*2.2. Ethics*

The NCHS Research Ethics Review Board (ERB) approved the 2013–2014 study protocol (protocol 2011-17). NHANES and all participants provided written informed consent.

#### *2.3. Interactions under Study*

Table 1 shows the drug–dietary supplement interactions studied. We considered medication groups if they represented a prevalence of use higher than 2% of the population included in the database.

Tetracycline interacts with divalent ions such as calcium, magnesium, and zinc, forming a relatively stable and poorly absorbed chelate, preventing absorption of the antibiotic due to a lower amount of calcium in the gut available to be absorbed. This interaction may reduce or even abolish the therapeutic effect of the antibiotic, thereby diminishing anti-infectious e fficiency. For this reason, tetracycline should be taken one hour before or two hours after meals [3,5].

Thiazide diuretics can cause increased calcium reabsorption in distal tubules of the kidneys, which contributes to hypercalcemia. Another cause of hypercalcemia is the excess of vitamin D, for example, through high doses of oral supplements, which increases the absorption of calcium in the gut. Due to the retention of calcium in the body, metabolic alkalosis may be developed [5].

Finally, angiotensin II receptor blockers are potassium-sparing and can, therefore, have additional hyperkalaemic e ffects if combined with potassium supplements or salt substitutes containing potassium. The use of potassium supplements is the main risk factor for developing hyperkalaemia, as this causes a rapid rate of increase in serum potassium levels. Other contributory risk factors such as poor renal function, heart failure, and diabetes should also be considered, as they are associated with a faster rate of hyperkalaemia progress [5,8].

#### **3. Population and Prescription Medication Information**

The sample was composed of tetracyclines, thiazides, and/or angiotensin II receptor blocker users. These drugs were chosen due to the potential severity of their interactions and their high prevalence of use in the American population. Prescription medication information was obtained through the Prescription Medication subsection included in The Dietary Supplement and Prescription Medication section of the Sample Person Questionnaire. This section provides personal information on the use of prescription medication in the month prior to the participant's interview. The name of the medication was provided by the participant to the interviewer, who entered it into the computer where it was automatically matched to a generic drug name and code. Medication is presented following the WHO Drug Statistics Methodology of ATC index [9].

*Tetracyclines*: We considered a patient to be a tetracycline consumer if he/she reported having taken a medication with a generic drug name included in the ATC group J01AA.

*Thiazides*: We considered a patient to be a thiazide consumer if he/she reported having taken a medication with a generic drug name included in the ATC group C03AA.

*Angiotensin II receptor blockers*: We considered a patient to be an angiotensin II receptor blocker consumer if he/she reported having taken a medication with a generic drug name included in the ATC group C09CA.

#### **4. Dietary Supplement Information**

Dietary supplement information was obtained through the dietary supplement subsection also included in The Dietary Supplement and Prescription Medication section of the Sample Person Questionnaire. This subsection allows for collection of personal data on the use of dietary supplements

in the month prior to the participant's interview. Interviewers reported the supplement product name, which was automatically disaggregated to up to 34 nutrients.

We considered a participant to be a nutrient supplement consumer if he/she had taken any supplement containing at least one of the nutrients under study (Table 1).

## **5. Other Covariates**

Demographic covariates were sex, age, race/ethnicity (Hispanic origin: Mexican-American, other Hispanic, non-Hispanic white, non-Hispanic black, other race), educational level (primary, secondary, university), civil status (married/with partner, widow/er, divorced, single), citizenship (American/non-American), and country of birth (U.S./Other country).

We also considered body mass index (BMI) and physical activity. BMI was determined from height and weight measured by health technicians previously trained by an expert anthropometrist. We categorised this variable as follows: underweight (<18.5), normal weight (18.5–24.9), overweight (25.0–29.9), and obesity type I (30.0–34.9) and obesity type II and type III (≥35.0).

Physical activity was self-reported and measured through a question asking if participants did any moderate-intensity sports in a typical week. The answer was dichotomic (yes/no).

## **6. Statistical Analysis**

Prevalence rates were calculated for each potential interaction described in Table 1. The reference population consisted of those who reported having taken one of the medications under study.

A multivariate logistic regression analysis was conducted to determine the factors associated with a higher probability of having a potential interaction using the presence/absence of the interaction as the dependent variable and demographic and clinical variables as independent variables. The regression model provided odds ratios (OR) and 95% confidence intervals for the associations between the dependent variable and each of the independent variables. Crude associations obtained from bivariate logistic regressions were also presented.

To test potential interactions between demographic and clinical variables, such as age and physical exercise or gender and BMI, we tested the association between the probability of having a potential interaction and the interacting term of the dependent variables. The interacting terms were not statistically significant and, therefore, were not included in the final model.

All analyses were performed taking into account the appropriate weights. This procedure was developed with the goal of obtaining nationally representative estimates and accounting for unequal probability of selection derived from study design and non-response.

STATA 13.1MP was used to perform the statistical analyses.


**10. Conclusion**

**9. Other transformations**

24 Alkenes

A wealth of further transformations have been found to be possible in combination with Wittig/HWE reactions. Thus, cyclopropanation of alkenes using sulfur-ylide reagent **166** can be run in tandem with a Wittig reaction with a conjugated phosphorane such as **21**. This combination of reactions can be performed with the preparation of the aldehyde as the Wittig sub-

Generally, non-stabilized phosphoranes are basic. This basicity has been used by Knüppel et al. in the transformation of α,α-dibromoenone **168** with excess methylenetriphenylphosphorane, where the phosphorane induces a Corey-Fuchs-reaction-type dehydrobromination/debromination to generate a terminal alkyne, which together with the concomitantly run Wittig-olefination delivers **169**, an intermediate to the trisnorsesquiterpene (−)-clavukerin A (**171**) (**Scheme 43**)

**Scheme 43.** Wittig-olefination—Corey-Fuchs-reaction-type dehydrobromination/debromination.

in one pot (**Scheme 42**) [177].

strate by oxidation of the corresponding alcohol **165** with MnO2

**Scheme 42.** One-pot oxidation—Wittig-olefination—cyclopropanation.

**Scheme 41.** Tandem Wittig-olefination—aza-Wittig-rearrangement.

Due to the fact that phosphoranes and phosphonates are stable under more diverse conditions than was initially realized, it has become possible to perform reaction cascades and one-pot reactions with Wittig- and HWE reactions as an integral part of the reaction sequence. Frequently, Wittig olefination reactions are carried out with *in situ* prepared phosphonium salts and phosphoranes [17, 22–27]. One-pot oxidation—Wittig olefination reactions are also quite common [40, 43–110], especially when the carbonyl component is labile [89, 97]. Often, the oxidant of choice is MnO2 [40, 43–46, 79–97], although a number of reactions are known where transformations were carried with air oxygen using metals and metal oxides as catalysts [72–78]. As many Wittig- and HWE reactions tolerate metal catalysts, this allows the running of Wittig/HWE reactions in combination with metal catalyzed cross coupling reactions and olefinations such as Heck [114–123], Suzuki [111–113], Sonogashira [119–121], and metathesis reactions [179–181]. The alkenes gained in the olefination reactions can be submitted to cycloaddition reactions, including Diels Alder reactions [69]. Furthermore, the alkenes lend themselves to 1,2-addition reactions [71, 140] in one-pot procedures. In cases where enones or enaldehydes are produced in the olefination reaction, a 1,4-addition becomes a possibility; this includes the Michael addition [149–151]. Also, the combination of ring opening of cyclic hemiacetals or acetals, olefination reaction and a 1,4-addition leading to ring closure is quite common [154–156]. The outcome of one-pot sequences of olefination reaction—electrocyclic rearrangement can be predicted less easily. Nevertheless, one-pot Wittig olefination—Claisen- [173], Wittig olefination—Cope- [169], and Wittig olefination—aza Wittig [176] rearrangement reactions have been published. Lastly, Wittig olefination and HWE reactions have been combined with functional group transformations, including the hydrolysis of an ester function [152] and the reduction of a carbonyl group [148].

The prospects of multi-step, one-pot reactions and reaction cascades incorporating Wittig reagents can be seen in the rich chemistry of ketenylidenetriphenylphosphorane (**178**) (**Scheme 45**) [182–185], which has been reviewed earlier [182, 186, 187]. Lastly, catalytic Wittig reactions can be seen as a subset of tandem reactions involving phosphoranes. Further research in specifically this area will help make the Wittig olefination more atom-economical and environmentally sustainable, so that this reliable alkene forming reaction will remain a competitive olefination strategy of choice.

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**10. Conclusions and future directions**

Insecticides resistance against malaria vectors has spread throughout the East African countries. Some of the countries like Tanzania and Rwanda have already established a national insecticide resistance monitoring and management plan, and others are in the process of developing the plan mainly to prevent the emergence of resistance or as a response to detected resistance. However, effective implementation of the plan requires national capacities in terms of trained human power and infrastructure to undertake surveillance and monitoring of resistance to advice policy to look for alternate control options or new vector control tools or ensure that current interventions remain a choice in vector control program. Effective imple‐ mentation of insecticide resistance monitoring and management also needs coordination and inter-sectorial collaboration in the respective countries.

The lack of enough funds in East African countries may delay the implementation of resistance monitoring and management strategies. This may hinder to start monitoring of resistance or responding to resistance, use of suggested insecticide of choice for vector control, change control strategy as soon as strong evidence on resistance is available. Internal sources of funding, internally driven resource mobilization and allocation of adequate resources are of paramount importance in implementing national insecticide resistance monitoring and management strategies in the context of integrated vector management. The NMCP of each country needs also to develop the working guideline with donors and other relevant partners to implement insecticides resistance monitoring and management strategies.


*Supporting open minds since 2005*

The Universe of http://dx.doi.org/10.5772/intechopen.73717 Edited by Marjanca Starčič Erjavec Escherichia coli

#### Contributors

Elif Bozcal, Isabel Scaletsky, Wan Keung Raymond Wong, Masahide Yasuda, Jin Matsumoto, Tomoko Matsumoto, Kazuya Yasuda, Angel Adrian Cataldi, Mariano Larzabal, Gozde Ekici, Emek Dumen, Marjanca Starčič Erjavec

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Chapter 3

*Irrigation - Water Productivity and Operation, Sustainability and Climate Change*

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9781771885522


This book gives a current review of the links between the structure and function of hydrolases and ligases, as well as ideas for better using these critical enzymes. The book is split into two sections: "Cleavage" and "Ligases." These enzymes are the biggest and most varied family of enzymes, allowing researchers to investigate the structural variety that underpins their different biological roles. In light of recent scientific advances, there is a desire to examine and update our knowledge of these enzymes' functional and structural changes.

### *Miroslav Blumenberg, Biochemistry Series Editor*

Published in London, UK © 2022 IntechOpen © monsitj / iStock

Hydrolases

IntechOpen Series

Biochemistry, Volume 29

Hydrolases

*Edited by Sajjad Haider, Adnan Haider and Angel Catalá*


**3.1 Prostaglandins**

Prostanoids (prostaglandins and thromboxanes) are synthesized by cyclo-oxygenase (COX), present in several tissues including the bladder wall (Khan et al., 1998; Lecci et al., 2000; Azadzoi et al., 2003; Andersson & Wein, 2004). Two COX isoforms exist. COX-1 is expressed constitutively and participates in normal bladder function whereas COX-2 is activated during cystitis (Lecci et al., 2000; Tramontana et al., 2000). Prostanoid synthesis can be induced by physiological stimuli (for example, detrusor muscle stretching), injuries of the mucosa, nerve stimulation, ATP and inflammatory mediators such as bradykinin and the chemotactic peptide N-formyl-l-methionyl-l-leucyl-l-phenylalanine (Khan et al., 1998; Andersson & Wein, 2004).

Prostaglandin (PG) E2 is one the most abundant prostanoid in the bladder (Jeremy et al., 1987; Khan et al., 1998). In rats, intravesical administration of PGE2 facilitates micturition, increases basal intravesical pressure and induces bladder hyperactivity (Ishizuka et al., 1995). In the urethra, topical application of PGE2 causes relaxation of the sphincter (Yokoyama et al., 2007). Likewise, intravesical instillation of an inhibitor of the COX-2 enzyme improved bladder function in an animal model of OAB (Jang et al., 2006). This supports a role for this prostanoid during bladder dysfunction and has justified a few inconclusive clinical trials regarding the use of non-steroidal anti-inflammatory drugs in the treatment of OAB. So, expectations were raised when Kim and co-workers found that levels of PGE2 and PGF2α were significantly higher in male and female OAB patients that in healthy controls (Kim et al., 2005; Kim et al., 2006). However, PG concentrations were not corrected for urine concentration. After correction for creatinine values, Liu and co-workers found no significant differences in PGE2 content in patients with OAB wet, OAB dry and controls (Liu et al., 2010).

Thus, at this moment the role of urinary PGs, most notably PGE2, as a putative tool for OAB diagnosis and follow-up is highly debatable. Moreover, the measuring methods rely on labour-intensive and expensive laboratory procedures. In addition, although it is relatively consensual that prostanoids participate in the mechanisms of OAB, it is not known if the recommended OAB therapies effectively reduce the PGs levels.


**Residue Determination in Honey Residue Determination in Honey**

Simone Moretti, Giorgio Saluti and

Simone Moretti, Giorgio Saluti and Roberta Galarini Roberta Galarini

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67135

#### **Abstract**

[58] Chua LS, Abdul-Rahaman N-L, Sarmidi MR, Aziz R. Multi-elemental composition and physical properties of honey samples from Malaysia. Food Chem. 2012;**135**(3):880–7.

[59] Aghamirlou HM, Khadem M, Rahmani A, Sadeghian M, Mahvi AH, Akbarzadeh A, Nazmara S. Heavy metals determination in honey samples using inductively coupled plasma-optical emission spectrometry. J Environ Heal Sci Eng. 2015;**13**:39. DOI: 10.1186/

[60] Kokot ZJ, Matysiak J. Inductively coupled plasma mass spectrometry determination of metals in honeybee venom. J Pharm Biomed Anal. 2008;**48**(3):955–9. DOI: 10.1016/j.

[61] Gualtieri Honório G, Chevitarese Azevedo G, Costa Matos MA, Leal de Oliveira MA, Camargo Matos R. Use of boron-doped diamond electrode pre-treated cathodically for the determination of trace metals in honey by differential pulse voltammetry. Food

Control. 2014;**36**(1):42–8. DOI: 10.1016/j.foodcont.2013.08.004

DOI: 10.1016/j.foodchem.2012.05.106

s40201-015-0189-8

324 Honey Analysis

jpba.2008.05.033

The use of antibiotics to fight bacterial and fungal honeybee diseases is documented since 1940s. Although at present in some countries certain antibiotics are authorized in apiculture, only few law systems provide maximum residue limits in honey. In addition, residues of worldwide banned antibiotics such as chloramphenicol, nitrofurans and nitroimidazoles have been frequently found. Therefore, the availability of reliable analytical methods able to detect concentrations at few parts per billions is fundamental. After a general overview of the available sample treatment strategies and analytical techniques, the most significantly published methods are discussed. Aminoglycosides and, to a lesser extent, tetracyclines are the more difficult classes to analyse. The current trends are the development of multiclass procedures and of micro-extraction techniques to improve the cost-effectiveness of residues control in the globalization era.

**Keywords:** honey, antibiotics, honeybee diseases, sample preparation, liquid chromatography-mass spectrometry