Reduced exposure to darunavir and cobicistat in HIV-1-infected pregnant women receiving a darunavir/cobicistat-based regimen.

OBJECTIVES: The aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV-1 infection. METHODS: This phase 3b, open-label study enrolled HIV-1-infected pregnant women (18-26 weeks of gestation) receiving combination antiretroviral therapy with once-daily darunavir/cobicistat 800/150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24-28 and 34-38 weeks of gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration-time curve over 24 h (AUC24 h ), maximum plasma concentration (Cmax ) and minimum plasma concentration (Cmin )] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated. RESULTS: Seven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC24 h , 50-56% lower; Cmax , 37-49% lower; Cmin , 89-92% lower); unbound darunavir exposure was also reduced (AUC24 h , 40-45% lower; Cmax , 32-41% lower; Cmin , 88-92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC24 h , 49-63% lower; Cmax , 27-50% lower; Cmin , 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV-1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother-to-child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants. CONCLUSIONS: In view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV-1-infected pregnant women.

Long-term survival of different deep dentin caries treatments: A 5-year clinical study.

OBJECTIVE: The aim of this in-vivo study was to evaluate the long-term clinical survival of different deep dentin caries treatment options. MATERIALS AND METHODS: : In total, 391 patients with at least one permanent tooth with clinically diagnosed deep dentin caries were inspected. Two hundred and fourteen patients were examined at recall visits. Inclusion criteria were teeth with deep caries lesions with pulp vitality but absence of spontaneous pain and periapical alterations. The subjects received either stepwise removal (SWR), complete caries removal (CCR), or direct pulp capping (DPC). The radiological and clinical exams were performed after a mean observation time of 62 months. Success was defined as pulp sensitivity to vitality test and absence of periapical lesions as well as a clinical symptom. Data were statistically analyzed using Kaplan-Meier and log-rank (Mantel-Cox) tests (α = 0.05). RESULTS: Of the total 214 patients evaluated, 126 received SWR, 88 received CCR, and 67 received DPC treatment. One hundred and twenty-seven restorations were amalgam and 141 were composite. The mean observation period was 62 months. Survival rates were 85.7%, 90.9%, and 59.7% for SWR, CCR, and DPC, respectively (P = 0.001). Success rates of amalgam restorations (86.6%) were similar to composite restorations (83%), and both were found to be successful (P = 0.401). CONCLUSION: SWR treatment should be considered to preserve pulp vitality of deep dentin lesions instead of CCR or DPC. CLINICAL RELEVANCE: SWR method for deep dentin caries management had acceptable results over 5 years.

The ameliorative effects of Ginkgo biloba on apoptosis, LH-R expression and sperm morphology anomaly in testicular torsion and detorsion.

Torsion/detorsion (T/D) induces testicular damages in both germinal epithelial and interstitial tissues. Ginkgo biloba extract (GbE) exerts antioxidant and free radical scavenger. We investigated the effect of GbE on testicular tissues, Leydig and sperm cells in rats injured with T/D. Twenty-eight Wistar albino rats were randomly assigned into four groups (Control, GbE, Treatment: T/D+GbE, T/D). T/D performed to the rats in torsion, treatment received GbE (50 mg/kg) 1 hr before T/D, GbE group received only GbE (50 mg/kg) and control was defined as sham group. After T/D, the testes along with epididymis were removed and processed. LH-R expression, apoptosis, sperm morphology and histopathological damage scores were determined for each group. Testicular T/D caused significant increases in apoptosis and sperm morphology anomaly, and a significant decrease in Johnsen's testicular biopsy scores, LH-R expression of Leydig cell and normal sperm cell count. GbE ameliorated testicular histopathology and caused significant increases in LH-R expression, normal sperm cell count in the treated and particularly GbE group. Consequently, GbE may prevent testicular injury and enhance Leydig and sperm cell activity following both T/D and normal situation owing to its antioxidant, anti-apoptotic, free radical scavenger and anti-inflammatory effects.

Association of oxidative stress and dynamic thiol-disulphide homeostasis with atopic dermatitis severity and chronicity in children: a prospective study.

BACKGROUND: Oxidative stress (OS) has an important effect on the pathogenesis of atopic dermatitis (AD). Thiols are antioxidants that regulate intracellular redox metabolism and protect keratinocytes against OS damage in the stratum corneum. AIM: To investigate dynamic thiol-disulphide homeostasis (dTDH) as a novel OS parameter in children with AD, and its relationship with disease severity and chronicity. METHODS: Severity of AD was determined by using the instruments SCORing Atopic Dermatitis (SCORAD) and Eczema Area And Severity Index (EASI) upon enrolment in the study (SCORAD1 and EASI1 ) and after 1 year (SCORAD2 and EASI2 ). Native thiol, total thiol and disulphide levels were measured as novel OS parameters, and the ratios of disulphide/native thiol, disulphide/total thiol and native/total thiol were calculated as dTDH. RESULTS: In the AD group, the serum disulphide level and the ratios of disulphide/native thiol and disulphide/total thiol were significantly lower than in healthy controls (P = 0.01, P < 0.01 and P < 0.01, respectively). There was no significant association between OS parameters and disease severity (P > 0.05). SCORAD2 and EASI2 were positively correlated with disulphide/native thiol ratio (r = 0.29, P < 0.03 and r = 0.35, P < 0.01, respectively), whereas they were negatively correlated with the native/total thiol ratio (r = -0.30, P = 0.02 for both). CONCLUSIONS: Both OS and impaired dTDH were found to be related to childhood AD. None of the OS parameters was associated with AD severity. dTDH is a possible diagnostic tool to predict AD chronicity.

Inhibition by Egb761 of the effect of cellphone radiation on the male reproductive system.

OBJECTIVES: To determine the effects of Egb761 on testicular tissues and semen parameters in rats exposed to cellphone waves. BACKGROUND: EGb761 has antioxidant properties as a free-radical scavenger. Cellphone electromagnetic radiation (EMR) induces oxidative stress in cells. METHODS: Twenty-one Wistar albino male adult rats were divided into three groups (control, experimental, treatment), including seven rats in each. The experimental and treatment groups were exposed to cellphone EMR (0.96 W/kg) for six weeks (4 hrs/day). Egb761 (100 mg/kg/day) was also added to the treatment. Testes, epididymal semen and blood plasma were used for analysis. RESULTS: Exposure to cellular phone radiation resulted in a significant impairment in testicular morphometry and histological structure, reduction of total and motile sperm numbers and plasma testosterone level. Egb761 administration improved testicular damage and led to a marked increase in plasma testosterone levels and total and motile sperm numbers. CONCLUSION: Male reproductive system is susceptible to cellphone radiation. Cellphone waves induce toxic effects in testicular tissues, impair spermatogenesis and cause an imbalance in testosterone hormone levels. Egb761 ameliorated these toxic effects by reversing testicular tissue damage, restoring normal spermatogenesis and hormone levels. This suggests that Egb761 is a potential therapeutic agent against EMR-induced male reproductive toxicity (Tab. 3, Fig. 6, Ref. 45).

Week 96 efficacy and safety of darunavir/ritonavir monotherapy vs. darunavir/ritonavir with two nucleoside reverse transcriptase inhibitors in the PROTEA trial.

OBJECTIVES: PROTEA is a randomized controlled trial to assess the efficacy and safety of darunavir/ritonavir (DRV/r) monotherapy as an alternative to triple therapy. METHODS: Patients fully suppressed on first-line antiretrovirals (viral load < 50 HIV-1 RNA copies/mL) were switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 137) or with two nucleoside reverse transcriptase inhibitors (NRTIs) (n = 136). Treatment failure was HIV-1 RNA level ≥ 50 copies/mL at week 96 or discontinuation of study treatment [Food and Drug Administration (FDA) snapshot algorithm]. RESULTS: Patients were mainly male and white, with mean age 44 years. In the primary efficacy analysis, the percentage of patients with HIV-1 RNA < 50 copies/mL by week 96 [intent to treat (ITT)] was lower in the DRV/r monotherapy arm (103 of 137 patients; 75%) than in the triple therapy arm (116 of 136 patients; 85%) [difference -10.1%; 95% confidence interval (CI) -19.5, -0.7%]. In the switch-included analysis, monotherapy was noninferior to triple therapy. In a post hoc analysis, for patients with nadir CD4 count ≥ 200 cells/µL, rates of HIV-1 RNA suppression were 82 of 96 patients (85%) in the DRV/r monotherapy arm and 88 of 106 patients (83%) in the triple therapy arm. No treatment-emergent primary protease inhibitor mutations were detected in either arm. The frequency of adverse events was similar in the two arms; however, one patient in the monotherapy arm was hospitalized with HIV encephalitis and elevated cerebrospinal fluid HIV-1 RNA. CONCLUSIONS: In this study, in patients with HIV-1 RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed lower efficacy vs. triple therapy at week 96 in the primary ITT switch-equals-failure analysis, particularly in patients with CD4 counts < 200 cells/µL.

Thiol/disulphide homeostasis as a novel indicator of oxidative stress in sudden sensorineural hearing loss.

OBJECTIVES: To investigate a novel oxidative stress marker, thiol/disulphide literature homeostasis, in patients with idiopathic sudden sensorineural hearing loss, and to compare the results with healthy controls for the first time. METHODS: Thirty-two patients with idiopathic sudden sensorineural hearing loss and 30 healthy individuals were included in the study. Serum native thiol, total thiol and disulphide levels were measured, and disulphide/native thiol and disulphide/total thiol ratios were determined in all subjects. RESULTS: Serum native thiol and total thiol levels were significantly lower in patients with sudden sensorineural hearing loss compared with controls (p < 0.05). Of the 32 patients, 25 had lower native thiol levels than controls (333.2 ± 73.9 vs 381.8 ± 35.6 µmol/l, p = 0.002) and 24 had lower total thiol levels (375.1 ± 74.3 vs 426.1 ± 39.3 µmol/l, p = 0.002). CONCLUSION: The changes in oxidative markers evident in a significant number of patients may be associated with oxidative stress, which may, in turn, have caused sudden sensorineural hearing loss in those patients.

The effect of levosimendan combined with 20% lipid emulsion treatment on survival from bupivacaine induced toxicity in experiment.

BACKGROUND: Recent reports demonstrated that levosimendan improved post-resuscitation myocardial function in rat and pig models. MATERIALS AND METHODS: Rabbits were randomized into 4 groups as 12 rabbits in each group. Bupivacaine 10 mg/kg was injected as an intravenous bolus to all groups. Basic life support was performed by mechanical ventilation and manual external chest compressions. After 1 min, animals in the group 1 received 1.5 ml/ kg saline 0.9% solution, and animals in the groups 2 and 4 received 5 ml/kg 20% lipid emulsion for 1 min through the ear vein followed by continuous infusion at 0.25 ml/kg/min. Three additional boluses of 1.5 ml/ kg lipid emulsion were repeated at 5-min intervals. The group 3 received fluid resuscitation plus levosimendan (3 µg/kg/min) 1 min after asystole and the group 4 received both levosimendan and lipid emulsion treatment. Return of spontaneous circulation and hemodynamic metrics were obtained in 20 minutes. RESULTS: The number of rabbits that survived after cardiac resuscitation was lower in the Groups 1 (0%) and 3 (33.3%) than in the Group 4 (91.7%) with a statistically significant difference (p < 0.001). The number of rabbits that survived resuscitation was higher in the Group 4 than in the Group 2 (66.7%), though not with a statistically significant difference (p = 0.317). The median duration of cardiac arrest in the Group 4 was significantly shorter than that in the other three groups (p < 0.001). CONCLUSIONS: In this rabbit model of bupivacaine-induced cardiac arrest, resuscitation with combined iv lipid emulsion and levosimendan was more efficacious than lipid alone (Tab. 3, Ref. 24).

Adding magnesium to levobupivacaine for axillary brachial plexus block in arteriovenous fistule surgery.

BACKGROUND AND OBJECTIVES: The aim of this study was to compare the effect of adding magnesium to levobupivacaine on sensory and motor block onset and duration for axillary brachial plexus block in chronic renal failure (CRF) patients scheduled for arteriovenous fistule surgery (AVFS). METHODS: 80 patients, ASA III, aged 30 to 70 years, randomized and divided into 4 groups: Group I (n = 20) received total 41 ml of levobupivacaine 0.5 % + 1 ml NaCl 0.9 % mixture; Group II (n = 20) received 41 ml of levobupivacaine 0.5 % + 1 ml magnesium sulfate (150 mg) mixture; Group III (n = 20) received total 41 ml of levobupivacaine 0.25 % + 1 ml NaCl 0.9 % mixture; and Group IV (n = 20) received total 41 ml of levobupivacaine 0.25 % + 1 ml magnesium sulfate (150 mg) mixture by perineural axillary brachial plexus block. All patients were evaluated with regard to motor and sensory blocks. Motor and sensory block ending times were recorded. RESULTS: Motor and sensory block onset times were statistically decreased in Group II when compared with Goup I, and also the motor and sensory block durations were increased in Group II when compared with Goup I (p < 0.05). Sensory block onset times were statistically decreased in Group IV when compared with Goup III (p < 0.05). CONCLUSIONS: We conclude that by its decreasing effect on local anesthetic dose, magnesium may reduce the side effects due to high local anesthetic doses in patients with CRF (Tab. 1, Ref. 11).

The effect of different doses of flumazenil on acetaminophen toxicity in rats.

BACKGROUND: Acetaminophen is an analgesic drug that is used safely in therapeutic doses. At high doses, it causes hepatotoxicity, resulting in hepatic necrosis. Some medications and methods are available for treatment of acetaminophen overdose. However, results are inconsistent, and sufficient outcomes cannot always be obtained. OBJECTIVE: The mechanism of action of acetaminophen has not been fully understood. It has been suggested that it exerts its effects on GABA receptors. Flumazenil has been experimentally proven to produce an antagonism on acetaminophen's analgesic effect.The purpose of this study was to determine whether flumazenil antagonized the toxic effects of acetaminophen overdose in rats. METHODS: A total of 49 Wistar albino rats weighing between 250 - 350 g were used in the study. Nine rats were examined for a preliminary study, and the other rats were randomly divided into five groups with eight subjects in each. CONTROL GROUP: Saline; Acetaminophen group: 3 g/kg acetaminophen; Experimental Group F1: 3 g/kg acetaminophen + 0.1 mg/kg flumazenil; Experimental group F2: 3 g/kg acetaminophen + 1 mg/kg flumazenil; Experimental group F3: 3 g/kg acetaminophen + 10 mg/kg flumazenil. Acetaminophen was administered in a 3 ml saline solution by way of gastric catheter. Flumazenil was administered by way of intraperitoneal injections. Serum levels of acetaminophen, AST, ALT, LDH, ALP and bilirubin were recorded over a 24-hour period. RESULTS: Serum acetaminophen levels were similar between the groups. The AST, ALT, ALP, LDH, total bilirubin and direct bilirubin levels of Group A were significantly higher compared with the Group C, Group F1, Group F2 and Group F3. There was not a statistically significant difference in the AST, ALT, ALP, LDH, total bilirubin or direct bilirubin levels of the flumazenil-administered groups. CONCLUSION: Flumazenil's prevention of the acetaminophen-induced increase in liver enzymes is promising. There is some indication that flumazenil could be used in treatment of acetaminophen intoxication (Tab. 2, Ref. 25).

The effects of intraoperative infusion of dexmedetomidine on early renal function after percutaneous nephrolithotomy.

BACKGROUND: Percutaneous nephrolithotomy (PCNL) may interfere with renal function because of continuous fluid irrigation and compression. The aim of this study was to evaluate the effects of an intraoperative infusion of dexmedetomidine on renal function in patients undergoing PCNL. METHODS: This study included 40 patients between the ages of 18 and 65 years who underwent PCNL. After induction of anesthesia, we administered 100 ml of normal saline to the patients in the control group (n=20) and 1 mcg/kg dexmedetomidine in 100 ml of normal saline to the patients in the dexmedetomidine group (n=20) over 10 min. Throughout the surgery, 1 mcg/kg/h dexmedetomidine and 1 ml/kg/h normal saline infusions were given to the dexmedetomidine and control groups, respectively. Renal function, electrolytes, serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C were analyzed after induction and post-operatively at 2, 8 and 24 h. Renin levels and blood gas analyses were performed after induction and before extubation. RESULTS: No statistically significant differences were found between the two groups with regard to renal function, creatinine clearance (CrCl), NGAL, cystatin C and serum electrolyte levels at 0, 2, 8 and 24 h post-operatively. End-surgery renin levels in the dexmedetomidine group were significantly lower than the baseline levels in the control group. CONCLUSION: In PCNL, an intraoperative infusion of dexmedetomidine was not found to have beneficial effects on CrCl, NGAL or cystatin C levels early after the procedure; however, it reduced renin levels.

Turban pin aspiration: non-asphyxiating tracheobronchial foreign body in young islamic women.

BACKGROUND: Foreign body aspiration is rare in adults. However, in recent years, the aspiration of pins which are used for securing turbans (headscarves) is seen frequently in young women. The aim of this article was to review 105 patients who were admitted to our hospital for turban pin aspiration. METHODS: Chest X-rays were used for diagnosis. Various methods of treatment were performed: laryngoscopy in 6 patients, flexible fiberoptic bronchoscopy in 16, rigid bronchoscopy in 93, and thoracotomy in one patient, while in the other patient the turban pin was spontaneously expectorated. RESULTS: Localization of the pin in the right bronchial system was common (52%). In 6 patients, turban pins located in the larynx were extracted successfully by direct laryngoscopy. Turban pins were successfully removed with a flexible fiberoptic bronchoscope in 4 patients of the 16 (25%) and by rigid bronchoscope in 93 patients of 94 (99%). The average time until discharge was 18 hours and there was no mortality. CONCLUSIONS: Turban pin aspiration is common in Islamic populations and treatment usually requires bronchoscopic procedures. In order to minimize turban pin aspiration frequency, we recommend that turbans should be secured by traditional fastening methods or with an apparatus which cannot be aspirated.

Dexmedetomidine and meperidine prevent postanaesthetic shivering.

BACKGROUND AND OBJECTIVE: This placebo-controlled study was performed to evaluate the efficacy of dexmedetomidine compared with meperidine and placebo in preventing postanaesthetic shivering. METHODS: We studied 120 patients (ASA I-II) scheduled for elective abdominal or orthopaedic surgery of about 1-3 h duration. Forty patients in each group randomly received 1 microg kg(-1) of dexmedetomidine, 0.5 mg kg(-1) of meperidine or saline 0.9% as placebo, intravenously (i.v.). Mean arterial pressure, heart rate, oxygen saturation and central body temperature were measured. Extubation, awakening and orientation times, shivering, pain, recovery and sedation scores were recorded. RESULTS: Postanaesthetic shivering was seen in 22 patients in the placebo group, four patients in the meperidine group and six patients in the dexmedetomidine group. Sedation scores were significantly higher in the dexmedetomidine group compared with meperidine and placebo groups. Both dexmedetomidine and meperidine caused a significantly prolonged extubation and awakening time compared with placebo. Also, dexmedetomidine caused a significantly prolonged orientation time compared with other two groups. CONCLUSION: Intraoperative intravenously administration of dexmedetomidine 1 microg kg(-1) reduces postanaesthetic shivering as does meperidine 0.5 mg kg(-1) in patients after major surgery.