablets of placebo in a post-hoc analysis of a subgroup of patients with severe headache. METHODS: Patients where included if they were used to treating their episodic tension-type headache or migraine attacks with non-prescription analgesics and reported a history of headache attacks characterized by at least severe pain and greatly impaired usual daily activities and treated headaches with pain intensity of at least 48 mm assessed on a 100-mm visual analogue scale and associated with greatly impaired usual daily activities. RESULTS: For the primary endpoint 'time to 50% pain relief' in this intention-to-treat subset (n = 179 patients), the fixed combination of ASA, paracetamol, and caffeine was statistically significantly superior to placebo (p = 0.0008). The superior efficacy of the triple combination could also be shown for all secondary endpoints such as time until reduction of pain intensity to 10 mm, weighted sum of pain intensity difference (%SPIDweighted), extent of impairment of daily activities, and global assessment of efficacy. Both treatments were well tolerated. The incidence of adverse events observed was low. The results for this subgroup analysis are consistent with respect to all endpoints and to the patients with non-severe headache and the overall patient population. As with all post-hoc subgroup analyses, the findings are hypothesis generating only and must be interpreted with caution. DISCUSSION: The results of this subgroup analysis confirm that the fixed combination of ASA (250 mg), paracetamol (200 mg), and caffeine (50 mg) is effective and well tolerated in a broad spectrum from mild to severe migraine and tension-type headache severity independently of the headache diagnosis.

Headache classification by history has only limited predictive value for headache episodes treated in controlled trials with OTC analgesics.

We investigated the consistency between the headache diagnosis based on medical history and three treated headache episodes diagnosed based on a diary. In a randomized double-blind study including individuals with either migraine or tension-type headache (TTH) we showed significant superiority of the fixed combination of acetylsalicylic acid + paracetamol + caffeine over the combination without caffeine, the single preparations, and placebo in the treatment of headache. A neurologist performed a classification of the usual headache episodes and each of the three treated ones in a blinded fashion based on a structured questionnaire. This was done for the 1734 patients included in the efficacy analysis who usually treated their episodic TTH or migraine attacks with non-prescription analgesics. The overall percentage of patients with migraine and TTH remained relatively stable. The treated headache episodes were between 75 and 77% migraine, 18-20% were TTH and 5-7% could not be classified. We observed some shift in headache type within patients from prior history and in treated attacks. In 60% of patients all three treated episodes were of the type initially diagnosed by the neurologist by history (56% migraine and 4% episodic TTH). Of those with an initial diagnosis of migraine, 24% had at least one attack meeting criteria for TTH. Of patients with an initial diagnosis of TTH, 54% had at least one attack meeting the diagnostic criteria for migraine. Our results demonstrate that an initial headache diagnosis does not accurately predict the headache type treated in a randomized trial. Symptom features of treated headaches should be captured to ensure that the attack is of the type targeted by the clinical trial. The International Headache Society Guidelines for controlled clinical trials should be updated accordingly.

Per-capita consumption of analgesics: a nine-country survey over 20 years.

There are no reliable data at present on use of analgesics in various countries. We compared per-capita consumption in nine different countries during the period 1986-2005. The per-capita consumption was calculated on the basis of the sales figures of distributors to pharmacies and direct purchases by pharmaceutical companies in a sample of 1,000 pharmacies. The countries studied were: Australia, Austria, Belgium, Canada, France, Germany, Sweden, Switzerland, and the USA. In international comparison Austria, Switzerland, and Germany showed the lowest per-capita consumption of analgesics (approx. 40-50 Standard Units (SU) per capita per year), while in Sweden and France consumption was three times as high. The correlation analysis over the various countries and time points confirmed a significant correlation between use of single analgesics and overall use of analgesics. In Germany, where an allegedly particularly high and constantly rising analgesic use has been discussed controversially (Meiner, Pharm Ind 49:1247-1251, 1987), per-capita consumption of analgesics from 1980 to 2005 remained practically unchanged at approx. 50 SU per capita per year. The prevalence of conditions inducing analgesic use shows appropriate analgesics use on an overall population level.

The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study.

We investigated efficacy, safety, and tolerability of two tablets of the fixed combination of 250 mg acetylsalicylic acid (ASA) + 200 mg paracetamol + 50 mg caffeine (Thomapyrin) in comparison with two tablets of 250 mg ASA + 200 mg paracetamol, two tablets of 500 mg ASA, two tablets of 500 mg paracetamol, two tablets of 50 mg caffeine, and placebo in patients who were used to treating their episodic tension-type headache or migraine attacks with non-prescription analgesics. For the primary endpoint "time to 50% pain relief" in the intention-to-treat dataset (n = 1743 patients), the fixed combination of ASA, paracetamol and caffeine was statistically significantly superior to the combination without caffeine (P = 0.0181), the mono-substances ASA (P = 0.0398), paracetamol (P = 0.0016), caffeine (P < 0.0001) and placebo (P < 0.0001). All active treatments except caffeine differed significantly (P < 0.0001) from placebo. The superior efficacy of the triple combination could also be shown for all secondary endpoints such as time until reduction of pain intensity to 10 mm, weighted sum of pain intensity difference (%SPIDweighted), extent of impairment of daily activities, global assessment of efficacy. All treatments were well tolerated. The incidence of adverse events observed was low.

The synthesis of Rantes, G-CSF, IL-4, IL-5, IL-6, IL-12 and IL-13 in human whole-blood cultures is modulated by an extract from Eleutherococcus senticosus L. roots.

An ethanol extract derived from the roots of Eleutherococcus senticosus was found to influence markedly the cytokine synthesis of activated whole blood cultures of ten healthy volunteers. Whereas the synthesis of Rantes was increased over a wide range of concentrations, the release of IL-4, IL-5 and IL-12 was significantly inhibited. An inhibition at higher concentrations, switching to a stimulation at lower doses of the extract was seen with G-CSF, IL-6 and IL-13. From these particular immuno-pharmacological effects of Eleutherococcus senticosus we suggest this herbal preparation possesses immuno-modulatory potency, rather than just being immuno-suppressive or -stimulating.

Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells.

Paracetamol has mild analgesic and antipyretic properties and is, along with acetylsalicylic acid, one of the most popular "over the counter" analgesic agents. However, the mechanism underlying its clinical effects is unknown. Another drug whose mechanism of action is unknown is caffeine, which is often used in combination with other analgesics, augmenting their effect. We investigated the inhibitory effect of paracetamol and caffeine on lipopolysaccharide (LPS)-induced cyclooxygenase (COX)- and prostaglandin (PG)E(2)-synthesis in primary rat microglial cells and compared it with the effect of acetylsalicylic acid, salicylic acid, and dipyrone. Furthermore, combinations of these drugs were used to investigate a possible synergistic inhibitory effect on PGE(2)-synthesis. Both paracetamol (IC(50)=7.45 microM) and caffeine (IC(50)=42.5 microM) dose-dependently inhibited microglial PGE(2) synthesis. In combination with acetylsalicylic acid (IC(50)=3.12 microM), both substances augmented the inhibitory effect of acetylsalicylic acid on LPS-induced PGE(2)-synthesis. Whereas paracetamol inhibited only COX enzyme activity, caffeine also inhibited COX-2 protein synthesis. These results are compatible with the view that the clinical activity of paracetamol and caffeine is due to inhibition of COX. Furthermore, these results may help explain the clinical experience of an adjuvant analgesic effect of caffeine and paracetamol when combined with acetylsalicylic acid.

The effect of the base on the kinetics of action of the capsaicinoid nonivamide: evaluation with a hyperemic test.

Because of their selective receptor-mediated action on cutaneous nociceptive C-fibers, the interest in capsaicinoids as topical analgetic drugs has been constantly growing over the past years. Knowledge of the pharmacokinetics seems particularly important for potential future clinical applications. Therefore, the aim of the present study was to investigate the influence of the type of preparation on the time course of action of the capsaicinoid nonivamide monitored by the axon-reflex-induced hyperemic action and area of erythema. Sixteen healthy subjects were included in the study. The hyperemic responses after application of nonivamide in an oil-in-water (O/W) emulsion and in a water-free ointment were assessed both by laser Doppler perfusion imaging and planimetry after 0, 15, 30, 45, 60, 120 and 240 min. They were compared with the reaction after application of the nicotinic ester nicoboxil and a combination of nonivamide and nicoboxil in the same preparations. Applied as a water-free ointment, nonivamide showed a slow onset of hyperemic action, reaching its maximum 45 min after application. When applied as an O/W emulsion, however, the increase in effect was high, reaching its maximum already after 30 min. Application of the nicoboxil preparations revealed a clearly lesser influence of the base regarding the onset of maximum effect. The combination of both substances showed an additive effect for both bases, and a maximum effect was found already after 15 min with both the water-free ointment and the O/W emulsion base. In conclusion, the results of the present study show that there appears to be a strong influence of the vehicle on the kinetics of action of capsaicinoids, and that the hyperemic test used in this paper is very useful for the quantitative determination of the pharmacokinetic properties of capsaicinoids. Moreover, the C-fiber-stimulating effect of capsaicinoids can, at least in part, be enhanced by combination with a nicotinic ester, even though these substances have no direct effect on the C-fibers.

Cellular redistribution of protein tyrosine phosphatases LAR and PTPsigma by inducible proteolytic processing.

Most receptor-like protein tyrosine phosphatases (PTPases) display a high degree of homology with cell adhesion molecules in their extracellular domains. We studied the functional significance of processing for the receptor-like PTPases LAR and PTPsigma. PTPsigma biosynthesis and intracellular processing resembled that of the related PTPase LAR and was expressed on the cell surface as a two-subunit complex. Both LAR and PTPsigma underwent further proteolytical processing upon treatment of cells with either calcium ionophore A23187 or phorbol ester TPA. Induction of LAR processing by TPA in 293 cells did require overexpression of PKCalpha. Induced proteolysis resulted in shedding of the extracellular domains of both PTPases. This was in agreement with the identification of a specific PTPsigma cleavage site between amino acids Pro821 and Ile822. Confocal microscopy studies identified adherens junctions and desmosomes as the preferential subcellular localization for both PTPases matching that of plakoglobin. Consistent with this observation, we found direct association of plakoglobin and beta-catenin with the intracellular domain of LAR in vitro. Taken together, these data suggested an involvement of LAR and PTPsigma in the regulation of cell contacts in concert with cell adhesion molecules of the cadherin/catenin family. After processing and shedding of the extracellular domain, the catalytically active intracellular portions of both PTPases were internalized and redistributed away from the sites of cell-cell contact, suggesting a mechanism that regulates the activity and target specificity of these PTPases. Calcium withdrawal, which led to cell contact disruption, also resulted in internalization but was not associated with prior proteolytic cleavage and shedding of the extracellular domain. We conclude that the subcellular localization of LAR and PTPsigma is regulated by at least two independent mechanisms, one of which requires the presence of their extracellular domains and one of which involves the presence of intact cell-cell contacts.

[Effectiveness of fixed analgesic combinations exemplified by thomapyrin]. / Zweckmässigkeit fixer Analgetikakombinationen am Beispiel von Thomapyrin.

Thomapyrin has been on the German market as analgesic for the past 50 years. It is the prescription-free preparation with the highest sales there. This is an occasion to survey current state of scientific knowledge concerning combination analgesics with acetyl salicylic acid, paracetamol and caffeine. For the assessment and registration of fixed preparations authorities of different European countries and also USA have defined special criteria. Analgesic preparations must agree with these defined criteria. The importance of these combination analgesics in pain therapy is described with the respect to the latest scientific results. Combination analgesics represent an important area of self-medication by the patient. The properties of the active substances alone and in combination are set forth, with respect to pharmacokinetics and efficacy. The experimental and especially clinical results clearly show a broader spectrum of action in consequence of the different modes of action of the individual active substances. Analgesic action is 1.4 fold higher owing to added caffeine. The fixed combination of active substances does not change the profile of side effects. The conclusion is that combination analgesics such as Thomapyrine show a positive benefit/risk ratio. Furthermore such combination analgesics are appropriate for self-medications and suited to combat pain of different kinds.

Quantification of cutaneous pharmacological reactions: comparison of laser Doppler scanning, colorimetry, planimetry and skin temperature measurement.

BACKGROUND/AIMS: 2-dimensional laser Doppler scanning distinguishes itself particularly by its good reproducibility with regard to both time and site. The aim of this study was to investigate this relatively new procedure in localised hyperaemic reactions and to compare it to already established techniques. METHODS: We used a pharmacological test system with the rubefacient substances nonivamide, nicoboxil, a combination of these 2 substances as well as the inactive ointment base. Prior to and for up to 8 h after application of the test substances, measurements were made of the flow by means of laser Doppler scanning, the skin temperature by means of a probe thermometer, the colour of the skin by means of tristimulus-color-imetry and the area of erythema by means of planimetry. RESULTS: With the parameters "maximum hyperaemic area" (laser Doppler scanning), planimetry and the a*-value of the lab.*-system (colorimetry), a significant difference was demonstrated between the combination of the active substances and the individual substances (p<0.0002; p<0.002; p<0.0469). The "maximum hyperaemic area" with laser Doppler scanning correlated significantly (p<0.0001) with the planimetrically determined area. The correlation coefficient was high (0.88≤r≤s0.92). The correlation between the "maximum hyperaemic area" and the * a-value was also significant (p<0.0001), but the correlation coefficient was smaller (0.64≪r≪.82). CONCLUSIONS: In summary, in our test system, laser Doppler scanning, colorimetry and planimetry had the same ability to quantify cutaneous pharmacological reactions. Laser Doppler scanning, however, has the advantage that it can be used without any contact whatsoever with the skin.