Editor—Isotretinoin, or 13-cis-retinoic acid, was approved for treatment of acne vulgaris since 1982 in the USA and since 1983 in the European Union. Isotretinoin, the only treatment with evidence of long-term remission of acne vulgaris, can be used topically as a first-line treatment. However, concerns raised relate to oral isotretinoin, a first-line treatment for severe acne vulgaris and a second-line treatment for moderate acne vulgaris. 1 Zaenglein A.L. Pathy A.L. Schlosser B.J. et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016; 74: 945-973 Abstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar ,2 Sitohang I.B.S. Isotretinoin for treating acne vulgaris. Int J App Pharm. 2021; 13: 20-25 Crossref Scopus (2) Google Scholar Over the years, millions of patients have been treated with oral isotretinoin for acne vulgaris and other off-label indications, such as rosacea, seborrhoeic dermatitis, hidradenitis suppurativa, ichthyosiform dermatoses, and various forms of malignant disease such as cutaneous T-cell lymphoma and neuroblastoma. 3 Pile H.D. Sadiq N.M. Isotretinoin. StatPearls. StatPearls Publishing, Treasure Island, FL2022https://www.ncbi.nlm.nih.gov/books/NBK525949/Date accessed: February 2, 2023 Google Scholar

Fluid comprises approximately 60% of total body volume with some variations with age and sex (1). The intracellular volume is about twice as large as the extracellular volume. About three-fourths of the extracellular volume comprises the interstitial space and the rest is plasma volume. The red blood cells belong to the intracellular compartment. Blood (intravascular volume) contributes to about 7% of body weight or 4 to 6 L in the adult man. At a normal hematocrit of about 40%, plasma volume in a 70 kg adult is about 3 L, but at lower hematocrit values, the plasma volume must be correspondingly larger to maintain normovolemia. In most organs of the body, the interstitial volume comprises 25% to 30% of total extravascular fluid volume of the tissue and the rest is intracellular volume. The relative interstitial volume is somewhat smaller in the brain (2).

OBJECTIVE:To evaluate effects of lipopolysaccharide (endotoxin) on protein and fluid permeability in a whole organ skeletal muscle preparation.DESIGN:Controlled, prospective laboratory study.SETTING:University research laboratory.SUBJECTS:Eleven adult male cats.INTERVENTIONS:The study was performed on the autoperfused and denervated calf muscles of the cat hindlimb placed in a fluid-filled plethysmograph. The endotoxin-induced change in the osmotic reflection coefficient for albumin was used as a measure of alteration in protein permeability of the microvascular wall, and the simultaneous change in capillary filtration coefficient was used as a measure of alteration in fluid permeability. Endotoxin as a bolus infusion (1 mg/kg iv) was given to six cats, and another five cats given only the vehicle (NaCl) were used as control.MEASUREMENTS AND MAIN RESULTS:Arterial blood flow, arterial and venous blood pressures, total vascular resistance, and tissue volume changes were measured continuously. The ratio between the osmotic reflection coefficients for albumin on two occasions (before and about 1.5 hr after endotoxin infusion) was calculated from the Starling fluid equilibrium equation. This was performed by measurement of the maximum absorption rate from an isovolumetric state by an intravenous bolus infusion of 20% human albumin (0.6 g/kg) and the capillary filtration coefficient. Albumin concentrations were measured before and after the albumin infusion to correct for effects of difference in plasma volume on the induced increase in colloid osmotic pressure. We found that the osmotic reflection coefficient for albumin was reduced by 30% (p <.05), and the capillary filtration coefficient was increased by 31% (p <.05) by endotoxin. No changes were seen in the vehicle experiments.CONCLUSION:Endotoxin causes a significant increase in both protein and fluid microvascular wall permeability. These effects may explain the marked leakage of plasma to the interstitium that is often seen in critically ill patients with sepsis and systemic inflammatory response syndrome.

Disturbances in intestinal metabolism and perfusion during SIRS can be direct effects of toxic substances, and/or effects secondary to hypovolemia. An attempt to evaluate the significance of hypovolemia for intestinal disturbances during SIRS was made in the present study on feline by evaluating the degree to which the intestinal alterations following endotoxin infusion were restored by a clinically relevant volume infusion. The results were compared with control animals treated identically except that they were not given a volume infusion. We analyzed effects of a colloid infusion during endotoxemia on intestinal perfusion, and on the metabolites lactate, pyruvate, glucose, and glycerol in the intestinal wall, the latter by a microdialysis technique. Arterial and central venous blood pressures, and superior mesenteric artery blood flow were measured, and intestinal oxygen delivery and uptake were calculated. To evaluate to what extent a restoring effect of a colloid infusion was dependent on the type of colloid solution used, three different colloids with about the same volume expanding effects (6% albumin, 6% dextran 70 and 6% hydroxyethyl starch, n = 3 × 6) were tested randomly and blinded. Four hrs after start of endotoxin (1 mg/kg + 1 mg/kg/h), the colloid was infused at a rate of 5 mL/kg for 30 min followed by 2.5 mL/kg/h. Endotoxin caused a marked deterioration of perfusion and metabolic parameters. Most of these parameters turned towards normalization, though not fully reaching baseline values within 4 hrs after start of the colloid infusion. In the control experiments (n = 4), the endotoxin-induced deteriorations persisted or were aggravated during the corresponding time period. The results indicated that hypovolemia is an essential factor but not the only one behind alterations in metabolism and perfusion in the intestine during SIRS, and the alterations can be significantly reduced by adequate volume substitution. In this respect no differences could be seen between the three colloids tested.

The aim of the study was to analyze effects of various plasma concentrations of the vasoconstrictor endothelin-1 on microvascular fluid permeability and on transcapillary fluid exchange. We also analyzed whether the permeability-reducing substance prostacyclin is involved in the permeability effects of endothelin-1, as prostacylin is suggested to be released via ET(B) receptor stimulation. The study was performed on an autoperfused cat calf muscle preparation, and a capillary filtration coefficient (CFC) technique was used to estimate variations in microvascular fluid permeability (conductivity). Intraarterial infusion of endothelin-1 in low doses (5 and 10 ng/min/100 g muscle) caused transcapillary absorption, whereas higher doses (20-40 ng/min/100 g) induced filtration despite further vasoconstriction. Low-dose endothelin-1 had no significant effect on CFC, while CFC was reduced to at most 55% of baseline at higher doses (P < 0.01). Simultaneous local intraarterial infusion of the prostacyclin synthesis inhibitor tranylcypromine restored CFC to 114% of baseline (P < 0.01) and further increased vascular resistance. A low, non-vasodilator dose of prostacyclin given intravenously counteracted the tranylcypromine effect on CFC. The decreased CFC induced by a high dose of endothelin-1 was counteracted by the ET(B) receptor antagonist BQ-788 with no change in vascular resistance (P < 0.05). We conclude that the decreased CFC following high doses of endothelin-1 can be attributed to a decrease in microvascular hydraulic conductivity, mediated by secondary release of prostacylin via stimulation of the ET(B) receptor. Endothelin-1 may induce edema through postcapillary vasoconstriction.

OBJECTIVE:To study the effects of the hypertonic solutions 15% mannitol, 3% and 7.5% saline, and 30% urea at clinically relevant plasma concentrations with regard to absorption and rebound effects on tissue volume in skeletal muscle.DESIGN:A prospective, experimental study.SETTING:University laboratory.SUBJECTS:Twenty-eight anesthetized cats.INTERVENTIONS:The study was performed on an autoperfused and denervated cat calf muscle placed in a fluid-filled plethysmograph. Muscle volume changes and capillary filtration coefficient (reflecting capillary fluid conductivity) were measured before, during, and after intra-arterial infusion (4 mL/hr) of the hypertonic solutions. Mannitol and 3% saline have the same osmolality and were compared specifically in an attempt to distinguish osmotic effects from those specific to the compound.MEASUREMENTS AND MAIN RESULTS:All solutions reduced muscle volume during the infusion (p < .05). The maximum volume reduction persisted after 2 hrs of infusion for 3% and 7.5% saline, whereas there was a tendency for volume recovery during the urea infusion and a complete recovery back to control for mannitol. After discontinuation of the infusions, the muscle volume increased for all four solutions, stabilizing at the initial control for 3% and 7.5% saline, whereas it increased to levels above control for mannitol and urea (p < .05). Capillary filtration coefficient was increased by hypertonic saline (p < .05) but was unaffected by mannitol and urea.CONCLUSIONS:The effectiveness of a hypertonic solution in reducing tissue volume and its tendency to cause a rebound volume increase depends not only on the osmolality of the solution. Hypertonic saline may in the long run be superior to mannitol and urea to increase plasma volume or decrease tissue volume of an organ, because it lacks rebound effects. Alterations in capillary filtration coefficient (fluid conductivity) may reflect volume changes of the capillary endothelial cell and thereby differences in cell membrane permeability for the hypertonic solutions, also consistent with the obtained differences in tissue volume effects.

OBJECTIVE:To evaluate the effects of the three commercially available colloid solutions, 6% dextran 70, 6% hydroxyethyl starch (HES) 200/0.5, and 3.5% urea-linked gelatin on permeability for human albumin in a skeletal muscle in vivo model by evaluating their effects on the reflection coefficient for albumin. DESIGN:Controlled laboratory study. SETTING:University research laboratory. SUBJECTS:Eighteen adult cats. INTERVENTIONS:The autoperfused and denervated calf muscles of the cat hindlimb were placed in a plethysmograph. The transvascular fluid absorption induced by an increase in the colloid osmotic pressure following a fixed intravenous bolus of human albumin was analyzed, first before start of, and then during an intra-arterial infusion to, the muscle preparation of the synthetic colloid to be analyzed. Capillary filtration coefficient as a measure of microvascular fluid permeability (conductance) was analyzed before and after start of the synthetic colloid. MEASUREMENTS AND MAIN RESULTS:Arterial blood flow, arterial and venous blood pressures, total vascular resistance, tissue volume changes, capillary filtration coefficient, and plasma volume were measured before and during the colloid infusion. According to the Starling fluid equilibrium, the ratio between the reflection coefficients for albumin on two occasions (before and after infusion of the synthetic colloid) can be calculated from the maximum osmotic absorption rates induced by a fixed intravenous bolus infusion of albumin and from the capillary filtration coefficients. Obtained data were adjusted for different plasma volume at the two occasions. We found that none of the three synthetic colloids analyzed had any significant effect on the reflection coefficient for albumin. CONCLUSION:An effect on albumin microvascular permeability of the synthetic colloids dextran 70, HES 200/0.5, and urea-linked gelatin could not be shown by a method analyzing their effect on the reflection coefficient for albumin.

Prostacyclin is suggested to reduce microvascular permeability, but the cellular mechanisms mediating this response in the microvascular endothelial cells are still unknown. Considering that prostacyclin relaxes vascular smooth muscle cells via opening of ATP-dependent potassium channels, and opening of ATP-dependent potassium channels in the endothelial cells is suggested to influence microvascular permeability, this study was designed to test (1) if ATP-dependent potassium channels are involved in the regulation of microvascular hydraulic permeability, (2) if the permeability-reducing effect of prostacyclin is mediated through opening of ATP-dependent potassium channels, and (3) if cAMP is involved in this process. An autoperfused cat calf hindlimb was used as experimental model, and microvascular hydraulic permeability (conductivity) was estimated by a capillary filtration coefficient (CFC) technique. The potassium channel opener PCO-400 (0.5 μg·min–1 per 100 g muscle, intra-arterially), prostacyclin (1 ng·min–1 per kg body weight, intravenously) and the cAMP analogue dibutyryl-cAMP (24 μg·min–1 per 100 g muscle, intra-arterially), decreased CFC to 77, 72 and 69% compared to control, respectively (p < 0.01). The decrease in CFC obtained by these substances was completely restituted after the start of a simultaneous infusion of the ATP-dependent potassium channel blocker glibenclamide (6 μg·min–1 per 100 g muscle, intra-arterially; p < 0.01). Infusion of glibenclamide alone increased CFC to 107% of control (p < 0.05). In conclusion, the ATP-dependent potassium channels contribute to the regulation of microvascular hydraulic conductivity, and the prostacyclin permeability-reducing effect may act through this mechanism via increase in intracellular cAMP.

potassium channels 516 Autosomal-dominant polycystic kidney disease 502 Balloon injury 272 Beta-2-receptor stimulation 245 Bone morphogenetic protein-2 120 Calcium 235, 404 cAMP 516 Candesartan 393 Capillary filtration coefficient 245 Carbon monoxide 114 Carotid artery 222 Cat skeletal muscle 245 Cell adhesion 47 -density 272 -migration 47, 120 -seeding 91 Cerebral blood flow 100 cGMP-dependent protein kinase 299 Cheek pouch 465 Chemiluminescence 456 Chemotaxis 120 Chloride 492 Cholesterol metabolism 261 Cobra venom 289 Collagen I 139 -III 139 Colloidal gold conjugate 59 Complement activation 289 Computer

Society of Critical Care Medicine; 27th Educational and Scientific Symposium; San Antonio, Texas, USA; February 4-8, 1998: Poster Hall: Thursday, February 5, 1998 5: 45-7: 15 pm; Friday, February 6, 1998 11: 40 am-1: 00 pm; Saturday, February 7, 1998 11: 40 am-1: 00 pm: Poster Presentations: Cardiovascular