Third Days Of Treatment Research Articles

Prevalence of chronic pain after herniorrhaphy, orchiopexy, and bernardi procedure in children. A retrospective-prospective study

Chronic postsurgical pain (CPSP) is defined as pain that develops or increases in intensity after a surgical procedure and persists for at least three months. Its prevalence rate ranges from 5% to 54%. Aim - to assess the prevalence of CPSP among children at the age of 7-18 years residing in the Precarpathian region at three and six months after herniorrhaphy, orchiopexy and Bernardi procedure. Materials and methods. There were observed 92 children at the age of 7-18 years, who underwent treatment for abdominal wall hernia, cryptorchidism, varicocele, and hydrocele at the surgical department. Children were divided into the following groups: Group 1a included children at the age of 7-12 years with acute pain syndrome in the postoperative period; Group 1b comprised children at the age of 13-18 years with acute pain syndrome in the postoperative period; Group 2a included children at the age of 7-12 years with chronic pain syndrome; Group 2b included children at the age of 13-18 years with chronic pain syndrome. Results. The prevalence of CPSP following surgery among children of the Precarpathian region was found to be 33.7%, with a male predominance (р<0.05). There was an increased need for postoperative pain management with paracetamol in children of Group 2a (р<0.05). The mean scores of the Face, Legs, Activity, Cry, Consolability (FLACC) scale were significantly higher in children of Group 2a, 2b as compared to Group 1a, 1b (р<0.05). The Visual Analogue Scale (VAS) confirmed greater pain intensity in children of Group 2a on the second and third days of treatment (р<0.05). Conclusions. The high prevalence of chronic pain in children after herniorrhaphy, orchiopexy by Petrivalsky / Schoemaker technique, Ross and Bernardi procedures is due to ineffective perioperative pain management that requires the use of additional analgesia techniques, including regional ones. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Pharmacokinetics of Intraperitoneal Vancomycin and Amikacin in Automated Peritoneal Dialysis Patients With Peritonitis.

Objective: The study aimed to evaluate the vancomycin and amikacin concentrations in serum and dialysate for automatic peritoneal dialysis (APD) patients. Methods: A total of 558 serum and dialysate samples of 12 episodes of gram-positive and 18 episodes of gram-negative peritonitis were included to investigate the relationship between vancomycin and amikacin concentrations in serum and dialysate on the first and third days of treatment. Samples were analysed 30, 120 min, and 48 h after intraperitoneal administration of vancomycin in peritonitis caused by gram-positive agents and 30, 120 min, and 24 h after intraperitoneal administration of amikacin in peritonitis caused by gram-negative agents. Vancomycin was administered every 72 h and amikacin once a day. The target therapeutic concentration of amikacin was 25–35 mg/l at the peak moment and 4–8 mg/l at the trough moment; and after 48 h for vancomycin, 15–20 mg/l at the trough moment. Results: For peritonitis caused by gram-negative agents, at the peak moment, therapeutic levels of amikacin were reached in dialysate in 80.7% of patients with evolution to cure and in 50% of patients evaluated as non-cure (p = 0.05). At the trough moment, only 38% were in therapeutic concentrations in the dialysate in the cure group and 42.8% in the non-cure group (p = 1). Peak plasma concentrations were subtherapeutic in 98.4% of the samples in the cure group and in 100% of the non-cure group. At the trough moment, therapeutic concentrations were present in 74.4% of the cure group and 71.4% of the non-cure group (p = 1). Regarding vancomycin and among gram-positive agents, therapeutic levels were reached at the peak moment in 94% of the cure group and 6% of the non-cure group (p = 0.007). After 48 h, 56.8% of the cure group had a therapeutic serum concentration whereas for the non-cure group it was only 33.3% (p = 0.39). Conclusion: Despite a small sample size, we demonstrated peak dialysate amikacin level and peak serum vancomycin level correlates well with Gram-negative and Gram positve peritonitis cure, respectively. It is suggested to study the antibiotics pharmacodynamics for a better understanding of therapeutic success in a larger sample.

Efficacy of Tocilizumab in the treatment of severe COVID-19 patients with respiratory failure

Objective: This study aimed to investigate the impact of tocilizumab, an IL6R inhibitor, on clinical features and laboratory tests of subjects admitted with severe COVID-19 and respiratory failure.
 Material and Methods: A total of 30 patients with positive polymerase chain reaction for COVID-19 and respiratory failure were analyzed in a retrospective manner. All patients received 8mg/kg body weight tocilizumab i.v. once in addition to the standard COVID-19 treatment protocol, including Oseltamivir phosphate 75mg twice daily, hydroxychloroquine 200 mg twice daily, and azitromycine 250 mg once daily following a 500 mg loading dose. Demographic characteristics, and clinical features including oxygen saturation, the concentration of oxygen inhalation, body temperature, mean arterial pressure and heart rate, and SpO2, end-tidal CO2, and blood tests including complete blood count, procalcitonin, C-reactive protein (CRP), Troponin-I, D-dimer, and liver and kidney function tests were recorded before and after treatment with tocilizumab.
 Results: A significant increase occurred in SaO2 on first and third days following treatment with tocilizumab (84.3 % and 90.3%, respectively, p<0.001 for both recordings compared to baseline). There was also a significant increase in end-tidal CO2. The increase in mean SaO2 after tocilizumab was followed by a decline in respiratory rate on the first and third days of treatment. A dramatic decline was observed in body temperature from the first day of treatment with tocilizumab. Lymphocyte count increased following tocilizumab and C-reactive protein and Troponin I levels were reduced.
 Conclusion: Tocilizumab appears as an effective therapeutic option for improving oxygenation, symptoms and laboratory surrogates of ongoing inflammation in subjects with severe COVID-19.

Risk assessment of febrile neutropenia and evaluation of G-CSF use in patients with cancer: a real-life study.

The guidelines suggest using granulocyte-colony stimulating factor (G-CSF) for febrile neutropenia (FN) as prophylaxis in chemotherapy protocols with the risk of 10-20% after assessment of patient's risk factors. Therefore, the aim of this study is to assess the risk of FN by using the Patient Risk Score (PRS) and evaluating G-CSF use and its side effects by a clinical pharmacist at an outpatient clinic. The study was conducted from May 2017 until November 2017 at the University Hospital oncology outpatient clinic. Patients who receive chemotherapy protocols with FN risk of 10-20% and > 20% and were initiated G-CSF were included. The patients' risk factors were assessed by the PRS, and the side effects were monitored for 3months by a clinical pharmacist via a patient self-reported monitoring card. A total of 118 patients were included (286 interviews) in the study. There was a significant increase between the first and third visits on the PRS total scores of patients (p = 0.034). The patterns of G-CSF use showed that 34.7% undertreated, 22.8% overtreated, and 42.3% of patients were correctly treated for the prophylaxis. The severity of G-CSF-related musculoskeletal pain was increased on the second and third days of treatment. The use of G-CSFs for FN prophylaxis is recommended; however, there may be a group of patients who are inadequately or unnecessarily treated. Therefore, patients should be assessed for the risk of developing FN in each cycle of chemotherapy and a regular risk assessment by using the PRS can be implemented in the monitoring process.

Superovulatory response to gonadotrophin FSH/LH treatment and effect of progestin supplement to recipients on survival of transferred vitrified embryos in goats

Two experiments were carried out in goats to evaluate the effects of the FSH/LH ratio during treatment on ovarian response and embryo production (experiment 1) and the efficiency of progestin supplementation on pregnancy and the survival of vitrified embryos (experiment 2). In experiment 1, 30 goats were synchronized and allocated to 2 groups (n = 15) corresponding to the following superovulatory treatments with p-FSH (250 IU, over 3 days) having different doses of purified FSH and LH: (group A) control, FSH/LH ratio of 1, kept constant during treatment; (group B) FSH/LH ratio of 2 and daily FSH/LH ratio of 5.0:1.0:0.3 for the first, second, and third days of treatment, respectively. Ovarian response and embryo production were assessed 7.5 days after estrus. In experiment 2, 46 vitrified blastocysts from p-FSH–superovulated donors were transferred to 26 recipients (2 blastocysts per goat) 7.5 days after estrus. The recipients were synchronized with donors and allocated to 2 experimental groups (n = 13). Group C received progestin supplement as fluorgestone acetate (FGA) inserted into the vagina at the time of embryo transfer, replaced with a new one 16 days later, and maintained until the 45th day of pregnancy; group D, no treatment (control). Pregnancy was diagnosed by transrectal ultrasound scanning on Days 30 and 45 after estrus and followed to term. The results indicated that the increase in FSH/LH ratio from 1 to 2 with decreasing daily FSH/LH (treatment B) did not improve the superovulatory response. Superovulatory treatment A (control) advanced (P < 0.05) the onset of estrus and showed a higher ovulation rate compared to group B (14.9 vs. 10.9; P < 0.05). Fertilization rate, embryo yield, and mean number of transferable embryos in group A (7.5) were higher (P < 0.05) than those in group B (3.2). Recipient goats receiving progestin supplementation (group C) showed a higher (P < 0.05) pregnancy rate and embryo survival (kids born per embryos transferred; 69.3% and 73.1%) than the controls (group D; 23.3% and 19.2%). In conclusion, regimen A with FSH/LH ratio of 1 kept constant during the treatment gave the best ovarian response and embryo production. The progestin supplementation as FGA-pessary administered at embryo transfer time to the 45th day of pregnancy improved the pregnancy rate, kidding rate, and embryo survival of transferred vitrified embryos. Intravaginal progestin supplement has the potential to reduce the incidence of pregnancy losses during early pregnancy.

Efficacy of Bacillus thuringiensis (Berliner) isolates on fig moth, Ephestia cautella (Walker) Larvae

The following dilution 5×10-1, 10-1, 10?2 , 10-3 gm/L for the indigenous isolate of Bacillus thuringiensis bacteria and the commercially isalate were used for experiments against the different stages of fig moth of E.cautella which exposed by filter paper method. The results showed that mortality of larval stages was increased with the increasing concentration of the biocide, in addition to increase in the mortality of the larval stages reached to the highest percentage in the third days of treatment of the larval stage in comparison with the first and second days of exposure. The results also showed that the sensitivity of larval stages was increased in first and second instars while reduced in the last instars .The high percentage of first instar mortality for the indigenous isolate in the concentration of 5×10-1 was 72.8% , while the low percentage of mortality showed in the concentration of 5×10-1 for the fifth instar larvae which was 13.3% in third days of treatment while a high percentage of mortality was showed for the first instar larvae for the commercially isulate in the concentration of 5×10-1 was 59.4% Furthermore, low percentage of mortality was shown in the concentration of 5×10-1 in fifth instar larval which was 8.3% in the third days of treatment. The results also showed that the indigenous isolated was more effective than the commercially produced bacteria for killing larval instars of fig moth E.cautella .The total percentage of larval instar mortality reached to 44.5 % after the third days of treatment in concentration 5×10-1 in the indigenous isolate , and it was 33.8 % in the commercially produced bacteria .

Efficacy of Bacillus thuringiensis (Berliner) isolates on fig moth, Ephestia cautella (Walker) Larvae

The following dilution 5×10-1, 10-1, 10?2 , 10-3 gm/L for the indigenous isolate of Bacillus thuringiensis bacteria and the commercially isalate were used for experiments against the different stages of fig moth of E.cautella which exposed by filter paper method. The results showed that mortality of larval stages was increased with the increasing concentration of the biocide, in addition to increase in the mortality of the larval stages reached to the highest percentage in the third days of treatment of the larval stage in comparison with the first and second days of exposure. The results also showed that the sensitivity of larval stages was increased in first and second instars while reduced in the last instars .The high percentage of first instar mortality for the indigenous isolate in the concentration of 5×10-1 was 72.8% , while the low percentage of mortality showed in the concentration of 5×10-1 for the fifth instar larvae which was 13.3% in third days of treatment while a high percentage of mortality was showed for the first instar larvae for the commercially isulate in the concentration of 5×10-1 was 59.4% Furthermore, low percentage of mortality was shown in the concentration of 5×10-1 in fifth instar larval which was 8.3% in the third days of treatment. The results also showed that the indigenous isolated was more effective than the commercially produced bacteria for killing larval instars of fig moth E.cautella .The total percentage of larval instar mortality reached to 44.5 % after the third days of treatment in concentration 5×10-1 in the indigenous isolate , and it was 33.8 % in the commercially produced bacteria .

No evidence for spread of Plasmodium falciparum artemisinin resistance to Savannakhet Province, Southern Laos.

We conducted an open-label, randomized clinical trial to assess parasite clearance times (PCT) and the efficacy of 4 mg/kg (group 1, n = 22) and 2 mg/kg (group 2, n = 22) of oral artesunate for three days followed by artemether-lumefantrine in patients with uncomplicated Plasmodium falciparum malaria at Xepon Interdistrict Hospital, Savannakhet Province in southern Laos. Slides were read in duplicate. The overall mean (95% confidence interval; range) PCT in hours was 23.2 (21.2–25.3; 12–46) and 22.4 (20.3–24.5; 12–46) for the first and second microscopists, respectively (P = 0.57). Ten (23%) patients remained parasitemic on day 1 after treatment (4 [18%] in group 1 and 6 [27%] in group 2; P = 0.47). No patient had patent asexual parasitemia on the second and third days of treatment. The 42-day polymerase chain reaction–corrected cure rates were 100% in both treatment groups. Serious adverse events did not develop during or after treatment in any patients. In conclusion, no evidence of P. falciparum in vivo resistance to artesunate was found in southern Laos.

Vancomycin pharmacokinetic–pharmacodynamic parameters to optimize dosage administration in critically ill children

Critically ill children may present changes in pharmacokinetic parameters and may not reach effective concentrations of vancomycin with current dosages. The objective of this study is to calculate vancomycin pharmacokinetic parameters in critically ill children and to estimate area under the curve at 24 hrs/minimal inhibitory concentration reached for Staphylococcus aureus. Children treated with vancomycin, hospitalized in the Intensive Care Unit of the Pediatric Hospital-Centro Hospitalario Pereira Rossell, were included. Samples to determine vancomycin serum concentration were obtained on first and third days of treatment, 1 hr after the end of the third daily dose administration (maximum drug concentration) and 15 mins before the fourth (minimum drug concentration). Half-life elimination, volume of distribution, clearance, and area under the curve at 24 hrs were estimated. Vancomycin concentration values of 20-40 μg/mL (maximum drug concentration) and 5-10 μg/mL (minimum drug concentration) were considered therapeutic. Twenty-two children were included. On day 1, seven of 18 children for maximum drug concentration and 16 of 22 for minimum drug concentration reached concentrations in therapeutic range; on day 3, seven of 16 children for maximum drug concentration and 11 of 17 for minimum drug concentration did. Mean values of maximum drug concentration and minimum drug concentration were higher in children with negative water balance. Mean value of half-life elimination increased from day 1 to day 3. Considering a value of minimal inhibitory concentration for S. aureus of 1 μg/mL, nine of 18 children reached a relationship area under the curve at 24 hrs/minimal inhibitory concentration >400 on day 1 and seven of 15 on day 3. Considering a minimal inhibitory concentration of 2 μg/mL, one child reached it on day 1 and one on day 3. Critically ill children show changes in pharmacokinetic parameters. Serum concentration monitorization is necessary for dosage individualization. Most children do not reach an area under the curve at 24 hrs/minimal inhibitory concentration >400 with current dosage.

Triple bothropic envenomation in horses caused by a single snake

In the present study, snakebites caused by a single Bothrops pauloensis simultaneously affecting three male adult horses are described. Whereas the first two affected horses were six years old, the third was 16 years old; they weighed respectively 555, 550 and 500 kg. All horses presented swollen muzzles. The first animal received an initial antivenom dose of 19 vials and adjuvant medication, it was also subjected to tracheostomy due to the progression of acute respiratory failure. The second and third horses respectively received 15 vials of antivenom each, in addition to adjuvant medication. Due to continuous changes in blood coagulation observed during hospitalization, the first and the second horses received five more vials of antivenom, respectively, in the second and third days of treatment. The first animal was discharged on 15th day and the other on the 8th day of hospitalization. Several factors including the main actions of Bothrops venom (coagulation, proteolytic and vasculotoxic activities), the importance of early diagnosis based on clinical history and clinical examination suggesting the diagnosis of Bothrops snakebite, the adequate doses of antivenom, and finally the immediate tracheostomy are herein discussed. The tracheostomy, required to save the life of the first horse, should only occur after the administration of antivenom and control measures for changes in blood coagulation.

Coumarin skin necrosis: a severe complication of oral anticoagulation

A 39-year-old white female with severe peripheral arterial disease, due to fibromuscular dysplasia, developed coumarin-induced skin necrosis. Owing to recurrent arterial thromboses, including one episode which resulted in left above-knee amputation, phenprocoumon therapy was initiated, at doses of 15, 9 and 3 mg on the first, second and third days of treatment, respectively. This treatment overlapped with a continuous intravenous infusion of heparin that was adjusted to aPTT levels of 1.5 to 2.5 times the normal range. On the third day of treatment she had an international ratio (INR) 4.5 (normal therapeutic range 2–4.5); the protein C level was below 5%. Heparin therapy was then stopped. Twenty-four hours later she developed severe pain of the left thigh, above the site of the amputation, associated with extensive erythema. Another 24 hours later, petechial hemorrhages had developed (Panel A) and were rapidly followed by necrosis (Panel B). Oral anticoagulation was discontinued and

Population pharmacokinetic assessment of a new regimen of mefloquine used in combination treatment of uncomplicated falciparum malaria.

A fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood sampling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modeling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life (t1/2) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t1/2 estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.

Clinical advantages of dual activity in allergic rhinitis.

Symptoms of allergic rhinitis include sneezing; itching of the eyes, nose, and throat; nasal obstruction; and rhinorrhoea; they may be seasonal or perennial, depending on the causative allergen. The major symptom of perennial allergic rhinitis is nasal obstruction. Sneezing and rhinorrhoea are often present, but are less troublesome than in seasonal allergic rhinitis. Symptom relief is a priority in allergic rhinitis because patients have a severely impaired quality of life. The nasal vascular system is complex. Histamine acts on postcapillary venules during both the immediate and late phase of reactivity and causes plasma extravasation. Other inflammatory mediators can also induce this reaction. Thus, histamine antagonists that also have some additional antiallergic properties have advantages in the treatment of allergic rhinitis. Mizolastine is a second-generation antihistamine that has been shown, in experimental studies, to possess 5-lipoxygenase inhibitory properties in addition to its H1-receptor antagonistic activity. In the treatment of seasonal allergic rhinitis, mizolastine 10 mg/day has been shown to be effective in reducing nasal and ocular symptoms. It has been shown to be significantly more effective than placebo with a greater percentage of responders. Another study has shown that symptoms of seasonal allergic rhinitis in mizolastine-treated patients were reduced more significantly than in cetirizine-treated patients on the second and third days of treatment. In perennial allergic rhinitis, mizolastine significantly improved symptoms of nasal obstruction compared with placebo and also significantly reduced nasal membrane colour, nasal secretions, and mucosal swelling as shown by rhinoscopy. These effects were maintained over a 5-month treatment period. Mizolastine has also been shown to be at least as effective as loratadine, and in one trial even superior in the treatment of perennial allergic rhinitis.

A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism

The calcimimetic agent R-568 lowers plasma parathyroid hormone (PTH) levels in hemodialysis patients with mild secondary hyperparathyroidism, but its efficacy in those with more severe secondary hyperparathyroidism has not been studied. Twenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg/mL were randomly assigned to 15 days of treatment with either 100 mg of R-568 (N = 16) or placebo (N = 5). Plasma PTH and blood ionized calcium levels were measured at intervals of up to 24 hours after oral doses on days 1, 2, 3, 5, 8, 11, 12, and 15. Pretreatment PTH levels were 599 +/- 105 (mean +/- SE) and 600 +/- 90 pg/mL in subjects given R-568 or placebo, respectively, and values on the first day of treatment did not change in those given placebo. In contrast, PTH levels fell by 66 +/- 5%, 78 +/- 3%, and 70 +/- 3% at one, two, and four hours, respectively, after initial doses of R-568, remaining below pretreatment values for 24 hours. Blood ionized calcium levels also decreased after the first dose of R-568 but did not change in patients given placebo. Despite lower ionized calcium concentrations on both the second and third days of treatment, predose PTH levels were 422 +/- 70 and 443 +/- 105 pg/mL, respectively, in patients given R-568, and values fell each day by more than 50% two hours after drug administration. Predose PTH levels declined progressively over the first nine days of treatment with R-568 and remained below pretreatment levels for the duration of study. Serum total and blood ionized calcium concentrations decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from study after developing symptoms of hypocalcemia, whereas three completed treatment after the dose of R-568 was reduced. The calcimimetic R-568 rapidly and markedly lowers plasma PTH levels in patients with secondary hyperparathyroidism caused by end-stage renal disease.

Behavioural effects of NKH-477, a forskolin analogue, on locomotion and rearing in rats.

NKH-477 is a water-soluble analogue of forskolin that stimulates adenylate cyclase and has antidepressant properties in the forced swim model of depression. The effect of chronic NKH-477 on locomotion and rearing and its behavioural interaction with lithium and inositol was tested. NKH-477 (1.5 mg/kg), administered acutely or chronically for 9 d to rats, induced a significant reduction in locomotor behaviour and rearing. In a second experiment, rats were pretreated with chronic dietary lithium, inositol or control diet for 3 wk before being injected with either saline or NKH-477. Inositol had no effect on the decreased locomotion and rearing induced by NKH-477. There was a significant, but transient, interaction between lithium and NKH-477 on rearing on the second and third days of treatment. The lithium group had lower baseline rearing than control or inositol-treated rats, and was not further affected by NKH-477 treatment. This is the first report of a marked effect of this forskolin analogue on locomotion and rearing, with no tolerance in the time frame examined. The interaction between NKH-477 and lithium suggests that the well-documented ability of lithium to inhibit stimulation of the cAMP system is relevant to its behavioural effects; however, the transient nature of this interaction, suggests that other biochemical mechanisms are involved in the behavioural effects of lithium.

INHIBITION OF CELLULAR GROWTH AND STEROID 11β-HYDROXYLATION IN RAS-TRANSFORMED ADRENOCORTICAL CELLS BY THE FUNGAL TOXINS BETICOLINS

The proliferation of GM16 and 4CDT ras-transformed newborn rat adrenocortical (RTAC) cells and Y1 mouse adrenal tumor cells was inhibited by beticolins, the fungal toxins extracted from Cercospora beticola, at submicromolar concentrations in a dose-dependent manner. Inhibitory concentrations for half the maximum inhibition were 150, 75 and 25 n Mfor beticolin-1 and 230, 150 and 50 n Mfor beticolin-2 in GM16, 4CDT and Y1 cells respectively. Beticolins strongly inhibited the production of 11β-hydroxysteroids on the second and third days of treatment in a dose-dependent manner between 0.1 and 1 μ M. Beticolins were shown by confocal microscopy to be localized in cytoplasmic organelles about 30–40 min after treatment. This finding favors a direct action of beticolins on mitochondrial steroid 11β-hydroxylase albeit another less direct mechanism involving a cytoplasmic signaling pathway cannot be excluded.

Efficacy and safety of moguisteine in comparison with levodropropizine in patients with cough associated with chronic obstructive pulmonary disease, lung cancer, or pulmonary fibrosis

The purpose of this study was to compare the efficacy and safety of moguisteine, a new antitussive drug with a peripheral mechanism of action, with levodropropizine, a reference antitussive compound. A randomized, single-blind, parallel-group, multicenter trial was conducted in 104 adult patients with persistent cough associated with chronic obstructive pulmonary disease, lung cancer, or pulmonary fibrosis. The drug regimen was 200 mg TID moguisteine and 60 mg TID levodropropizine, each given orally for 6 days. The primary efficacy variable was the sum of daytime and nighttime cough frequency scores assigned by the patients according to a 0 to 10 ladder scale. Secondary efficacy variables were the number of coughs in the morning at baseline and on the third day of treatment, rated by hospitalized patients with manual counters and tape recorders for a period of 2 hours; the scores were separately assigned by patients to daytime and nighttime cough frequency; and the patients' final evaluation of the antitussive treatment received. Safety variables were the clinical laboratory test values and the adverse events reported by the patients or observed by the investigators. Both drugs were highly effective and significantly reduced daytime and nighttime cough frequency scores. Patients receiving moguisteine showed a significantly greater reduction in these scores than those receiving levodropropizine on the third and fourth days of treatment. The cough count significantly decreased after both treatments—the number of baseline coughs recorded for patients receiving moguisteine and levodropropizine was 44 and 43, respectively; on the third day of treatment it dropped to 17 in both groups. Both drugs were well tolerated; adverse events were reported by only 2 patients receiving moguisteine (moderate epigastric pain for both patients) and 3 patients receiving levodropropizine (2 patients reported epigastric pain, 1 moderate and 1 mild in intensity; 1 patient presented with moderate anxiety and insomnia). No event was serious, but treatment was stopped for the patient in the levodropropizine group who presented with anxiety and insomnia. The results of this study suggest that moguisteine, 200 mg TID, is at least as effective and safe an antitussive agent as levodropropizine, 60 mg TID.

Developmental Toxicity of Fleroxacin and Comparative Pharmacokinetics of Four Fluoroquinolones in the Cynomolgus Macaque (Macaca fascicularis)

The potential developmental toxicity of fleroxacin was studied (Phase I) and its pharmacokinetics was compared to ciprofloxacin, temafloxacin, and norfloxacin (Phase II) in the cynomolgus macaque (Macaca fascicularis). Phase I studies involved oral administration of fleroxacin (35 and 70 mg/kg-day) during Gestational Days (GD) 20-34 or 35-49 (N = 10/group); controls received vehicle only. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality (4/10, 40%; GD 20-34) were observed at 70 mg/kg-day. Urinary excretion of estrogen conjugates was reduced for females with nonviable pregnancies during both treatment periods (GD 20-34 and 35-49), although steroid hormone levels in serum remained unchanged during treatment; no malformations or growth retardation were observed at gross examination. For Phase II studies, the pharmacokinetics of fleroxacin (70 mg/kg), ciprofloxacin (100 mg/kg), temafloxacin (100 mg/kg), and norfloxacin (150 mg/kg) were studied during a 3-day oral treatment regimen in the nonpregnant (N = 12; 3/quinolone) and pregnant (N = 3; fleroxacin only) macaque. Serial blood samples were collected on the first and third days of treatment in all animals; for pregnant females, the conceptus was removed on GD 31 for analysis of fleroxacin levels. Marked differences between the quinolones were noted in the AUC0-24 hr for nonpregnant females. Based on AUC0-24 hr on the first day of treatment, the rank order was fleroxacin > temafloxacin > ciprofloxacin > norfloxacin. On the third day of treatment, the rank order for exposure was temafloxacin> fleroxacin > ciprofloxacin > norfloxacin. Overall, results indicated (1) no marked differences in pharmacokinetic parameters in pregnant versus nonpregnant females, (2) fleroxacin levels in embryonic tissues were similar to maternal plasma levels, and (3) there was a correlation between exposure and embryolethal doses for all fluoroquinolones which resulted in embryolethality except norfloxacin.

Effects of the Short-Acting Benzodiazepine Triazolam, Taken at Bedtime, on Circadian and Sleep-Related Hormonal Profiles in Normal Men

Studies in rodents have shown that triazolam, a commonly used hypnotic, may shift circadian rhythms, with the direction and magnitude of the phase-shifts being dependent on the time of drug administration. To determine whether benzodiazepine, taken at standard bedtime, modifies the amount and/or temporal organization of hormonal secretion, six normal men were studied during basal conditions and on the first and third days of treatment with 0.5 mg triazolam. In each study, sleep was polygraphically monitored and plasma cortisol, growth hormone (GH), melatonin, and prolactin (PRL) (i.e., hormones influenced by circadian rhythmicity and/or sleep) were measured at 20-min intervals for 24 h. The sleep latency and the number and duration of awakenings were reduced during triazolam treatment as compared to baseline conditions. The only alteration of sleep architecture was a partial suppression of stages III + IV (SW) in late sleep. Triazolam did not affect the mean cortisol and melatonin levels or the total amount of GH secreted over the 24-h span. The circadian timings of the onsets of cortisol and melatonin secretions were essentially unaltered. The nocturnal rise of melatonin was prolonged by 45 to 60 minutes. Sleep-associated GH release was not modified by triazolam. Sleep-associated PRL secretion persisted, but in half of the nights studied was enhanced almost threefold. This effect of the drug on nocturnal PRL secretion was not specific to either the first or the third night of treatment, nor was it specific to certain subjects. Irrespective of the magnitude of the nocturnal elevation, morning PRL levels were slightly but consistently higher after triazolam treatment than under basal conditions. Normal PRL levels resumed around noon. In conclusion, administration of 0.5 mg triazolam at normal bedtime (2230) for three consecutive days may induce a transient hyperprolactinemia, but does not abolish sleep-related hormone secretion and does not affect the timing of endocrine events controlled by the circadian clock. These findings are consistent with studies in hamsters where treatment with triazolam in the early subjective night was also without effect on the rodent circadian clock.

Fetal and uteroplacental haemodynamics during short-term atenolol treatment of hypertension in pregnancy.

Fetal circulation was studied by means of combined real-time and pulsed Doppler ultrasound in 14 women with pregnancy-associated hypertension before and during the first and third days of treatment with the beta 1-selective blocker, atenolol; in seven of the women the maternal uterine arcuate blood velocity waveform was also studied. Blood flow characteristics were normal both in the fetus and in the maternal arcuate artery, compared with those in uncomplicated pregnancies of corresponding gestational ages. Volume blood flow remained unchanged in the fetal descending aorta, and in the umbilical vein during atenolol treatment, whereas the pulsatility index increased in the fetal descending aorta and in the arcuate artery. This suggests that the peripheral vascular resistance, both on the maternal and fetal side of the placenta, increased during short-term antihypertensive treatment with atenolol.