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Although HF management has improved over the years, many patients experience repeated hospital admissions for fluid overload marked by worsening of congestive symptoms. Intravenous (IV) furosemide is the foundation of treatment for patients with decompensated HF (4) . However, IV therapy may only be administered by a certified health care professional, typically done in emergency rooms or in a hospital setting, which limits more timely access and inherently drives up the cost of treatment.

There is a large gap between chronic oral diuretic therapy given at home versus IV diuretics administered in the naturally more expensive hospital setting. A potential intermediate step would be that of access to an “IV-like furosemide” for use outside the hospital. This would enable development of a new care model with access to a more predictable and/or intensive diuresis in the outpatient setting, thereby preventing (re-)hospitalizations and reducing length of hospital stay.

Several small studies have reported that furosemide administration via the subcutaneous (SC) route can result in significant diuresis in both healthy volunteers (5) , as well as patients with advanced stage HF (6–9) . However, furosemide is insoluble at physiological pH, and commercially available furosemide injectable products (furosemide injection USPor BP) have a pH of approximately 9.0. Alkaline products can cause significant irritation and discomfort, which currently precludes SC administration of available furosemide solutions.

A novel proprietary furosemide formulation was developed with a pH of 7.4 to minimize the risk of tissue irritation and discomfort. The aim of this report is to present the first pharmacokinetic and pharmacodynamic results of this novel furosemide formulation administered via the SC route using a biphasic delivery profile.

Subjects and study design

This article reports on 2 separate studies designed to: 1) characterize the pharmacokinetic profile of a novel formulation of furosemide administered SC and measure the resulting diuresis and natriuresis; and 2) estimate the bioavailability of SC furosemide compared with an equivalent dose of oral or IV furosemide in subjects with chronic stable HF.

In the first study, a first-in-man, proof-of-concept study (FUROPHARM-HF [Furosemide Pharmacodynamics and Pharmacokinetics After Subcutaneous or Oral Administration]; NCT02350725 ), eligible subjects (n= 10) were randomized (1:1) to receive 80 mg of oral furosemide (Lasix, Sanofi Belgium, Diegem, Belgium) or 80 mg (8 mg/ml in 10 ml) of a novel furosemide buffered solution administered SC with an external infusion pump using a biphasic pattern (30 mg over the first 60 min followed by 12.5mg/h for 4 h). After a 14-day fluid re-equilibration washout, all subjects received the alternate treatment. Plasma furosemide levels were evaluated over8 h.

In the second study (PK/PD Pivotal study) (Crossover Study to Compare the Pharmacokinetics and Bioavailability of a Novel Furosemide Regimen Administered Subcutaneously vs. the Same Dose Administered Intravenously in Subjects With Chronic Heart Failure; NCT02329834 ), eligible subjects (n=16) were randomized (1:1) to receive 80 mg of furosemide administered IV (40 mg over 2 min followed by a second 40-mg dose 2 h later) or 80 mg (8 mg/ml in 10 ml) of a novel furosemide buffered solution administered SC with an external infusion pump using a biphasic pattern (30 mg over the first 60 min followed by 12.5 mg/h for 4 h). After a 7-day fluid re-equilibration washout, all subjects received the alternate treatment. During the course of both studies, all subjects discontinued oral furosemide therapy at least 24 h before the administration of the study treatment. Furosemide therapy was reinitiated at the end of each study period.

Both studies aimed to recruit similar patient populations of men and women of at least 18 years of age, who were on chronic oral loop diuretic therapy with a documented history of chronic HF. Patients had to be symptomatic with the presence of moderate symptoms of chronic fluid overload as the baseline for oral diuretic therapy (see the Supplemental Table for a full list of inclusion and exclusion criteria).

The 2 studies were conducted in accordance with the Declaration of Helsinki. The study protocols were reviewed and approved by an institutional review board or ethical committee, and all patients provided written informed consent before enrollment.

SC furosemide

The SC furosemide formulation (scPharmaceuticals, Burlington, Massachusetts) consists of furosemide reconstituted in a buffered solution containing tromethamine at a physiological pH of approximately 7.4 (range 7.2 to 7.6). To achieve a rapid onset of diuresis lasting 8 h and equivalent to that of IV furosemide, SC furosemide is delivered according to a biphasic dosing profile of 30 mg over the first 60 min followed by 12.5 mg/h for 4 h. For both studies, drug delivery was achieved by means of an external infusion pump (Perfusor Space Infusion Pump, B. Braun Medical, Bethlehem, Pennsylvania) and standard infusion set with the needle placed on the upper lateral abdominal wall.

Pharmacokinetic assessment

Programming of tables, figures, and listings was performed using R version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria), as validated per Nuventra (Research Triangle Park, North Carolina) validation VAL.002.03. Pharmacokinetic parameters were calculated by Nuventra using Phoenix WinNonlin 6.3 (Pharsight, St.Louis, Missouri), as validated per Nuventra validation VAL.001.03. Data management and generation of the pharmacokinetic input file was performed usingR version 3.0.3 (R Foundation for Statistical Computing). To quantify furosemide in plasma, venous blood samples were collected immediately before and throughout the entire time period of study drug administration. For IV furosemide, samples were collected at 5 (immediately after the first IV bolus injection), 15, 30, 45, 60, 90, 120, 125 (immediately after the second bolus injection), 135, 150, 165, 180, and 210 min, and at 4, 5, 6, 8, 10, 12, 14, and 16 h post-dose. For SC furosemide in the PK/PD Pivotal study, samples were collected at 30, 60, 90, 120, 180, 240, 300, 305 (immediately after completion of the infusion), 315, 330, and 345 min, and at 6, 8, 10, 12, 14, 16, and 24 h post-dose. For the First-in-Man study, a modified sampling procedure was used with a reduced number of sampling points. All plasma samples were processed and stored at−70° C until assayed using a validated liquid chromatography tandem-mass spectrometry analytical method (range 5.00 to 5,000.00 ng/ml, Algorithme Pharma, Laval, Quebec, Canada).

For the PK/PD Pivotal study of both the IV and SC administration routes, the following pharmacokinetic parameters were determined: the peak plasma concentration (), the time to , the area under the plasma concentration time curve (AUC) from time 0 (pre-dose) to the last measurable plasma concentration () and to infinity (), the apparent terminal phase elimination rate constant, the terminal phase elimination half-life (), the apparent systemic clearance (for SC furosemide only), the systemic clearance (for IV furosemide only), the apparent systemic volume of distribution (for SC furosemide only), and the systemic volume of distribution (for IV furosemide only). The following equation was used to calculate the absolute bioavailability of SC furosemide: ( / dose of SC furosemide) / ( / dose of IV furosemide). All parameters were calculated using a noncompartmental analysis (Nuventra). In the First-in-Man study, the plasma levels were plotted for proof-of-principal evaluation.

Pharmacodynamic assessment

For the PK/PD Pivotal study of both the SC and IV administration routes, urine samples were collected from spontaneous voids during the time periods (0 to 1 h), (1 to 2h), (2 to 4h), (4 to 6 h), (6 to 8 h), (8 to 10 h), (10 to 12h), (12to18h), and (18 to 24 h) after initiation of each furosemide treatment. Aliquots of urine samples were processed and then stored under refrigeration until assayed for sodium concentration, and therein an excretion amount, using standard biochemistry testing.

Assessment of local tolerance

In the PK/PD study, pain was assessed on a 0 to 10 point scale with 0 representing “No Pain” and 10 representing to the “Worst Pain Imaginable.” Additionally, the skin at the SC infusion site was evaluated and photographed at various time points. Erythema was scored on a 0- to 4-point scale with 0 representing “No Erythema” and 4 representing “Severe Erythema to Slight Eschar Formation.” Edema formation was scored using a 0- to 4-point scale with 0 representing “No Edema” and 4 representing “Severe Edema (raised more than 1mm and beyond exposure area).”

Follow-up

For the PK/PD Pivotal study, clinical follow-up was scheduled per protocol at 7 ± 1 day from discharge and included changes in physical status (physical exam and electrocardiogram), HF symptoms, concomitant medications, and the occurrence of adverse or serious adverse events. The monitoring of the PK/PD study was overseen by an independent clinical research organization (Cardiovascular Clinical Studies, Boston, Massachusetts).

Sample size calculation and statistical analysis

Assuming the average coefficients of variation for furosemide following a 20-mg dose administered by the IV, oral, and sublingual routes are 50%, 25%, and 33%, respectively (10) , and assuming the relative bioavailability is equal to unity and the intrasubject variability for would fall within 25% to 50%, a sample size of 16 subjects completing the PK/PD Pivotal study in each treatment group would provide reasonably precise estimates of the systemic exposure of furosemide (AUC and ).

All pharmacokinetic analyses of the PK/PD Pivotal study were performed by Nuventra using Phoenix WinNonlin 6.3 (Pharsight, St. Louis, Missouri). Furosemide concentrations were tabulated by treatment group and summarized for each sampling time points as descriptive statistics (mean, SD, coefficient of variation, median, minimum, and maximum). For thecalculation of mean concentrations and mean concentration–time profiles, all below the limit of quantification values were set to zero except when a subject fell between 2 quantifiable values, in which case it was treated as missing data.

An analysis of variance (ANOVA) was performed on the ln-transformed furosemide and to assess the difference in overall systemic exposure between the IV and SC furosemide treatments. The ANOVA model included treatment as a fixed effect, and subject as a random effect. Each ANOVA included the calculation of least squares means (LSM) and the difference between treatment LSM. The 90% confidence intervals (CIs) for the ratios were derived by exponentiation of the CIs obtained for the difference between treatment LSM (SC furosemide/IV furosemide) resulting from the analyses on the furosemide ln-transformed and . A p value<0.05 was considered statistically significant. The statistical analysis was performed by an independent clinical research organization (Nuventra). The first-in-man study was a proof-of-concept study to gain initial experience with SC administration of the novel formulation. No formal statistical analysis was applied, and the number of participants was based on empirical considerations.

In both the First-in-Man and PK/PD Pivotal studies, the SC administration of furosemide was well tolerated with no evidence of any drug-induced skin reactions. In the First-in-Man study, all 10 subjects completed each of the cross-over treatments. The mean age of the subjects was 69.9 ± 8.6 years, 80% were male, the body mass index was 27.5 ± 4.5 kg/m 2 , and all were New York Heart Association (NYHA) functional class II ( Table1 ).

Now that we’re using the tick counter (with reset-ticks ), we should tell NetLogo that it only needs to update the view once per tick, instead of continuously updating it.

This makes your model run faster and ensures a consistent appearance (since the updates will happen at consistent times). See the Programming Guide for a fuller discussion of view updates.

Now make a button called “go”. Follow the same steps you used to make the setup button, except:

The “Forever” checkbox makes the button stay down once pressed, so its commands run over and over again, not just once.

The “Disable until ticks start” prevents you from pressing go before setup.

tick is a primitive that advances the tick counter by one tick.

But what is move-turtles ? Is it a primitive (in other words, built-in to NetLogo)? No, it’s another procedure that you’re about to add. So far, you have introduced two procedures that you added yourself: setup and go .

Note there are no spaces around the hyphen in move-turtles . In Tutorial #2 we used red - 2 , with spaces, in order to subtract two numbers, but here we want move-turtles , without spaces. The “-” combines “move” and “turtles” into a single name.

Here is what each command in the move-turtles procedure does:

Why couldn’t we have just written all of these commands in go instead of in a separate procedure? We could have, but during the course of building your project, it’s likely that you’ll add many other parts. We’d like to keep go as simple as possible, so that it is easy to understand. Eventually, it will include many other things you want to have happen as the model runs, such as calculating something or plotting the results. Each of these things to do will have its own procedure and each procedure will have its own unique name.

The ‘go’ button you made in the Interface tab is a forever button, meaning that it will continually run its commands until you shut it off (by clicking on it again). After you have pressed ‘setup’ once, to create the turtles, press the ‘go’ button. Watch what happens. Turn it off, and you’ll see that all the turtles stop in their tracks.

Note that if a turtle moves off the edge of the world, it “wraps”, that is, it appears on the other side. (This is the default behavior. It can be changed; see the Topology section of the Programming Guide for more information.)

We suggest you start experimenting with other turtle commands.

Type commands into the Command Center (like turtles> set color red ), or add commands to setup , go , or move-turtles .

Note that when you enter commands in the Command Center, you must choose turtles> , patches> , links> , or observer> in the popup menu on the left, depending on which agents are going to run the commands. It’s just like using ask turtles or ask patches , but saves typing. You can also use the tab key to switch agent types, which you might find more convenient than using the menu.

I began using an organic vegan based B12 spray after I had an oral surgery that left my lip and chin numb for weeks after surgery was done. I developed severe recurrent yeast infections. I realized that this was in part due to the antibiotics which were given to me after surgery. BUT as Chris Kresser states if the only true form of B12 comes from animals and the vegan version of B12 spray uses Brewers yeast (saccharomyces cerevisiae) to derive B12 then does that mean it’s pointless to be taking vegan B12 supplements? This seems to be the appropriate conclusion. So my question is: how do B12 injections differ from vegan sources of methocobalymin? Is it safe to inject B12 if the vegan methocobalymin (derived using Brewers yeast) may have been the culprit in my yeast infection? How are the shots different?

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framistat says

Candida albicans is the yeast that causes yeast infections. You can combat it with Primal Defense ULTRA (contains Saccharomyces boulardii, very beneficial), caprylic acid, gymnema sylvestre, etc.

Before abandoning the spray, have your B12 levels tested. Sublingual B12 can be comparable to shots and much less expensive. Best of luck.

Reply

Can anyone chime in on this process to make homemade B12 mineral brews. You ferment a mineral solution which contains trace amounts of cobalt. The idea being the bacteria can produce b12. Here is the process…

“What I have been doing is to buy a very high quality probiotic with more than twelve strains (I would like to synthesize one myself from a pristine organic source when I learn the process). I then add this probiotic to water or coconut water in a good sized mason jar or a fresh local organic fruit juice you may have ripe in your area… then I add some ionic minerals and I fill up the jar with liquid and place a loose cap on it and let it brew for one to three days in a warm and dark place- if you have water kefir grains this is better to add to as well- if you are using only water and no juice then it is important to add about one to two ounces of sugar to a quarter to half gallon of water this way the bacteria can “wake up” and start metabolism and proliferation using the sugar as a fuel source. After one to three days the brew will not have sugar and it will have bubbles because of bacteria releasing Carbon Dioxide. The Key is to give the bacteria enough minerals to convert into usable forms for the body for example high quality Ionic Minerals Eco Organics Augustus Dunning in Texas is well made and he can give you an idea how this process works by the analogy of making compost tea. In essence instead of making compost tea for your garden you are making a highly utilizable mineral brew for your body, these bacteria will become house cleaners in the body. One the brew is done you can drink half of it in a day, at the end of the day refill with water and add sugar- or add fresh juice or coconut water and let brew again, because of the activity being present in the brew it will be ready in around twelve hours at around 75 degrees F. So this may well be a source of B twelve if cobalt is present in the trace minerals you feed the brew”

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kristy says

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Marc A. Russo , Danielle M. Santarelli , Dean O’Rourke
Breathe 2017 13: 298-309; DOI: 10.1183/20734735.009817
Marc A. Russo
Hunter Pain Clinic, Broadmeadow, Australia
Danielle M. Santarelli
Hunter Pain Clinic, Broadmeadow, Australia
Dean O’Rourke
Hunter Pain Clinic, Broadmeadow, Australia ATUNE Health Centres, Warners Bay, Australia

Slow breathing practices have been adopted in the modern world across the globe due to their claimed health benefits. This has piqued the interest of researchers and clinicians who have initiated investigations into the physiological (and psychological) effects of slow breathing techniques and attempted to uncover the underlying mechanisms. The aim of this article is to provide a comprehensive overview of normal respiratory physiology and the documented physiological effects of slow breathing techniques according to research in healthy humans. The review focuses on the physiological implications to the respiratory, cardiovascular, cardiorespiratory and autonomic nervous systems, with particular focus on diaphragm activity, ventilation efficiency, haemodynamics, heart rate variability, cardiorespiratory coupling, respiratory sinus arrhythmia and sympathovagal balance. The review ends with a brief discussion of the potential clinical implications of slow breathing techniques. This is a topic that warrants further research, understanding and discussion.

Key points

Slow breathing practices have gained popularity in the western world due to their claimed health benefits, yet remain relatively untouched by the medical community.

Investigations into the physiological effects of slow breathing have uncovered significant effects on the respiratory, cardiovascular, cardiorespiratory and autonomic nervous systems.

Key findings include effects on respiratory muscle activity, ventilation efficiency, chemoreflex and baroreflex sensitivity, heart rate variability, blood flow dynamics, respiratory sinus arrhythmia, cardiorespiratory coupling, and sympathovagal balance.

There appears to be potential for use of controlled slow breathing techniques as a means of optimising physiological parameters that appear to be associated with health and longevity, and that may extend to disease states; however, there is a dire need for further research into the area.

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