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The objective of this article was to determine a 7-year naturalistic progression of depression as well as a number of potential prognostic factors among Finnish primary care and psychiatric care patients. Depression-screened patients from primary care and psychiatric care, aged 18-64, were interviewed in 1991-92 with the Present State Examination (PSE) as the diagnostic instrument. The patients were re-contacted in 1998-99, and their depression at final assessment (FinalA) and during the follow-up period (F-up) was assessed by telephone interview using the Composite International Diagnostic Interview--Short Form (CIDI-SF). 250 primary care (58.1%) and 170 (40.2%) psychiatric care patients were successfully followed. Of the primary care patients with severe depression at baseline, 42.4% had had depression during F-up and 21.2% had depression at FinalA. For the patients with mild depression at baseline, the corresponding figures were nearly the same, but for the patients with depressive symptoms clearly lower. Of the psychiatric care patients with severe depression at baseline, 61.0% had had depression during F-up and 26.2% had depression at FinalA. As with primary care patients, the corresponding figures were nearly the same for mild depression at baseline but clearly lower for depressive symptoms. Experienced lifetime mood elevation was associated with having depression during F-up in both primary care and psychiatric care patients. High Depression Scale (DEPS) score at baseline was associated with having depression at FinalA in primary care patients, but in psychiatric care patients, it was the high Hamilton Rating Scale for depression (HAM-D) and drinking problems. Severe depression and mild depression are predictive for subsequent depression at both levels of care. The long-term prognosis for depression is better in primary care. DEPS and HAM-D are useful, prognostic instruments.

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Penciclovir is a drug active against herpes simplex viruses located in the epidermis basal layer. The aim of this study was to compare the suction blister technique and microdialysis as methods to measure the penciclovir concentration in the skin after a single dose (250 mg) of its prodrug, famciclovir. Suction blister fluid, microdialysates and plasma were sampled from 11 healthy volunteers for 5 h after famciclovir administration. Both the suction blister technique and microdialysis showed that penciclovir reaches the skin in concentrations sufficient to inhibit herpes virus replication. The maximum concentration in both suction blister fluid and in microdialysate was observed later than in plasma. The microdialysis concentration was decreased by cooling of the skin surface and by adrenaline-mediated vasoconstriction. The microdialysis recovery of penciclovir was studied with respect to the flow-rate of perfusion medium through the microdialysis probe. Microdialysis and the suction blister technique can be used to study the time-concentration profile of penciclovir in the skin and microdialysis allows a continuous sampling of the drug for a prolonged time after administration.

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Microdialysis makes it feasible to study compounds in the extracellular space of cutaneous tissue in vivo. The insertion of the microdialysis probe causes a trauma, which may be anticipated to influence the microdialysis process. The effect of anaesthesia on basal skin blood flow and the trauma in the skin after insertion of a microdialysis probe were investigated. Hairless rats were anaesthetized either with halothane or pentobarbital sodium. Basal skin blood flow and the effect of insertion of a microdialysis probe were measured by laser Doppler perfusion imaging. Trauma-induced histamine release was investigated. Rats anaesthetized with pentobarbital sodium showed a stable skin perfusion in contrast to rats anaesthetized with halothane. A significant increase in blood flow was seen after insertion of the microdialysis probe in the dermis of rats anaesthetized with pentobarbital sodium, while a change in skin blood flow was not observed in rats anaesthetized with halothane. Probe insertion caused histamine release in rats. A minimum equilibration period of 30 min between probe insertion and the start of the experiment is recommended in future studies, allowing immediate events of the trauma to subside and stabilize.

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Our aim was to assess the microdialysis technique for determining in vivo drug levels of a lipophilic and a protein-bound model drug in the dermis. Forearm skin of healthy volunteers received topical 2% fusidic acid or 0.1% betamethasone-17-valerate formulations twice daily as occluded treatment on irritative dermatitis. Microdialysis sampling in the dermis after 48 h was without measurable drug. Hairless rats received maximized treatment with occluded applications of 10% fusidic acid or 4% betamethasone-17-valerate in ethanol for 72 h followed by microdialysis. Mean levels of betamethasone-17-valerate were 11-45 ng/ml; fusidic acid was not measurable. Systemic administration in clinical doses to rats was without measurable drug levels; increasing doses to 312 mg/kg of fusidic acid and 158 mg/kg of betamethasone-17-valerate yielded betamethasone-17-valerate levels of 25-44 ng/ml and fusidic acid levels of 10-90 ng/ml. This study demonstrates the challenges arising when using microdialysis for measuring in vivo-drug levels. For the drugs chosen it was necessary to administer very high systemic doses or apply a high topical drug concentration to obtain measurable drug levels in the dialysates. Drug levels were in the nanomolar range and demonstrated reproducible and dynamic monitoring of in vivo drug levels in the skin. Using microdialysis for sampling highly protein-bound or lipophilic drugs in the skin requires very sensitive analytical methods, and the sensitivity of the analysis is likely to be the limiting factor.

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Cutaneous microdialysis is a method of measuring endogenous and exogenous compounds in the dermal interstitial fluid. The microdialysis probe is inserted in the dermis using a guide cannula. The insertion trauma was studied in dorsal forearm skin in a total of 28 human healthy volunteers. Twenty-four volunteers received local anaesthesia (Xylocain 10 mg/ml) in both forearms and a microdialysis probe was inserted in one of the arms. In 12 volunteers the insertion trauma and the effect of anaesthesia on skin blood flow and erythema were studied by laser Doppler perfusion imaging, Minolta Chromameter CR 200 and Dermaspectrometer. In the other 12 subjects trauma-induced oedema and effects on skin thickness were studied by ultrasound imaging. In addition, a microdialysis probe was inserted without prior anaesthesia in 4 volunteers, and the effects on skin blood flow and erythema were investigated. Significant increases in skin blood flow, erythema and skin thickness were found after insertion of the microdialysis probe. Local anaesthesia prior to the insertion reduced the effects of trauma. Probe depth in dermis did not influence the effects of trauma. At least 90-120 min is required after insertion in order to allow the vascular reaction to needle trauma to return to the baseline range.

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Microdialysis is a method by which compounds can be studied in the extracellular space in skin, in vivo. The microdialysis probe is inserted in the dermis using a guide cannula. It is expected that intradermal oedema associated with insertion trauma as well as the probe depth can influence the results of microdialysis studies. The aim of the present study was to assess the effects of insertion trauma and, additionally, the probe depth by ultrasound. High-frequency (20 MHz) ultrasound is a noninvasive method for measuring the thickness and echostructure of skin. Hairless rats were anaesthetized with either halothane (n = 7) or pentobarbital sodium (n = 6). The insertion of the microdialysis probe resulted in a 38% relative increase in skin thickness. At 120 min the skin thickness had not reached the pre-insertion value. Thus, significant skin thickening, representing traumatic oedema, developed due to insertion of the microdialysis probe in the skin. The microdialysis probe could be inserted reproducibly in the lower dermis.

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This thesis describes the methodology and validation of cutaneous microdialysis for the study of skin penetration of various topically applied substances in experimental dermatological research. Microdialysis is a sampling technique which makes it possible to measure substances in the extracellular water space in human and animal skin in vivo. A microdialysis probe, i.e. a tubular semipermeable membrane connected to afferent and efferent tubings, is placed in the dermis and perfused. Substances from extracellular space may diffuse through the pores of the membrane and be collected in the dialysate for further analysis. Glucose, sodium fusidate, betamethasone 17,21-dipropionate and calcipotriol were chosen as model substances and were investigated by in vitro microdialysis. The perfusion rate, the length of the membrane, stirring rate and temperature influenced recovery of the substances. Lipophilic compounds tend to have low recoveries and differ in recovery and loss. Insertion of the microdialysis probe causes a trauma in the skin. Rat and human skin were studied in vivo. Increase in skin blood flow, erythema and skin thickness were demonstrated by laser Doppler perfusion imaging, Dermaspectrometer colorimetry, Minolta Chromameter colorimetry and ultrasound imaging of cross-sectional skin structure. In addition histamine was released in rat skin due to the needle insertion. An equilibration period of minimum 90 min in human skin and 30 min in rat skin after the insertion is necessary to allow the effects of trauma to diminish. To obtain measurable concentrations in the dialysate in rats treated topically with the lipophilic drug betamethasone 17-valerate, unrealistic high doses and penetration enhancement were required. The highly protein-bound drug fusidic acid was not measurable in the dialysate after topical application, probably due to very low concentrations of free diffusible drug. Measurable concentrations were only observed after high doses of oral administrations of fusidic acid. Calcipotriol could not be detected in the dialysate. The microdialysis technique is probably primarily useful for the study of hydrophilic substances and substances with low protein binding and low molecular weight. However, application of cutaneous microdialysis for the study of lipophilic substances need further methodologically development.

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