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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
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It is known as statins a group of drugs used to lower cholesterol in patients suffering from hypercholesterolemia and who have therefore increased risk of developing atherosclerosis and have episodes cardiovascular disease. From the pharmacological point of view, fall within the HMG-CoA reductase. Enzyme inhibition is precisely this which justifies the reduction of certain fractions of cholesterol in the body and explains its importance: their positive intervention on cardiovascular risk factors, leading to numerous cardiovascular diseases, which are the leading cause of death in the developed world [1,2]. Despite its short history (less than forty years) are many studies that have been done on statins and hundreds of thousands of patients who have taken these drugs. This has given rise to an extensive knowledge of the characteristics of these drugs has led to the synthesis of new substances that improve the properties of the above statins; in this line part of pharmaceutical research is still moving. However, it has also given rise to broadly meet the real toxicological profile for each substance. The phase IV studies have revealed the risks of using these substances for long periods or in certain basal conditions, which has led, among other things, the withdrawal of any member of the family due to their increased incidence of severe adverse reactions. Because of the variability in origin, the pharmacokinetics of statins differ greatly, however, its pharmacodynamic similarities allowed their joint study group them because, in terms of mechanism of action and effects of statins, and especially, regarding the clinical consequences of its use, there is an important congruence group, which has been widely studied (Table 1). All developed statins are used orally and absorbed by this route on a variable range from 30% of lovastatin to 35% of pravastatin, decreasing its absorption in the presence of food in the stomach. However, the changes in peak concentrations or the respective curves of assimilation have no impact on the final results in the modification of cholesterol levels, so it is generally advisable to take them at any time of day and in most cases with or without food. Also, there appears to be accumulation due to multiple doses, which is general consensus decision single dose. The recommendations do not drink grapefruit juice while being treated with statins is due to interference with the metabolism, not altered absorption. Generally, the bioavailability of the statins is low, ranging from 5% of lovastatin and 17% of pravastatin. Binding to plasma proteins is variable, but in general very high lines. Except 50% of pravastatin, all have a 95% binding to proteins. The tissue distribution is broad, crossing the blood-brain and placental barriers, even going to milk in lactating women. Liver specificity of these drugs is determined by its degree of lipophilicity and by the presence of some organic anion transporter proteins that allow more hydrophilic statins such as pravastatin and rosuvastatin, entering the hepatocyte [3]. Moreover, some statins may inhibit P-glycoprotein (multidrug resistance protein), a carrier protein of many drugs in the cell, which could predispose to drug interactions. [4]
\n\t\t\t\t | \n\t\t|||||||
\n\t\t\t | Sinvastatin | \n\t\t\tPravastatin | \n\t\t\tLovastatin | \n\t\t\tFluvastatin | \n\t\t\tAtorvastatin | \n\t\t\tRosuvastatin | \n\t\t\tPitavastatin | \n\t\t
\n\t\t\t\t | \n\t\t\tYES | \n\t\t\tNO | \n\t\t\tYES | \n\t\t\tNO | \n\t\t\tNO | \n\t\t\tNO | \n\t\t\tNO | \n\t\t
\n\t\t\t\t | \n\t\t\tNo influence | \n\t\t\t | \n\t | \n | \n | \nNo influence | \n\n |
\n\t\t | \n\t≤5% | \n\t17% | \n\t≤5% | \n\t24% | \n\t14% | \n\t20% | \n\t≥30% | \n
\n\t\t \n\t\t | \n\t94% | \n\t50% | \n\t>95% | \n98% | \n98% | \n88% | \n- | \n
\n\t\t | \n\tYES | \n\tNO | \n\tYES | \n\tNO | \n\tNO | \n\tNO | \n\tYES | \n
\n\t\t | \n\tCYP3A4 | \n\tsulphation | \n\tCYP3A4 | \n\tCYP2C9 | \n\tCYP3A4 | \n\tCYP2C9 | \n\tCYP2C9 CYP2C8 | \n
\n\t\t | \n\t60% | \n\t70% | \n\t83% | \n\t95% | \n\t- | \n\t90% | \n\t- | \n
\n\t\t | \n\t13% | \n\t20% | \n\t10% | \n\t5% | \n\t<2% | \n\t30% | \n\t3% | \n
\n\t\t | \n\t2-3h | \n\t0.8h | \n\t1-4h | \n\t2.5h | \n\t20h | \n\t20h | \n\t- | \n
Pharmacological characteristics of statin
The metabolism of statins is liver, undergoing first pass metabolism. In most, there are differences in the metabolism regarding sex and age, but not enough to change the doses in the absence of other pathologies. It seems clear that are substrates of CYP450: lovastatin, simvastatin and atorvastatin are metabolized exclusively by CYP3A4, and fluvastatin does exclusively by 2C9. For rosuvastatin, only 10% use the CYP2C9 and 2C19. Pitavastatin has a low affinity for CYP2C9, so not a major metabolic pathway. Pravastatin is not metabolised by the cytochrome, but does so by enzymes present in the cytoplasm of hepatocytes. The metabolites may be hydroxylated derivatives, omega or beta-oxidized methylated glucuronide. The pharmacological activity of the same is very variable. Thus, the range is wide, from lovastatin, simvastatin, which are really a pharmacologically inactive lactones and performing their pharmacological activity through its metabolites, to fluvastatin, which has virtually inactive metabolites. For the most part, excretion in feces is due to its poor absorption. According to each type of statins, renal excretion ranges from 2% to 20%.
Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is a key metabolite in the biosynthesis of cholesterol. Blocking occurs due to the high structural resemblance with these drugs exhibit HMG-CoA. The affinity of the enzyme by statins is 1.000 to 10.000 times that of the natural substrate (Figure 1).
Biosynthesis of cholesterol
The blockade of hepatic cholesterol synthesis causes an activation of the regulatory proteins SREBP (sterol regulatory elements-binding proteins), which activate transcription of protein and thus result in higher expression of the LDL receptor gene and increased the number of functional receptors on hepatocytes [5]. Moreover, it has been shown that statins also produced inhibition associated antigen-1 with the function of lymphocytes (LFA-1: lymphocyte function-associated antigen-1) [6]. The LFA-1 is a glycoprotein integrin family expressed on the surface of leukocytes. When the LFA-1 is activated by certain receptors, binds to the intracellular molecule-1 adhesion (ICAM-1 or CD-54) and stimulates the extravasation of leukocytes and activation of T lymphocytes. This means that the LFA-1 is a proinflammatory agent and its inhibition is beneficial in conditions such as rheumatoid arthritis and rejection of homograft. It was shown that statins and particularly, lovastatin, bind to a site of LFA-1 domain, lovastatin currently designated site. This is the molecular mechanism by which lovastatin, simvastatin and other statin lesser extent inhibit the LFA-1 [7]. This would be one of the anti-inflammatory mechanisms and hence possessing antiatherogenic statins.
The consequences of the inhibition of HMG-CoA may be grouped into two groups:
By inhibiting HMG-CoA reductase inhibitors, statins interfere with the formation of isoprenoids from mevalonate. [10] Isoprenoids are molecules such as farnesyl pyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), derived from the metabolism of mevalonate, which serve as lipid-tags for the posttranslational modification of a variety of proteins, including the gamma subunit of G proteins and small GTP unidoras proteins. As a result, the prenylation of the G proteins (Rho, Rac, Ras and Rab Rac1) is reduced. Prenylation of these molecules is necessary for anchoring to the cell membrane and thus to exercise their mechanism of action related to migration, differentiation and cell proliferation. Generally, stimulate and inhibit proinflammatory pathways useful mechanisms for endothelial homeostasis. Through these potential effects on cellular proteins, statins may have a number of antiatherosclerotic and antithrombotic properties, such as inhibiting the growth of smooth muscle cells, cell adhesion, platelet activation and secretion of C-reactive protein among other. The mevalonic acid, may also act directly by inhibiting the synthesis of nitric oxide (NO) in a process dependent transferase inhibiting genilgeranil. NO is an essential molecule for proper function and vasodilatation of endothelium. To this should be added the effects resulting from inhibition of LFA-1, which in turn significantly impacting on endothelial function in blood vessels. These pleiotropic effects are constant source of research, since they can extend the usage profile of statins. Moreover, these drugs maintain and improve endothelial function to increase the bioavailability of NO, which is synthesized by the enzyme NO synthase (eNOS). NO is the principal regulator of the homeostasis of the arteries and endothelium-dependent vasodilation. The functions are, among others, inhibiting proinflammatory mechanisms and act as an antioxidant on lipoproteins [12].
Statins preserve and increase the bioavailability of NO in several ways:
Inhibition of Rho protein increases the expression of the enzyme nitric oxide synthase.
Increasing the half-life of the messenger RNA of the enzyme nitric oxide synthase.
Reduce excess caveolin molecule that acts as an inhibitor of nitric oxide synthase enzyme.
Inhibit the production of superoxide.
To protect the NO statins decrease platelet aggregation and reducing thromboxane A2 by platelets and thus limit the formation of unstable plaque.
Increasing the expression of tissue plasminogen activator and inhibit the expression of endothelin-1, a potent vasoconstrictor with mitogenic action [12].
The hypolipidemic action itself inherently reduces oxidative stress. However, of statins have their own antioxidant mechanisms that inhibit the production of superoxide anion radical. Superoxide is synthesized by NADPH oxidase, an enzyme which can be activated by the action of membrane receptor of angiotensin II, type I (R-1) receptors. Statins block the R-AT1 and also inhibit the phosphorylation of the NADPH oxidase, inactivating it [13].
Statins also block RhoA, one of the mediators of smooth muscle proliferation. The smooth muscle proliferation is a central phenomenon in the pathogenesis of vascular lesions, including post-angioplasty restenosis, transplant atherosclerosis and occlusion of the coronary vein grafts [14].
Atherosclerosis is a strong inflammatory component characterized by the presence of monocytes, macrophages and T cells in the plate. This process is induced by proinflammatory cytokines, free radicals and NO deficiency. Statins increase the bioavailability of NO and inhibit several proinflammatory cytokines [1].
A marker of inflammation and predictor of coronary heart disease risk is C-reactive protein (PCR). It is considered that PCR is also proinflammatory as joining the cLDL of the atheromatous, activates complement plate and induces the expression of inhibitor-1, plasminogen activator (PAI-1), reduces the expression of eNOS and increases the expression of adhesion molecules [15]. Therefore, it is valid to assume that the decrease in plasma CRP levels might be beneficial. Large studies with statins, as the AFCAPS/TexCAPS showed reduced blood PCR. For its anti-inflammatory action, statins increase the stability of the atheromatous plaque, and much of the reduction in coronary events attributable to the mechanism. Preclinical studies demonstrated that statins reduce the accumulation of macrophages in the atheromatous plaque and inhibit metalloproteinase production by activated macrophages. Metalloproteinases are capable of degrading proteins support and are therefore partly responsible for the accident plaque with thrombus formation [16].
Clinically the effects of statins lead to a reduction in cardiovascular risk, through the following mechanisms:
Directly decreasing cholesterol levels.
Improving endothelial function and inflammatory response.
Stabilizing atherosclerotic plaque.
Preventing thrombus formation.
Then offer recommendations for clinical practice for the treatment of hypercholesterolemia in adults and reduce the risk of atherosclerotic cardiovascular disease, which includes coronary heart disease, cerebrovascular disease, peripheral artery disease and other atherosclerotic probable origin.
Statins are indicated as an adjunct to diet to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides; and to increase HDL cholesterol in patients with:
Primary hypercholesterolaemia.
Mixed dyslipidemia.
Homozygous familial hypercholesterolemia.
Also present clear indication in cardiovascular prevention [17]:
Primary prevention of coronary events: in hypercholesterolemic patients without clinical evidence of coronary heart disease.
Reduce the risk of myocardial infarction.
Reduce the risk of myocardial revascularization procedures.
Reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes.
Secondary prevention of cardiovascular events: in patients with clinical evidence of cardiovascular disease.
Reduce the risk of total mortality by reducing coronary death.
Reduce the risk of myocardial infarction.
Reduce the risk of myocardial revascularization procedures.
Reduce the risk of stroke and transient ischemic attacks (TIA).
Slow the progression of coronary atherosclerosis.
The latest evidence recommends an individualized approach (tailored treatment approach) identified four risk groups associated with therapeutic strategy (Figure 2). Groups that benefit from the use of statin therapy in moderate intensity: LDL reduction of 30-49% or high intensity, LDL reduction of >49% both demonstrate reduction cardiovascular risk (RCV) [17].
The main therapeutic strategies are (Table 2),
\n\t\t\t \n\t\t\t | \n\t\t\n\t\t\t \n\t\t\t | \n\t\t\n\t\t\t \n\t\t\t | \n\t
Daily doses lowers LDL on average >50% | \nDaily dose lowers LDL on average 30-50% | \nDaily dose lowers LDL on average 30% | \n
\n\t\t \n\t\t | \n\t\n\t\t \n\t\t \n\t\t \n\t\t \n\t\t \n\t\t \n\t\t \n\t\t | \n\t\n\t\t \n\t\t \n\t\t \n\t\t \n\t\t | \n
Low, moderate and high-intensity statin therapy categories in treating patients with varying risks.
Statin therapy of high, moderate and low intensity according to studies is classified:
* FDA approved but not tested in randomized controlled trials.
Primary prevention with LDL ≥ 160 mg/dL.
Genetic testing hyperlipidemias.
Family history of premature cardiovascular disease with onset <55years in a male first-degree relative or <65 years female.
C-reactive protein levels of high sensitivity (hs-CPR) >2 mg /L,
Coronary artery calcium (CAC) score ≥300 Agatston units or ≥ 75th percentile for age, sex and ethnicity.
Ankle-brachial index <0.9.
Statin therapy for atherosclerotic cardiovascular disease prevention
In general, statins are well tolerated and the dropout rate in clinical trials as a result of any adverse effect is <10%, similar to that of patients taking placebo, and less than 1% are serious side effects (Table 3).
\n\t\t\t | \n\t||||
\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t \n\t\t\t | \n\t\t\n\t\t\t | \n\t
\n\t\t\t | \n\t\t6% | \n\t\tyes | \n\t\tSimvastatin/atorvastatin Pravastatin/atorvastatin Pravastatin/rosuvastatin | \n\t\t- | \n\t
\n\t\t\t | \n\t\t2% | \n\t\t- | \n\t\t- | \n\t\t- | \n\t
\n\t\t\t | \n\t\t1% | \n\t\tyes | \n\t\tSimvastatin/atorvastatin Simvastatin/fluvastatin Pravastatin/atorvastatin Pravastatin/fluvastatin Rosuvastatin/atorvastatin Rosuvastatin/fluvastatin | \n\t\tAtorvastatin Fluvastatin | \n\t
\n\t\t\t | \n\t\t0.6% | \n\t\tyes | \n\t\tFluvastatin/others | \n\t\tPitavastatin | \n\t
\n\t\t\t | \n\t\t9% | \n\t\t- | \n\t\t- | \n\t\t- | \n\t
Differences in adverse effects between statins
The drugs and clinical conditions that increase the risk of myopathy are,
Chronic diseases (renal failure and diabetes).
Multiple drugs.
Surgical interventions.
High doses of statins.
Statins in combination with:
Fibrates.
Nicotinic acid (not clearly stated)
Cyclosporine.
Antifungal azoles.
Macrolide antibiotics
Inhibitors of HIV protease.
Verapamil.
Amiodarone.
Abuse of alcohol.
Grapefruit juice (> 1/4 liter daily)
Hepatotoxicity: active hepatopathy or unexplained persistent elevations of serum transaminases (hypertransaminasemia). An elevation of three times the upper limit of normal transaminases in patients treated with statins occurs between 0.5% to 2% of cases and is directly related to the dose [20]. Hypertransaminasemia is reversible with drug discontinuation and progression to liver failure rarely occurs.
Hypersensitivity to any statin or any of the excipients of commercial presentations.
Dyspepsia.
Less common: sleep disturbances and memory, depression,....
Pregnancy and lactation.
Concomitant administration of potent inhibitors of CYP3A4 (itraconazole, ketoconazole, protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) or CYP2C9 (relative contraindication not dependent on CYP450 statins).
Elderly (age >70 years).
Renal failure.
Uncontrolled hypothyroidism.
Personal or family history of hereditary muscular disorders.
History of muscular toxicity with a statin or fibrate.
Alcoholism.
Concomitant weak inhibitors of CYP3A4 (Table 4)
\n\t\t\t | \n\t|
\n\t\t\t | \n\t\t | \n
\n\t\t | \n\t | \n
\n\t\t | \n\t | \n
\n\t\t | \n\t | \n
\n\t\t | \n\t | \n
\n\t\t | \n\t | \n
Other drug that interact with statin
Select the dose and type of statin, according to the type of patient cardiovascular risk and potential adverse effects.
Use moderate intensity therapy if the patient has renal or hepatic dysfunction including unexplained persistent transaminase elevations, history of muscular disorders or intolerance to statin use, ALT elevations >3 times the upper limit, concurrent use of medication known interactions with statin, age greater than 75 years, history of hemorrhagic stroke event, asian ancestry. This behavior can substantially reduce adverse events with statin use. The use of simvastatin is not recommended at doses of 80 mg/day because of the risk of toxicity. Liver function tests should be performed before starting statin therapy, with dose changes with the change of drug. During treatment should be monitored signs and symptoms of muscle toxicity.
Whenever a statin prescribing or replaced by another is important to analyze the other co-administered drugs due to the risk of clinically relevant interactions. In the absence of abnormal liver function and potential interactions with coadministered drugs, statins are all interchangeable. In the presence of inducing drugs or inhibitors of CYP3A4, fluvastatin, pravastatin and rosuvastatin are interchangeable. In the presence of inducers or inhibitors of CYP2C9 drugs, statins are all interchangeable, except fluvastatin. In the presence of drugs inducing activad or inhibitors of P-gp, fluvastatin and rosuvastatin are interchangeable. In the presence of inducers or inhibitors of OATP1B1 drugs, is not recommended therapeutic interchange of pravastatin and rosuvastatin. For all other statins, the exchange must be made with caution.
Monitoring of CK at baseline in patients with or without a history of myopathy, have no solid evidence. It could only be recommended if the patient has muscle symptoms, weakness or fatigue. The only test that is fully justified, prior to initiating statin is the measurement of ALT. The liver function should be measured if the patient is suspected of hepatotoxicity statin use. With the same level of evidence is regular monitoring of blood glucose, the onset of diabetes mellitus associated with treatment [21].
Clarify if the symptoms actually developed or intensified therapy. If there is a causal relationship apparent, and muscle symptoms are intolerable, discontinue medication. If rhabdomyolysis is suspected, measure CK-creatinine and urinalysis. If muscular symptoms are mild or moderate statin should be discontinued to reassess symptoms and assess whether the patient has conditions that increase risk of muscle symptoms (hypothyroidism, renal or hepatic dysfunction, polymyalgia rheumatica, steroid myopathy, vitamin D or primary) myopathies. If symptoms are resolved and there are no contraindications, restart the same statin at a lower dose. If symptoms relapse: start another statin at a lower dose and increase slowly. If after 2 months, the symptoms do not improve or CK levels do not decrease, consider alternative etiologies. If muscle symptoms persist after stopping statin or other clinical condition correspond to restart therapy [21].
In summary, the adverse events associated with statin therapy are uncommon. Statins are not associated with cancer risk, but on the contrary there is a greater chance of diabetes. Simvastatin and pravastatin appear to be safer and better tolerated than other statins [22]. It has not been able to show that there are real differences between the effects generic statin drug and reference mark to the modification of the lipid profile, nor in adverse reactions, assessed according to the elevation of transaminases and CPK [23,24].
Atherosclerotic cardiovascular disease is one of the most important public health problems of our time, both in Europe and in the rest of the world. Consistency of clinical care, incorporating new evidence and synthesis of recommendations from current practice is common task in various committees for clinical practice worldwide (Europe-ESC, American-AHA / ACC, British-NICE, Australian, Canadian...). This has generated discrepancies with the publication of the latest guidelines of the 2013 AHA/ACC compared to its European namesake 2011 ESC/EAS. The innovation of greatest impact of the latest guidelines, has been the abandonment of the therapeutic strategy based on the target values LDL. The individualized strategy (tailored treatment approach) is recommended identifying four risk groups associated with therapeutic strategy. Are advised to use statins as well as healthy habits and lifestyle changes for all patients. The CK should not be measured routinely in patients on statins and there is no reason to monitor LDL levels.
It is generally considered that crop yield and soil fertility can be maintained by the adequate input of fertilizer elements to soil. However, in the case of irrigated paddy soil, there are several farmers’ fields in Japan which have not received any fertilizers for more than a decade but sustained rice yield at around 400 g m−2, i.e., about 80% of the conventionally fertilized fields [1, 2, 3].
The wonder of sustaining rice yield without fertilizer input may be explained by the unconscious input of nutrients to lowland fields through irrigation, rainfall, and biological nitrogen (N) fixation [4]. The advantage of lowland rice over upland rice can be found in the nutrient omission trials carried out throughout the country before chemical fertilizer was prevailed [5]. As shown in Figure 1, N was the most limiting element for both lowland and upland rice. For lowland rice, however, the percentage of yield loss caused by the omission of fertilizers differed with the growth conditions; 22 and 47% under field and pot conditions, respectively. Such a discrepancy was not observed for upland rice. With a closer look at the response of lowland rice to the omission of potassium (K) and phosphorus (P) under field conditions, the omission of these elements also caused more than 10% decrease of the yield in more than 20% of the paddy fields surveyed (Figure 2). Accordingly, K or P began to limit rice yield in some of the paddy fields when N limitation was removed by the application of N fertilizer.
Response of the yield of lowland rice and upland rice to the omission of N, P, and K fertilizers in Japan (adapted from [
Response of the yield of lowland rice to the omission of N, P, and K fertilizers in Japan (adapted from [
These results contributed to predict the necessary amount and type of chemical fertilizers applied to paddy fields. Figure 3 shows the temporal changes in the average rates of chemical fertilizer applied to paddy fields in Japan [6]. In 1950, N was applied at a higher rate than P and K. With time, the rates of P and K became comparable to the rate of N. This is probably because of the alleviation of N limitation and the use of compound fertilizer containing N and other nutrients. In 1970, more than 60% of N, P, and K were applied together in the form of compound fertilizer. The application rates of all nutrients increased rapidly by 1970 and reached a plateau around 1980. Then, the rates decreased from 1990 to 2015. The amount of N applied in 2011–2015 (60 kg ha−1) became smaller than the amount of N applied in 1950 (65 kg ha−1). This would be partly because the percentage of fertilizer N recovered by rice plants was significantly increased by the development of new techniques, e.g., side-dressing of polyolefin-coated urea that can supply N to rice roots according to crop demand. But a more plausible reason is the introduction of the
Rates of chemical fertilizer application to paddy fields in Japan from 1950 to 2015. The values before 1970 were cited from FAO [
From these backgrounds, rice and other crops produced with reduced input of chemical fertilizers and agrochemicals have been attracting more attention by consumers. In 2001, the Japanese government established the guidelines for the certification of crops produced with chemical fertilizers and agrochemicals at less than 50% of the conventional dosage in each region. The area of production of such crops amounted to 0.12 million ha (2.6% of total arable land) in 2017. Organic farming, where chemical fertilizer is fully replaced with organic fertilizer, is also increasing gradually, although the area of organic-farming fields is still 0.5% of the total area of arable land in 2017. The most extreme way of farming is the production of crops without using any chemical fertilizers and agrochemicals. Such no-input farming is called
These histories clearly show that no-input farming in Japan has been developed as a result of the past high-input farming, and it does not represent various types of no-input farming systems in the world. Almost all no-input paddy fields in Japan had received chemical fertilizers and agrochemicals before no-input farming was introduced, and these fields are different from the absolutely no-input fields in other countries that have not received any chemicals since land reclamation.
Recently, no-input rice farming in Japan has been recognized as an economically feasible farming system. Due to the very limited availability, rice produced by no-input farming has been sold at twice or more the price of rice produced by conventional farming [10]. Besides the price of the products, the level of rice yield and its sustainability are also important for farmers [1]. Several researchers have compared rice yield among no-input paddy fields with different periods after introducing no-input farming [1, 2, 3]. However, most of the previous studies have used a space-for-time substitution approach instead of monitoring rice yield and soil fertility over years. Thus, it is uncertain how much and how long such no-input farming can sustain rice yield and soil fertility under various environmental conditions.
In order to better understand the sustainability of no-input rice farming in Japan, I briefly review previous results obtained from the long-term field experiments including our no-input trial. The main topics in this review are (1) rice yield and soil fertility under no-input farming, (2) the environmental factors affecting rice growth and soil fertility under no-input farming, and (3) the dynamics of soil K under no-input and high-input rice farming systems.
In 1990, Neera et al. [1] surveyed 542 no-input fields in 17 prefectures in Japan and compared rice yield with the average yield by conventional farming according to the corresponding municipal statistics. The sampling of rice plants was performed at one representative site in a paddy field at the rate of 30 hills per field [11]. On average of the surveyed fields, the period of no-input farming was 10.7 years, and the yield of brown rice by no-input farming (445 g m−2) amounted to 87% of the yield by conventional farming (511 g m−2). When the results were compared among different regions, the yield by no-input farming was significantly lower than the yield by conventional farming at six prefectures in Tohoku district located in northern Japan (Figure 4). The yield was relatively high in Tohoku district, and the average yield after no-input farming for 28–40 years amounted to 456 g m−2 (
Relationship between rice yields obtained from municipal statistics and from no-input farming (adapted from [
Following this pioneering work, however, only a few researchers have attempted to identify the factors affecting rice yield under no-input farming. Hosoya and Sugiyama [2] surveyed 16 no-input fields in four prefectures (Aomori, Iwate, Miyagi, and Niigata) in northern Japan. The yield of brown rice in no-input fields was positively correlated with the number of panicles (
Compared to rice yield, much less attention has been paid to soil fertility under no-input farming. When the results in the above two reports [3, 12] were combined, total N content in the surface soil showed a large variation among the fields (Figure 5), and the coefficient of variation became 47%. The content was similar to or higher than the national average (2.39 g kg−1) in several fields with a no-input history for more than 5 years. The highest content was recorded in a field with no fertilizer input for 21 years. The soil in this field was classified as one of the Andosols, whereas the soil in all the other fields was classified as non-Andosols according to the digital soil map of Japan [13].
Relationship between the period after ceasing fertilization to paddy fields and the content of total N in the surface soil (adapted from [
For other soil properties, Kuwamura [8] evaluated the characteristics of soil chemical properties under no-input farming by using a space-for-time substitution approach. An extensive survey was conducted by analyzing 654 soil samples collected from no-input paddy fields throughout Japan from 1992 to 1996. The period of no-input farming ranged from 0 to 49 years. The results were compared with the contemporary national soil inventory data (third survey from 1989 to 1993 in [14]). The average depth of a plow layer in no-input fields (18.5 cm) was larger than that in the conventional paddy fields (14.6 cm). The average content of total N in the surface soil (2.6 g kg−1) was slightly higher than the national average (2.42 g kg−1). On the other hand, the average content of mineralizable N in the surface soil (118 mg kg−1) was slightly lower than the national average (145 mg kg−1). The average content of available P (Truog P) in the surface soil (126 mgP2O5 kg−1) was much lower than the national average (298 mgP2O5 kg−1). When the soil samples were limited to those classified as non-Andosols (
The above results were obtained from the one-time survey of no-input fields. Due to the lack of long-term monitoring data, it is difficult to make a simple conclusion. Nevertheless, it can be roughly concluded that rice yield and soil fertility in no-input paddy fields were influenced not only by the period of no-input farming but also by various environmental and management factors operating at regional and field scales.
In this section, I introduce our results obtained from a 5-year no-input trial [15]. To estimate the environmental factors that enable soil fertility to be maintained without fertilization, application of fertilizers to a paddy field at Kyoto University Farm in Takatsuki, Japan, was ceased in 2010. Both planted and unplanted plots were installed in the field (Figure 6). Then, changes in rice yield and soil fertility in the field were evaluated until 2015. Surface soil samples were collected from both planted and unplanted plots before transplanting and after harvesting of rice plants. At harvesting, rice straw was also removed from the field. The physicochemical properties of the samples were monitored. Rice yield and the uptake of N and K by rice plants were also analyzed. The soil in this field was classified as non-Andosol (Gley lowland soil) according to Digital Soil Map of Japan [13]. The surface soil was relatively sandy (sand content higher than 60%) and had the following properties at the start of the experiment: pH(H2O)—5.95; total C—20.2 g kg−1; total N—1.99 g kg−1; mineralizable N—156 mg kg−1, available P (Bray no.2 P)—484 mgP kg−1; and cation exchange capacity—10.4 cmolc kg−1. As the soil was relatively rich in available P due to the long-term application of chemical fertilizers, we focused on the dynamics of N and K in this field.
Rice plants (cv. Hinohikari) at panicle initiation stage grown without fertilization in Kyoto University farm (right side). In the field with an area of 10 a, two unplanted plots were equipped next to the planted plots. The color of rice leaves in this field was yellower than the color in a fertilized field (left side), suggesting that N was the most limiting nutrient in the unfertilized field. The photograph was taken by the author on July 30, 2012, the third year after ceasing fertilization to this field.
During the experimental period, the yield of unhulled rice was relatively stable; 630, 621, 618, 551, and 639 g m−2 from 2010 to 2014, respectively. On the other hand, the levels of mineralizable N, total N, and nonexchangeable K (boiling 1 mol L−1 HNO3-extractable K minus exchangeable K) in the surface soil of both planted and unplanted plots began to significantly decrease after three cropping seasons (Figure 7). The amount of total N and boiling HNO3-extractable K (exchangeable K plus nonexchangeable K) decreased from the surface soil (0–10 cm) of the unplanted plot during the 5 years was estimated to be 55 and 7.2 g m−2, respectively, assuming a bulk density of 1.0 g cm−3. On the other hand, the amount of N and K taken up by a single cropping of rice plants in 2012 was 8.3 and 11.5 g m−2, respectively. Accordingly, N was lost from the unplanted plots with the magnitude comparable to the removal of N by rice plants. The results in Figure 7 also indicated that the continuous removal of N and K from soil caused the significant depletions of mineralizable N and nonexchangeable K but not of more readily extractable fractions (NH4+-N and exchangeable K). By more frequent soil sampling and analysis conducted in 2012, it was revealed that the concentration of exchangeable K in soil decreased from transplanting to the maximum tillering stage and then recovered to the initial level from the booting stage to winter [15]. The reason for the lack of depletion of exchangeable K after continuous removal of K is discussed in the last section.
Temporal changes of surface soil properties at planted (open circle) and unplanted (filled circle) plots in the unfertilized field (adapted from [
In 2013, the fourth year after ceasing fertilization, fertilizer trials with N or K application were conducted under both field and pot conditions to identify which element limited rice growth (Figure 8). Distilled water was used for irrigation in the pot experiment, whereas river or underground water was used for irrigation in the field experiment; total N and K concentration was measured at each irrigation event. The fertilizer trials demonstrated that the element limiting rice growth was K or N under pot or field conditions, respectively (Figure 8). To confirm this result, another nutrient omission trial was conducted in 2016 by using the surface soil collected after six harvests of rice without fertilization. Among the nutrients omitted (N, K, and Si), K was the most limiting nutrient when distilled water was used for irrigation (Figure 9). These results indicate that K, but not N, was the most limiting nutrient in the unfertilized soil and that the amount of K supplied by irrigation was sufficient to overcome the low K status of the unfertilized soil and meet plant demand. This should be the main reason why fertilizer responses were different between pot and field conditions. In other words, previous results on the nutrient omission trials (Figures 1 and 2) may have overestimated the ability of soil to supply nutrients to rice plants by allowing the external input of nutrients through irrigation.
Dry matter weight of rice shoot (cv. Hinohikari) at maturity stage as influenced by the fertilizer application and growth conditions (adapted from [
Rice plants (cv. Hinohikari) at milk ripe stage grown in Takatsuki soil collected from the field without fertilizer application for 6 years (Moritsuka, unpublished). Distilled water was used for irrigation. The values indicate the average ± standard deviation of the shoot dry matter weight (g pot−1,
In our field, the average concentration of K in irrigation water was 3.8 mg L−1 in 2013. If the amount of irrigation was assumed to be 1000 kg m−2, the input of K to the field through irrigation becomes 3.8 g m−2. This amount is slightly higher than the amount of K in rice panicles at maturity stage (3.0 g m−2 in our study). Thus, the input of K by irrigation may meet the plant’s demand if rice straw is not removed from the fields and the irrigation water is rich in K (>2 mg L−1).
Figure 10 shows the average K concentration in river water sampled from 225 rivers throughout Japan [16]. The sampling was carried out in 1940s and 1950s, when the eutrophication of river water was not a serious problem. The national average of the K concentration in river water was 1.20 mg L−1 with a large spatial variation (coefficient of variation = 57%). The concentration of K was higher than 2 mg L−1 in 24 rivers (10.7%), and 13 out of 24 rivers were located in Kyushu district in southern Japan. Several rivers originating from the Aso and Kirishima volcanic areas in Kyushu district showed very high concentrations of both K and Si. These results suggest that, in some of the watersheds in Japan, the input of K by irrigation of river water can meet the plant’s demand even without the application of K fertilizer.
Average K concentration in river water sampled from 225 rivers in Japan (adapted from [
In contrast to K, the national average of inorganic N (NH4+ and NO3−) concentration in river water was 0.28 mgN L−1 (coefficient of variation = 99%) [16]. The input of N by irrigation cannot meet the plant’s demand unless river water is polluted by eutrophication. As shown in Figure 5, there was a large variation in total N content in no-input paddy soils even when an outlier classified as an Andosol was removed. Such a large variation may have originated from the capacity of soil clay particles to accumulate organic matter containing N. This is because a significant negative correlation was observed between the sand content and the total N content in agricultural surface soils frequently used for paddy fields (Figure 11) [17].
Relationship between the sand content and the total N content in soils frequently used for paddy fields (adapted from [
Summarizing the results of this section, the input of K through irrigation and high-clay content in soil were considered the key environmental factors that enable to continue no-input farming. These factors are indebted to geographical conditions. Furthermore, the accumulation of fertilizer-derived P in the surface soil before ceasing fertilization may be another important factor. As a result of the alleviation of K and P deficiencies in the field, N became the most limiting nutrient in our experimental field. Enhancing the biological N fixation by growing leguminous plants after rice harvest and returning the plant residue to soil before transplanting may help to alleviate the N limitation to rice growth.
In the last section, I focus on the dynamics of K in paddy soil. In our experimental field, the concentration of nonexchangeable K in soil decreased significantly by the no-input farming, whereas the concentration of exchangeable K in soil was relatively constant and tended to increase from harvest to next transplanting (Figure 7). In this section, these observations are compared with previous results.
Srinivasa Rao et al. [18] evaluated the long-term changes in soil K forms under rice-rice cropping system with different fertilizer management. The experiment was carried out at Hyderabad in India. Surface soils were collected four times over 20 years, and the samples were analyzed for the different forms of K, including nonexchangeable K (boiling 1 mol L−1 HNO3-extractable K minus exchangeable K). Figure 12 shows the temporal changes in the concentrations of soluble, exchangeable, and nonexchangeable K in surface paddy soil as influenced by different fertilizer treatments. Among the three K forms, nonexchangeable K showed the largest depletion over 20 years (Figure 12). The amount of HNO3-extractable K decreased over 20 years was quantitatively comparable to the net output of K estimated from the total amount of crop removal and fertilization. Thus, continuous cropping of rice caused a significant depletion of nonexchangeable K, while the concentrations of more readily extractable K fractions were relatively constant. In a soil test, we usually measure the sum of soluble and exchangeable K by extracting soil with neutral 1 mol L−1 ammonium acetate. However, compared with nonexchangeable K, these K forms were much less sensitive to the long-term removal of K by rice plants. Based on these results, the authors concluded that the analysis of nonexchangeable K in soil should be added to a conventional soil test for better predicting K fertilizer requirements for long-term operation.
Effect of 20 years of rice-rice cropping and fertilizer application on the concentrations of soluble, exchangeable, and nonexchangeable K in surface paddy soil (adapted from [
The results of Srinivasa Rao et al. [18] agree well with our results (Figure 7) and also with the results from an extensive survey by Khan et al. [19]. By reviewing previous results from the long-term field experiments in the world and comparing the net changes of exchangeable K in the surface soil at the beginning and end of the study period with the net inputs of K due to long-term fertilization and crop removal, Khan et al. [19] revealed that the changes in the soil exchangeable K pool during the study period were much smaller than the net input of K to the field estimated from the total amount of K added and removed (Figure 13). In the case of our field, the net decrease of soil exchangeable K during the 5-year experiment amounted to only 5.2% of the cumulative K removed by rice plants (Figure 13). From these results, the authors concluded that a one-time measurement of soil exchangeable K cannot account for the highly dynamic interchange of K between exchangeable and nonexchangeable pools. Khan et al. [19]) also reported that the concentration of exchangeable K in soil was increased significantly by air-drying soil samples to the soil moisture content below 50 g kg−1, which is a conventional soil pretreatment required for sample homogenization.
Relationship between the net input of K due to long-term fertilization and crop removal and the net change of soil exchangeable K (adapted from [
In the case of Srinivasa Rao et al. [18], the application of farmyard manure in combination with chemical fertilizer contributed to recover the concentration of HNO3-extractable K to some extent (Figure 12). However, a few researchers have reported contrasting results; the co-application of manure over long periods did not necessarily increase the concentration of nonexchangeable K in soil [20, 21]. For example, Kitajima et al. [20] evaluated the effect of long-term co-application of farmyard manure on the K forms in the surface soil at three locations in Japan. As shown in Figure 14, the co-application of farmyard manure increased the concentration of exchangeable K (including soluble K) but decreased the concentration of nonexchangeable K (boiling 1 mol L−1 HNO3-extractable K minus exchangeable K) at all the locations. The authors suggested that farmyard manure accelerated the dissolution of K-bearing minerals in soil, by which nonexchangeable K was irreversibly transformed to exchangeable K. Regardless of the processes involved, the results in Figure 14 cannot be explained by the dynamic equilibrium between the exchangeable K and the nonexchangeable K which operates to minimize the concentration changes of both K forms.
Effect of long-term co-application of farmyard manure (FYM) on the concentrations of exchangeable and nonexchangeable K in surface paddy soil (adapted from [
Yamashita et al. [22] recently reported that microbial biomass K in the surface paddy soil is detectable by the conventional fumigation-extraction approach and that the concentration of microbial biomass K was increased by the continuous application of compost to paddy fields. Combining these results with those by Khan et al. [19], it is plausible to consider that exchangeable K pool evaluated by using air-dried soil samples inevitably includes microbial biomass K. The increase of exchangeable K by the long-term application of farmyard manure (Figure 14) may be due to the contamination of microbial biomass K in the exchangeable K fraction. From these interpretations, the dynamics of soil K forms in the soil-plant-microbe systems are depicted in Figure 15 by referring to the concept proposed by Asakawa and Yamashita [23]. The soundness and practical usefulness of this concept need to be evaluated in future experiments.
Dynamics of K in the surface agricultural soil driven by crop plants, soil microbes, and fertilization (adapted from [
In summary, our results on soil K dynamics agreed well with previous results from long-term field experiments. Accordingly, it can be generally concluded that soil K depletion caused by long-term exhaustive cropping should be evaluated by monitoring the decrease of soil nonexchangeable K rather than that of exchangeable K. Furthermore, I hypothesized that the dynamics of soil microbial biomass K may cause the fluctuations of soil exchangeable K measured after air-drying pretreatment.
In this review, no-input rice farming in Japan was evaluated from the viewpoint of soil sustainability. It can be concluded that soil fertility under this farming system has been supported by various environmental and management factors, especially the input of K through irrigation, high-clay content in soil, and accumulation of fertilizer P applied previously to the soil. In the case of our no-input trial for 5 years, a significant depletion of mineralizable N and nonexchangeable K was observed after three cropping seasons, and rice growth was limited by soil K supply when the input of K by irrigation was restricted. These results highlight the importance of monitoring the dynamics of multiple soil nutrients for several years.
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\\n\\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\\n\\nAdrian Assad De Marco
\\n\\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\\n\\nDr Alex Lazinica
\\n\\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
\\n"}]'},components:[{type:"htmlEditorComponent",content:"Our business values are based on those any scientist applies to their research. We have created a culture of respect and collaboration within a relaxed, friendly and progressive atmosphere, while maintaining academic rigour.
\n\nCo-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
\n\nBut, one thing we have in common is -- we are all scientists at heart!
\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\nAdrian Assad De Marco
\n\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\n\nDr Alex Lazinica
\n\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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