MNKD technology patent notice web page

[afrezzamiracle]

www.mannkindcorp.com/our-technology-patent-notices.htm

I don't remember seeing this in the past.

[cm5]

8,119,593     Method of treating diabetes type 2 by metformin and an ultrarapid acting insulin

Publication number US20050153874 A1
Publication type Application
Application number US 11/032,278
Publication date Jul 14, 2005
Filing date Jan 10, 2005
Priority date Jan 12, 2004
Also published as CA2552707A1, 4 More »
Inventors Wayman Cheatham, Anders Boss, Andreas Pfuetzner
Original Assignee Mannkind Corporation

Method of reducing serum proinsulin levels in type 2 diabetics

ABSTRACT

Methods are provided for reducing serum proinsulin levels, lessening post-prandial pancreatic stress, and reducing risk factors for atherosclerosis in subjects with diabetes mellitus, type 2. The method includes administration of insulin in a manner that mimics the meal-related first phase insulin response, using a dose sufficient to reduce serum levels of proinsulin. In some embodiments of the method insulin administration is commenced early in the course of the disease. Mimicking first phase kinetics, peak serum insulin levels can be reached within about 18 minutes of administration. In increasingly preferred embodiments peak serum insulin levels can be reached within about 15, 12, or 10 minutes of administration. Serum insulin levels return to baseline within about two hours of administration.

[cm5]

More re: Patent 8,119,593 Method of treating diabetes type 2 by metformin and an ultrarapid acting insulin


Yes, this is not "New News". Yes, it's time to refresh the discussion, especially given the ADA and ongoing discussion of the abstracts. Yes, it's a good time to review/inspect the patents now listed on Mannkind's site. 

 See:  www.google.com/patents/US8623817

Treatment of diabetes has traditionally focused on controlling average blood glucose concentrations, as reflected by Hb1Ac levels.


The presently disclosed methods are designed to minimize not only Hb1Ac levels (average blood glucose concentration) and attendant glucose toxicity; but also to control acute fluctuations in glucose concentration (glucose excursions).


The reduction of glucose excursions also relieves the general inflammatory burden and oxidative damage to microvasculature resulting from oxidative stress.


Thus even for patients in whom substitution of ultrarapid insulin for one or more oral medications may result in only similar control of HbA1c levels the treatment can confer a benefit over treatment with oral medications alone.


Indeed this is a benefit that is also not attainable by addition of basal insulin to the treatment regimen. Nor can the merely rapid acting insulins be expected to deliver this benefit in full measure, especially as compared to an optimized dose of an ultrarapid acting insulin.

[cm5]

More: Mannkind Patents   8,258,095

Again, critical time to bring attention/focus to the below:

Method of controlling glycemia by ultrarapid acting insulin without adjusting an insulin dose for meal content
www.google.com/patents/US8258095B2

Current treatment of diabetes generally aims to reduce HbA1c levels to 7% or below.


HbA1c levels above 8% indicate that patient's current therapy should be re-evaluated.


It may be desirable to achieve normal HbA1c levels, but with the currently marketed insulin products this could only be accomplished at an unacceptable risk of severe hypoglycemia.


Thus patients with HbA1c levels below 8% would not usually be considered candidates for more intensive treatment, that is, for treatment with insulin especially the current prandial insulins.


Even those with HbA1c above 8% but not yet receiving basal or mixed insulin would not be considered to be candidates for treatment with a prandial insulin regimen.


In embodiments disclosed herein the risk of hypoglycemia is much reduced, in part due to the lack of a tail of insulin activity exhibited by ultrarapid acting insulin, and it is possible to treat patients with HbA1c below 7%.


Additionally, benefit can be expected from lowering blood glucose even at the high end of the normal range. For example one study showed that the risk of cardiovascular disease events was 5-8 times higher for individuals with HbA1c >7% as compared to those with HbA1c<5%.


Another study showed a progressive increase in risk of kidney disease as HbA1c went from <6% to >8%. Accordingly, in some embodiments, patients with HbA1c levels ≦6.5% or ≦6% are selected for treatment.

[peppy]

Jun 4, 2016 7:33:19 GMT -5 cm5 said:

More re: Patent 8,119,593 Method of treating diabetes type 2 by metformin and an ultrarapid acting insulin


Yes, this is not "New News". Yes, it's time to refresh the discussion, especially given the ADA and ongoing discussion of the abstracts. Yes, it's a good time to review/inspect the patents now listed on Mannkind's site. 

 See:  www.google.com/patents/US8623817

Treatment of diabetes has traditionally focused on controlling average blood glucose concentrations, as reflected by Hb1Ac levels.


The presently disclosed methods are designed to minimize not only Hb1Ac levels (average blood glucose concentration) and attendant glucose toxicity; but also to control acute fluctuations in glucose concentration (glucose excursions).


The reduction of glucose excursions also relieves the general inflammatory burden and oxidative damage to microvasculature resulting from oxidative stress.


Thus even for patients in whom substitution of ultrarapid insulin for one or more oral medications may result in only similar control of HbA1c levels the treatment can confer a benefit over treatment with oral medications alone.


Indeed this is a benefit that is also not attainable by addition of basal insulin to the treatment regimen. Nor can the merely rapid acting insulins be expected to deliver this benefit in full measure, especially as compared to an optimized dose of an ultrarapid acting insulin.

quote; oxidative damage to microvasculature resulting from oxidative stress.

Reply: A few years ago, when the term, "it's an antioxidant" was being used, I looked to find out what the...

it led me to oxidative stress. I have to have things dumbed down. oxidative stress turned out to be an oxygen molecule in the cell looking for an electron.

Vitamins, vitamin c for instance will donate an electron, it's an anti-oxidant.

As best as I have been able to figure out, if a human being stands bare feet on the ground, bare feet in the beach, lake, (mudpuddle, hehe) charge should stabilize. It is an anti oxidant.

Decrease inflammation, ground yourself. charge based in this instance.

<--- twisted sister

[cm5]

More:  Oxidative Stress

CELLULAR STRESS CONDITIONS ARE REFLECTED IN THE PROTEIN AND RNA CONTENT OF ENDOTHELIAL CELL-DERIVED EXOSOMES
Olivier G. de Jong1, Marianne C. Verhaar1, Yong Chen2, Pieter Vader3, Hendrik Gremmels1, George Posthuma4, Raymond M. Schiffelers3, Marjan Gucek2 and Bas W.M. van Balkom1*
Department of Nephrology and Hypertension, UMC Utrecht, Utrecht, The Netherlands; 2National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA; 3Department of Clinical Chemistry and Hematology, UMC Utrecht, Utrecht, The Netherlands; 4Department of Cell Biology, UMC Utrecht, Utrecht, The Netherlands
www.journalofextracellularvesicles.net/index.php/jev/article/view/18396

The healthy vascular endothelium, which forms the barrier between blood and the surrounding tissues, is known to efficiently respond to stress signals like hypoxia and inflammation by adaptation of cellular physiology and the secretion of (soluble) growth factors and cytokines. Exosomes are potent mediators of intercellular communication. Their content consists of RNA and proteins from the cell of origin, and thus depends on the condition of these cells at the time of exosome biogenesis. It has been suggested that exosomes protect their target cells from cellular stress through the transfer of RNA and proteins. We hypothesized that endothelium-derived exosomes are involved in the endothelial response to cellular stress, and that exosome RNA and protein content reflect the effects of cellular stress induced by hypoxia, inflammation or hyperglycemia.

Exosomes from METABOLIC SYNDROME PATIENTS induce endothelial dysfunction through mitochondrial-generated oxidative stress
Archives of Cardiovascular Diseases Supplements
Volume 8, Issue 3, April 2016, Pages 216
Marine Malloci1, , , Séverine Dubois2, Ramaroson Andriantsitohaina1, Gilles Simard1, Carmen Martinez1
Printemps de la Cardiologie : Recherche Fondamentale et Clinique - Centre de Congrès Dijon, 7-8 avril 2016
www.sciencedirect.com/science/article/pii/S1878648016303950

Metabolic syndrome (MetS) is characterized by a cluster of interrelated risk factors hyperglycemia, dyslipidemia, hypertension and obesity leading to an increased risk of cardiovascular events.

Exosomes are nanoscaled vesicles (30 100 nm) released by cells, that bear proteins and nucleic acids. It has been demonstrated that circulating exosome rate is positively correlated with (i) an increase of inflammation, (ii) a decrease of HDL cholesterol and (iii) prevalence of MetS.

We demonstrated that treatment of human endothelial aortic cells with exosomes from MetS patients induce endothelial dysfunction associated with decreased nitric oxide and increased reactive oxygen species (ROS) production.

The increase on fluorescence associated to Mitosox suggests an enhanced production of mitochondrial ROS following 4 hours of MetS exosome treatment.

Altogether, we show exosomes as novel players implicated in endothelial dysfunction associated with MetS and consequently potential targets to prevent and treat vascular consequences of this syndrome.

INTRACEREBRAL MICROHEMORRHAGES IN AGING: ROLE OF INCREASED OXIDATIVE STRESS AND MMP ACTIVATION
Zoltan, UNGVARI (1), Anna, CSISZAR (1)
University of Oklahoma HSC, United States
journal.medsys-site.com/index.php/JISANH/article/view/723

Aging exacerbates hypertension-induced cognitive decline, but the specific age-related mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function.

Collectively, aging promotes CMHs in mice likely by exacerbating hypertension-induced oxidative stress and MMP activation. Therapeutic strategies that reduce microvascular oxidative stress and MMP activation may be useful for the prevention of CMHs, protecting neurocognitive function in high-risk elderly patients.

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress
Ravi K Sajja1
Shafiqur Rahman2
Luca Cucullo1⇑
Center for Blood-Brain Barrier Research, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX, USA
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD, USA
Luca Cucullo, Texas Tech University Health Sciences Center, School of Pharmacy, 1300 S. Coulter Street, Amarillo, TX 79106, USA. Email: [e-mail]
jcb.sagepub.com/content/36/3/539

Psychostimulants and nicotine are the most widely abused drugs with a detrimental impact on public health globally. While the long-term neurobehavioral deficits and synaptic perturbations are well documented with chronic use of methamphetamine, cocaine, and nicotine, emerging human and experimental studies also suggest an increasing incidence of neurovascular complications associated with drug abuse.

Short- or long-term administration of psychostimulants or nicotine is known to disrupt blood-brain barrier (BBB) integrity/function, thus leading to an increased risk of brain edema and neuroinflammation.

Various pathophysiological mechanisms have been proposed to underlie drug abuse-induced BBB dysfunction suggesting a central and unifying role for oxidative stress in BBB endothelium and perivascular cells.

This review discusses drug-specific effects of methamphetamine, cocaine, and tobacco smoking on brain microvascular crisis and provides critical assessment of oxidative stress-dependent molecular pathways focal to the global compromise of BBB. Additionally, given the increased risk of human immunodeficiency virus (HIV) encephalitis in drug abusers, we have summarized the synergistic pathological impact of psychostimulants and HIV infection on BBB integrity with an emphasis on unifying role of endothelial oxidative stress. 

[cm5]

Reading carefully through all of Mannkind's patents and pertinent literature should be a wake-up call----

So---here is why control/diminishment/eradication of immediate post prandial hyperglycemia is critical, and why Mannkind's Technosphere (R) inhaled human monomoric insulin is the ultimate disruptive medical/pharmaceutical/device creation of our times---

Uncovering the Beginning of Diabetes: the cellular redox status and oxidative stress as starting players in hyperglycemic damage

Molecular and Cellular Biochemistry
April 2013, Volume 376, Issue 1, pp 103-110
João Soeiro Teodoro, Ana Patrícia Gomes, Ana Teresa Varela, Filipe Valente Duarte, Anabela Pinto Rolo, Carlos Marques Palmeira
Faculty of Science and Technology, Center for Neuroscience and Cell Biology, University of Coimbra
Department of Life Sciences, Faculty of Science and Technology, University of Coimbra

link.springer.com/article/10.1007/s11010-012-1555-9

Early hyperglycemic insult can lead to permanent, cumulative damage that might be one of the earliest causes for a pre-diabetic situation.

Despite this, the early phases of hyperglycemic exposure have been poorly studied.

We have previously demonstrated that mitochondrial injury takes place early on upon hyperglycemic exposure.

In this work, we demonstrate that just 1 h of hyperglycemic exposure is sufficient to induce increased mitochondrial membrane potential and generation

[cm5]

Re: stated concerns "proving" HgbA1C, see following. Also read resources about post prandial blood sugar levels and consequent HcbA1C.

And, undoubtedly, given below, studies are underway. 

Jun 4, 2016 7:48:59 GMT -5 cm5 said:

More: Mannkind Patents   8,258,095

Again, critical time to bring attention/focus to the below:

Method of controlling glycemia by ultrarapid acting insulin without adjusting an insulin dose for meal content
www.google.com/patents/US8258095B2

Current treatment of diabetes generally aims to reduce HbA1c levels to 7% or below.


HbA1c levels above 8% indicate that patient's current therapy should be re-evaluated.


It may be desirable to achieve normal HbA1c levels, but with the currently marketed insulin products this could only be accomplished at an unacceptable risk of severe hypoglycemia.


Thus patients with HbA1c levels below 8% would not usually be considered candidates for more intensive treatment, that is, for treatment with insulin especially the current prandial insulins.


Even those with HbA1c above 8% but not yet receiving basal or mixed insulin would not be considered to be candidates for treatment with a prandial insulin regimen.


In embodiments disclosed herein the risk of hypoglycemia is much reduced, in part due to the lack of a tail of insulin activity exhibited by ultrarapid acting insulin, and it is possible to treat patients with HbA1c below 7%.


Additionally, benefit can be expected from lowering blood glucose even at the high end of the normal range. For example one study showed that the risk of cardiovascular disease events was 5-8 times higher for individuals with HbA1c >7% as compared to those with HbA1c<5%.


Another study showed a progressive increase in risk of kidney disease as HbA1c went from <6% to >8%. Accordingly, in some embodiments, patients with HbA1c levels ≦6.5% or ≦6% are selected for treatment.

[mango]

Jun 4, 2016 8:58:20 GMT -5 cm5 said:

Reading carefully through all of Mannkind's patents and pertinent literature should be a wake-up call----

So---here is why control/diminishment/eradication of immediate post prandial hyperglycemia is critical, and why Mannkind's Technosphere (R) inhaled human monomoric insulin is the ultimate disruptive medical/pharmaceutical/device creation of our times---

Uncovering the Beginning of Diabetes: the cellular redox status and oxidative stress as starting players in hyperglycemic damage

Molecular and Cellular Biochemistry
April 2013, Volume 376, Issue 1, pp 103-110
João Soeiro Teodoro, Ana Patrícia Gomes, Ana Teresa Varela, Filipe Valente Duarte, Anabela Pinto Rolo, Carlos Marques Palmeira
Faculty of Science and Technology, Center for Neuroscience and Cell Biology, University of Coimbra
Department of Life Sciences, Faculty of Science and Technology, University of Coimbra

link.springer.com/article/10.1007/s11010-012-1555-9

Early hyperglycemic insult can lead to permanent, cumulative damage that might be one of the earliest causes for a pre-diabetic situation.

Despite this, the early phases of hyperglycemic exposure have been poorly studied.

We have previously demonstrated that mitochondrial injury takes place early on upon hyperglycemic exposure.

In this work, we demonstrate that just 1 h of hyperglycemic exposure is sufficient to induce increased mitochondrial membrane potential and generation

Do you realize how amazing you are?


Modulation of cellular redox homeostasis by the endocannabinoid system

Abstract
The endocannabinoid system (ECS) and reactive oxygen species (ROS) constitute two key cellular signalling systems that participate in the modulation of diverse cellular functions. Importantly, growing evidence suggests that cross-talk between these two prominent signalling systems acts to modulate functionality of the ECS as well as redox homeostasis in different cell types. Herein, we review and discuss evidence pertaining to ECS-induced regulation of ROS generating and scavenging mechanisms, as well as highlighting emer-ging work that supports redox modulation of ECS function. Functionally, the studies outlined reveal that interactions between the ECS and ROS signalling systems can be both stimulatory and inhibitory in nature, depending on cell stimulus, the source of ROS species and cell context. Importantly, such cross-talk may act to maintain cell function, whereas abnormalities in either system may propagate and undermine the stability of both systems, thereby contributing to various pathologies associated with their dysregulation.

• The dysregulation of redox homeostasis has been linked with the development of various pathologies, including those associated with metabolic disorders such as type 2 diabetes and obesity, cardiovascular disease, as well as various neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis; figure 1) [6–11].

• There is evidence to suggest that stimulation of CB2R may also convey beneficial free radical scavenging effects. Indeed, in a study by Ribeiro et al. [60], and co-workers, the selective CB2R agonist AM1241 was shown to almost completely block ROS generation in response to lipopolysaccharide (LPS) in BV-2 cells. Consistent with this, CB2R activation has also been reported to attenuate oxidative stress damage in various tissue types, including brain [59], kidney [63], heart [64] and liver [65].

• Previous work using CB2R agonists and/or knockout mice indicates that activation of CB2R confers protection against hepatic ischaemia–reperfusion (I/R) injury, concomitant with its ability to alleviate tissue free radical damage [66–68]. Allied to this, further evidence supporting a protective role for the ECS was provided in a study by Cao et al. [65], who demonstrated that pharmacological inhibition of monoacylglycerol lipase, the enzyme which catalyses the hydrolysis of 2-AG, led to the suppression of oxidative stress and associated inflammation in liver tissue following hepatic I/R injury in mice [65].

• The protective effects of MAGL inhibition against hepatic I/R injury involved increased endocannabinoid signalling via CB2R [65]. Therefore, modulation of these distinct cannabinoid receptors can promote differential responses with respect to cellular redox homeostasis, even within one specific cell type.

• To conclude, there is growing appreciation that the ECS may play an important role in the regulation of cellular redox homeostasis. Collectively, the evidence presented in this review indicates that ECS activation or inhibition can convey detrimental and/or beneficial biological effects through altering cellular ROS levels, depending on the cell type and/or stimulus involved. Indeed, the studies highlighted in this review show that ECS function can impact upon free radical production in a number of different ways (figure 3). Crucially, given the importance of redox status in the development of numerous pathologies, these findings identify ECS components as potential therapeutic targets for the treatment of oxidative stress-related neurological, cardiovascular and metabolic disorders.

Modulation of cellular redox homeostasis by the endocannabinoid system



I always knew my lovely friend cm5 would figure it out. Left this little crumb sitting there unnoticed for over year. She is a badass genius. 

[mango]

Jun 4, 2016 7:53:52 GMT -5 peppy said:

Jun 4, 2016 7:33:19 GMT -5 cm5 said:

More re: Patent 8,119,593 Method of treating diabetes type 2 by metformin and an ultrarapid acting insulin


Yes, this is not "New News". Yes, it's time to refresh the discussion, especially given the ADA and ongoing discussion of the abstracts. Yes, it's a good time to review/inspect the patents now listed on Mannkind's site. 

 See:  www.google.com/patents/US8623817

quote; oxidative damage to microvasculature resulting from oxidative stress.

Reply: A few years ago, when the term, "it's an antioxidant" was being used, I looked to find out what the...

it led me to oxidative stress. I have to have things dumbed down. oxidative stress turned out to be an oxygen molecule in the cell looking for an electron.

Vitamins, vitamin c for instance will donate an electron, it's an anti-oxidant.

As best as I have been able to figure out, if a human being stands bare feet on the ground, bare feet in the beach, lake, (mudpuddle, hehe) charge should stabilize. It is an anti oxidant.

Decrease inflammation, ground yourself. charge based in this instance.

<--- twisted sister

I'm a bastid. You are equally amazing.

[itellthefuture777]

Whenever I see Shark Tank they always ask..is it patented? Yup! Solidly!