Retrospective study of hypersensitivity reactions to chemotherapeutic agents in a thoracic oncology service.

WHAT IS KNOWN AND OBJECTIVE: With the increasing use of cancer chemotherapy agents, hypersensitivity reactions are commonly encountered. The allergic clinical symptoms are variable and unpredictable. The aim of this study was to identify the characteristics of hypersensitivity reactions and to assess the value of skin tests for platinum salts and pemetrexed in the treatment of patients with non-small cell lung cancers or malignant pleural mesothelioma. METHODS: A single-centre retrospective study was performed for 2 years. Patients treated with the drugs of interest for an advanced or metastatic non-small cell lung cancers or malignant pleural mesothelioma and who experienced hypersensitivity reactions symptoms were eligible for this study. Clinical symptoms of hypersensitivity reactions, population characteristics and administered chemotherapy regimens were identified. RESULTS: The hypersensitivity reactions frequency was rare (1.2%) and concerned 17 patients in our study. Typical clinical features of immediate hypersensitivity reactions associated with treatment were observed for nine patients (anaphylactic reactions for three cases, angioedema and hypotension associated with asthenia and heat in one case, respectively, and other cutaneous symptoms in the remaining four cases). Skin tests were positive in three patients, but only for platinum salts. The outcome after reintroduction of a negatively tested platinum salt allowed us to calculate a negative predictive value for platinum salt skin tests of 100%. For pemetrexed, skin tests were negative for all patients. WHAT IS NEW AND CONCLUSION: Skin tests could be used to diagnose hypersensitivity reactions with platinum salts or to evaluate the possibility of cross-reactions between two platinum salts. A negative skin test may predict with reasonable reliability the absence of future hypersensitivity reactions in case of reintroduction of drug infusion. Because the IgE-mediated mechanism has never been demonstrated for pemetrexed, skin tests are not valid and have no diagnostic value for this molecule. Because hypersensitivity reactions are potentially fatal adverse events, we recommend that patients who experience a hypersensitivity reactions onset should be monitored closely and clinicians must be aware of hypersensitivity reaction signs.

Epidural needle insertion : A large registry analysis.

BACKGROUND: Dural puncture, paraesthesia and vascular puncture are the most common complications of epidural catheter insertion. Their association with variation in midline needle insertion depth is unknown. OBJECTIVE: This study evaluated the risk of dural and vascular punctures and the unwanted events paraesthesia and multiple skin punctures related to midline needle insertion depth. MATERIAL AND METHODS: A total of 14,503 epidural catheter insertions including lumbar (L1-L5; n = 5367), low thoracic (T7-T12, n = 8234) and upper thoracic (T1-T6, n = 902) insertions, were extracted from the German Network for Regional Anaesthesia registry between 2007 and 2015. The primary outcomes were compared with logistic regression and adjusted (adj) for confounders to determine the risk of complications/events. Results are presented as odds ratios (OR, [95% confidence interval]). MAIN RESULTS: Midline insertion depth depended on body mass index, sex, and spinal level. After adjusting for confounders increased puncture depth (cm) remained an independent risk factor for vascular puncture (adjOR 1.27 [1.09-1.47], p = 0.002) and multiple skin punctures (adjOR 1.25 [1.21-1.29], p < 0.001). In contrast, dural punctures occurred at significantly shallower depths (adjOR 0.73 [0.60-0.89], p = 0.002). Paraesthesia was unrelated to insertion depth. Body mass index and sex had no influence on paraesthesia, dural and vascular punctures. Thoracic epidural insertion was associated with a lower risk of vascular puncture than at lumbar sites (adjOR 0.39 [0.18-0.84], p = 0.02). CONCLUSION: Variation in midline insertion depth is an independent risk factor for epidural complications; however, variability precludes use of depth as a reliable guide to insertion in individual patients.

Transient severe tricuspid regurgitation after transplantation of an extremely oversized donor heart in a child-Does size matter? A case report.

In pediatric heart transplantation, the size of the donor organ is an important criterion for organ allocation. Oversized donor hearts are often accepted with good results, but some complications in relation to a high donor-recipient ratio have been described. Our patient was transplanted for progressive heart failure in dilated cardiomyopathy. The donor-to-recipient weight ratio was 3 (donor weight 65 kg, recipient weight 22 kg). The intra-operative echocardiography before chest closure showed excellent cardiac function, no tricuspid valve regurgitation, and a normal central venous pressure. After chest closure, central venous pressure increased substantially and echocardiography revealed a severe tricuspid insufficiency. As other reasons for right ventricular dysfunction, that is, myocardial ischemia, pulmonary hypertension, and rejection, were excluded, we assumed that the insufficiency was caused by an alteration of the right ventricular geometry. After 1 week, the valve insufficiency regressed to a minimal degree. In pediatric heart transplant patients with a high donor-to-recipient weight ratio, the outlined complication may occur. If other reasons for right ventricular heart failure can be ruled out, this entity is most likely caused by an acute and transient alteration of the right ventricular geometry that may disappear over time.

Tunnelling of thoracic epidural catheters is associated with fewer catheter-related infections: a retrospective registry analysis.

BACKGROUND: Catheter-related infections are a serious complication of continuous thoracic epidural analgesia. Tunnelling catheters subcutaneously may reduce infection risk. We thus tested the hypothesis that tunnelling of thoracic epidural catheters is associated with a lower risk of catheter-related infections. METHODS: Twenty-two thousand, four hundred and eleven surgical patients with continuous thoracic epidural analgesia included in the German Network for Regional Anaesthesia registry between 2007 and 2014 were grouped by whether their catheters were tunnelled (n=12 870) or not (n=9541). Catheter-related infections in each group were compared with Student's unpaired t and χ(2) tests. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with logistic regression, adjusting for potential confounding factors, including age, ASA physical status score, use of catheter for ≥4 days, multiple skin puncture, hospital, and surgical department. RESULTS: There were fewer catheter-related infections in patients with tunnelled catheters (4.5 vs 5.5%, P<0.001). Mild infections were also less common (4.0 vs 4.6%, P=0.009), as were moderate infections (0.4 vs 0.8%, P<0.001). After adjustment for potential confounding factors, tunnelling remained an independent prevention for any grade of infection (adjusted OR 0.51, 95% CI 0.42-0.61, P<0.001) and for mild infections (adjusted OR 0.54, 95% CI 0.43-0.66, P<0.001) and moderate and severe infections (adjusted OR 0.44, 95% CI 0.28-0.70, P=0.001). CONCLUSION: Tunnelling was associated with a lower risk of thoracic epidural catheter-related infections.

ABO-compatible retransplantation after ABO-incompatible infant heart transplantation: absence of donor specific isohemagglutinins.

Implementation of ABO-incompatible (ABOi) pediatric heart transplantation has contributed to significant reduction in the mortality of infants on the waiting list, without increasing the risk of rejection. This has been attributed to the immature and therefore not fully competent immune system in this population group, which results in lower production of isohemagglutinins compared to older children and adults. Serial evaluations of isohemagglutinin titers in infants revealed cases with absence of donor specific anti-blood group antibodies. However, it is currently unknown whether continuous exposure to donor antigens is necessary to prevent formation of donor specific isohemagglutinins (DSI) in recipients. We are reporting a case of an infant who underwent ABOi heart transplantation, with no evidence of DSI even 4 years after ABO-compatible retransplantation. Hence, temporary exposure to donor antigens in infants may contribute to permanent absence of donor specific anti-blood group antibodies, suggesting the possibility of induced permanent B cell tolerance.

Component-resolved diagnosis with commercially available D. pteronyssinus Der p 1, Der p 2 and Der p 10: relevant markers for house dust mite allergy.

OBJECTIVE: To establish the prevalence and serum levels of IgE to commercial Der p 1, Der p 2, Der p 10 and the carbohydrate MUXF3 in house dust-mite allergic patients. To compare individual vs. allergen microarray methods. METHODS: Prevalence and serum levels of IgE to Dermatophagoides pteronyssinus extract and components Der p 1, Der p 2, Der p 10 and MUXF3, specific IgG4 to D. pteronyssinus, total serum IgE levels, and clinical features (age, asthma, rhinitis and atopic dermatitis) were determined in 123 patients (64 children) with the ImmunoCAP® method. ImmunoCAP ISAC® was performed in 24 patients. RESULTS: All patients had serum IgE to D. pteronyssinus. Prevalences of serum IgE to commercial components were Der p 1 93%, Der p 2 77% (Der p 1 or Der p 2 94%), Der p 10 28% and MUXF3 25%. Levels of D. pteronyssinus IgE strongly correlated with Der p 1 and Der p 2 IgE (r = 0.89 and 0.85 respectively), but not Der p 10 and MUXF3. ImmunoCAP® and ImmunoCAP ISAC® were concordant, but the quantitative correlation was poor. No clinical implication for the prevalence, levels, or molecular IgE reactivity profile to house dust mite components was found. CONCLUSIONS AND CLINICAL RELEVANCE: Commercially available Der p 1 and Der p 2 strongly correlate with IgE D. pteronyssinus. The lack of Der p 1 and Der p 2 IgE may help with differential diagnosis. Der p 10 serum IgE prevalence and levels suggest different patterns in food and mite-related tropomyosin sensitization. Serum IgE to carbohydrate MUXF3, although unexpectedly prevalent, were low and did not modify D. pteronyssinus IgE levels. Follow-up may be best carried out with individual rather than microarrayed components.

[Levobupivacaine vs. ropivacaine for continuous femoral analgesia after anterior cruciate ligament reconstruction]. / Levobupivacain und Ropivacain zur kontinuierlichen Nervenblockade des N. femoralis nach Rekonstruktion des vorderen Kreuzbandes.

BACKGROUND: Levobupivacaine and ropivacaine are both used for continuous femoral analgesia after anterior cruciate ligament reconstruction; however it is unknown whether both drugs are equally effective regarding pain control, preservation of mobility and patient satisfaction. METHODS AND MATERIALS: In this randomized, placebo-controlled trial 84 patients undergoing anterior cruciate ligament (ACL) reconstruction with quadruple hamstring tendons were studied. For postoperative pain therapy levobupivacaine 0.125%, ropivacaine 0.2% or placebo control with NaCl 0.9% at a rate of 6 ml/h were used for 48 h using a femoral nerve catheter. All patients also received an i.v. patient-controlled analgesia (IVPCA) pump with piritramide. RESULTS: Patient satisfaction was significantly higher and night rest was better in both treatment groups compared to the placebo group but there appeared to be no major differences between the two local anesthetics. Opioid consumption was significantly higher in the placebo group compared to the levobupivacaine group but not the ropivacaine group. The pain scores showed a trend towards higher scores in the placebo group throughout but the difference only reached statistical significance on postoperative day 1. No statistical significant differences in motor block were found between the three groups. CONCLUSION: Postoperative analgesia for ACL reconstruction during the first 48 h using femoral block with a continuous infusion of levobupivacaine 0.125% or ropivacaine 0.2% in combination with an IVPCA is similarly effective and better than a placebo. Both studied drugs seem to be equally appropriate for this purpose.

[Hymenoptera venom allergy: Management of venom extracts shortage or sanitary crisis (Covid-19 pandemic). Stinging Insects Task Force recommendations]. / Allergie aux venins d'hyménoptères : conduite à tenir en cas de pénurie d'extraits de venins ou de crise sanitaire (pandémie Covid-19). Recommandations du Groupe de Travail Insectes Piqueurs (GTIP).

Recurrent venom extracts shortages as well as the COVID-19 pandemic have prompted the SFA/Anaforcal Stinging Insects Task Force to develop recommendations on venom immunotherapy (VIT), in accordance with international guidelines, to be able to offer and maintain VIT to patients with life-threatening risks. How to diagnose allergy to hymenoptera venoms, indications and duration of VIT, maintenance intervals and doses, interchangeability of venom extracts and monitoring of patients on VIT have been adapted to this time of crisis, allowing clinicians to treat their patients with the most benefit and lowest constraint. These recommendations are temporary and will be reviewed after returning to a normal situation.

Absence of donor-specific anti-HLA antibodies after ABO-incompatible heart transplantation in infancy: altered immunity or age?

Specific B-cell tolerance toward donor blood group antigens develops in infants after ABO-incompatible heart transplantation, whereas their immune response toward protein antigens such as HLA has not been investigated. We assessed de novo HLA-antibodies in 122 patients after pediatric thoracic transplantation (28 ABO-incompatible) and 36 controls. Median age at transplantation was 1.7 years (1 day to 17.8 year) and samples were collected at median 3.48 years after transplantation. Antibodies were detected against HLA-class I in 21 patients (17.2%), class II in 18 (14.8%) and against both classes in 10 (8.2%). Using single-antigen beads, donor-specific antibodies (DSAs) were identified in six patients (all class II, one additional class I). Patients with DSAs were significantly older at time of transplantation. In patients who had undergone pretransplant cardiac surgeries, class II antibodies were more frequent, although use of homografts or mechanical heart support had no influence. DSAs were absent in ABO-incompatible recipients and class II antibodies were significantly less frequent than in children with ABO-compatible transplants. This difference was present also when comparing only children transplanted below 2 years of age. Therefore, tolerance toward the donor blood group appears to be associated with an altered response to HLA beyond age-related effects.

Computers: a survey of trends and limitations.

Enormous progress in electronic technology is accelerating the use of computers in everyday life. In this article trends in hardware, input-output technology, computer architecture, software, communications, and artificial intelligence are examined and complexity is identified as a limitation to further progress. Promising directions of research, which may extend the range of computer applications, are discussed.

A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus.

A new, competitive, nonpeptide cholecystokinin (CCK) antagonist, asperlicin, was isolated from the fungus Aspergillus alliaceus. The compound has 300 to 400 times the affinity for pancreatic, ileal, and gallbladder CCK receptors than proglumide, a standard agent of this class. Moreover, asperlicin is highly selective for peripheral CCK receptors relative to brain CCK and gastrin receptors. Since asperlicin also exhibits long-lasting CCK antagonist activity in vivo, it should provide a valuable tool for investigating the physiological and pharmacological actions of CCK.

[Electrical nerve stimulation for peripheral nerve blocks. Ultrasound-guided needle positioning and effect of 5% glucose injection]. / Elektrische Nervenstimulation bei peripheren Nervenblockaden. Sonographisch gesicherte Kanülenlage und Einfluss einer G5%-Injektion.

BACKGROUND: The use of nerve stimulation is a common standard procedure for peripheral nerve blocks. However, ultrasound guidance is increasingly being used as an alternative. This study explored the relationship between needle positioning defined by ultrasound guidance and the electrical nerve stimulation before and after injection of 5% glucose solution (G5%). PATIENTS AND METHODS: After obtaining permission from the ethics committee, 60 patients were enrolled in the study and the results from 51 patients could be analyzed. For sonographically defined correct needle placement the lowest electrical threshold of the elicited motor responses before and after injection of 1 ml G5% was determined. RESULTS: In 76% of cases nerve structures could be visualized with high quality and 90% of the blocks were successful. Only 29% of patients with a successful block showed a motor response with a stimulation current < or = 0.5 mA. There was a relationship only between the quality of the visualization and the success of the blockade. Addition of G5% did not result in significant changes in stimulation thresholds. CONCLUSION: With the protocol used the success of a blockade depends only on the quality of visualization. With correct ultrasound-guided needle tip positioning the electrical information seems to be skewed and doubtful.

Impact of combined C1 esterase inhibitor/coagulation factor XIII or N-acetylcysteine/tirilazad mesylate administration on leucocyte adherence and cytokine release in experimental endotoxaemia.

We determined the effects of combinations of C1 esterase inhibitor (C1-INH) with factor XIII and of N-acetylcysteine (NAC) with tirilazad mesylate (TM) during lipo-polysaccharide (LPS)-induced endotoxaemia in rats. Forty Wistar rats were divided into four groups: the control (CON) group received no LPS; the LPS, C1-INH + factor XIII and NAC + TM groups received endotoxin infusions (5 mg/kg per h). After 30 min of endotoxaemia, 100 U/kg C1-INH + 50 U/kg factor XIII was administered to the C1-INH + factor XIII group, and 150 mg/kg NAC + 10 mg/kg TM was administered in the NAC + TM group. Administration of C1-INH + factor XIII and NAC + TM both resulted in reduced leucocyte adherence and reduced levels of interleukin-1beta (IL-1beta). The LPS-induced increase in IL-6 levels was amplified by both drug combinations. There was no significant effect on mesenteric plasma extravasation. In conclusion, the administration of C1-INH + factor XIII and NAC + TM reduced endothelial leucocyte adherence and IL-1beta plasma levels, but increased IL-6 levels.

Effects of N-acetylcysteine and tirilazad mesylate on intestinal functional capillary density, leukocyte adherence, mesenteric plasma extravasation and cytokine levels in experimental endotoxemia in rats.

INTRODUCTION: The study's objective was to determine the effects of the administration of N-acetylcysteine (NAC) and of tirilazad mesylate (TM) on intestinal functional capillary density, mesenteric plasma extravasation, leukocyte adherence and on cytokine release during experimental endotoxemia in rats. METHODS: In a prospective, randomized, controlled animal study, 80 male Wistar rats were examined in 2 test series. Both series were divided into 4 groups. Group 1 served as control group (CON group). Group 2 (LPS group), group 3 (NAC group) and group 4 (TM group) received endotoxin infusions (10 mg/kg over 2 h). In NAC group 150 mg/kg body weight NAC was administered after the first 30 minutes of endotoxemia intravenously. In TM group, 10 mg/kg body weight TM was administered after the first 30 minutes of endotoxemia intravenously. Animals of the series 1 underwent studies of leukocyte adherence on submucosal venular endothelium of the small bowel wall and intestinal functional capillary density (FCD) in the intestinal mucosa and the circular as well as the longitudinal muscle layer by intravital fluorescence microscopy (IVM). Plasma levels of interleukin 1beta (IL-1beta), interferone gamma (IFN-gamma) and soluble intercellular adhesion molecule1 (s-ICAM 1) as well as white blood cell count (WBC) were estimated. In the animals of the series 2 mesenteric plasma extravasation was determined by IVM and plasma levels of tumor necrosis factor alpha (TNF-alpha), IL-4, IL-6, IL-10 and malondialdehyde (MDA) were estimated. RESULTS: After LPS administration, FCD in the villi intestinales was unchanged and in the longitudinal muscularis layer it was increased. There was no effect of NAC or TM administration on FCD.Although the plasma extravasation was not significantly influenced by LPS administration, TM administration resulted in a lower plasma extravasation in the TM group compared to the other groups. After endotoxin challenge, the firmly adherence of leukocytes to vascular endothelium as a parameter of leukocyte activation in endotoxemia was increased but NAC or TM administration had no influence on leukocyte adherence. The plasma levels of IL-1beta, IL-6, IL-10, TNF-alpha, IFN-gamma and sICAM-1 were increased in the endotoxemic groups (LPS group, NAC group and TM group) and the WBC was decreased compared to controls. IL-4 levels were unchanged during observation period. Plasma MDA levels were not influenced by LPS administration compared to controls. The administration of NAC resulted in lower sICAM-1 and MDA levels compared to the LPS group. The IL-1beta, IL-6, IL-10, TNF-alpha and IFN-gamma plasma levels were not influenced by NAC or TM administration. CONCLUSIONS: In this posttreatment sepsis model in rats, NAC administration resulted in lower sICAM-1 and MDA levels compared to the LPS treated animals. TM administration reduced the plasma extravasation in this model.

Relationship Between Neuromyelitis Optica Spectrum Disorder and Sjögren's Syndrome: Central Nervous System Extraglandular Disease or Unrelated, Co-Occurring Autoimmunity?

OBJECTIVE: Sjögren's syndrome (SS) patients may be affected by the neuromyelitis optica spectrum disorder (NMOSD), a severe demyelinating syndrome associated with anti-aquaporin 4 antibodies (anti-AQP-4 antibodies). The relationship between SS and NMOSD has been a sustained focus of investigation. Among SS patients, anti-AQP-4 antibodies have been detected exclusively in those with NMOSD. It has therefore been speculated that NMOSD is not a neurologic complication of SS. However, such studies evaluated small numbers of SS patients, often mixed with other inflammatory disorders. METHODS: We compared frequencies of anti-AQP-4 and SS-associated antibodies in 109 SS patients, including 11 with NMOSD, 8 with non-NMOSD demyelinating syndromes, and 90 without demyelinating syndromes. RESULTS: When assessed using a fluorescence-activated cell sorting (FACS) assay, anti-AQP-4 antibodies were seen exclusively in those SS patients with NMOSD (72.7%), but not in SS patients without NMOSD (P < 0.01). In contrast, anti-Ro 52, anti-Ro 60, and other autoantibodies were not more prevalent in SS patients with NMOSD versus those without. Anti-AQP-4 antibodies were detected more frequently among NMOSD patients by FACS assay than with a commercial immunohistochemical assay (72.7% versus 54.5%), despite assessment after a more prolonged period of immunosuppressive therapy (median 38 months versus 5 months; P < 0.01). CONCLUSION: The syndrome-specificity of anti-AQP-4 antibodies, along with an otherwise similar antibody profile in SS NMOSD patients, indicates that NMOSD is not a direct central nervous system manifestation of SS. Anti-AQP-4 antibodies can persist and be refractory to prolonged immunosuppressive therapy.

Intensive care unit stay of more than 14 days after cardiac surgery is associated with non-cardiac organ failure.

Some studies have shown an association between a prolonged intensive care unit (ICU) stay and risk factors such as mediastinal re-exploration, advanced age, low ejection fraction, lung disease and organ failure. The aim of this retrospective study was first to evaluate peri-operative risk factors (n = 2683) and secondly to evaluate long-term survival (n = 2563) in cardiac surgery patients with an ICU stay > 14 days. Long-term survival was assessed in an observational 3-year follow-up study. An ICU stay of > 14 days was associated independently with respiratory failure and dialysis-dependent acute renal failure, and with a significantly lower survival rate. Since an ICU stay is associated with a higher hospital and long-term mortality, measures should be taken throughout the entire hospital stay to identify and reduce the risk of organ failure.

Calcium flux-independent NMDA receptor activity is required for Aß oligomer-induced synaptic loss.

Synaptic loss is one of the major features of Alzheimer's disease (AD) and correlates with the degree of dementia. N-methyl-D-aspartate receptors (NMDARs) have been shown to mediate downstream effects of the ß-amyloid peptide (Aß) in AD models. NMDARs can trigger intracellular cascades via Ca(2+) entry, however, also Ca(2+)-independent (metabotropic) functions of NMDARs have been described. We aimed to determine whether ionotropic or metabotropic NMDAR signaling is required for the induction of synaptic loss by Aß. We show that endogenous Aß as well as exogenously added synthetic Aß oligomers induced dendritic spine loss and reductions in pre- and postsynaptic protein levels in hippocampal slice cultures. Synaptic alterations were mitigated by blocking glutamate binding to NMDARs using NMDAR antagonist APV, but not by preventing ion flux with Ca(2+) chelator BAPTA or open-channel blockers MK-801 or memantine. Aß increased the activity of p38 MAPK, a kinase involved in long-term depression and inhibition of p38 MAPK abolished the loss of dendritic spines. Aß-induced increase of p38 MAPK activity was prevented by APV but not by BAPTA, MK-801 or memantine treatment highlighting the role of glutamate binding to NMDARs but not Ca(2+) flux for synaptic degeneration by Aß. We further show that treatment with the G protein inhibitor pertussis toxin (PTX) did not prevent dendritic spine loss in the presence of Aß oligomers. Our data suggest that Aß induces the activation of p38 MAPK and subsequent synaptic loss through Ca(2+) flux- and G protein-independent mechanisms.

Effects of reserpine, epidermal growth factor, and cyclic nucleotide modulators on epidermal mitosis.

The mouse ear G2 mitosis assay was modified for the screening of potential antimitotic agents. An inhibitory adrenergic influence, which maintains mitotic rate at a normally low level, was removed by pretreatment of mice with reserpine. This depletes endogenous catecholamines, produces a state of enhanced mitotic activity, and makes the epidermal cells particularly sensitive to mitotic inhibition by agents which elevate the levels of cyclic AMP. Isoproterenol [IC 50 approximately 1 X 10(-9) M], prostaglandins, dibutyryl cyclic AMP [IC 50 approximately 2 X 10(-5) M], papaverine, theophylline and 5' AMP were inhibitory in the assay, whereas dibutyryl cyclic GMP and the cholinergic stimulator carbamylcholine either stimulated or had no effect on mitosis. Epidermal growth factor was employed as an alternate means of stimulating cell division. Skin fron newborn mice or rats pretreated with this substance had increased epidermal mitotic activity which was inhibited cyclic AMP elevators.

Cyclic AMP-phosphodiesterase and epidermal mitosis.

The relationship between cyclic AMP-phosphodiesterase (cAMP-PDE) inhibition and inhibition of epidermal mitosis was examined for several compounds using a soluble, low Km PDE activity from hairless mouse skin and the G2 mouse ear mitosis assay. Orders of potency determined at IC50 levels (concentrations required for 50% inhibition) were SQ 20009 greater than RO 20-1724 greater than papaverine greater than bufexamac greater than indomethacin greater than theophylline greater than p-biphenylylacetic acid greater than or less than glycyrrhetinic acid for inhibition of both PDE and mitosis. The disproportionately high antimitotic potency of puromycin relative to PDE inhibition was believed to reflect effects on protein biosynthesis. Activity of the three nonsteroidal anti-inflammatory agents (bufexamac, indomethacin, and p-biphenylylacetic acid) was unrelated to their effect on prostaglandin synthesis in homogenates of hairless mouse skin. The results suggest that the epidermal antimitotic activity of the compounds tested is related to their inhibition of cAMP-PDE and provide additional support for cAMP as a regulator of the G2 stage of the epidermal cell cycle.

Retinoic acid induces cyclic changes in epidermal thickness and dermal collagen and glycosaminoglycan biosynthesis rates.

The effects of daily topical application onto guinea pig ears of a therapeutic concentration of all trans-retinoic acid (RA) on epidermal thickness and dermal collagen and glycosaminoglycan (GAG) biosynthesis rates were studied during a 40-day period. Clinically, the RA-treated skin became erythematous and scaly beginning at 5-6 days, conditions which persisted throughout the experiment. The epidermis became thickened and hyperplastic with marked psoriasi-form histologic features, and the phenomenon was dependent on RA concentration. The initial hyperplasia resulted from a transient 4-fold increase in epidermal basal cell replication during the first 3-4 days, as shown by the rise and fall of [3H]thymidine labeling index which preceded the hyperplasia. The extent of epidermal hyperplasia as measured by epidermal thickness was not constant throughout the 40-day treatment period, but exhibited maxima on days 11, 25, and 36. These maxima were followed by periods of decreased thickness, although the minima were always greater than the untreated controls. Retinoic acid induced similar temporal cycles in GAG and collagen biosynthesis rates, but the collagen cycles occurred at different times with maxima on days 6, 20, and 34. After 8 weeks' treatment, the blood flow rates in the ear microcirculation (laser Doppler photometry) were increased 81% above that of the water-treated controls. The demonstration of these RA-induced cyclic changes in epidermal hyperplasia and dermal fibroblast biosynthetic activities have revealed the presence of control mechanisms in these tissues which normally operate to maintain tissue homeostasis.