Daily Release Rate Research Articles

Tailoring drug release from long-acting contraceptive levonorgestrel intrauterine systems

The wide array of polydimethylsiloxane (PDMS) variants available on the market, coupled with the intricate combination of additives in silicone polymers, and the incomplete understanding of drug release behavior make formulation development of levonorgestrel intrauterine systems (LNG-IUSs) formidable. Accordingly, the objectives of this work were to investigate the impact of excipients on formulation attributes and in vitro performance of LNG-IUSs, elucidate drug release mechanisms, and thereby improve product understanding. LNG-IUSs with a wide range of additives and fillers were prepared, and in vitro drug release testing was conducted for up to 12 months. Incorporating various additives and/or fillers (silica, silicone resins, silicone oil, PEG, etc.) altered the crystallization kinetics of the crosslinked polymer, the viscosity, and the microstructure. In addition, drug-excipient interactions can occur. Interestingly, additives which increased matrix hydrophobicity and hindered PDMS crystallization facilitated dissolution and permeation of the lipophilic LNG. The influence of additives and lubricants on the mechanical properties of LNG-IUSs were also evaluated. PDMS chemical substitution and molecular weight were deemed to be most critical polymer attributes to the in vitro performance of LNG-IUSs. Drugs with varying physicochemical characteristics were used to prepare IUSs, modeling of the release kinetics was performed, and correlations between release properties and the various physicochemical attributes of the model drugs were established. Strong correlations between first order release rate constants and both drug solubility and Log P underpin the partition and diffusion-based release mechanisms in LNG-IUSs. This is the first comprehensive report to provide a mechanistic understanding of material-property-performance relationships for IUSs. This work offers an evidence-based approach to rational excipient selection and tailoring of drug release to achieve target daily release rates in vivo. The novel insights gained through this research could be helpful for supporting development of brand and generic IUS products as well as their regulatory assessment.

Spatial and temporal patterns of fuelwood consumption and its associated CO2 emissions in Muzaffarabad division, a western Himalayan region

BackgroundIn the Himalayan region, fuelwood serves as a critical energy source for rural communities. Being vital for meeting energy needs, fuelwood combustion is a source of carbon dioxide (CO2) emission and, consequently, global warming, as well as deforestation and public health damage. Therefore, quantifying fuelwood consumption patterns and its associated CO2 emissions is essential to understand the environmental impact and promote sustainable resource management.MethodsThis research conducts an evaluation of fuelwood burning patterns and the associated CO2 emissions in Azad Jammu and Kashmir (AJK), situated within the western Himalayan region. The study entails an extensive survey of 24 villages representing 240 households, equally distributed between the subtropical and temperate regions, each comprising 120 households. Data collection was executed through a combination of direct queries and the weight survey method, following standard protocols.ResultsIn the study area, the mean annual fuelwood comsumption per household amounts to 24.28 ± 3.1 Mg (or 3.195 ± 1 Mg capita−1). A variance was observed between subtropical and temperate zones, with the latter exhibiting higher consumption rates. The consequential CO2 emissions were assessed as 41.88 ± 4.5 Mg per household (5.51 ± 0.6 Mg capita−1). On a daily basis, households consumed an average of 66.52 ± 6.4 kg of fuelwood (8.75 ± 1.5 kg capita−1), resulting in a daily CO2 release rate of 114.745 ± 8.6 kg (15.095 ± 2 kg capita−1). The findings unveiled seasonal variations, indicating increased fuelwood consumption and emissions during the winter season. Statistical analysis shed light on the significance of altitude and family size in shaping the patterns of fuelwood use.ConclusionsThe results revealed the importance of prioritizing forest conservation and strategically implementing sustainable practices, including reforestation, afforestation, responsible harvesting, and actively promoting sustainable fuel sources. This research highlights the vital role of well-designed policies focused on preserving ecosystems and improving energy management. Policy intervention can ensure the sustainable stewardship of local and regional forest resources.

Repellent activity of the non-host semiochemical (E)-2-octenal against Amblyomma sculptum and Amblyomma dubitatum ticks under field conditions.

Amblyomma ticks pose a significant public health threat due to their potential to transmit pathogens associated with rickettsial diseases. (E)-2-octenal, a compound found in donkeys (Equus asinus), exhibits strong repellent properties against Amblyomma sculptum nymphs under laboratory conditions. This study assessed the effectiveness of the (E)-2-octenal in wearable slow-release devices for personal human protection against Amblyomma ticks under natural conditions. Slow-release devices treated with (E)-2-octenal and untreated controls were prepared and tested on two volunteers walking through a tick-infested area in Goiania, Brazil. The experiment was conducted twice daily for three series of 10 days, with each volunteer wearing two devices attached to each leg, one on the ankle and one just above the thigh. Volunteers with control and treated devices exchanged them between rounds. Also, the daily release rate of (E)-2-octenal from the slow-release devices was determined in the laboratory, increasing significantly from 0.77± 0.14µg/day on the first day to 9.93 ± 1.92µg/day on the 4th day and remaining constant until the 16th day. A total of 5409 ticks were collected from both volunteers. Treated devices resulted in recovering fewer ticks (n = 1,666; 31%) compared to untreated devices (control: n = 3,743; 69%). (E)-2-octenal effectively repelled Amblyomma spp. larvae, A. sculptum adults, and exhibited pronounced repellency against A. dubitatum nymphs and adults. These findings suggest the potential of (E)-2-octenal delivered by wearable slow-release devices as a green-based repellent. Further improvements, however, are necessary to provide better protection for humans against A. sculptum and A. dubitatum in field conditions.

Physicochemical considerations in the formulation development of silicone elastomer vaginal rings releasing 5-nitroimidazole drugs for the treatment of bacterial vaginosis

Bacterial vaginosis (BV) is a common dysbiosis of the human vaginal microbiota characterized by depletion of hydrogen peroxide and lactic acid-producing Lactobacillus bacteria and an overgrowth of certain facultative anaerobic bacteria. Although short-term cure rates following treatment with frontline antibiotics (most notably oral metronidazole (MNZ), clindamycin vaginal cream, and MNZ vaginal gel) are generally high, longer-term recurrence rates are an issue. The development of vaginal formulations offering continuous/sustained administration of antibiotic drugs over one or more weeks might prove useful in reducing recurrence. Here, we report the manufacture and preclinical testing of matrix-type vaginal rings offering sustained release of four 5-nitroimidazole antimicrobial drugs either being used clinically or having potential in treatment of BV – MNZ, tinidazole (TNZ), secnidazole (SNZ) and ornidazole (ONZ). All four drugs showed good compatibility with a medical-grade addition-cure silicone elastomer based upon thermal analysis experiments, and matrix-type rings containing 250 mg (3.125 %w/w) of each drug were successfully manufactured by reaction injection molding. 28-day in vitro drug release studies demonstrated root-time kinetics, with daily release rates of 25, 22, 9 and 6 mg/day½ for SNZ, ONZ, MNZ and TNZ, respectively. The rank order of drug release from rings correlated with the simple molecular permeability parameter S/V, where S is the measured drug solubility in silicone fluid and V is the drug molecular volume. The relative merits of SNZ and ONZ over MNZ (the current reference treatment) are discussed. The data support development of vaginal rings for sustained release of 5-nitroimidazole compounds for treatment of BV.

Development of an Intrauterine Device Releasing Both Indomethacin and Levonorgestrel During the First Months of Use: Pharmacokinetic Characterization in Healthy Women.

Post-placement menstrual bleeding pattern changes with intrauterine contraceptives (IUCs), including levonorgestrel-releasing intrauterine systems (LNG-IUS), can be a reason for avoidance or early discontinuation. Prostaglandins play an important role in menstrual bleeding and pain. The key drivers of prostaglandin synthesis are cyclooxygenase (COX) enzymes, which are inhibited by non-steroidal anti-inflammatory drugs. In this study, we report the findings from pharmacokinetic (PK) analyses undertaken with an LNG-IUS (LNG-IUS8) modified with an additional reservoir containing indomethacin (IND). The IND/LNG-IUS8 is a proof-of-concept device studied in a phase II proof-of-concept/dose-finding study. IND/LNG-IUS8 contains the same LNG content as the unmodified LNG-IUS8 (13.5 mg) but was prepared with three different IND doses (low, 6.5 mg; middle, 12.5 mg; and high, 15.4 mg), resulting in different daily release rates. Overall, 174 healthy, premenopausal women were randomized to one of the four treatment arms (low-, middle-, high-dose IND/LNG-IUS8 or LNG-IUS 8). Initial and residual IND and LNG content were collected and the amount of IND and LNG released in vivo over the period of use was calculated. A subset of 62 participants underwent dense blood sampling for PK analysis. Concentrations of IND and LNG in plasma were determined by validated liquid chromatography-tandem mass spectrometry methods and plotted over time. Descriptive statistics were calculated for plasma drug concentrations and PK parameters. High-dose IND/LNG-IUS8 initially released much higher levels of IND than expected based on in vitro release data, followed by a steep decline, with the reservoir emptied by 4.5 months. Middle- and low-dose IND/LNG-IUS8 demonstrated steady sustained release of IND over time, emptying after 7.4 and 8.4 months, respectively. Peak plasma concentrations of IND for low- and middle-dose IND/LNG-IUS8 remained below the 20% maximal inhibitory concentration (IC20) values for COX enzymes. The average daily IND release rate in vivo was 49 µg/day for low-dose and 112 µg/day for middle-dose IND/LNG-IUS8. The IND release rate profile and IND plasma concentrations in vitro both decreased steadily over time with low- and middle-dose IND/LNG-IUS8. The LNG release rate profile was comparable for all IND/LNG-IUS8 dose groups and LNG-IUS8. This PK study demonstrates that two different drugs can be released at different rates from an IUS designed with two drug reservoirs. Inclusion of IND does not impact the LNG PK profile. Low- and middle-dose IND/LNG-IUS8 were associated with a systemic IND exposure that should preclude the occurrence of adverse events typically observed after oral IND dosing. ClinicalTrials.gov identifier number: NCT03562624.

Impacts of poplar harvesting residue additions on soil nutrients and CO 2 emission

Objective Impacts of the addition of poplar harvesting residues on soil nutrients and CO2 emission were investigated in controlled conditions to provide a reference for its potential utilization. Method The indoor incubation experiment was carried out by selecting logging residues of twigs, barks, and leaves from a poplar plantation and the rice straw as research materials. Based on the litter amount in the unit area of the poplar plantation, the fresh soil equivalent to 100 g of dry soil weight and biomass materials equivalent to 2% of dry soil weight were mixed evenly. Then the mixed soils were loaded into a homemade polyethylene plastic box, and incubated in a constant temperature incubator at 25℃ for 180 days in darkness. During the culture period, the soil moisture content was controlled to 60% of the field moisture capacity. Dynamic variations in microbial biomass carbon (MBC) and nitrogen (MBN), inorganic nitrogen (NH4 +-N and NO3 −-N), available phosphorus (AP) and available potassium (AK) as well as CO2 in the soil were measured. Result (1) The addition of all four residue biomass significantly affected microbial biomass and nutrient availability in the soil (P＜0.05). Compared with the control, the soil MBC contents treated by the residue biomass of poplar twigs, barks, leaves and straw increased by 50%, 31%, 80% and 109% respectively, while the soil MBN contents increased by 54%, 40%, 72% and 203%, respectively. The contents of NH4 +-N in the soil treated with bark and twigs residues were higher than those in the control and rice straw treatments, whereas the NO3 −-N content in the soil was in the order of control>rice straw>leaf residue>bark residue>twig residue treatments. The highest AP content was observed in the soil treated with twigs, while the AK content in the soil treated with rice straw was higher than that treated with other biomass residues. (2) After adding biomass residues into the soil, the daily release rate of CO2 from the soil showed a tendency with being relatively fast in the initial period, gradually slowing down in the middle stage, and tending to be stable in the later stage of the incubation. After 180 days of indoor incubation, the cumulative CO2 emission from the soil treated with rice straw was significantly higher than that of the other treatments (P＜0.05), followed by the soil treated with poplar leaves. (3) Correlation analysis showed that microbial biomass, nutrient contents and CO2 daily release rate in the soil were obviously correlated to the properties of biomass residues. Of them, a significantly positive correlation of soil microbial biomass to the contents of total nitrogen, total phosphorus and total potassium but a significantly negative correlation to the total carbon content and C/N ratio in the biomass residues were detected (P＜0.05). Meanwhile, the CO2 daily emission rate was positively correlated to the contents of MBC, MBN, NH4 +-N, AP and AK in the soil (P＜0.05), whereas a significantly negative correlation of the CO2 daily emission rate to the contents of NO3 −-N was observed (P＜0.01). Conclusion From the views of soil nutrients and environmental effects, application of poplar harvesting residues not only can increase the contents of soil available nutrients, but also relatively reduce carbon emissions compared with the rice straw. [Ch, 3 fig. 3 tab. 47 ref.]

Development of mesoporous bioactive glass‐containing macroporous titanium for controlled release of antimicrobial drugs

AbstractBiofilm‐associated infections pose a serious threat to the long‐term survival of metal‐based bone implants, which can potentially be resolved by the controlled delivery of antimicrobial agents locally at the implant surface. Mesoporous bioactive glasses (BAGs) are multifunctional materials able to combine bone‐bonding properties with such a drug release functionality. Here, we propose for the first time to modify a macroporous Ti implant material with an antimicrobial‐releasing BAG phase. The feasibility of a sol‐gel synthesis route, including the structure‐directing agent (SDA) Pluronic F127, and its effect on the mesoporous structure and concomitant drug release performance was evaluated. Mesopore sizes ranged from 3.4 nm for SDA‐free to 3.7 nm for SDA‐derived BAG, thereby both enabling configurational diffusion of the antiseptic chlorhexidine (CHX), but the latter showed a more narrow pore size distribution leading to a slower, more controlled release. Adjusting the feed concentration allowed fine‐tuning the daily CHX release through the SDA‐derived Ti/BAG composite to 1.4 μM. Even though just below the biofilm inhibitory concentration, this daily release rate was sufficient to effectively prevent Streptococcus mutans biofilm formation on the surface of the material. This proof‐of‐concept for a temporary antimicrobial‐releasing bioceramic surface modification on Ti can be of interest for orthopedic implants.

Fabrication of a Reservoir Ring for Sustained and Prolonged Release of Levonorgestrel for Vaginal Administration

Introduction: More than one-third of women experience abnormal uterine bleeding (AUB) during their lifetime. One of the treatment methods of this disease is hormone therapy. Vaginal rings (VRs) containing progesterone hormones could be a good choice for treatment. In this study, the design and construction of a reservoir ring with the ability to release levonorgestrel hormone has been investigated. Methods: In this experimental study, to make vaginal rings containing levonorgestrel, biocompatible silicone fibers were used, the two ends of which were connected with special caps. Different amounts of LNG including 0.1, 0.2 and 0.4 weight percent relative to paraffin were loaded into the fibers. These three prototypes were named RSC1, RSC2, and RSC3, respectively. The daily and cumulative release of LNG from these rings was measured by spectrophotometer and compared using SPSS software version 16 and analyzed by one-way ANOVA method. Results: On the first day, there was a burst release that was different for these three prototypes depending on the drug loading percentage. From the second until thirtieth day for RSC3 and from forth until thirtieth day for RSC1 and RSC2, prolonged release was achieved and average daily release for RSC1, RSC2, and RSC3 were 24.10 ± 8.22, 41.77 ± 9.02 and 83.29 ± 5.07µg, respectively. Conclusion: According to the findings, it is possible to design VRs capable of prolonged and sustained release of LNG for up to 30 days and control their daily release rate based on initial drug loading. This method may be a suitable alternative to oral hormonal pills in the treatment of AUB.

Levonorgestrel 52 mg intrauterine system (Levosert®)/Liletta®) in contraception: a profile of its use

Levosert® (EU)/Liletta® (USA) is a levonorgestrel (LNG)-releasing intrauterine system (IUS) containing 52 mg of LNG. It was the first LNG-releasing IUS approved for use for up to 6 years, with daily LNG release rates being sufficient to provide contraception over at least this time period. In the efficacy population (1600 women aged 16–35 years) of the key ongoing 10-year ACCESS IUS trial, Levosert/Liletta 52 mg was highly effective in preventing pregnancy and improving bleeding patterns. Levosert/Liletta 52 mg also reduces heavy menstrual bleeding (HMB), with no differences in improvements in HMB outcomes between Levosert/Liletta 52 mg and Mirena® 52 mg in a 1-year trial, and no reports of HMB by the end of cycle 2 in 75% of 150 women with self-reported baseline HMB in ACCESS IUS. In the ACCESS IUS safety population (1751 women aged 16–45 years), the tolerability of Levosert/Liletta 52 mg was consistent with the known profile of LNG-releasing IUSs, with few treatment-related serious adverse events or complications. IUSs releasing LNG 52 mg offer the convenience of less frequent insertion than IUSs releasing LNG 13.5 or 19.5 mg, and may be of particular value in women with HMB wanting long-acting reversible contraception.

Ovulation inhibition with a new vaginal ring containing trimegestone

ObjectivesThe primary objective was to determine the lowest trimegestone (TMG) dose, administered via a vaginal ring, that effectively inhibited ovulation. Study designSingle-centre, open-label, single-dose, parallel-group clinical trial with adaptive design. Eighty healthy female volunteers with proven ovulatory cycles were allocated to treatment with a vaginal ring during 28 days, with an average daily release rate of either 46 µg, 94 µg, 147 µg, or 184 µg TMG (20 women/group). Ultrasound measurements of follicular growth and endometrial thickness, and blood sampling for follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone determinations were performed every 3rd (±1) day from treatment day 4 (±1) until day 28 (±1), and in a follow-up phase after ring removal, until study day 39 (±1). Trimegestone concentrations were measured at each visit in the treatment phase. ResultsMean age and body mass index were 28.8 years and 23.15 kg/m2. One subject in the lowest dose group (46 µg/day) ovulated, no ovulations were seen in the higher dose groups. The degree of ovarian suppression increased with the dose. Median estradiol levels were 119, 36.5, 33.2 and 27.2 pg/mL in the 46, 94, 147 and 184 µg/day groups, respectively. Ovarian activity was resumed in the follow-up phase. Plasma TMG levels gradually declined over the treatment period and showed dose proportionality. The study treatment was safe and well tolerated. ConclusionThe release rate of 94 µg TMG per day was the lowest effective dose for ovulation inhibition. The study results justify further development of the TMG-ring as progestogen-only contraceptive. ImplicationsThe vaginal ring releasing TMG seems to be an effective new progestogen-only contraceptive preparation, having the advantage of once-a-month vaginal insertion.

Characterizing Nutrient Composition and Concentration in Tomato-, Basil-, and Lettuce-Based Aquaponic and Hydroponic Systems

Aquaponic nutrient studies often use various types of water containing high levels of mineral nutrients for water supply, making it difficult to accurately determine deficient nutrients limiting crop yield and quality across the systems. To avoid interference with background nutrients, we used reverse osmosis water in this study. The objectives were to identify critical nutrients that affect the yield and quality of cherry tomato-, basil-, and lettuce by characterizing nutrient composition and concentration in aquaponic systems in comparison to hydroponic systems. Daily release rate (mg L−1) of macronutrients derived from fish feed (41% protein, 1.1% phosphorus, 1% fish weight) was in decreasing order of SO4–S (16) > PO4–P (2.4) > NO3–N (1.0) > K (0.8) > Cl (0.5) > NH4–N (0.4) > Ca (0.2) > NO2–N (0.13) > Na (0.11) > Mg (0.02), in which daily inputs of Mg and Ca in aquaponics were found to be only 1–2% and 4–6%, respectively, of those in hydroponics. Subsequently, the average concentrations of all nutrients were significantly lower in aquaponics than in hydroponics during a 3-month production except for Cl, NH4–N, NO2–N, and Na. The concentration of Mg remained below 5 mg L−1 in all aquaponic systems, while the concentration of Ca rapidly decreased in tomato-based aquaponics, especially during fruiting. SPAD value (chlorophyll content) was associated with concentrations of leaf N, Mg, and/or Ca. Specifically, lower SPAD value was correlated with lower leaf Mg and Ca for tomato and lower leaf Mg for basil but neither Mg nor Ca for lettuce. The aquaponic solution contained nearly six-times higher Na than the hydroponic solution, resulting in three-times higher Na concentration in the edible portion of the crops. Compared to a lettuce-based aquaponic system, tomato- and basil-based systems retained more desirable water quality parameters (i.e., stable pH, lower temperature), had lower electrical conductivity (EC) via greater biomass production and, therefore, more efficient nutrient removal, and had lower feed conversion rate and higher fish biomass increment. Regardless of crop species, vegetative shoot biomass was significantly reduced in aquaponics than in hydroponics. However, the marketable yield of tomatoes was similar between aquaponics and hydroponics, while those of basil and lettuce were reduced in aquaponics by 56% and 67%, respectively, in comparison to hydroponics. Our results highlighted potential solutions to design proper nutrient management practices essential for the development of successful aquaponic production systems. Considering that ingested fish feed does not provide sufficient levels of Mg and/or Ca for crop production, it is suggested to supplement Mg before crop transplanting and Ca before fruiting of fruity crops to improve crop growth and quality in aquaponic systems, especially when high-quality water is used for water supply.

Impact of product design parameters on in vitro release from intrauterine systems.

Polydimethylsiloxane (PDMS)-based levonorgestrel intrauterine systems (LNG-IUSs) contain a large amount of potent LNG, and therefore it is important to understand the impact of product design parameters on the in vitro and in vivo performance to ensure safety and efficacy, as well as to avoid serious side effects resulting from dose dumping. LNG-IUS is a complex drug-device combination product, and its formulation design, requires consideration of additional factors such as device configuration and dimensions, in addition to formulation and processing parameters. In this study, ten qualitatively (Q1) and quantitatively (Q2) equivalent LNG-IUSs were manufactured with differences in source (supplier) and dimensions (i.e., thickness) of the outer membrane, drug particle size, dimensions of the drug reservoir (i.e., inner diameter), as well as configuration of the entire IUS. A real-time in vitro release testing method was developed for the LNG-IUSs. In addition, an accelerated release testing method was developed using hydro-alcoholic media in order to reduce the time associated with formulation design. Source variations and thickness of their outer membranes had a great impact on the in vitro drug release from the LNG-IUSs. It was demonstrated that the thicker the outer membrane, the slower the drug release rate. The physicochemical properties of the outer membranes obtained from different sources were characterized to understand their impact on the in vitro drug release of the LNG-IUSs. The composition and mechanical strength may play a role in differences in drug release. The LNG-IUS formulation prepared with the larger drug particle size showed a slightly slower daily release rate. The drug release rates from the compositionally equivalent LNG-IUSs linearly correlated to the surface area of the corresponding drug reservoirs. Another factor that affected the drug release rate was the configuration of the entire IUS. It was shown that the placement of the outer membrane was significant, i.e. whether the ends of the drug reservoir were covered or not. It is important to note that real-time release showed zero-order release kinetics over the test period of approximately 900days. The current study provides a comprehensive understanding of the impact of product design parameters on the in vitro drug release of LNG-IUSs. In addition, the developed real-time and accelerated release testing methods showed good discriminatory ability for compositionally equivalent LNG-IUSs prepared using different product design parameters.

Characterization of a Reservoir-Style Implant for Sustained Release of Tenofovir Alafenamide (TAF) for HIV Pre-Exposure Prophylaxis (PrEP).

Long-acting (LA) HIV pre-exposure prophylaxis (PrEP) offers the potential to improve adherence by lowering the burden of daily or on-demand regimens of antiretroviral (ARV) drugs. This paper details the fabrication and in vitro performance of a subcutaneous and trocar-compatible implant for the LA delivery of tenofovir alafenamide (TAF). The reservoir-style implant comprises an extruded tube of a biodegradable polymer, poly(ε-caprolactone) (PCL), filled with a formulation of TAF and castor oil excipient. Parameters that affect the daily release rates of TAF are described, including the surface area of the implant, the thickness of the PCL tube walls (between 45 and 200 µm), and the properties of the PCL (e.g., crystallinity). In vitro studies show a linear relationship between daily release rates and surface area, demonstrating a membrane-controlled release mechanism from extruded PCL tubes. Release rates of TAF from the implant are inversely proportional to the wall thickness, with release rates between approximately 0.91 and 0.15 mg/day for 45 and 200 µm, respectively. The sustained release of TAF at 0.28 ± 0.06 mg/day over the course of 180 days in vitro was achieved. Progress in the development of this implant platform addresses the need for new biomedical approaches to the LA delivery of ARV drugs.

Diurnal and seasonal variation of particle and dissolved organic matter release by the coralAcropora tenuis

Release rates of particulate organic carbon and nitrogen (POC and PON) and dissolved organic carbon (DOC) from the scleractinian coral Acropora tenuis were measured during the day and night in summer and winter seasons. Physiological parameters including calcification, photosynthesis and respiration rates were also measured simultaneously. The release rate of both POC and DOC was significantly higher in summer compared to winter and higher during the day compared to the night. The daily release rate of total organic carbon (POC + DOC) was 1,094 and 219 μmol C cm−2 d−1 for summer and winter, respectively, being 4.9 times higher in summer. The POC:PON ratios of the particulate organic matter released during daytime in both seasons (summer: 12.8 ± 5.7, winter: 12.0 ± 4.1) were significantly higher than those during nighttime (summer: 6.1 ± 2.5, winter: 2.2 ± 1.8). The DOC:POC ratio was 0.5 ± 0.03 during summer and 0.32 ± 0.98 during winter, suggesting higher mucus release in particulate form. Daily net production was estimated to be 199 and 158 μg C cm−2d−1 for summer and winter, respectively, with the amount of carbon released as mucus accounting for 6.5% and 1.6% of the net carbon fixation, respectively. The study reveals diurnal and seasonal changes in the quantity and quality of mucus released from this coral species. Since coral mucus is used as a food source by reef macro-organisms, and can also serve as an energy source for micro-organisms, the observed changes in mucus release rates are expected to influence the seasonal dynamics of organic carbon and nitrogen cycling over coral reefs.

Intravaginal rings for continuous low-dose administration of cervical ripening agents

Intravaginal rings (VRs) have been widely reported for administration of pharmaceutical drugs – most notably estrogens, progestogens and antiretrovirals – to the vagina for clinical benefit. Here, for the first time, we describe the design, manufacture and preclinical testing of VRs for sustained/controlled release of the cervical ripening agents isosorbide mononitrate (ISMN) and misoprostol (MP), either singly or in combination. Matrix-type silicone elastomer VRs containing ISMN showed declining daily release rates, ranging from 31 to 168 mg (Day 1) to 3–25 mg (Day 11). Novel orifice-type rings, in which a MP-containing silicone elastomer core is partially exposed to the external environment by overmolding with a non-medicated silicone elastomer sheath containing orifices, provided relatively constant daily MP release rates over 14 days (∼20 or 60 μg/day depending on the formulation type). Combination VRs offered simultaneous release of both ISMN and MP over 14 days, with an almost constant MP release rate (60 μg/day) and steadily declining daily ISMN release (295 mg on Day 1 and 24 mg on Day 11). The VR design can be readily tailored to provide sustained or controlled release of ISMN and MP at rates potentially useful for cervical ripening.

Phase II dose-finding study on ovulation inhibition and cycle control associated with the use of contraceptive vaginal rings containing 17β-estradiol and the progestagens etonogestrel or nomegestrol acetate compared to NuvaRing

Purpose: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing® (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%.Methods: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18–35 years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 µg 17β-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 µg/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 µg/day), or the active control NuvaRing® (ENG/ethinylestradiol 120/15 µg), for three 28-day cycles.Results: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16 nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 µg/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing® with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups.Conclusions: Contraceptive rings releasing 300 µg E2 and 75–125 µg/day of ENG or 500–900 µg/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing® was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control.

Influence of pheromone emission on the attraction of California red scale males in citrus orchards

ABSTRACTAttraction of California red scale males, Aonidiella aurantii (Maskell), to different release rates of the sex pheromone compound 3-methyl-6-isopropenyl-9-decen-1-yl acetate was evaluated in field trials. This study was aimed to study pheromone emission-response correlations and the existence of an optimum release rate that maximizes trapping efficacy. Release profiles of the pheromone dispensers deployed were determined by gas chromatography to estimate the various emission rates tested. The results reveal that the mean number of A. aurantii males caught correlates with the daily pheromone release rates by means of a quadratic model. The obtained model indicates the existence of a relative maximum of the captures corresponding to an optimum release rate of ca. 300 μg/day. Higher emission rates (up to 1 g/day) resulted in lower captures. Implications for the mating disruption technique are discussed.

Gap locations influence the release of carbon, nitrogen and phosphorus in two shrub foliar litter in an alpine fir forest.

Gap formation favors the growth of understory plants and affects the decomposition process of plant debris inside and outside of gaps. Little information is available regarding how bioelement release from shrub litter is affected by gap formation during critical periods. The release of carbon (C), nitrogen (N), and phosphorus (P) in the foliar litter of Fargesia nitida and Salix paraplesia in response to gap locations was determined in an alpine forest of the eastern Qinghai-Tibet Plateau via a 2-year litter decomposition experiment. The daily release rates of C, N, and P increased from the closed canopy to the gap centers during the two winters, the two later growing seasons and the entire 2 years, whereas this trend was reversed during the two early growing seasons. The pairwise ratios among C, N, and P converged as the litter decomposition proceeded. Compared with the closed canopy, the gap centers displayed higher C:P and N:P ratio but a lower C:N ratio as the decomposition proceeded. Alpine forest gaps accelerate the release of C, N, and P in decomposing shrub litter, implying that reduced snow cover resulting from vanishing gaps may inhibit the release of these elements in alpine forests.

Letter to the editor: dexamethasone intravitreal implant in the treatment of diabetic macular edema.

Dear editor I read “Dexamethasone intravitreal implant in the treatment of diabetic macular edema” published July 2015 by Dugel et al.1 This article is very interesting in terms of providing an outline of the role of inflammation in the pathogenesis of diabetic macular edema and explaining the value of corticosteroids in the treatment of diabetic macular edema. However, I would like to draw your attention to the data presented for ILUVIEN® (fluocinolone acetonide; FAc) in Table 2, which has been presented incorrectly and does not reflect the approved product and dose in Europe. ILUVIEN is indicated in Europe for the treatment of vision impairment associated with chronic diabetic macular edema, considered insufficiently responsive to available therapies2 and is approved in Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Ireland, Italy, Luxembourg, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, and the United Kingdom. ILUVIEN was launched in the United Kingdom in April 2013, Germany in May 2013, and Portugal in January 2015.3 ILUVIEN contains 190 µg of FAc and delivers 0.2 µg of FAc per day. Dugel et al1 presented the data for the 0.5 µg of FAc per day, which was studied in the FAME studies but is not the approved dose in Europe. This needs to be explained to the reader as the data that are relevant to the currently marketed product are those of the 0.2 µg of FAc per day release rate.2,4 Thus, Table 2 presented in Dugel et al has been amended to reflect the data for ILUVIEN. Parameter ILUVIEN Therapeutic indication For the treatment of vision impairment associated with chronic DME, considered insufficiently responsive to available therapies2 Active drug Fluocinolone acetonide (FAc)2 Formulation Non-biodegradable implant (polyimide tube)2 Dose 190 µg of FAc with a daily release rate of 0.2 µg2 Duration of action (months) Up to 36 months. This is underpinned by a pharmacokinetic study in human eyes, which showed that following a single intravitreal injection of ILUVIEN, there was a stable delivery of 0.2 µg of FAc per day that was sustained and therefore detectable after 36 months.2,4 This is complemented by efficacy data that show mean improvements in BCVA and central foveal thickness, from baseline levels, for up to 36 months2,5 License approval Status: a. European countries where an ILUVIEN license has been granted b. European countries where ILUVIEN has been launched a. Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Ireland, Italy, Luxembourg, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, the United Kingdom3 b. United Kingdom, April 2013; Germany, May 2013; and Portugal, January 20153 Phase III clinical trial in DME: FAME studies: FAME A and FAME B2,5 Trial design: a. Description of the FAME studies b. The primary endpoint c. The number of patients studied in the FAME studies a. FAME A and B studies were performed under a single protocol as randomized, double-masked, sham injection-controlled, parallel-group, multicenter studies conducted over a 36-month period and included a pre-planned subgroup analysis to assess efficacy in chronic DME patients2,5 b. The primary endpoint for the FAME studies was 24 months but the studies show ILUVIEN was efficacious for up to 36 months, and this is the basis for the license and indication being approved in Europe. Both FAME A and B trials independently met the primary efficacy endpoint of ≥15 letter improvement in BCVA over baseline c. A total of 956 subjects were randomized2,5 Efficacy (% patients): Chronic DME patients: 15-ETDRS-letter BCVA gain at 3 years 34.0% vs 13.4% (0.2 µg FAc per day vs sham control) of subjects achieved a ≥15 letter improvement from baseline BCVA after 3 years2,5 Ocular safety (% patients): Release rate of 0.2 µg FAc per day vs sham control: a. Elevated IOP a. 38.4% vs 14.1% required IOP-lowering drops2,5 b. Cataract-related adverse events b. 81.7% vs 50.4% where cataract was considered an adverse event2,5 c. Incisional glaucoma surgery (IOP-lowering surgery) c. 4.8% vs 0.5% underwent IOP-lowering surgery2,5 View it in a separate window Abbreviations: DME, diabetic macular edema; BCVA, best-corrected visual acuity; FAME, Fluocinolone Acetonide for Diabetic Macular Edema; ETDRS, Early Treatment Diabetic Retinopathy Study; IOP, intraocular pressure. A number of papers have been published on the pharmacokinetic,4 safety, and efficacy of ILUVIEN,5 and the reader can access the summary of product characteristics for ILUVIEN online.2

Impact of Hydroxychloroquine-Loaded Polyurethane Intravaginal Rings on Lactobacilli.

The use of polymeric devices for controlled sustained delivery of drugs is a promising approach for the prevention of HIV-1 infection. Unfortunately, certain microbicides, when topically applied vaginally, may be cytotoxic to vaginal epithelial cells and the protective microflora present within the female genital tract. In this study, we evaluated the impact of hydroxychloroquine (HCQ)-loaded, reservoir-type, polyurethane intravaginal rings (IVRs) on the growth of Lactobacillus crispatus and Lactobacillus jensenii and on the viability of vaginal and ectocervical epithelial cells. The IVRs were fabricated using hot-melt injection molding and were capable of providing controlled release of HCQ for 24 days, with mean daily release rates of 17.01 ± 3.6 μg/ml in sodium acetate buffer (pH 4) and 29.45 ± 4.84 μg/ml in MRS broth (pH 6.2). Drug-free IVRs and the released HCQ had no significant effects on bacterial growth or the viability of vaginal or ectocervical epithelial cells. Furthermore, there was no significant impact on the integrity of vaginal epithelial cell monolayers, in comparison with controls, as measured by transepithelial electrical resistance. Overall, this is the first study to evaluate the effects of HCQ-loaded IVRs on the growth of vaginal flora and the integrity of vaginal epithelial cell monolayers.