A study of the analgesic potency of indoprofen and pentazocine in postoperative pain.

The relative potency of intravenous indoprofen and intramuscular pentazocine in postoperative pain was evaluated. Indoprofen was administered in 200- and 400-mg single doses and pentazocine was given in 15- and 30-mg doses. Pain was assessed at different time intervals, and additional medication consumption was recorded, as well as side effects and overall evaluations. An analysis of peak pain intensity difference (PID) has shown a significant dose-effect relationship for both drugs and a potency ratio of 1:7 between indoprofen and pentazocine (mg to mg). Based on the frequency of patients requiring remedication and those reporting total pain relief in at least one instance, the potency ratio of indoprofen:pentazocine was 1:13 and 1:10, respectively. The mean peak PID of the pooled data for both doses of each drug was significantly greater for indoprofen. Intravenous indoprofen 400 mg was ranked the most effective overall.

A double-blind clinical trial of fenticonazole (2%) spray versus naftifine (1%) spray in patients with cutaneous mycoses.

A multi-centre, double-blind trial was carried out in 100 patients with cutaneous mycotic infections, confirmed by direct microscopy and/or culture, to compare the efficacy and tolerability of spray formulations of 2% fenticonazole and 1% naftifine. On entry, patients were allocated at random to receive once daily topical applications of one or other drug over a period of 2 to 4 weeks, treatment being stopped when patients had recovered or substantially improved. Clinical and mycological assessments were made before (baseline), at weekly intervals during treatment and, if possible, 2 to 3 weeks after the end of treatment (drug-free period). Treatment was continued for 19.25 days with fenticonazole and 19.62 days with naftifine. All patients had positive mycological findings on entry. The most frequently isolated pathogens were dermatophytes, mainly Trichophyton rubrum; however, Candida albicans was present in 33.3% of patients in the fenticonazole group and in 20.8% of those treated with naftifine. At the end of treatment, only 3 (6.3%) and 5 (10.4%) patients, respectively, of the 48 patients assessed in each group still had positive mycological findings. Assessments of symptoms indicated comparable, significant improvement in both groups, and at the end of treatment the overall opinion of doctors and patients was that about 90% of patients were cured or greatly improved. The end of the drug-free period evaluation showed that, of the patients assessed as cured or greatly improved at the end of treatment, only 1 (3.2%) patient who had received fenticonazole and 2 (6.3%) who had received naftifine were confirmed mycologically as having relapsed.(ABSTRACT TRUNCATED AT 250 WORDS)

Flavoxate, a drug with smooth muscle relaxing activity.

Flavoxate hydrochloride is a flavone derivative with smooth muscle relaxing activity. The product has a broad range of indications and has found one major application in the treatment of urge incontinence. Information on different forms of incontinence and epidemiologic data are summarized. Differences between the myolytic agent flavoxate and anticholinergics are highlighted. The vast amount of information deriving from some 20 years of clinical experience is analysed and major conclusions are drawn. The compound has valid therapeutic efficacy and excellent tolerability. By this token flavoxate is the agent of choice for therapy of disorders caused by smooth muscle spasms.

[Surgical options in the treatment of perianal Crohn's disease]. / Opzioni chirurgiche nel trattamento della malattia di Crohn a localizzazione perianale.

INTRODUCTION: About 40% of patients with Crohns disease (CD) have a perianal involvement. Despite the recent introduction of anti-TNF antibody, this therapy has uncertain long-term results and surgery still remains a major treatment option. AIMS & METHODS: This study relates our experience in surgical management of perianal CD without anti-TNF treatment. From July 92 to February 02, 37 patients with perianal Crohns disease were treated, 43 underwent local operations or faecal diversion for fistulas and/or abscesses. Patients not requiring surgery or in therapy with anti-TNF. were excluded from the study. We analysed the outcome of surgical treatment for perianal CD. RESULTS: Male to female ratio was 1:0.6, median age was 36,9 years (range 17-62). Perianal disease included 32 fistulas (16 trans-sphincteric, 2 superficial, 2 ano-vaginal, 10 multiple and complex, 2 horseshoe) and 7 abscesses (5 perianal, 2 ischio-rectal). Local surgery included 1 abscess drainage, 5 abscess drainage and fistula incision with seton insertion, 2 fistulotomy, 9 partial fistulectomy and seton insertion. At surgery, 40% of patients were ongoing a medical treatment with 5-ASA and/or antibiotics, 40% with steroids and/or immunosoppressors, 15% only with 5-ASA and 5% no ongoing treatment. The horseshoe fistulas were managed with a fistulotomy and seton insertion. One patient with ano-vaginal fistula required proctectomy and the other one total proctocolectomy. Patients treated by diverting colonostomy (3) had fistula recurrence after its closure in 100%. 20% of patients required total proctocolectomy and ileostomy for extensive intestinal disease. Of the 27 patients undergoing seton insertion or fistulotomy none had faecal incontinence due to the operation and 38% had a 1 year recurrence. CONCLUSIONS: Perianal CD is a heterogeneous entity, therefore its management is still controversial. Moreover, a high percentage of patients (18% in our series) requires a major surgery due to the extension and seriousness of rectal involvement. In our survey only 12 patients (39%), with trans-sphincteric fistula, could have been theoretically treated with anti-TNF. We wonder if the cost-and-benefit of this medical treatment justifies its application on patients that could undergo a surgical treatment with good long-term results.

[Strictureplasty in the surgical treatment of complicated Crohn's disease]. / Le stricturoplastiche nel trattamento chirurgico della malattia di Crohn complicata.

INTRODUCTION: Crohns disease is a panintestinal chronic inflammatory condition. Its remitting-relapsing behaviour may require in the single patient repeated surgeries, with the aim of resolving the complications of the disease. The awereness that surgery cannot resolve the disease has led, in the last years, to the development of new "conservative surgical techniques", which preserve as much of the intestinal tissue as possible. These techniques are minimal resection and strictureplasty (SP). Aim of the study was to perform a prospective analysis of the long-term outcome of SP in a consecutive series of patients undergoing surgery for complicated Crohns Disease at the Division of general surgery, L. Sacco University Hospital, Milano, Italia. METHODS AND RESULTS: During the period of October 1992 to June 2002, 286 patients underwent surgical procedures for jejunoileal Crohns disease. 116 of them underwent SP resulting in a total of 217 procedures, of which: 111 Heineke-Mikulicz SP (51.2%), 36 ileoileal side-to-side SP (16.6%), 40 ileoceacal SP (18.4%) and the remaining 30 ileocolic SP (13.8%), as previously described by A.M. Taschieri. Fiftyone of the patients (23.5%) had concomitantly a minimal bowel resection. Postoperative mortality was nil, while in 3 cases (2.59%) repeated surgery was necessary due to postsurgical complications. Time-to-event estimates were performed using the Kaplan-Meier function. CONCLUSIONS: mortality, morbidity, and long-term results in this population of patients who underwent SP are encouraging and in line with reports in the international literature. It is suggested that SP together with minimal bowel resections, may be considered as first line surgical therapy in patients with Crohns Disease.

[Bowel ultrasound in Crohn's disease. Surgical importance]. / L'ecografia intestinale nel morbo di Crohn. Rilevanza chirurgica.

The use of ultrasound in Crohns disease has a recent history. This method is useful in various situations like: the diagnosis of the disease, the diagnosis of intra-abdominal complications and the follow-up of the operated patient. Moreover, thanks to its practicality of use, ripetibility and accuracy, ultrasounds can represent a first line diagnostic instrument for Crohns disease both in elective and emergency conditions. The authors, in this paper, consider its usefulness and various aspects in these conditions.

Preoperative localization and surgical margins in conservative breast surgery.

Breast-conserving surgery (BCS) is the treatment of choice for early breast cancer. The adequacy of surgical margins (SM) is a crucial issue for adjusting the volume of excision and for avoiding local recurrences, although the precise definition of an adequate margins width remains controversial. Moreover, other factors such as the biological behaviour of the tumor and subsequent proper systemic therapies may influence the local recurrence rate (LRR). However, a successful BCS requires preoperative localization techniques or margin assessment techniques. Carbon marking, wire-guided, biopsy clips, radio-guided, ultrasound-guided, frozen section analysis, imprint cytology, and cavity shave margins are commonly used, but from the literature review, no single technique proved to be better among the various ones. Thus, an association of two or more methods could result in a decrease in rates of involved margins. Each institute should adopt its most congenial techniques, based on the senologic equipe experience, skills, and technologies.

Incarcerated massive incisional hernia: extensive necrosis of the colon in a very obese patient. Surgical treatment and vacuum-assisted closure therapy: a case report.

We discuss a diabetic obese patient with an extensive necrosis of the ascending and transverse colon plus segmental necrosis of the small bowel incarcerated in a massive median incisional hernia below the umbilicus. After a blood test and an abdominal CT scan (without contrast dial), the patient underwent an urgent operation. We performed an extended right hemicolectomy, multiple segmental small bowel resections and a terminal ileostomy. The defect of the abdominal wall was treated with vacuum-assisted closure (VAC) therapy with good results.

[Vacuum-assisted breast biopsy for diagnosis of non-palpable lesions: experience with 226 cases]. / Biopsia mammaria "vacuum-assisted" per la diagnosi di lesioni non palpabili: descrizione dei primi 226 casi.

Vacuum-assisted breast biopsy (VABB) is now available for non-palpable lesions. The present study describes the results obtained from 226 consecutive VABBs performed at "L. Sacco" Hospital, Milan, from November 2005 to July 2007 (198 stereotactic and 28 ultrasonographic procedures). Adequate tissue samples for histopathological evaluation were obtained in 225 cases (99.6%). The diagnoses were as follows: 9 normal tissues (4%), 97 benign (43%), 25 "probably benign" (11%), 4 "suspicious for malignancy" (2%) and 90 malignant (40%, 53 in situ and 37 infiltrating carcinoma). Of the 90 malignant cases, 38 (42.2%) underwent subsequent surgical excision in our Unit; 84.2% (32/38) had concordant histopathological findings. In conclusion, VABB is an accurate and safe technique for diagnosis of non-palpable lesions, and in experienced hands avoids unnecessary surgical procedures.

Painless thyroiditis followed by autoimmune disorders of the thyroid. A case report with biopsy.

Painless thyroiditis is a clinical entity of unknown origin. We report a case of a woman first seen with painless thyroiditis, who consequently developed a true hyperthyroidism, then exophthalmos and finally permanent hypothyroidism. The biopsy findings and serum antibodies determinations at the final stage were of Hashimoto's thyroiditis. The case is discussed and the need for a long follow-up after a painless thyroiditis is stressed.

HLA antigen in Jewish patients with juvenile diabetes mellitus.

Fifteen diabetic families and fifty non related diabetic patients were studied for their HLA antigen pattern. The patient group was compared to controls matched to compensate for ethnic variations. In this group the data analysis revealed a decrease in HLA-A1 as opposed to increased HLA-A2 frequency, both of no statistical significance; HLA-Aw26 was found significantly increased (p less than .0005; corrected p less than .015); HLA-B8 was found to be increased (p = ,0025) but not significantly after correction (p = .075). Family analysis revealed that whenever B8 was present it was inherited to the affected sib only. Where B8 was not present, the same haplotypes were shared by healthy and affected sibs. Bw16 although not significantly increased, was found in all patients but one, when part of the family pattern, although non affected sibs shared it as well,

Lercanidipine: short plasma half-life, long duration of action and high cholesterol tolerance. Updated molecular model to rationalize its pharmacokinetic properties.

Calcium-channel antagonist drugs of the 1,4-dihydropyridine type have been shown to bind to the L-type calcium channel. These drugs are not only amphiphilic, but new molecular designs have become increasingly lipophilic and can readily transport across cell membranes, accessing both hydrophilic and hydrophobic environments, despite becoming more soluble in the membrane bilayer. This biophysical understanding appears not only to define the molecular pathways for drug binding to the calcium-channel receptor, but also to explain differences in the overall clinical pharmacokinetics observed for different drugs in this class. The pharmacokinetic profile of calcium antagonists, although influenced to some degree by interactions with their target calcium-channel receptor, appears to be largely dictated by their interactions with cell membranes at the molecular level. There appears to be a correlation between the duration of action of such membrane-active drugs and the membrane partition coefficient in conjunction with the washout rate. This class of drugs has evolved from a drug such as amlodipine, with a long duration of action related to prolonged plasma half-life, to lercanidipine, which has the shortest plasma half-life relative to its intrinsically long duration of action. Recently, it was discovered that membrane cholesterol reduces the amount of calcium-channel antagonist that can partition into the membrane. Atherosclerotic disease results in increased levels of membrane cholesterol in smooth muscle cells. Latest generation calcium antagonist, which have a long duration of action, can better overcome this negative effect. Lercanidipine has now been shown to have one of the highest measured tolerances to cholesterol, which may indicate its ability to treat a broad range of hypertensive patients with varying degrees of progressive atherosclerotic disease. On what criteria should the effectiveness of calcium antagonists be evaluated? A good calcium antagonist needs to exhibit a placebo-like side-effect profile, thus ensuring good patient compliance. However, an intrinsically long-lasting, once-a-day dose is also pharmacokinetically desirable. To be a truly optimal calcium antagonist, it should function and be efficacious over a broad range of hypertensive patients. It should be able to control blood pressure in light of other complications such as progressive atherosclerotic disease. Recent studies indicate that during the progression of atherosclerosis, cholesterol levels within cell membranes of the arterial wall increase, a process that can reduce the effective concentration of calcium antagonists in these membranes. What is needed is a calcium antagonist that is slow acting to reduce vasodilatory induced side-effects and intrinsically long lasting to ensure once-a-day dosage, and that possesses a high cholesterol tolerance factor to overcome the molecular and compositional changes taking place in the arterial wall, so that it can treat effectively a broad range of hypertensive patients.

Fenticonazole tissue levels after the application of 3 different dosage forms of vaginal ovules.

Fenticonazole vaginal ovules of 200 mg, 600 mg and 1,000 mg were administered to 42 women prior to gynecological surgery. Tissue concentrations in the vaginal mucosa were determined after 3 h and 12 h in biopsy specimens taken from the same position in the posterior fornix. Tissue concentrations were higher at 3 h in comparison to 12 h with all 3 doses. There was no statistical difference between the concentrations yielded by the 3 different ovules at 3 h, while after 12 h the concentrations were dose-dependent and significantly higher after 1,000 mg in comparison to 200 mg, but not to 600 mg.

Fenticonazole cream once daily in dermatomycosis, a double-blind controlled trial versus bifonazole.

A randomized, double-blind clinical trial was undertaken in 41 patients with dermatomycosis to compare topical 2% fenticonazole cream (group A: 21 patients) with topical 1% bifonazole cream (group B: 20 patients). Treatment was performed as a once daily application. Mycological and clinical parameters were assessed before treatment and after 7, 14, 21 and 28 days. At the control visits the clinical investigator also expressed an overall judgement on the patient's state of disease. This parameter was based on a combined clinical and mycological assessment by the physician; laboratory screening investigations were undertaken before and at the end of treatments. All patients were checked for their state of disease 3-4 weeks after the end of treatment. All assessment criteria showed fenticonazole to be at least as efficacious as bifonazole. Several trends in favor of fenticonazole were also found: fenticonazole achieved superior results in the overall clinical evaluation, and after 3 weeks of treatment 15 patients out of 21 on fenticonazole were cured in mycological and clinical terms, whereas treatment with bifonazole resulted in complete healing of only 7 patients out of 20. This difference is statistically significant (p = 0.021) and indicates a more rapid therapeutic activity of fenticonazole. At the posttreatment rechecks no recurrent disease was registered, irrespective of whether patients had received fenticonazole or bifonazole. Laboratory screening investigations revealed no evidence of significant treatment-related changes or abnormalities in both treatments. No adverse events were noted for either treatment.

Effect of metergoline on prolactin, follicle stimulating hormone, luteinizing hormone and thyroid stimulating hormone response to TRH and LHRH in normal men and women.

Metergoline, a prolactin (PRL)-lowering drug with an antiserotoninergic activity, is known to restore menstruations and fertility in hyper-PRL patients even when PRL levels are not normalized. This suggests that metergoline might also affect gonadotropins release. In a double-blind cross-over study in 8 normal males, repeated administration of metergoline enhanced the LH response to LHRH and reduced the PRL response to TRH; for females, three different tests were performed on days 5, 8 and 21 of two different menstrual cycles, each test being preceded by metergoline or by placebo administration. Metergoline always reduced the PRL response to TRH; on the 5th day, metergoline reduced the FSH response to LHRH and on the 21st day enhanced the LH response to LHRH. Basal levels of LH, FSH, T3, T4, Testosterone, 17 beta-estradiol and progesterone as well as the FSH response to LHRH (in males) and the TSH response to TRH (in both males and females) were not modified by metergoline. The data suggest that tests with TRH and LHRH can yield different results when performed during metergoline administration and that metergoline, acting through an unknown mechanism, can modify gonadotropins release.

Puerperal lactation, gonadotropin release and estradiol release: effects of metergoline and bromocriptine.

The exact cause of amenorrhea during the puerperium is still a matter of debate. PRL might inhibit primarily the release of FSH and LH or their stimulating effects on the ovary. In the study presented here, 28 healthy women were investigated, 13 of them lactating puerperae. In the other 15, lactation was prevented by drugs (metergoline in 9, bromocriptine in 6). The women's serum PRL, FSH, LH, beta-HCG and 17 beta-estradiol as well as their FSH and LH response to LHRH (100 micrograms i.v.) were tested 1, 3, 7 and 14 days after vaginal delivery. Serum PRL levels remained elevated in the lactating puerperae and dropped in the puerperae treated with metergoline or bromocriptine. The pattern of FSH, LH and beta-HCG levels as well as the FSH and LH response to LHRH were superimposable in lactating and in nonlactating women. 17 beta-estradiol levels dropped in all puerperae from day 1 to 7, but rose from day 7 to 14 only in the puerperae treated with metergoline or bromocriptine and not in the lactating women. These data indicate that PRL directly affects the ovarian response to FSH and LH, whereas the release of FSH and LH remains unaffected. A stimulatory effect of metergoline and bromocriptine on the ovarian steroidogenesis cannot be excluded.

Functional antagonistic activity of Rec 15/2739, a novel alpha-1 antagonist selective for the lower urinary tract, on noradrenaline-induced contraction of human prostate and mesenteric artery.

The aim of this study was to compare with known reference standards the functional in vitro alpha-1 antagonistic activity of Rec 15/2739 on noradrenaline-induced contractions of human prostate and mesenteric artery. We also characterized these tissues with regard to the alpha-1 adrenoceptor subtypes present. Comparing the apparent pKB values revealed Rec 15/2739 to be one of the most potent compounds action on the prostate. Its potency was slightly lower than that of tamsulosin and was higher than the potencies of prazosin, terazosin and 5-methylurapidil. On the mesenteric artery, tamsulosin was the most potent compound. Comparing the results from the functional studies with those obtained from radioreceptor binding studies, we found that the potency (pKB value) in inhibiting the contraction of prostatic tissue showed a close and significant correlation with the affinity for native and recombinant alpha-1A adrenoceptors. No significant correlation was found with affinity for either the native or the recombinant alpha-1B adrenoceptor subtype, or for recombinant alpha-1d receptors. Similar results were obtained for mesenteric artery. In order to characterize further the alpha-1 adrenoceptor subtypes present in the examined tissues, we investigated the functional effects of chloroethylclonidine, an alpha-1B-D subtypes selective alpha-1 adrenoceptor irreversible antagonist, and those of nifedipine, which antagonizes the extracellular calcium influx primarily mediated by alpha-1A adrenoceptor stimulation. The results indicate the presence of both chloroethylclonidine-sensitive and -insensitive alpha-1 adrenoceptor subtypes in the human prostate, whereas in mesenteric artery the alpha-1A subtype seems to be present exclusively. The possibility that the functionally relevant alpha-1 adrenoceptor subtype could be classified as alpha-1L in both tissues shoul also be considered.

Effect of the new calcium antagonist lercanidipine and its enantiomers on the migration and proliferation of arterial myocytes.

The in vitro effects were investigated of the new dihydropyridine calcium antagonist (CA) lercanidipine and its enantiomers on arterial myocyte (smooth muscle cell; SMC) migration and proliferation as related to L-type calcium channel inhibition. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in concentration ranging from 10 to 50 microM. The antiproliferative effect of lercanidipine, evaluated as cell number, was dose dependent, with a potency similar to that of lacidipine and nifedipine, and was unrelated to the stereoselectivity of enantiomers to bind L-type calcium channels. The cell doubling time increased with drug concentration < or = 122 versus 38 h for controls. The cell growth inhibition induced by lercanidipine and its enantiomers was reversible. Lercanidipine dose dependently decreased [3H]thymidine incorporation into DNA; the (R)-enantiomer, displaying the lowest CA activity, was the most potent in this respect. The tested compounds were able to inhibit fibrinogen-induced myocyte migration in a dose-dependent manner, with the (R)-enantiomer showing the more pronounced effect. To directly rule out the role of calcium channels in the antiatherosclerotic properties of lercanidipine, we examined the effect of the compounds on serum-stimulated calcium influx in SMC. Fluorimetry of Fluo 3 was used to measure changes in free cytosolic Ca2+ concentration ([Ca2+]i) in SMC after long-term preincubation (24 h) with the tested CA. Lercanidipine and its enantiomers (25 microM) decreased the serum-induced elevation of [Ca2+]i in SMC with the (S)-enantiomer (69% inhibition) 2.4-fold more active than the counterpart and the racemate (29% inhibition). In conclusion, our in vitro results suggest that lercanidipine may directly interfere with events involved in atherogenesis. The studies performed with enantiomers of lercanidipine suggest that the observed effects are not related to the blockade of voltage-dependent Ca2+ channels and confirm at least in vitro a pharmacologic potential of the compound to negatively influence the process of atherogenesis.

The new calcium antagonist lercanidipine and its enantiomers affect major processes of atherogenesis in vitro: is calcium entry involved?

Atherosclerosis results from multiple factors and involves several mechanisms, including endothelial monocyte and smooth muscle cell (SMC) changes, cholesterol accumulation, plaque rupture and thromboembolism. Calcium ions play a role in the initial and chronic development of atherosclerotic lesions. Several studies in experimental animal models have demonstrated the potential direct antiatherosclerotic effects of calcium antagonists. In this study the antiatherogenic activity of lercanidipine, a new lipophilic, second-generation calcium antagonist, was investigated. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in concentrations ranging from 10 to 50 microM. The antiproliferative effect of lercanidipine was dose dependent, with a potency similar to that of lacidipine and nifedipine, and was unrelated to the stereoselectivity of enantiomers to bind L-type calcium channels. Lercanidipine and its enantiomers (25 microM) decreased the serum-induced elevation of [Ca2+]i in SMC, with the (S)-enantiomer (69% inhibition) being 2.4-fold more active than the (R)-counterpart (29% inhibition). The studies performed with enantiomers of lercanidipine suggest that the observed effects are not related to the blockade of voltage-dependent Ca2+ channels and confirm, at least in vitro, the pharmacological potential of the compound to influence negatively the process of atherogenesis.