Plasmapheresis and cyclophosphamide as successful treatments for pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is an ulcerative skin disorder of unknown aetiology. We describe a 40-year-old woman with long-standing PG and who did not respond to the usual treatments; however, she was treated successfully with plasmapheresis followed by pulse intravenous cyclophospamide therapy.

Continuous and intermittent itraconazole dosing schedules for the treatment of onychomycosis: a pharmacokinetic comparison.

This multicentre, double-blind, randomized study compared the pharmacokinetics of itraconazole given at 200 mg once daily for 3 months and intermittently at 200 mg twice daily for 1 week per month followed by a 3-week drug-free period for 3 months in the treatment of onychomycosis. Patients were followed for 9 months after treatment. Itraconazole and hydroxy-itraconazole plasma concentrations and itraconazole nail tip concentrations were determined at regular intervals. With intermittent therapy (n = 64), increases of consistent magnitude were seen in the mean itraconazole and hydroxy-itraconazole plasma concentrations at the end of each 1-week treatment phase; values returned towards baseline during each subsequent 3-week drug-free period. The mean concentration of itraconazole in fingernail tips increased steadily from week 4, reached a maximum value at week 24 (213 ng/g), declined sharply between weeks 24 and 36 and returned to baseline by week 48; the mean concentration profile was similar for toenail tips (maximum value 305 ng/g at week 24) but decreased at a slower rate. With continuous therapy (n = 65), steady-state mean plasma concentrations of itraconazole and hydroxy-itraconazole were obtained within 4-5 weeks of the start of treatment and remained reasonably constant between weeks 4 and 12. The mean concentration of itraconazole in fingernail tips reached a maximum value at week 12 (524 ng/g) and returned towards baseline by week 48; in contrast, the maximum mean concentration of itraconazole in toenail tips was 698 ng/g at week 36 and did not return to baseline by week 48. No clear relationship was observed between response to treatment and concentration of itraconazole or hydroxy-itraconazole in plasma or itraconazole in nails, suggesting that concentrations exceeded therapeutic levels. In conclusion, intermittent therapy resulted in higher maximum itraconazole plasma concentrations but lower total drug exposure, and hence lower itraconazole nail concentrations, than continuous therapy. However, the intermittent schedule was not associated with a lower cure rate, which indicates that itraconazole nail concentrations remained within the therapeutic range.

Transfer of clonidine and dexmedetomidine across the isolated perfused human placenta.

BACKGROUND: The placental transfer of the alpha 2 receptor agonist clonidine, earlier used as an adjuvant in obstetric epidural analgesia, was compared with the transfer of the newer and more alpha 2-selective agonist dexmedetomidine. METHODS: Term placentas were obtained immediately after delivery with maternal consent and a 2-hour recycling perfusion of a single placental cotyledon was performed. Disappearance from the maternal circulation, accumulation in placental tissue and appearance in the fetal circulation of clonidine or dexmedetomidine with the reference compound antipyrine were followed in 4 experiments for both drugs. RESULTS: At 2 hours the percent dexmedetomidine found in the fetal circulation was 12.5 (SD 5.1)%, while 48.1 (SD 20.3)% was found in the perfused placental cotyledon. A higher mean clonidine than dexmedetomidine concentration was achieved in the fetal circulation (1.90 vs. 0.56 nmol/l, P < 0.05). At 2 hours the percent clonidine found in the fetal circulation was 22.1 (SD 2.4)% (P < 0.05), while 11.3 (SD 3.3)% (P < 0.05) was retained in the perfused placental cotyledon. The transfer indexes, describing maternal-to-fetal transfer of dexmedetomidine and clonidine normalized with the transfer of antipyrine, were 0.88 (SD 0.07) and 1.04 (SD 0.08) respectively (P < 0.05). CONCLUSIONS: Dexmedetomidine disappeared faster than clonidine from the maternal circulation, while even less dexmedetomidine was transported into the fetal circulation. This was due to its greater placental tissue retention, the basis for which probably is the higher lipophilicity of dexmedetomidine.

A double-blind, randomized study comparing itraconazole pulse therapy with continuous dosing for the treatment of toe-nail onychomycosis.

In this multicentre, double-blind, parallel group study, we evaluated the efficacy and safety of continuous treatment with itraconazole, 200 mg daily for 3 months, in comparison with itraconazole pulse therapy, 400 mg daily 1 week per month for 3 months, in the treatment of toe-nail onychomycosis. The study included 129 patients with distal subungual onychomycosis of the toe-nails, confirmed by microscopy and positive for dermatophyte culture; 65 received continuous treatment and 64 received pulse therapy. Patients were followed up for 9 months after treatment. After 12 months, there were 62 evaluable patients in the continuous group and 59 evaluable patients in the pulse group. The clinical response (i.e. the size of the affected area and the progress of the infection) and mycological cure (i.e. negative results on microscopy and culture) were the main outcome measures. A clinical response was defined as a cure or a marked improvement. Clinical response rates were 69%, in the continuous group, and 81% in the pulse group at month 12; the corresponding mycological cure rates were 66 and 69%. A better improvement in signs and symptoms was noted in the pulse group. Six patients were withdrawn from treatment because of adverse events, not all of which were thought to be drug-related. There were no clinically relevant laboratory abnormalities. We conclude that both regimens are effective, safe and well tolerated. The superiority of one treatment over the other was not established, but the results tended to favour pulse therapy. Equivalence testing confirmed that pulse therapy was at least equivalent to continuous treatment.

A clinical and pharmacokinetic comparison of ropivacaine and bupivacaine in axillary plexus block.

The clinical and pharmacokinetic properties of ropivacaine and bupivacaine, both 5 mg/mL, used in axillary plexus block were compared in 60 patients in this randomized, double-blind, parallel-group study. The axillary plexus was identified with a nerve stimulator and 30, 35, or 40 mL of drug, depending on body weight, was injected into the perivascular sheath. In 20 patients, venous blood samples for the pharmacokinetic measurement were obtained over 24 h. The median onset times for anesthesia and complete motor block were in the range of 12-48 min and 5-20 min, respectively. Thirty-eight percent of patients in the ropivacaine group and 29% in the bupivacaine group needed additional nerve block(s) or supplementary analgesia and 7% in the bupivacaine group needed general anesthesia for surgery. Anesthesia was achieved in 52%-86% of the evaluated six nerves in the ropivacaine group and in 36%-87% in the bupivacaine group; the lowest figures were seen in the musculocutaneous nerve. In the pharmacokinetic study the mean peak plasma concentrations (Cmax) were 1.28 +/- 0.21 mg/L in the ropivacaine group and 1.28 +/- 0.47 mg/L in the bupivacaine group and the median times to peak plasma concentration (tmax) were 0.86 h and 0.96 h, respectively. The median terminal half-lives (t1/2) were 7.1 h and 11.5 h in the ropivacaine group and the bupivacaine group, respectively (P = 0.07). No statistically significant differences were found between ropivacaine and bupivacaine in either the clinical or the pharmacokinetic comparisons.

Transfer of lidocaine and bupivacaine across the isolated perfused human placenta.

Drug permeability and pharmacokinetics through the placenta are important factors determining foetal drug exposure. The purpose of the present study was to establish a perfused human placental cotyledon system to assess the placental transfer of lidocaine and bupivacaine, widely used local anaesthetics in obstetric anaesthesia. Term placentas were obtained immediately after delivery with maternal consent and a two-hour recycling perfusion of a single placental cotyledon was performed. Bupivacaine or lidocaine with antipyrine as a reference compound were added to the maternal reservoir and their disappearance from the maternal circulation and appearance to the foetal circulation were followed in five experiments for each drug. Drug concentrations were measured by gas chromatography. Bupivacaine disappeared more rapidly from the maternal circulation than lidocaine. At 2 hr, bupivacaine foetal:maternal concentration ratio was 0.56 +/- 0.12 and 14.6% +/- 2.99 of the total circulating amount was found in the foetal circulation. Lidocaine concentration increased more in the foetal circulation and the foetal:maternal concentration ratio at 2 hr was 0.90 +/- 0.09 (P < 0.01), and 22.1% +/- 2.21 (P < 0.01) was found in the foetal circulation. The maternal to foetal transfer of bupivacaine and lidocaine were 67.2% +/- 0.153 and 98.9% +/- 0.07 (P < 0.05) of that of freely diffusable antipyrine, respectively. Both amide local anaesthetics crossed the dually perfused human placenta rapidly. Bupivacaine disappeared faster than lidocaine from the maternal circulation but less was transferred to foetal circulation. This difference is probably explained by the greater lipophilicity of bupivacaine and hence higher placental binding. These results suggest less foetal drug exposure with bupivacaine than lidocaine.

The effects of epidural ropivacaine and bupivacaine for cesarean section on uteroplacental and fetal circulation.

BACKGROUND: Ropivacaine is a new long-acting amide local anesthetic that has been shown in animal studies to have less dysrhythmogenic and cardiotoxic potential than bupivacaine. The intravenous administration of ropivacaine has not been associated with any detrimental effects on uterine blood flow in pregnant ewes. The purpose of this randomized, double-blind study was to examine the effects of epidural ropivacaine for cesarean section on blood flow velocity waveforms in uteroplacental and fetal arteries with color Doppler ultrasound and to assess whether the block modified fetal myocardial function. METHODS: Healthy parturient women with singleton, uncomplicated pregnancies at term received 115-140 mg 0.5% ropivacaine (n = 11) or 0.5% bupivacaine (n = 10) in incremental epidural doses. The first ultrasound measurement was performed before injection of the study drug. Pulsatility indexes (PI) were derived for the blood flow velocity waveforms of the maternal placental and nonplacental uterine arteries; the placental arcuate artery; and the fetal umbilical, middle cerebral, and renal arteries. The fetal heart then was examined by echocardiography. The PI of the maternal uterine arteries and the fetal umbilical artery were measured 5 min after the injection of the local anesthetic. When sensory analgesia had reached the T6-T4 level, the ultrasound measurement was repeated with the same methods and targets as in the baseline measurement. RESULTS: Both drugs provided adequate surgical anesthesia for cesarean section. In the bupivacaine group, the PI values for the maternal placental and nonplacental uterine arteries increased significantly 5 min after the main dose (P = 0.01, P = 0.002) and when sensory analgesia had reached the T6-T4 level (P = 0.004, P = 0.01) as compared with the baseline measurement. Simultaneously, the PI in the fetal middle cerebral artery decreased significantly (P = 0.02). The PI for the maternal uterine artery increased significantly (P = 0.01) after ropivacaine administration but only on the nonplacental side and not until sensory analgesia had reached the T6-T4 level. No effect on the Doppler indexes obtained from the umbilical artery was observed in either group. There were no significant differences relative to baseline values in any fetal myocardial measurement or in any ultrasound measurement between the groups. Neither drug had any detrimental effect on Apgar scores or umbilical cord acid-base status. None of the neonates' conditions was markedly depressed according to neurobehavioral testing. CONCLUSIONS: Within this small study, epidural 0.5% ropivacaine for cesarean section did not compromise the utero-placental circulation in healthy parturient women with uncomplicated pregnancies. It provided surgical anesthesia that was equally effective as that provided by 0.5% bupivacaine.

Hand eczema in Finnish farmers. A questionnaire-based clinical study.

In a population of 2005 Finnish farmers, 172 (8.6%) reported hand or forearm dermatoses in a self-administered questionnaire. 138 (80%) of them attended a clinical examination. Skin prick tests (SPTs) were done to 80% and patch tests (PTs) to 77% of the examined farmers. 93% of hand dermatoses were eczema and 70% were considered work-related. Cow allergy was found in 41 of 104 prick- and patch-tested farmers (39%). Immediate allergy to cow epithelium was encountered in a total of 28/41, in 20 with SPTs, and in 8 only with 20 min PTs. Delayed contact allergy to cow dander was found in 27/41. The result suggests that in addition to SPTs using commercial cow epithelium extract, PTs using fresh cow dander should also be done, and both immediate and delayed responses should be read.

Dermatoses determined in a population of farmers in a questionnaire-based clinical study including methodology validation.

OBJECTIVES: The study analyzed skin diseases in a population sample of Finnish farmers descriptively and in the process validated the question "Do you have a skin disease now?" METHODS: All farmers from one Finnish municipality were surveyed for dermatoses, first with a questionnaire and then with a clinical examination of those who reported dermatoses. Another population of farmers answered a set of questions immediately before a clinical examination, and the self-report of current dermatosis was validated. RESULTS: Eczema was diagnosed for 66% of the women and 53% of the men who had reported dermatosis in the questionnaire study 6 to 12 months earlier. Toe-web maceration, psoriasis, folliculitis, and acne were, after eczema, the most frequent diagnoses (in that order). In more than 50% of the cases, the location of clinically determined dermatoses corresponded with the skin disease areas reported 6 to 12 months earlier. In the validation study, everyone who reported a skin disease immediately before the clinical examination were found to have a skin disease. In addition 22% of those not reporting dermatosis were found to have a skin disease. Toe-web maceration was the most common dermatosis not reported by the farmers. CONCLUSIONS: Finnish farmers suffered from the same type of dermatoses as other populations. The prevalence of eczema and hand eczema was similar to that of other risk populations. A self-report of current dermatosis is probably a good indicator of the point prevalence of explicit skin diseases in populations.

Maternal expectations and experiences of labour pain--options of 1091 Finnish parturients.

A prospective survey of 1091 Finnish parturients was conducted in order to ascertain mothers' expectations for labour pain relief, to measure the actual pain during all three stages of labour and to question their satisfaction and the adequacy of pain relief on the third day following delivery. Antenatal expectations for pain relief were surveyed. Mothers were questioned on pain levels in the delivery room and 3 days after giving birth. Pain levels were ascertained using a visual pain score method. Antenatally, 90% of all parturients anticipated a need for pain relief during labour. In the delivery room over 80% of all parturients described their pain as very severe to intolerable, only 4% of the multiparous had low pain scores (0-2). After pain treatment 50% of multiparous women still had pain scores from 8 to 10, which reflects a lack of effective pain relief. Dissatisfaction with the childbirth experience was very low, and was associated with instrumental deliveries, but not with the usage of analgesia. 51% of all parturients complained of inadequate pain relief during childbirth, which, in multiparous women, was significantly associated with the second stage of labour.

Uteroplacental haemodynamics during spinal anaesthesia for caesarean section with two types of uterine displacement.

The effects of two types of uterine displacement, on uterine and umbilical artery blood flow waveforms were investigated in 22 healthy parturients undergoing elective caesarean section. Displacement was accomplished with either a wedge under the right hip or a mechanical displacer plus 5 degrees left lateral tilt of the operating table. The first 14 patients were assigned randomly into one of the two displacement methods and the left (underlying) uterine and umbilical artery blood flow waveforms were recorded. In a further 8 patients the displacer was used and flow velocity waveforms for both the right and left uterine arteries and the umbilical artery were recorded. Arterial resistance was expressed in terms of the pulsatility index (PI). There were no significant changes in Doppler velocimetry recordings after preloading in either group, but blood flow velocity waveform indices for the underlying left uterine artery increased significantly (P < 0.001) following spinal anaesthesia when the mechanical device was used. This finding indicates increased vascular resistance in the left uterine artery and is probably due to mechanical compression. A wedge as a method for displacing the gravid uterus seems preferable since its use had no effect on the blood flow indices. The unaltered umbilical artery index values in the groups suggest a great tolerance of minor changes in maternal uterine circulation on the part of the fetus.

Parturients' assessment of water blocks, pethidine, nitrous oxide, paracervical and epidural blocks in labour.

This prospective study evaluated the extent to which the analgesic procedures available resulted in efficient pain relief in 833 Finnish parturients. Their pain ratings were recorded according to their own assessment of pain intensity during labour before and after pain management and according to their total pain experience recalled on the third day after delivery. Only regional blocks significantly diminished pain scores during labour and a striking decrease in pain level (P < 0.0001) was maintained until the second stage by epidural analgesia (EDA) alone. The EDA-group consisted mainly of the primiparous (71%) with induced (17%) and most painful deliveries. After delivery 60% of parturients in this group recalled labour pain as being very severe or intolerable. This was partly due to delays in receiving epidural blockade and partly due to the parturient's reticence in requesting analgesia. Pain relief was rated as excellent or good by 94% of the EDA group but by only 50% of the remaining patients.

Uteroplacental and fetal circulation during extradural bupivacaine-adrenaline and bupivacaine for caesarean section in hypertensive pregnancies with chronic fetal asphyxia.

We have studied the effects of an extradural block during Caesarean section using either bupivacaine plain or with adrenaline 85-100 micrograms on blood velocity waveforms of maternal uterine and placental arcuate arteries and fetal umbilical, renal and middle cerebral arteries, in 20 hypertensive parturients with chronic fetal asphyxia. Fetal myocardial function was investigated at the same time by M-mode echocardiography. Extradural anaesthesia resulted in a significant decrease in maternal mean systolic and diastolic arterial pressures in both groups, but this was more marked after plain bupivacaine. There were no significant differences in any of the Doppler recordings relative to baseline values after plain bupivacaine, but after bupivacaine with adrenaline there were significantly increased blood flow velocity indices for the maternal uterine and placental arcuate arteries and significantly decreased indices in the fetal renal and middle cerebral arteries. Neonatal outcome as evaluated by Apgar scores and acid-base values in the umbilical cord were similar in the two groups. The results suggest that adrenaline added to the solution of bupivacaine increased vascular resistance in the uteroplacental circulation, indicating impaired blood flow.

Mucha-Habermann disease: a diagnostic possibility for prolonged fever associated with systemic and skin symptoms.

The severe form of Mucha-Habermann disease with systemic symptoms is a rarely diagnosed disease which should be considered for children with prolonged fever, impaired general condition, skin manifestations and elevated C-reactive protein concentration and/or erythrocyte sedimentation rate. Eleven cases have been described previously in children. We describe two acute episodes of this syndrome in a three-year-old child; the diagnosis was based on clinical, dermatological and histological findings. During both episodes, the fever lasted for more than one week, C-reactive protein concentration increased to more than 150 mg/l, and there was extensive lymph node enlargement. Skin eruption was initially maculopapulous, then vesiculous and finally pustulous. On skin biopsy, vasculitic changes were observed. We treated the second attack of our patient with high-dose gamma globulin; the first attack appeared to resolve itself spontaneously.

Epidural sufentanil and bupivacaine for labor analgesia and Doppler velocimetry of the umbilical and uterine arteries.

BACKGROUND: The pain of parturition is associated with major physiologic alterations mediated by neurohumoral factors and increased activation of the sympathetic nervous system. Epidural local anesthetics abolish or alleviate many of the pain-mediated responses by reducing maternal catecholamine levels, inducing sympathectomy and consequent vasodilatation. The hormone response to surgical stress is not attenuated after epidural opioids as efficiently as after local anesthetics. Opioid receptors may modulate sympathetic outflow at a spinal level. This study was performed to compare the effects of epidural sufentanil and bupivacaine on the uterine and placental circulation. METHODS: Utilizing a prospective randomized, double-blind study design, 30 healthy women at term were examined employing a color Doppler technique to assess and compare the effects of analgesia using sufentanil or bupivacaine epidurally during the first stage of labor on blood flow velocity waveforms in the uterine and umbilical arteries. RESULTS: Effective analgesia was provided by both drugs, bupivacaine and sufentanil. Uterine and umbilical blood velocity waveform indices did not change significantly. There was, however, a significantly greater incidence of fetuses with changes in heart rate tracings in the sufentanil group, decreased variability being the most frequent. Maternal side effects attributable to sufentanil were common but mild. No patient became hypotensive in either group. CONCLUSIONS: Epidural sufentanil and bupivacaine provide effective analgesia with acceptable side effects during the first stage of labor in healthy parturients. Neither drug had any detrimental effects on blood flow indexes reflecting peripheral vascular resistance in the umbilical and uterine arteries in healthy parturients.

Ephedrine and phenylephrine for avoiding maternal hypotension due to spinal anaesthesia for caesarean section. Effects on uteroplacental and fetal haemodynamics.

The effects of i.v. vasopressors on Doppler velocimetry of the maternal uterine and placental arcuate arteries and the fetal umbilical, renal and middle cerebral arteries were studied during spinal anaesthesia in 19 healthy parturients undergoing elective caesarean section. Fetal myocardial function was investigated at the same time by M-mode echocardiography. The patients were randomized into two groups, to be given either ephedrine or phenylephrine as a prophylactic infusion supplemented with minor boluses if systolic arterial pressure decreased by more than 10 mmHg from the control value. Both the vasopressors restored maternal arterial pressure effectively. The ephedrine group showed no significant differences in any of the Doppler velocimetry recordings relative to the baseline values, but during the phenylephrine infusion the blood flow velocity waveform indices for the uterine and placental arcuate arteries increased significantly and vascular resistance decreased significantly in the fetal renal arteries. Healthy fetuses seem to tolerate these changes in uteroplacental circulation well, however, since the Apgar scores for the newborns and the acid-base values in the umbilical cord were within the normal range in both groups. The results suggest that some caution is required when selecting the specific vasopressor agent, the dosage and the mode of administration for the treatment of maternal hypotension secondary to spinal anaesthesia for caesarean section.

Efficacy and safety of itraconazole in the long-term treatment of onychomycosis.

Sixty-one patients with a clinical diagnosis of onychomycosis in finger or toe nails were treated with itraconazole 100 mg/day or griseofulvin 500 mg/day for six to nine months. The infective causes were Trichophyton rubrum, Trichophyton mentagrophytes, or Trichophyton violaceum, and in two cases Candida albicans. A total of 27 finger and 390 toe nails were infected. Statistically significant intragroup reductions from baseline symptom severity values were seen at endpoint (month 6 or 9) for both treatment groups for all parameters: colour change, thickness, brittleness and unaffected area. No clinically or statistically significant differences between the treatment groups were seen at endpoint. However, the itraconazole group continued to improve during the follow-up, while the mean symptom severity ratings remained the same in the griseofulvin group. All itraconazole patients and 85% of griseofulvin patients were rated as cured or markedly improved at endpoint. Nineteen out of 26 evaluable itraconazole patients (73%) remained cured during the three month follow-up period, compared with 12 out of 17 griseofulvin patients (71%). The rather large number of drop-outs, especially among griseofulvin patients, makes it difficult to draw definitive conclusions of the symptom recurrence. Two itraconazole patients stopped medication due to an adverse event, compared to four patients in the griseofulvin group. The clinical laboratory data on itraconazole-treated patients did not show any statistically or clinically significant changes. In conclusion, itraconazole was at least as effective as griseofulvin in the treatment of onychomycosis. The itraconazole group continued to improve after the treatment was stopped. The results show that itraconazole 100 mg/day is safe and efficient in the long-term treatment of fungal nail infections.

Effects of extradural bupivacaine with adrenaline for caesarean section on uteroplacental and fetal circulation.

We have studied the effects of an extradural block using bupivacaine with adrenaline 90-100 micrograms on blood flow in the maternal uterine and placental arcuate arteries and the fetal umbilical, renal and middle cerebral arteries, using a colour Doppler technique in eight healthy parturients undergoing elective Caesarean section. Fetal myocardial function was investigated simultaneously by M-mode echocardiography. Maternal heart rate increased and diastolic arterial pressure decreased after extradural administration of bupivacaine with adrenaline. The latter effect was relieved by increasing the infusion rate in every case and none of the patients required vasopressors. There were no significant differences in maternal or fetal blood velocity waveforms, and no significant changes were found in any of the fetal myocardial measurements relative to control values. These observations suggest that extradural anaesthesia using bupivacaine with adrenaline does not have an adverse effect on vascular resistance in the uteroplacental or fetal circulations or on fetal myocardial function in normal pregnancy when bupivacaine-adrenaline is administered fractionally and maternal hypotension is prevented by rapid crystalloid volume loading.

Uteroplacental and fetal haemodynamics during extradural anaesthesia for caesarean section.

We have studied the effects of extradural anaesthesia with bupivacaine (plain) in eight healthy parturients undergoing elective Caesarean section, on blood flow in maternal uterine and placental arcuate arteries and in fetal umbilical, renal and middle cerebral arteries, using a colour Doppler technique. Simultaneously, fetal myocardial function was investigated by M-mode echocardiography. Maternal and fetal blood velocity waveform indices did not change significantly. We found no changes in fetal myocardial function with extradural anaesthesia, except for an increase in the right ventricular inner end-diastolic dimensions. These results suggest that extradural anaesthesia has no detrimental effects on uteroplacental and fetal circulations in the uncomplicated pregnancy when maternal hypotension is avoided with rapid prehydration.