Safety and tolerability of gamma-hydroxybutyric acid in the treatment of alcohol-dependent patients.

Gamma-hydroxybutyric acid (GHB) has been in clinical use in Italy since 1991 for treatment of alcohol dependence. Results of phase III and phase IV studies have shown that the drug is effective and well tolerated in the treatment of alcohol withdrawal syndrome and in reducing alcohol consumption and alcohol craving. Pharmacosurveillance indicates that abuse of gamma-hydroxybutyric acid is a limited phenomenon in clinical settings when the drug is dispensed under strict medical surveillance and entrusted to a referring familiar member of the patient.

Gamma-Hydroxybutyrate inhibits excitatory postsynaptic potentials in rat hippocampal slices.

Gamma-Hydroxybutyrate (GHB) has been shown to mimic different central actions of ethanol, to suppress alcohol withdrawal syndrome, and to reduce alcohol consumption both in rats and in humans. The aim of the present study was to determine if GHB shared with alcohol the ability to inhibit glutamate action at both NMDA and AMPA/kainate receptors. The NMDA or the AMPA/kainate receptors-mediated postsynaptic potentials were evoked in CA1 pyramidal neurons by stimulation of Schaffer-collateral commissural fibers in the presence of CGP 35348, bicuculline to block the GABA(B) and GABA(A) receptors, and 10 microM 6,7-dinitroquinoxaline-2,3-dione (DNQX) or 30 microM DL-2-amino-5-phosphonovalerate (d-APV) to block AMPA/kainate or NMDA receptors, respectively. GHB (600 microM) produced a depression of both NMDA and AMPA/kainate receptors-mediated excitatory postsynaptic potentials with recovery on washout. The GHB receptors antagonist, NCS-382, at the concentration of 500 microM had no effect per se on these responses but prevented the depressant effect of GHB (600 microM) on the NMDA and AMPA/kainate-mediated responses. In the paired-pulse experiments, GHB (600 microM) depressed the amplitude of the first and the second evoked AMPA/kainate excitatory postsynaptic potentials, and significantly increased the paired-pulse facilitation (PPF). These results suggest that GHB inhibits excitatory synaptic transmission at Schaffer-collateral commissural-pyramidal neurons synapses by decreasing the probability of release of glutamate.

Effects of two different bisphosphonates on Paget's disease of bone: ICTP assessed.

Clodronate and alendronate were compared in 27 patients with active Paget's bone disease. Carboxyterminal crosslinked telopeptide of type I collagen (ICTP) was evaluated as a marker of bone turnover in Paget's bone disease. Group 1. Nineteen patients received clodronate infusions (300 mg/daily) on 5 consecutive days. After 1 year, 12 patients (63%) were still in remission; urinary hydroxyproline (64.8%) and serum alkaline phosphatase (59.4%) were significantly reduced and had returned to normal in 30%. Patients in remission had significantly higher basal values of urinary hydroxyproline. No adverse side effects were observed. Group 2. One year after clodronate, seven relapsing patients retrospectively underwent five consecutive infusions of alendronate (5 mg/daily). Within 12 months, urinary hydroxyproline fell by 74.7%, alkaline phosphatase dropped by 75.2%, osteocalcin by 47.3%, and ICTP by 56.4%. In all patients, urinary hydroxyproline and alkaline phosphatase returned to normal within 3 months and remained within the normal range during the 12-month follow-up. Most patients had mild, short course fever and arthromyalgia. Group 3. Eight newly diagnosed pagetics, received alendronate alone (5 mg/daily for 5 days). All patients responded well to alendronate within the first month. None suffered a relapse during the follow-up. At month 12, urinary hydroxyproline was down by 71.4%, alkaline phosphatase by 75.3%, osteocalcin by 58.1%, and ICTP by 67.4%. In all patients, markers of bone remodeling were in the normal range at the end of the follow-up. Moderate, transitory arthromyalgia, and fever (high and lasting for 7 days in only one case) were observed in half of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Heterologous lyophilized collagen in the secondary healing of pilonidal fistulae]. / Il collagene eterologo liofilizzato nella guarigione per seconda intenzione delle fistole pilonidali.

The authors evaluate heterologous lyophilized collagen efficacy and tolerability in second intention healing of pilonidal sinus fistulae. This therapeutical approach seems to be characterized by a lower relapse incidence. The use of heterologous lyophilized collagen relevantly reduces the prolonged healing time required by such method.

[Diabetes mellitus, hypercholesterolemia, and therapeutic prospects with simvastatin. General considerations and personal contribution]. / Diabete, ipercolesterolemia e prospettive terapeutiche con Simvastatina. Considerazioni generali e contributo personale.

The Authors examine the relationship between diabetes mellitus, lipid metabolism and atherosclerosis with particular emphasis on the role of insulin and on the therapeutic consequences. The results of a study on the efficacy and tolerability of simvastatin in the treatment of hypercholesterolemia in non insulin-dependent diabetic patients are reported. Simvastatin administration induce a significant reduction and increase in total and HDL cholesterol levels respectively contributes to the decrease of triglycerides without interfering with the metabolic control of diabetic condition.

Adhesion, growth, and matrix production by osteoblasts on collagen substrata.

A number of studies have demonstrated the pivotal role of collagen molecules in modulating cell growth and differentiation. In order to analyze the direct effects of collagen type I on the osteoblastic phenotype, we have devised an in vitro culture system for studying the interactions between bovine collagen type I and Saos-2 cells, a human osteoblastic cell line. Saos-2 cells were cultured both on top of collagen-coated culture dishes as well as inside a three-dimensional collagen network. Plating on dishes treated with collagen induced maximal adhesion of Saos-2 cells after 24-hour incubation. Cells cultured on collagen gel matrix expressed about 2.5-fold more alkaline phosphatase when compared with untreated plastic dishes. On collagen-coated dishes the responsiveness of Saos-2 cells to parathyroid hormone was decreased, whereas no modifications were observed in the effect of vasoactive intestinal peptide on these cells. Using a microfluorimetric measurement of DNA, an increase of proliferation was observed in Saos-2 cells cultured on collagen gel. Saos-2 cells were also able to colonize collagen sponges and in this three-dimensional network they were able to synthesize osteocalcin, as assessed both by immunocytochemistry and radioimmunoassay. In this study we have demonstrated that bovine collagen type I exhibits favorable effects on attachment and functional and growth activities of a human osteoblastic cell line, encouraging its use as a bone graft material.

[The structural aspects of the pharmacological activity of calcium antagonists. A general profile and the results of a pilot study of nicardipine]. / Aspetti strutturali dell'attività farmacologica dei calcio-antagonisti. Profilo generale e risultati di uno studio pilota con nicardipina.

The authors examine the most recent findings on arterial hypertension with particular emphasis to morphological changes of the arterial wall and to the results of nicardipine treatment in spontaneous hypertensive rats (SHR). According to these assumptions the authors evaluate the effects of nicardipine on the microvascular network by means of a funduscopic examination in 8 hypertensive patients. The preliminary data suggest that nicardipine has a positive structural and morphological effect on the vessel network.

Collagen as a pharmacological approach in wound healing.

The authors have reviewed the most important biological mechanisms involved in wound healing, the main agents that modify the healing process and the physiological and pharmacological role of collagen. Putative mechanisms of collagen in wound repair are described with particular emphasis on haemostatic effect, interaction with platelets and fibronectin, properties of of increasing fluid exudate and its cellular component (macrophages) and the "scaffold" role for fibroblastic proliferation. Experimental and clinical data clearly suggest that the potential use of collagen in wound repair and its main therapeutical applications: treatment chronic leg ulcers and pressure sores, burns, urological surgery, gynaecological surgery, dentistry and oral surgery, reconstructive surgery, abdominal and vascular surgery, orthopaedy.

Lyophilized non-denatured type-I collagen (Condress) extracted from bovine Achilles' tendon and suitable for clinical use.

On account of the biological role of collagen in wound healing, and because of its biocompatibility, the use of heterologous collagen-based devices is becoming more widespread. Here we describe the extractive procedure and properties of a lyophilized type-I collagen (Condress) suitable for clinical use. Condress is extracted from bovine Achilles' tendon through a non-denaturing procedure in the absence of proteolytic enzymes. It has not been submitted to a chemical cross-linking process before lyophilization. Chemical identification of Condress as type-I acid-insoluble collagen has been carried out by evaluation of total nitrogen and hydroxyproline contents and by chromatographic examination. Electrophoretic analysis and morphological examination by electron microscopy confirm that the procedure employed to extract collagen does not alter the polypeptidic composition of the molecule and its structure. A gamma-ray dose between 0.5 and 1.5 Mrad is quite adequate to sterilize the final product and certainly devoid of degradative effect. The finished product has a special (peculiar) absorbing capacity, immersion time, strain resistance, wrinkling temperature and enzymatic digestion time. It is a nonallergenic product suitable for clinical use. When it has been applied in chronic leg ulcers, pressure sores, or reconstructive surgery, Condress seems to substantially improve wound repair.

Lyophilized collagen in the treatment of diabetic ulcers.

Diabetic foot ulcers are a significant clinical problem. Lyophilized type I collagen (LC) can stimulate wound healing by promoting platelet adhesion and aggregation and acting as a chemotactic factor for macrophages. The aim of the present study was to evaluate the efficacy of LC in the treatment of diabetic ulcers. Twenty patients (twelve males and eight females, age range 60-78 years) affected by non-insulin-dependent diabetes and ulcers (19 foot ulcers and 1 post-traumatic wrist ulcer) were, consecutively and at random, treated with LC or hyaluronic acid medicated gauze. The two groups were comparable in age, sex, size and etiopathogenesis of ulcers, metabolic state. The mean time for wound healing in the group treated with LC was 32.4 +/- 8.6 days, and in the group treated with hyaluronic acid medicated gauze was 49.0 +/- 11.0 days (p less than 0.001). The data suggest that LC significantly improves wound healing and is more active than medicated gauze in the treatment of diabetic ulcers.

Tolerability and safety of clodronate therapy in bone diseases.

A review is made of 126 publications on clinical studies concerning the use of clodronate in the therapy of bone disease involving 1930 patients in order to evaluate the tolerability and the effects following the short-and long-term administration of this drug. The results of the large number of studies indicate that clodronate therapy does not have any clinically significant side-effects and confirm its tolerability and safety.

Controlled clinical study on the use of dichloromethylene diphosphonate in patients with breast carcinoma metastasizing to the skeleton.

Thirty-eight normocalcemic patients with bone metastases from breast carcinoma were randomized to receive dichloromethylene diphosphonate (CL2MDP) in addition to their specific antitumor treatment (chemotherapy and/or hormone therapy), at a dose of 300 mg/day/i.v. or placebo for the first 7 dys. The CL2MDP treatment then continued at a dose of 100 mg day/i.m. for 3 weeks and finally at 100 mg i.m. on alternate days for at least another 2 months. In both groups of patients there was a reduction in the intensity of pain (Scott-Huskisson analog), but there was a more frequent reduction in the daily consumption of analgesics in patients treated with CL2MDP (p = 0.02). Unlike the controls, the patients who received CL2MDP presented a significant reduction in urinary calcium (p = 0.003) and in hydroxyproline (p = 0.05) on the 7th day. As regards the clinical evolution, negative events such as the appearance of hypercalcemia, pathological fractures, new bone lesions or a substantial increase in the preexisting ones, were observed in 9 of the 12 evaluable patients treated with placebo and in 3 out of 9 treated with CL2MDP. Thickening of the preexisting osteolytic lesions was reported in 2 patients treated with CL2MDP. Tolerance was excellent: only a few patients complained of pain at the intramuscular drug injection site.

Lyophilized type-I collagen and chronic leg ulcers.

Lyophilized type I collagen (L.C.) can stimulate wound healing by recruiting a number of different cell types (i.e. platelets and macrophages) and proteins (i.e. fibronectin). Platelets and macrophages produce locally-acting growth factors that in turn induce fibroblast and epidermal migration, angiogenesis and increase matrix synthesis. Chronic leg ulcers (C.L.U.) are the end result of microvascular failure owing to ischemia and stasis. When L.C. has been used in the treatment of C.L.U. we have observed that: a) it is significantly more effective in stimulating the healing of chronic venous ulcers when compared to hydrocolloids (p less than .05), the two products being applied upon half of the same ulcer; b) in the treatment of C.L.U. due to arterial obstruction L.C. is more effective than hydrocolloids without achieving statistical significance; c) it is very effective in the treatment of C.L.U. in thalassaemic patients; d) telethermographic studies have demonstrated an increase of blood perfusion and histological studies have shown the stimulation of angiogenesis, fibropoiesis and epidermal growth; e) the application of L.C. determines the maximum obtainable increase also under conditions of proven cicatrization difficulty; and f) enzymatic degradation of L.C. has not promoted any bacterial infection and no local or generalized sensibilization phenomena have been observed. We can conclude that L.C. is a pharmacological approach to wound healing, directly interfering with cellular and non-cellular components, and significantly improves the reparative process when delayed.

Disodium clodronate in the treatment of pain due to bone metastases.

Disodium clodronate (dichloromethylene bisphosphonate) a drug belonging to the class of bisphosphonates, inhibits osteoclastic bone resorption and therefore it may be used in the palliative treatment of patients affected by osteolytic bone metastases. The authors have evaluated the activity and tolerability of disodium clodronate in providing pain relief and improving the quality of life in patients with bone metastases, who were not improved by radiotherapy or chemotherapy. Out of 37 patients, 32 could be evaluated for pain relief. Of these, 62.5% had their pains improved by disodium clodronate administration without regard to the type of ongoing analgesic therapy, which had no implications on the outcome of the treatment.

Bone densitometry of the peripheral skeleton with a new photon counting and imaging device.

We present a new method for the assessment of bone mineral content of the peripheral skeleton. The method employs a new photon counting and imaging area device, the multi-wire proportional counter. The system can work as a single photon absorptiometer at the energies of both I-125 and Gd-153. It can work also as a dual photon absorptiometer using one of the two pairs of isotopes (I-125, Gd-153) or (I-125, Am-241). Both the calcaneus and the forearm can be imaged in a few minutes, with either single or dual photon absorptiometry. To test this new method in a clinical environment we compared it with the standard dual photon absorptiometry of the forearm. The data collected in a cross-sectional study of bone mineral content and bone mineral density in a group of 76 patients show a good correlation between the two measurement techniques (r = 0.931). The multi-wire proportional counter, due to its imaging capabilities, has a much lower repositioning error. This allows its use in regions with a large gradient of bone mineral density, such as the calcaneus or the very distal site of the forearm, which recent data have indicated to be superior to more proximal measurements in identifying osteoporosis.

Prevention of glucocorticoid-induced osteopenia: effect of oral 25-hydroxyvitamin D and calcium.

Twenty-four patients (9 M and 15 F, age range 51-82) with polymyalgia rheumatica receiving 6-methylprednisolone for a period of 9 months (16 mg/daily/two weeks, 14 mg/daily/two weeks, 12 mg/daily/1 month, 10 mg/daily/1 month, 8 mg/daily/1 month, 6 mg/daily/1 month and 4 mg/daily for the last four months) were randomly assigned to receive either 250HD3 (35 mcg/day for 25 days/month) (Group A) or placebo (Group B) in a double-blind study. All patients also received 500 mg elemental calcium daily. Before and at 3, 6 and 9 months ESR, tenderness on palpation and subjective pain were evaluated. At the same times, mineral metabolism parameters (serum calcium, phosphorus, alkaline phosphatase, 24-h urinary calcium, phosphate and 24-h hydroxyproline excretion) and radial bone mineral content (BMC) were evaluated. Activity indexes (ESR and clinical parameters) improved in both groups. Furthermore, serum alkaline phosphatase and 24-h hydroxyproline excretion decreased significantly only in Group A, and BMC decreased significantly in Group B but rose slightly in Group A. No side effects were observed in any of the patients.