Lupine Publishers | Health Benefits of Camel Milk

 Lupine Publishers | Journal of Dairy & Veterinary Sciences

Abstract

The camel is domesticated in various regions of Asia and Africa, it is considered as a friendly and harmless animal that can survive in hard environmental conditions and provides sources of income to its owners in form of milk, meat, and skin by-products. Camel milk is highly nutritive and possesses some unique characteristics which are being investigated nowadays by many researchers and surprising results revealed that it can be utilized as a natural cure for various life-threatening diseases. This work is aimed to review and highlight the importance of camel milk and its therapeutic properties.

Keywords: Camel; Milk; Health

Mini Review

The Camels also called ship of the desert is one of the most abundant type of animal present in mostly arid zones of Asia and Africa. Since ancient times camels have been domesticated for their products like skin, meat and milk [1]. Milk is the most valuable by product of camel, so it is called as “white gold of desert”. According to some researchers, the camel produces more milk than any other livestock species and its duration of milk production is also longer. The whole lactation periods are comprising of almost 12- 18 months and daily production of milk is almost 3-10kg. The milk of camel consists of a 30 % annual caloric intake of the pastoral community diet [2]. The camel milk is having sharp salty taste with pungent smell and appears as dark white in color. Its taste can vary slightly depending on breed, feeding, health status as well as amount of water consumption by camel. When compared to cow milk which retains its properties for just 2-3 days the camel milk retains its quality for up to 12 days when stored at 2 °C temperature. Moreover, it is also stable for 8-10 hrs. at room temperature. The pH of fresh camel milk is normally neutral but can be tasted slightly acidic if kept for longer period of time [3]. The camel milk has some unique physiological characters like the fat globule diameter is also bigger than that of cow, goat, sheep milk (Figure 1).

Camel milk is very much healthy and is consumed in many regions of the world to cure some diseases as well [4]. It contains many vitamins and also higher amount of zinc so it plays a major role in immune system of body as cells of immune system are sensitive to zinc deficiency [5]. Moreover, some studies have revealed that camel milk also possesses insulin-like properties and can control blood sugar due to hypoglycemic properties in diabetic patients. It can be used as a natural medicine for diabetic patients. Along with that properties this miraculous milk has been also proved by many scientists as a natural medicine for autism and some food allergies [6]. Camel milk naturally consists low lactose as compared to cow milk so according to research, it was suggested that camel milk can be utilized by patients having lactose intolerance issues [7]. An animal study carried out in 2010 revealed that fermented camel milk possess increased number of electrolytes including sodium and potassium and it has therapeutic effects on diarrhea in rats. Thus, it can be decided that fermented camel milk can be consumed food for improving nutritive status of the body and also as therapeutic applications [8]. Naturally camel milk has various enzymes that have immunological as well as antibacterial properties and contains varieties of bacteriocins as shown in Table 1. The main enzyme is lysozyme which attacks common invading pathogens by developing primary immune system of the body. Camel milk is naturally rich in this enzyme. Moreover, it possesses natural lactoferrin which prevents microbial growth within the body and kills germs. The concentration of lactoferrin is much more in camel milk as compared to cow, sheep and goat milk [9].

Figure 1: Comparison of fat globule diameter of different animals’ milk [16].

Table 1: Experimental data on isolation of bacteriocin from camel milk from different countries.

The Lacto-peroxidase enzyme has negative effects on tumor growth and is associated with the iodination of thyroid hormones by acting on thyroid peroxidase enzymes they are naturally present in camel milk. The highest concentration of these enzymes is also having impacts on suppressing metastasis of breast cancer cells [10]. A previous study has revealed that camel milk has effect on oxidative stress in autistic children by increasing the concentration of some antioxidant enzymes like glutathione peroxidase, superoxide dismutase along with myeloperoxidase enzyme when they consumed camel milk for two weeks the levels of these antioxidant enzymes were significantly increased as well as autistic behavior was also improved [11]. More experiments were conducted to evaluate the therapeutics properties of Camel milk in some case reports, invitro as well as in vivo experiments and in some clinical trials also. These studies suggest that camel milk can be utilized to cardiovascular diseases, tuberculosis, hepatitis, autoimmune disorders, rickets and liver cirrhosis [12-16] Although various reviews have been done on properties of milk of different domestic animals the camel milk properties are still lacking till now. Thus, this paper is designed to review accessible evidence on the dietary as well as medicinal worth of camel milk and indorse further study regarding the nutritional and medicinal worth of camel milk built on the data from this literature review.

Conclusion

Camel milk is consisting of important nutrients that are required to keep the body healthy. It contains adequate ratio of antibacterial and antifungal agents that are useful for the prevention of various diseases, like diabetic, cancer, cardiovascular diseases, autism, Rota virus diarrhea, lactose intolerance, autoimmune disorders. It is miraculous milk but lacks plenty of research on its qualities, therefore many people are still unaware of its qualities. Thus, further research should be done at molecular levels to evaluate its qualities and impacts on health.

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Lupine Publishers | Prevention Methods of Posttraumatic Stress Disorder (PTST) in Cancer Survivors

 Lupine Publishers | Journal of Psychology and Behavioral Sciences

Introduction

It is quite appropriate to say, people are less likely to look for diagnostic ways of cancer because of the fear of having cancer. In addition, many people have phobias of cancer treatment methods (such as surgery, chemotherapy, and radiotherapy) [1,2]. The fact remains that, many people are unwittingly exposed to the posttraumatic stress disorder (PTST) because of severe stress [3]. Nevertheless, many researchers do not believe to the psychology complications of cancer, but psychological distress during and after cancer treatment increased concerns about sexuality, intimacy, and physical well-being. These disorders can occur after the stressor agent such as cancer [4]. It is widely supposed that PTSD is psychological disease and separate from physiological system. Whereas, PTSD can have physiological consequences such as elevated blood pressure, cholesterol, and cortisol levels [4]. However, disabling subsyndromal PTSD symptoms is not known for each individual, but the consequences of this disorder make it more important to treat it [4,5]. Distress and anxiety and less optimal quality of life are caused by PTSD in cancer survivor. It would be better to say that PTSD has a direct effect on the quality of cancer treatment. As detailed, patient’s spirit has a great impact on the positive response of cancer to chemical drugs and radiation doses during treatment. Also, treatment conditions can get worse PTSD. So that, the treatment environment, the attitude of the treatment technicians plays an important role in the recovery and doesn’t involve them to PTSD. Passing on now to treatment methods of PTSD, we should try to suppress PTSD and comorbid symptoms by utilize treatment methods. Variety of psychotherapy (such as eye movement desensitization and reprocessing and cognitive restructuring method) and pharmacotherapy (such as prazosin, anticonvulsants and risperidone) that have been practiced on patients who suffer from PTSD symptoms induced by cancer that we will discuss below. Prazosin Utilize in PTSD is effective, particularly in reducing nightmares and improving sleep. PTSD is often associated with alcohol misuse, prazosin can reduce alcohol dependence [6]. Anticonvulsants have some beneficial attributes in treatment PTSD, particularly where irritability and a startle response are prominent [7]. Risperidone is associated with improvement in overall PTSD symptoms and specific sleep variables [8]. Some resources presented that benzodiazepines (BZDs) are treatment drugs for PTSD [9], But to be honest BZDs should be considered relatively contraindicated for patients with PTSD. Because it caused to worse psychotherapy outcomes, aggression, depression, and substance use [10]. Eye movement desensitization and reprocessing (EMDR) is faster and more effective psychotherapy method than other treatments. This method is a complex treatment that incorporates many different interventions, including imaginal exposure and free association [11]. Cognitive restructuring method included socratic questioning, guided discovery, the devil’s advocate technique and determining the pros and cons of the validity of the assumption. Also, it has vital role for the effectiveness of the intervention [12]. Patients follow up after treatment is one of the most important in radiotherapy. Important considerate to the PTSD symptoms besides clinical examination after cancer treatment can help improved patient cancer. However, the emergence of PTSD can have a direct effect on the cancer treatment benefits. Thereby PTSD can pose a big challenge for cancer treatment researchers. The importance of this issue could provide the basis for a new collaboration between psychologists and oncologists to treat cancer with high therapeutic benefit without side effects.

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Lupine Publishers| Development of Novel Composite Biomaterials for Use as Biodegradable Adsorbents and or Bio-Carriers During Wastewater Treatments Using Galerkin’s Finite Element Analysis

  Lupine Publishers| Journal of Robotics & Mechanical Engineering

Abstract

In this study, the development of novel composite biomaterials for use as biodegradable adsorbents and or bio-carriers during wastewater treatments was carried out using Galerkin’s finite element analysis. Several literatures in the past showed that the increment in number of wastewater treatment plants, made it difficult to manage the wastewater systems. Therefore, to ensure proper discharge from the wastewater treatment plants, new and stricter regulations for nutrient removal have to be incorporated. Several wastewater treatment measures that have been adapted to date includes: bio filtration, ion exchange, sedimentation, solvent extraction, chemical oxidation, membrane processes, coagulation, oxidation, Fenton process, and electro coagulation. The data used in this analysis were obtained from various literature sources and were analyzed using Galerkin’s finite element analysis method in order to develop models that would analyze the empirical parameters affecting wastewater treatments. The result obtained showed that the removal efficiencies for wet season are TDS (16), BOD (63), COD (55.8) and N (72%) respectively. The results justified the presence of high impurities as a result of influx of wastes from industries, households etc into the river body.

Introduction

Freshwater is the chief constituent of the planet and is essential for the survival of all living organisms [1-5]. The continuous addition of undesirable chemicals, agricultural wastes [11], civilization, industrial wastes, other environmental and global changes etc. reduced the quality of water resources [18]. Over the last century, major part of the world has been facing degradation of environment because of the continuous growth in population [12]. With the growing population, there is a striking increase in usage and wastage of water for domestic purposes. Domestic wastewater is usually the water discharged from household purposes such as toilets, dishwashers, showers, sinks, washing machines etc. [8]. The contamination due to organic pollutants is very dangerous due to their various side effects and carcinogenic nature. Several literatures reveal some methods for the removal of organic pollutants from water. The methods used in literature suggested that the methods might depend on their physical, chemical, electrical, thermal and biological properties [13-17].

While other researchers proposed that oxidation, reverse osmosis, ion exchange, electro-dialysis, electrolysis, adsorption as another method of wastewater removal etc. Of course, reverse osmosis, ion exchange, electro-dialysis, electrolysis and adsorption are excellent wastewater removal technologies. Several reviews were made in the past in order to determine the best wastewater removal technique. Others argued that before talking about wastewater removal technique, that it is imperative to firstly divide the wastewater treatment procedures into primary and secondary treatment processes depending on either the removal of solid particles physically by using screens or biological treatment where microorganisms consume organic matter and convert it into inorganic compounds. [6-7] Nitrogen and phosphorus removal are the major goals of wastewater treatment which can be carried out biologically in an economically feasible and environmentally friendly manner in recent years [19]. In case of phosphorus, sometimes biological methods are not efficient because of lack of carbon. Hence, to make up for the lack of carbon, some additional organic matter is added to the biological reactors which increases the cost of operation and results in generation of one more pollutant. However, there is an alternative for this problem which is the use of enhanced biological phosphorus removal which works efficiently for domestic waters with Low C/N ratio [1]. Nowadays, with the increment in number of wastewater treatment plants, it has become challenging to manage the wastewater systems. Therefore, to ensure proper discharge from the wastewater treatment plants, new and stricter regulations for nutrient removal have been incorporated. Several wastewater treatment measures that have been adapted to date include bio filtration, ion exchange, sedimentation, solvent extraction, chemical oxidation, membrane processes, coagulation, oxidation, Fenton process, and electro coagulation [1,2].

Adsorption is today regarded as the best water treatment procedure because of its universal nature, ease of operation and inexpensiveness.it has a removal capacity rate of 99.9% .The adsorption has some limits which made its removal rates not to perfect [9-20]. To comply with these limits, there is a need for modeling and operation control of wastewater treatment plants. However, the modeling of wastewater treatment systems tends to become intricate due to certain characteristics such as unusually long residence times, plenty of tunable kinetic parameters and large variations in influent component flow rates. Nevertheless, with the advancements in technology, activated sludge modeling, flow sheet simulators and computational fluid dynamics have emerged as some significant tools for modeling Wastewater treatment plants. Over the years, dynamic modeling has come across as a remarkable approach for developing operational models in process design and management. Moreover, these Models help in establishing operating policies and control strategies for the wastewater treatment plants which in turn maximizes the plant performance and comply with the required permit limits. The mathematical modeling of wastewater, the performance of the pH, dissolved oxygen demands, and other wastewater analytical parameters were not captured in literature

Mathematical Formulation:

The mathematical formulation can be carried out by considering the following assumptions

1. The evolution of the biological oxygen demand and the dissolved oxygen for freshwater treatment are governed by partial differential equations

2. The outfalls are located at points

3. The convex functions are known

4. The fluid medium is continuous.

5. The soil matrix is continuous.

6. The fluid is in mot ion.

7. The soil medium undergoes consolidation.

8. The fluid is incompressible.

9. The air phase is continuous and is at atmospheric pressure.

10. Flow is laminar and Darcy’s law is valid.

The biological oxygen demand and dissolved oxygen concentrations in a point u and a time t be denoted by ρ1(u,t) and ρ2(u,t) respectively .The boundary equations can be obtained by

Considering the following boundary value problems

Let h(u,t) and x ⃗(u,t) be the height and the mean horizontal velocity of the fluid layer obtained as a solution of saint venant equation. ∂(x-p_J) is the dirac measure for point p_i and the parameters β1> 0, β2 >0 represents the horizontal viscosity coefficients involving the dispersion and turbulence effects. Parameters k1> 0, k2 >0 represents the kinetic coefficients related to temperature and transference of oxygen through the surface and ds is the oxygen saturation density which can be drawn from experimental measurements.

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Lupine Publishers| Painfull Posterior Cruciate Ligament Ganglion Cyst. A Case Report

Lupine Publishers| Journal of Orthopedics and Sports Medicine

Introduction

Ganglion cysts (GC) are benign tumor-like lesions usually going out from mucinous degeneration of collagenous structures [1,2]. They could occur in several anatomic areas but GC arising from cruciate ligaments are rare [3,4] with a prevalence of 0.36% or 0.8% respectively when diagnosed by magnetic resonance (MR) or by arthroscopy [3,5-6] However other studies of GC prevalence refer ranges from 0.2% to 1.9% [7-9], with posterior cruciate ligament ganglion cysts (PCLGC) being five times less frequent than those identify in anterior cruciate ligament [5,10]. This lesion is mainly diagnosed in people aged 20-40 years-old and a male predominance has been reported [5,11-13]. The etiology of PCLGC is not clear. They could appear from synovial herniation or congenital translocation of synovial cells. Mesenchymal stem cells proliferation with cysts formation or mucoid degeneration occurring in areas suffering chronic injuries are also reported [7,14-16]. Many of PCLGC are asymptomatic. When symptomatic the main clinical symptoms and signals includes knee pain and / or movement restrictions [17].

The knee joint could present a slight effusion, restriction to extension and particularly in extreme flexion [1,4]. The common classification of cruciate ligament cysts is supported on the position of the cyst, anterior, posterior or between cruciate ligaments [7]. MR is the gold standard for detecting GC1. Recently observation by ultrasonography is considered useful for identifying and locating the lesion, as well as being a conservative approach to treat cystic lesions [1].

Case Report

A 17-year-old Caucasian female, a soccer player, presented with a 9 month history of left knee pain, mainly in the posterior and medial aspects of the knee, combined with slightly back swelling. Pain was exacerbated with exercise, especially squatting, and partially alleviated with rest. She had no history of a knee major traumatic event (Figure 1). She complained of knee pain on soccer playing, one of the main reasons to suspend this practice. She alsorefers no confidence on demanding tasks.

Figure 1: Knee MRI of PCL GC; A: T2 sagittal view FS; B: T2 sagittal view FSE; C: T2* coronal view.

In clinical examination we identified a light quadriceps atrophy, compared to the opposite side, and symmetry in active range of motion (ROM). Passive ROM was limited (10 degrees) and painful in extreme flexion and symmetric in hyperextension. Meniscal tests and varus-valgus stress tests were negative. Some tenderness on palpation of the popliteal aspect but no pain or even tenderness was verified in medial or lateral joint line. Plain radiographs were normal. A knee magnetic resonance image (MRI) was then performed regarding the potential diagnosis of a joint cyst so it was acquired weighted T2 sagittal sequences with and without fat suppression and T2* coronal. The MRI revealed a high-signal well-defined, ovoid shaped formation extending along PCL on both T2-weighted images and fat-suppression sequences, measuring 18mmm length compatible with a PCL cyst. Considering that in the last consultation there is no pain or appreciable impairment of mobility, and also the athlete does not intend to continue the practice of soccer, the choice was made for conservative treatment. Proprioceptive closed-chain training and quadriceps and hamstrings muscle strengthening were prescribed for 3 months, 3 x week. Currently she runs 5 x week (40min per day) without pain and functional disability. A new appointment will be made in six months.

Discussion

Etiology and pathogenesis of PCLGC are unclear, however it is proposed that repetitive microtrauma of joint and soft tissue can promote expansion of mucin from ligament fibers and acting as a potential trigger [20]. Recognition of PCLGC as a clinical entity leading knee pain and impairment is increasing due to the sensitivity of MRI to identify intra-articular abnormalities. The typical finding is an ovoid fluid filled cystic lesion which can frequently be multilocular in the intercondylar notch of the knee [22,25]. In our case report MRI shows a cystic multilocular mass with fluid signal intensity within the synovial layer of the PCL. Although most knee cysts are asymptomatic, in some case they could be a relevant source of pain [20,21]. Clinical manifestations of a knee cyst are mostly dependent on the pathologic process involved, along with its location, size, mass effect, and relationship to surrounding structures [26]. The typical presentation of symptomatic PCLGC include posterior knee pain, restriction of ROM, stiffness and mild swelling [20,21].

Limited ROM is a typical finding with an intra-articular ganglion arising from the PCL, mainly with inability and pain to extreme flexion due to the compression of the cyst mass between the PCL and the posterior joint capsule. With this clinical picture in mind, athletes between 20 and 40 years old who present knee pain with restriction on hyperextension or full flexion, with no previous macrotraumatic report or knee instability, should raise a high level of suspicion for intra-articular ganglion cysts. Only symptomatic PCLGC need to undergo treatment. There a broad spectrum of treatments described for these lesions, from a rehabilitation program focused on ROM, strengthening and proprioception to avoid kinetic impairment, to ultrasound or CT-guided aspiration or infiltration, or even arthroscopic excision. Treatment choice must take into account several criteria such as level of activity, time for recovery, risk of joint damage and recurrence of the cyst. Arthroscopic treatment has demonstrated good outcomes with up to 95% of patients reporting good results and associated with the lowest recurrence rate, but it needs an hospitalization, anesthesia and a longer recovery period, which can become a major problem when we are dealing with competitive sports [23,24].

Athletes require quick return to play with minimal side effects, so we need to take into account less invasive treatments like US or CT-guided procedures, or even load management in addition to a rehabilitation program.

Conclusion

CCP is a rare and often asymptomatic condition. Its pathogenesis and prognosis are still unclear. In a young adult with posterior knee pain (popliteal aspect), no history of major event, limited ROM (hyperextension and extreme flexion), meniscus and ligament test negative and no confidence in demanding tasks it is important to think about this condition. The therapeutic option stems from the patient’s characteristics, but US or CT- guided puncture should be considered.

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Lupine Publishers| Outpatient Latarjet Procedure: Early Complications and Feasibility Validation

  Lupine Publishers| Journal of Orthopedics and Sports Medicine

Abstract

Background: The Latarjet procedure may be amenable to outpatient elective surgery as it is often performed on young and healthy patients. Thus, ambulatory surgery for Latarjet procedure is recently rapidly increasing in France with very few validation studies. This feasibility study presents early adverse events following outpatient Latarjet surgery compared to Latarjet surgery performed as an inpatient procedure.

Hypothesis: There is no difference between outpatient or inpatient Latarjet procedure.

Patients and Methods: Thirty patients operated on an outpatient basis and prospectively followed were compared to 30 patients operated on an inpatient basis. All procedures were performed by the same surgeon. Complication rates as well as clinical outcomes at one year were compared between groups.

Results: Post-operative hematomas which did not require surgery occurred more frequently in outpatient group in which no drain was used. No other differences occurred between groups. All outpatients but one was satisfied with the procedure.

Discusion: The latarjet procedure was found to be safe when performed on an outpatient basis. The addition of wax to the base of the coracoid seemed to diminish hematoma formation.

Level of Evidence: level III

Keywords: Shoulder; Latarjet; Instability; Complications; Ambulatory surgery

Introduction

Outpatient surgery provides benefits to patients including a decreased exposure to nosocomial infections, a higher rate of satisfaction [1], and a up to a 68% decrease in direct costs [2]. The Latarjet procedure is now frequently performed on an outpatient basis in up to one third of cases in France in 2017 (Figure 1).

However, the literature regarding the feasibility of outpatient Latarjet surgery is very poor and there is still a need of validation studies [3]. Our aim was to confirm the feasibility of the outpatient Latarjet procedure by comparing the incidence of adverse events and clinical outcomes between patients who underwent inpatient or outpatient Latarjet surgery. Our hypothesis was that the outpatient procedure is both feasible and safe.

Patients and methods

Patients

Study inclusion criteria were as follows: patients were considered if they had a diagnosis of recurrent anterior shoulder instability; were deemed candidates for surgical stabilization; had not undergone prior shoulder surgery, and did not have any significant shoulder co-morbidities. All patients underwent primary surgery for anterior shoulder instability using transfer of the coracoid process (Latarjet procedure). All procedures were performed by a Single Surgeon (SZ). Thirty consecutive patients underwent surgery on an outpatient basis between 2013 and 2017 and were prospectively followed. This group was compared to 30 patients who underwent the Latarjet procedure on an inpatient basis between 2007 and 2012 by the same surgeon.

Surgical protocolA standardized general anaesthesia protocol was followed. An additional interscalene block was administered under ultrasound guidance (single bolus of 20ml of 0.375% ropivacaine) associated with 8mg of a dexamethasone intravenous injection. An open minimally invasive technique was used. The osteotomy of the coracoid process was performed through a deltopectoral approach after the coraco-acromial ligament and pectoralis minor tendon were released and following conjoint tendon exposure and dissection. All harvested coracoid grafts were a minimum of 20mm in length. The subscapularis tendon and muscle was split horizontally. Following glenohumeral capsulotomy, bone on the ventral aspect of the coracoid process and on the anteroinferior aspect of the glenoid rim was decorticated. Any remaining anteroinferior bone bankart fragments were resected. The ventral aspect of the coracoid graft was fixed to the inferior portion of the anterior scapular neck such that the transplant was level with the anterior glenoid rim. The coracoid process was drilled with two 3.5mm holes and fixed with two 3.5 diameter cortical screws; whilst the glenoid neck was drilled with 2.5mm holes to enable compression.

Care was taken to avoid lateral overhang of the graft across the joint line as described by Alain et al. [4]. No additional capsular suture was used. The subscapularis tendon was closed lateral to the graft. Traction on the coracoid graft was avoided all along the procedure to decrease the risk of musculocutaneous nerve injury. The wound was closed in layers with continuous absorbable skin suture. All inpatients had a suction drain inserted. No drain was used in the outpatient group. Sling immobilization was used for one week following surgery. Simple activites of daily living (shower, eating, writing) were immediately permitted. Following one week, self-assisted stretching in all planes was permitted. Running and swimming were allowed after two months, and high-risk sports (rugby, judo…) were allowed after 4 months. All patients were assessed on post-operative day one (by telephone for outpatients); further assessments took place at 1 week, 1 month, 4 months and 12 months post-operative.

Evaluation criteria and statistical analyses

Readmission rates and early complications were recorded. Shoulder range of motion, recurrent instability, persistent subjective apprehension and shoulder pain were compared between groups at one year. Satisfaction rate with the outpatient protocol was assessed. Continuous variables were compared with the independent t-test and categorical variables with the Fisher exact test; statistical significance was set at 0.05.

Results

The 2 groups were comparable at baseline (Table 1). Mean hospital stay in the inpatient group was 2.2±0.4 days. One admission for one night occurred in the outpatient group due to dizziness which resolved without further treatment. No complications occurred related to the interscalene block. There were no reoperations, no nerve injuries and no infections in the series.

In the inpatient group, drained blood volume prior to drain removal was negligible in 18 patients, less than 100cc in 11 patients and > 100 cc in one patient. All drains were removed on post-operative day one. Seven hematomas occurred within the first 3 weeks following surgery: two in the inpatient group and five in the outpatient group (Figure 2). Four of these hematomas, two in each group, discharged and healed spontaneously. All others healed spontaneously without fistulization. One of these hematomas occurred in a patient with the Factor V Leiden defect (outpatient group). Three of these hematomas, with fistulization twice, occurred in the first 9 patients in the outpatient group and induced a change in the surgical technique. In the following 21 patients, prior to closure, the osteotomy of the coracoid feet was explored, washed and waxed prior to closure during which time a blood clot was typically found. Wax was never used for patients in the inpatient group.

Figure 1: Latarjet procedures statistics in France between 2013 and 2017 (ATIH, technical agency of information on hospitalization, www.atih.sante.fr).

Figure 2: Hematomas formation by group. There was more hematomas in the outpatient group (p<0.01), all hematomas healed spontaneously.

All outpatients but one were satisfied with the procedure. One patient indicated that he would have preferred a one night hospital stay due to postoperative discomfort. At final 12 month followup, no patient had experienced further instability. Six patients answered positively for subjective persistent apprehension in both group (20%). One third of patients of each group have reported occasional shoulder pain. Loss of external rotation was found in half of patients of each group (Table 1).

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Lupine Publishers | Two Consecutive Successful Pregnancy Outcomes in a woman with Eisenmenger’s Syndrome: A Case Report

 Lupine Publishers | Journal of Gynaecology and Women's Healthcare

Abstract

Eisenmenger’s syndrome is a very rare condition in pregnant women. The incidence of ES is about 3% of the pregnant patients with congenital heart defects; however, it can be accompanied with high incidence of maternal and neonatal morbidity and mortality. Therefore, these patients should have efficient contraception or termination of pregnancy in the first trimester. We present two poorly-controlled consecutive pregnancies with good outcomes in a woman with ES to clarify the appropriate function of teamwork in the management of emergency situations in similar cases. Alongside teamwork, good prenatal care is also important because it can result in elective termination in higher gestational age of pregnancy.

A 21-year old woman, Repeat II cesarean belonging to a very low socioeconomic class, with ES was admitted to the emergency ward of Imam Hossein teaching hospital affiliated to Shahid Beheshti University of Medical Sciences with labor pain and severe dyspnea in 28 weeks of pregnancy. Echocardiography indicated a PAP of 120 mmHg. The patient had supportive treatment in intensive care unit until she was discharged. Despite previous reports of poor pregnancy outcomes in women with ES, high quality and significant treatment through labor and postpartum period lead to good outcomes in both mother and neonate.

Keywords:Eisenmenger complex; outcome; pregnancy; pulmonary hypertension

Introduction

Several congenital heart defects may result in Eisenmenger’s syndrome (ES) [1]. The progress of ES in patients with congenital heart defects depends on the heart defect size and location [2]. Signs and symptoms of ES include right ventricular (RV) failure due to right ventricular hypertrophy, nail clubbing, cyanosis, dyspnea, edema, fatigue, dizziness, and arrhythmia [1]. For the first time in 1897, Victor Eisenmenger described a 23-year-old man with a large ventricular septal defect and pulmonary arterial hypertension and termed the condition as ES [3]. The major causes of death in ES are right ventricular failure, pulmonary hypertension crisis, arrhythmia and stroke [1]. ES is a very rare condition in pregnant women. The incidence of ES is about 3% of the pregnant patients with congenital heart defects [4]. Although ES progresses slowly in non-pregnant women, the increased blood volume during pregnancy may advance the disease during a relatively short time [5]. When pulmonary hypertension exceeds 70% of systemic blood pressure, pregnancy may be associated with complications and cause maternal death [6]. In a review, the maternal mortality rate from 1978 through 1996 due to ES was 36% and the risk of maternal death remained unchanged over the period [5]. Neonatal outcome of pregnancy with ES is also poor. ES is a strong risk factor for spontaneous abortion, preterm birth, and intrauterine growth retardation (IUGR) [7].

As a rule, pregnancy in women with ES must be prevented or terminated in the first trimester [1,4,8,9]. In women who choose to continue pregnancy, a team consists of an obstetrician, perinatologist, cardiologist and an anesthesiologist is needed to care the pregnancy and labor [4,9]. Women with ES should be hospitalized in the second trimester of pregnancy [10]. Pulmonary vasodilator agonists have been used for lowering pulmonary hypertension with good results [9,11,12]. The best mode of delivery is a non-instrumental vaginal delivery using a labor pain relief through epidural block. Spinal analgesia is also preferred for cesarean in these women [5,9]. In general, treatment of ES is supportive [13] and includes oxygen therapy, the use of digitalis, diuretics, vasodilators and anticoagulants [4]. Usually anticoagulant therapy is prescribed to prevent thrombotic events; however, it may increase the risk of hemorrhage in the postpartum. Kahn reported a pregnancy in a 23-year old woman G4P3 with ES who was transferred to the hospital at 38 weeks with a two-month history of dyspnea and edema. After vaginal birth, she was treated with heparin to prevent thromboembolism. In the next day, severe vaginal bleeding developed and finally she expired [8]. We present two consecutive pregnancies with ES and good outcomes in a 21- year old woman, with poor prenatal care. If she had regular visits during her pregnancy by specialists in obstetric, perinatology and cardiology she would have a higher chance of elective termination in later gestational age of her pregnancies; however, in emergent situations, a good teamwork can lead to saving both the patient and her neonate as it happened in both pregnancies in this patient. Therefore, women with ES may have a chance to experience motherhood.

Case Presentation

A 21-year old mother G1P0 in 34 weeks of pregnancy was admitted in the emergency ward of Imam Hossein teaching hospital affiliated to Shahid Beheshti University of Medical Sciences with labor pain and dyspnea. She was a known case of ES since 25 weeks of her pregnancy. The most important findings were pulse rate (PR) of 100beat/min, respiratory rate (RR) of 24/min, blood pressure (BP) of 100/60 mmHg, O2 SAT of 92% and no cyanosis was seen. The echocardiography revealed a mild right ventricular enlargement, a mild left atrial enlargement, a mild reduced right ventricular function, a mild left ventricular hypertrophy (LVH), ejection fraction (EF) of 50%, Pulmonary artery systolic pressure (PAPs) of 50mmHg, and a large ventricular septal defect (VSD) progressing to ES. She continued her pregnancy until presented dyspnea and cyanosis in the 34th week of pregnancy. The vital signs were as follows: PR=100 beat/min, RR=34/min and BP=100/70mmHg. The second echocardiography reported EF of 50% and PAP of 98 mmHg. O2 SAT was 86%. Due to severe pulmonary hypertension, viability of fetus and low Bishop score, cesarean was performed, and a neonate was born with Apgar score 9/10 and birth weight of 2kg. She was admitted to the intensive care unit (ICU) and after four days, she was discharged from the hospital in good condition.

Again, in her second pregnancy, she was admitted for an elective therapeutic abortion in the 16th week of pregnancy but she did not accept and left the hospital. In physical examination she had PR of 110 beat/min, RR of 32/min, BP of 110/70mmHg and O2 SAT of 85%. The patient also presented acrocyanosis. Echocardiography in the 16th week of pregnancy detected EF of 50%, PAP of 80mmHg, mild systolic dysfunction and mild right ventricle enlargement. In electrocardiography, a sinus tachycardia was seen. After 12 weeks, she hospitalized in emergency ward with labor pain and dyspnea. Blood pressure, pulse rate, and respiratory rate were 100/70 mm Hg, 112 beat/min, and 30/min, respectively. Finding in arterial blood gas analysis (ABG) were as follows: PH = 7/52, partial pressure of carbon dioxide (PCO2) = 18mm Hg, bicarbonate (HCO3) = 27mEq\L and O2 SAT = 90%. In the electrocardiogram, a sinus tachycardia was detected. Echocardiography indicated a PAP of 120mmHg. Immediately oxygen was administered, emergency consultation with a cardiologist was done According to consultation with an anesthesiologist, pethidine was injected to reduce the labor pain. Supportive management such as oxygen and pain control continued. While stabilizing the patient, magnesium sulfate for neuroprophylaxis of the baby and betamethasone for fetal lung maturity were administered. The patient was admitted to the ICU. After 8 hours, because of intensified labor pain, cesarean was done under general anesthesia and a preterm baby girl with Apgar score of 7/8 and birth weight of 1800gm was born. Tubal ligation was performed and again she was transferred to the ICU ward. Enoxaparin was administered to prevent thromboembolic events in the postpartum period. The result of the echocardiography after cesarean showed PAPs of 110mm Hg and EF of 48%. Four days later, she transferred to the post-cesarean ward and after one week, she discharged with good general condition.

Ethics

We obtained patient’s informed consent for publishing this report.

Discussion

It is strongly recommended that women with ES be discouraged having pregnancy or be advised to terminate in the first trimester of pregnancy [4,9]; however, few reviews and case reports indicated that outcomes for women with ES have been improved [11-16]. Geohas and McLaughlin reported a 21-year old woman G3P2 in the 34th week of pregnancy with ES who suffered from dyspnea and edema in the third trimester. She was treated with epoprostenol and was terminated by cesarean. The outcome was good and a newborn with good Apgar score was born [13]. Our patient was belonging to an underprivileged social group and did not have appropriate prenatal care during her pregnancies. She was a known case of ES since second trimester of her first pregnancy which was continued until gestational age of 34 weeks. In her second pregnancy, she maintained her pregnancy and finally was terminated in 28 weeks of pregnancy. The outcome of both pregnancies was good similar to the results reported in previous studies [10,13,17] while in Duan’s report, the perinatal outcome of pregnant women with ES were poor [1]. In a systematic review from 1978 through 1996 on 73 women with ES, patient`s age was a risk factor of maternal death [5]. Our patient was young, and it can be one of the reasons leading to good outcome. In addition, O2 sat and hemoglobin did not show any relationship to the outcome in ES [5].

Although vaginal delivery is preferred in these patients [4] other factors such as Bishop score and maternal and fetal condition are important to determine delivery route. In our case cesarean was preferred. In three reviews, 65% to 100% of patients gave birth by cesarean due to deteriorating maternal condition during the third trimester of pregnancy [4,12,18]. In a review study by Wang, and colleagues on 13 pregnancies, no pregnancy continued to term [19]. In our study, both pregnancies were preterm and terminated at the gestational age of 34 and 28 weeks of pregnancy, respectively. Despite poorly controlled prenatal care, the mother saved because she was young and received proper care in a tertiary center during labor and postpartum period. Besides, preterm labor at the 34th and 28th week of pregnancy may contribute to the successful outcomes of the patient due to stopping the progress of hemodynamic changes and worsening the condition. On the other hand, the patient was referred to the same hospital and we had access to her past medical history. Because she was not supervised between her pregnancies, we were not aware of the medications and the cares she received and whether she was adherent to the treatment.

Conclusion

Although prevention of pregnancy or termination in the first trimester is usually recommended in patients with ES, in this case, two consecutive pregnancies developed with good outcomes. Although the patient received no proper prenatal care including visiting a cardiologist before pregnancy and having timely care by a perinatologist or even an expert obstetrician in managing high risk patients, receiving a significant treatment in a tertiary center during labor and postpartum period resulted in good outcomes in this patient. Women with ES may have a chance to experience motherhood.

Acknowledgment

Authors thank the patient for agreeing to publish this report

Ethical Approval

We obtained patient consent for publishing this report.

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Lupine Publishers | Water Quality Assessment in Sindh, Pakistan: A Review

 Lupine Publishers | Journal of Environmental & Soil Sciences

Abstract

Increasing detrimental impacts of water pollution on environment and serious health issues, this review aims to investigate water quality status of Sindh, Pakistan.it also help us to determine current and future water demand of the province as well as adverse impact on human health in regards with water borne disease. To conclude, some recommendations are also outlined.

Keywords: Water borne disease; Quality assessment; Water supply; Water contamination; Sindh; Pakistan

Introduction

Although surplus amount of water is available on the planet of earth, but only small portion is available for human utilization. Overall population wholly depend upon the water sources mainly consist on groundwater and surface water. Currently, countries around the world are facing water pollution as well as water scarcity problems. Following the report of UN, the total populace increases exponentially while accessibility of water decline with time. WHO announced that by 2025, half of the total populace will live in water-stressed zones? Unfortunately, water pollution stresses the remaining small portion. During last decades, Urbanization and industrialization further added burden on water resources around the globe. Quality of water around the world has been deteriorated with chemicals discharged into water bodies directly and improper dumping of solid waste. According to Joint Monitoring Programme (JMP) report 2017 on “Progress on drinking water, sanitation and hygiene” 2.1 billion people lack access to safe drinking water at home. Globally, 448 million lack to have basic drinking water services from which 159 million individuals are those who rely upon surface water. According to speech of UNO secretory on world water day 2002, each year 5 million people died of water disease i.e.10 times more than people died in war. Furthermore, several studies have documented various contaminants such as organic (Pesticides), inorganic (heavy metals), minerals (arsenic and chromium) and microbial (pathogens) are responsible for water pollution. Recently, water contaminated with arsenic has been documented around the world, especially in Asian countries including Pakistan, Bangladesh, India, Cambodia, Vietnam, China, Taiwan, Hungary, Chile and Argentina [1-4].

Pakistan has been blessed by natural resources i.e. surface as well as groundwater resources. Sudden rise in population, industrialization and urbanization have brought huge stress on water resources of country. The country once has surplus amount of water is not including in water stressed zone. Most of the population belong to different cities of country rely upon groundwater for survival. While, current water supply is about 79% in Pakistan. Pakistan has experienced six noteworthy floods between 2000- 2015, which killed many people and posed negative impact on groundwater through salinization CRED [5]. Furthermore, Per capita availability of water has been decreased from 5,600 cubic meters in 1947 to 1,038 cubic meters in 2010. It is expected to decrease further to 575 cubic feet in 2050 [6,7]. In addition to this, quality of water resources has been declined due to intermixing of municipal sewage with water supply line and direct release of industrial wastewater into water bodies. Pollutants such as heavy metals, pathogens and other dangerous chemicals have been found in different regions of the country. Only 20% of the population have accessibility to safe drinking water while 80% is compelled to consume unsafe water for drinking. Each year 2.5 million deaths from endemic diarrheal disease has been reported [8-13]. Pakistan ranks 80th, out of 122 nations of the world, on the basis of water quality [14-16]. According to a Worldwide Fund for Nature (WWF) report titled, “Pakistan’s Waters at Risk”20-40% health centers are filled with the patients of water borne disease which include diarrhea, gastroenteritis, typhoid, cryptosporidium infections, giardiasis intestinal worms, and some strains of hepatitis [17].

Quality of drinking water in Sindh province is unfit like other provinces of Pakistan. Large portion of water available is contaminated with pathogens, chemicals and toxic materials. Several studies have documented that the four major contaminants are responsible for water quality deterioration in Sindh i.e.69% bacteria, 24% arsenic, 14% nitrate and 5% fluoride. According to the report of Inquiry commission appointed by Supreme Court of Pakistan “78.1 % of all water sample tested were found unsafe for drinking”. The aim of this review is to analyses the status of water quality in different divisions of Sindh, Pakistan. It also describes the impacts of water quality on human health as well as outline some recommendations.

Study Area

Sindh is second most populated province (Figure 1) with population of 30.44 million situated in south-eastern part of Pakistan. It is stretched from 66°8’ East Longitude to 71°, lies between 24°4›N to 28°7’N and covers about 46,569 miles2 . Province is bounded by the Thar Desert to east, the Kirthar Mountains to the west, and the Arabian Sea in the south. It is divided into six divisions namely Karachi, Hyderabad, Sukkur, Shaheed Benazirabad, Mirpurkhas and Larkana. Karachi i.e. the capital of Sindh province ranked at the top with 14.91 million and Hyderabad ranked the 8th most populated with 1.73 million population among the list of 10 most populated cities of Pakistan. Large number of populations of the province depend upon the fresh water for domestic and irrigation purpose. Indus basin is the major source of water provision in the area. In Sindh Province, only 10 % of land area had availability of fresh groundwater and occurs in shallow aquifers [18]. Following high average annual temperatures, semi-arid climate, sea water intrusion and high rate of evapotranspiration shallow aquifers are highly saline [19]. Irrigated land i.e. almost 78% of the province rely on saline groundwater which is not fit for irrigation. As the ground water is saline in most areas, rural population is also depending on supplies from the canal system. According to the survey conducted by Pakistan Council of Research in Water Resources (PCRWR) in 22 districts of Sindh province out of 1247 surveyed water supply schemes only 529 (42%) were functional with average duration supply of 5 hrs/day. From which only 25% water samples were fit for drinking while remaining are contaminated with microorganisms and arsenic.

Figure 1: Map of Study Area (Sindh Pakistan). Source: Modified from (Sindhidunya 2015).

Current Demand and Future Requirement of Sindh

In next 20 years, Province will undergo demographic change. Current population of 33 million is expected to increase to 52.6 million and urbanization will increase from 50% to 64% in 2025. Currently, Karachi’s demand for water supply is about 1,220 MGD against which has an allocation of 34,000 l/s (1,200 cusecs) from the Indus water which is expected to increase 65,460 l/s (2,320 cusecs), with increased population to about 23 million in 2025. Likewise, water demand for other urban cities will also increase which will put burden on water resources. In addition to this, rural population of about 18.8 million will need an additional about 7,125 l/s (250 cusecs) for drinking purposes. Hence, total municipal water requirement of the province in 2025 will be of the order of 94,000 l/s (about 3.300 cusecs). Besides municipal water requirement, water requirements for agriculture would also increase by about 50%. Current water use is about 52.6 Bm3 (42.6 MAF) which means an additional 26.3 Bm3 (about 21.3 MAF) required to meet the future demand of agriculture products (FAO).

Water Quality

Alarming increase in population is the single important driving force affecting the water sector and cause water scarcity problem in the province. Water pollution is another major problem which is deteriorating the quality of remaining small portion of water. According to Director General of Sindh Environmental Agency Baqa Ullah Unar “every day almost 500 million gallons of industrial waste and human consumption falls into Arabian Sea”. 80% samples from 14 different districts of Sindh are not safe for drinking as well as 78% of water used in hospitals is above standard limits. 90% of water had bacterial contamination and not fit for drinking in Karachi only (PCRWR). Several studies have been conducted in different cities of Sindh, Pakistan (Table 1) [20-29].

Table 1: Water quality in different districts of Sindh, Pakistan [20-29].

Abdul Hussain Shar [30] analysed the samples from Rohri for the presence of total coliform (TC), E. coli (Ec) and heterotrophic plate count (HPC) which result the contamination of all samples with TC (100%), Ec (41.6%) and with HPC (100%). In Hyderabad bacteriological tests on drinking water has been conducted by PCRWR found that 15 monitored sources as unfit for drinking mainly due to bacteriological contamination (93pc), excessive levels of iron (47pc) and turbidity (93pc). Mashiatullah [31] carried out a study on Malir and Lyari rivers, he analysed different Physiochemical and biological parameters. The coliform contamination i.e.156-542 per 100 ml in high tide and 132- 974 per 100 ml in low tide were observed which exceeded WHO guidelines. Aziz et al. [32] reported a study for drinking water quality in Pakistan including both urban and rural areas which results that total coliform and fecal coliform were 150–2400/100 ml and 15–460/100 ml respectively. The investigation reported the presence of anthropogenic activities which resulted.

Mahmood et al. [33] measured the physical, chemical and microbiological parameters for the different groundwater samples collected from Thatta in pre-monsoon and post-monsoon seasons, respectively. It was observed that concentration of heavy metals were; As (0.0045 to 0.0055 mg/l), Cd (0.15-0.22 mg/L), Zn (0.040 to 0.046 mg/l), Pb (1.40-1.49 mg/l) and Cu (0.001- 0.87 mg/L) in both the seasons and were in order of Pb > Cu > Cd > Zn > As in premonsoon and Pb> Cd > Cu > Zn > As in post- monsoon respectively. Other parameters Electrical conductivity (233-987 μs/cm), pH (6.9-8.9), TDS (161.1-690.9 ppm), Temperature (24-33°C), chloride (81.79-131.78 ppm), total hardness as CaCO3 (124.40-188.81 ppm), nitrate (2.10-5.20 ppm) were within prescribed standard limits. Some common diseases were found to be nausea, vomiting and kidney damage.

Suresh Kumar Panjwani [34] collected Thirty-five groundwater samples and analysed for 22 different parameters including physicochemical parameters and bacteriological contamination. Three drinking water samples (9%) contain Fluoride as 1.83 mg/l to 0.44 mg/l which exceeds WHO limits. Two water samples (5%) were contaminated with nitrate–nitrogen i.e. 23.61 mg/l to 0.97 mg/l. (45%) 16 water samples were contaminated with E. coli ranges from 01-too numerous to count CFU/ml exceeding the prescribed limit by WHO (0/100ml). None of the drinking water samples (0%) were found bacteriological safe for drinking purpose. In 2014, another study examined water quality in Thatta, Karachi and Hyderabad found presence of heavy metals that exceeded the WHO drinking water guidelines [35].

Outbreak of Water Borne Disease

Improper treatment and dumping of waste in water bodies accounted for rise in water borne disease. Deteriorated quality of water in Sindh province had badly affected the human health. More than 20,000 children die annually in Karachi only, from which majority of deaths caused by drinking contaminated water. Outbreak of water borne disease have been noticed in different parts of Sindh including typhoid, cholera and diarrhea. According to Zahid J [36] areas surrounded by poor households, children with mothers married in early ages, children having small size at birth and ages less than 24 months and children belonging to uneducated mothers are found most vulnerable where prevalence of diarrhea found non-ignorable. In Sindh, Tando Allahyar (46%), Matiati (50%), Hyderabad(44%), Badin (40%), Mirpur Khas (40%) Karachi East (40%) and Karachi South (52%) have highest rate of cases while lowest rate found in children from rich house holds’ of Larakana (6%) and Jacobabad (8%). In some areas including Gadap, Kathore and coastal areas 30-35% of people have been found infected with viral hepatitis. While 20-25% of the population is infected with the deadly viral disease said by Dr Shahid Ahmed, consultant gastroenterologist and patron of the PGLDS on World Digestive Health Day 2018 (WDHD 18).

Recently, a drug-resistant typhoid strain identified first in Hyderabad, spread from the city to various parts of the country. 5,274 cases of XDR typhoid have been reported by Provincial Disease Surveillance and Response Unit (PDSRU) from 1 November 2016 through 9 December 2018.69 % (3658) of cases were reported in Karachi only, following 27% (1405) in Hyderabad, and 4% (211) in other districts of the province. On 9th July 2017, outbreak of acute watery diarrhea and abdominal pain in village Mir Khan Otho, District Shaheed Benazirabad were reported to the DG Health Office Sindh in Hyderabad. A total of 30 cases were identified (22 through active case finding) and n=16 (53.7%) were females. Mean age was 25.3 years (range: 1-50 years). Overall attack rate was 23%. People aged 21-30 years were the most affected (n=10; AR 43.5%). Apart from diarrhea, abdominal cramps (n=28; 93%) was the most common symptom. On bivariate analysis, consumption of water from the hand-pump near the swamp was significantly associated with the disease (OR=8.4, 95% CI: 3.1-22.7) [37].

In 2016, 22,000children have been hospitalized and more than 190 have died in Tharparkar district due to drought-related waterborne and viral diseases. According to the Joint UN Needs Assessment, water scarcity has been severely affected several districts (62% in Jamshoro and 100% in Tharparkar) which resulted in reduced harvest by 34-53% and livestock by 48% UNICEF [38]. According to local media, the total under- 5 deaths were rising from 173 in 2011, 188 in 2012, 234 in 2013, 326 in 2014, and 398 in 2015. According to the provincial health secretary, 450 children lost their lives in 2017, 479 died in 2016 and 398 in 2015 while reasons for the deaths vary. Furthermore, According to authorities in Tharparkar district, Sindh province, 99 children and 67 adults (43 men and 24 women) have reportedly died in Tharparkar since the beginning of 2014 as well as an outbreak of sheep pox occurred which has killed thousands of small animals (Pakistan: Drought - 2014-2017) [39]. Furthermore, three months after floods began in Pakistan, 99 cases of cholera were reported from across the floodaffected areas of the country (WHO).

In 1994, first ever case of dengue has been reported in Pakistan, sudden rise in cases first occurred in Karachi in November 2005. Since 2010, Pakistan has been encountering dengue fever that has caused 16 580 affirmed cases and 257 deaths in Lahore only also about 5000 cases and 60 death confirmed from other parts of the country (WHO) [40]. The three provinces have faced the epidemic are Khyber Pakhtunkhwa, Punjab and Sindh. In Sindh province, 2088 dengue positive cases had been reported as well as two people had died of dengue in Karachi city in 2018. Currently, according to the weekly report issued by Prevention and Control Programmed for Dengue (PCPD) in Sindh, from January 1 to January 7, 2019 a total of 38 dengue positive cases were detected. From which 36 were reported in Karachi only while two were in other districts of Sindh (PPI).

Contamination Sources

Climate Change

For water resources, climate change is a long term and unmitigated risk. Water demands is expected to increase up by 5 percent to 15 percent by 2047 due to climatic change. In the upper Indus Basin, climate change will increase the risk of flood outbreak by accelerate glacial melting while in the lower Indus Basin, sea level rise and increases intensity of coastal storms also exacerbate seawater intrusion into the delta and into coastal groundwater. Furthermore, in coastal Sindh, groundwater quality will further be deteriorated and also impact the ecosystems, and irrigation productivity of the province. In addition to this, Sediment dynamics in the Indus sourcing, transport, and deposition have been significantly altered by water resources development. Past floods in Pakistan not only posed physical damage but also affected human lives in terms of flood-related death and illness as well as clean water and sanitation facilities. The flood destroyed 54.8% of homes and caused 86.8% households to move, with 46.9% living in an IDP camp. Lack of electricity increased from 18.8% to 32.9% (p = 0.000), lack of toilet facilities from 29.0% to 40.4% (p=0.000). Access to protected water remained unchanged (96.8%); however, the sources changed (p=0.000) [41].

Since 2013, Tharparkar has been influenced by a drought‐like circumstance affecting employments, nourishment and wellbeing conditions. In south-eastern Sindh, low rain fall throughout 2016 in districts including Tharparkar, Umerkot and Sanghar sharply reduced the cereal production also causes loss of small animals due to diseases and severe shortages of fodder and water. Moreover, it has aggravated food insecurity and caused acute malnutrition [42].

Poor Water Supply and Sanitation

USAID reported that in Pakistan about 60% of the total number of child mortality cases are caused by water and sanitation-related diseases. Pakistan Strategic Environmental Assessment of the World Bank, 2006 stated that about 2,000 mgd of wastewater is discharged to surface water bodies in Pakistan. 13,000 tons of municipal waste daily generated in Karachi only, following 3,581 in Hyderabad while 48 million tons a year around the country. Water and sanitation sector have the highest financial cost to Pakistan from environmental degradation at Rs112bn a year as reported by WB. This is based on health cost of only diarrhea and typhoid and accounts for 1.81 per cent of the GDP. While figures for Sindh are not available. According to the media (The news) “More than 50 per cent of the people were suffering from diseases related to water and sanitation due to the lack of proper sanitation in the Sindh province” speakers told on‘ World Toilet Day with the 2018 theme ‘Toilets and Nature, the Pathway to Neat and Clean Sindh’. In Karachi, 42 percent of the city’s total population have no access to a proper toilet and appropriate sanitation system and live in 539 slums. Furthermore, Karachi Metropolitan Corporation and Cantonment boards have public toilets at only 13 places.

Poor Water Management

According to Rubina Jaffri, the general manager of Health and Nutrition Development Society (Hands), only 440 MGD is being filtered out of 640 MGD of water supplied to Karachiat seven filtration plants. A recent survey accounted that 40% water samples collected from different parts of Karachi were not properly chlorinated. In Karachi, long transmission route also causes leakages and water thefts problems which account for the loss of almost 30% of the city’s water supply, said by Jawed Shamim, former chief engineer at KWSB (The Karachi Water and Sewerage Board).Moreover, Parallel water supply and sewage pipes currently lead to cross contamination and corrosion. Chief Minister Syed Murad Ali Shah, in Sindh there were 2,109 water filtration plants, including 1,620 RO plants, and 818 of them were non-functional. He also added that there were 5,091 water supply and drainage schemes and 2,494 of them were non-functional and 244 of them had been abandoned (PPI).

Agriculture sector consumes up to 90% of the available fresh water of the country. About 70% of the canal water is lost from river to the end user. The larger portion of canal water (35%) is wasted at field level which needs proper attention of the policy makers. furthermore, 30 MAF is equal to 10 trillion gallons which can feed a population of more than 500 million people has been dumped into Arabian sea instead of storage. Problem is the absence of efficient conservation, storage and usage of water [43-50].

Recommendations

a) Basic filtrations units and 24 hours water quality monitoring stations should be established

b) Proper usage, efficient storage and conservation strategies are utmost practices to deal with water scarcity problem

c) Rearranging of water supply line to deal mixing of municipal sewage into water supply

d) Latest and technical irrigation strategies to use water efficiently such as drip irrigation and sprinkling.

e) Proper waste management system and treatment of industrial effluent should strictly implement

f) Institutional capacity management in order to operate and maintain the water supply schemes

g) Proper design of water distribution network to deal with the water loss.

h) Education on the water conservation and utilization practice should be provided to people by arranging seminars and utilizing media

i) Water thief and corrupted people should be deal according to law and regulations

j) Construction of new water reservoirs and proper check in balance on old ones to enhance storage capability by resolving siltation problem

k) Encouragement of new polices and proper implementation as well as check in balance

l) Awareness campaign should be encouraged about water quality and water borne disease

m) Basic health care and relief facilities should be provided at doorsteps when needed to reduce death related to water borne disease

n) Involvement of community to reduce water pollution by providing basic knowledge and changing lifestyle.

o) Proper check in balance on water filtration plants to provide safe drinking water to communities.

p) Mitigation strategies to improve the response to climate change-induced effects on health and agriculture

Conclusion

Conclusively, water quality status of Sindh Pakistan has been reviewed. Most of the water in different areas of the province is contaminated with bacteria which causes outbreak of waterborne disease including, diarrhea, cholera, hepatitis and typhoid in many cities and caused millions of deaths simultaneously. Arsenic is the second hazardous chemical found in water of Sindh mostly in coastal areas. Fluoride and nitrite are other metal which pose threat to human lives in Sindh Pakistan. Thus, many policies have been established and many schemes were organized by provincial government to deal with the water crisis but still some gaps related to implementation exist that needs to be executed. Moreover, new reservoirs and flow distribution line should be constructed to deal with water scarcity and water loss problem of the province.

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Lupine Publishers | Preparation of Morphine Derivatives Using Ionic Liquids

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

Dextromethorphan, an anti tussive drug belongs to the morphinan family, and is mostly available in the market as a combination therapy. Most of the reported preparation procedures involve the use of racemic starting materials that give lower yields. (S)- Octa base is one of the key starting raw materials used in our process and this easy, convenient and eco-friendly preparation (single step) is reported in this manuscript. This drug, Dextromethorphan is produced in large volumes annually (> 150 tons/year). Most reported synthetic procedures make use of huge amounts of volatile organic solvents which are hazardous for environment. This will be a major issue in the near future. To overcome this problem, we have tried using Ionic liquid as a solvent in the preparation and successfully arrived at best results, thereby decreasing the use of organic volatile solvents.

Keywords: Dextromethorphan, Morphine derivatives, Alkaloids, Formylation, Ionic liquid

Introduction

Dextromethorphan, a drug of the morphinan family, is having tranquilizing, dissociative, and restorative properties (especially at higher doses). It is a cough suppressant (ANTI-TUSSIVE) in several over-the-counter cold and cough medicines including generic labels and store brands, Benylin, Mucinex, Camydex 20 tablets, Robitussin, NyQuil, Vicks, Delsym, TheraFlu, Cheracol D, and others. It has also found plentiful other uses in medication, extending from analgesic effect to psychological submissions useful in the treatment of addiction. It is sold in syrup, capsule, and lozenge forms. In its unadulterated form, Dextromethorphan ensues as a white powder. Currently, Dextromethorphan is not registered in the Schedules of the United Nations 1961 Convention on Narcotic Drug [1].

Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It’s IUPAC name is (+)-3-methoxy-17-methyl-9α, 13α, 14α-morphinan. It occurs as an odorless, opalescent white powder. It is freely soluble in chloroform and insoluble in water; the hydro bromide salt is water-soluble up to 1.5g/100mL at 25 °C. It is usually accessible as the monohydrated hydro bromide salt. However, some newer extended-release formulations contain Dextromethorphan bound to an ion-exchange resin based on polystyrene sulfonic acid (Picture 1).

Picture 1: Chemical structure of Dextromethorphan Hydro bromide.

Mechanism of Action

Dextromethorphan is a synthetic compound and acts as a dissociative anesthetic when taken in higher doses. Its mechanism of action is via multiple effects, plus actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist [2]. Dextromethorphan and its major metabolite, Dextrorphan, also act as NMDA receptor antagonist at high doses, which produces effects similar to other dissociative anesthetics such as ketamine and phencyclidine [3]. The metabolic pathway continues from dextrorphan to 3-methoxymorphinan to 3-hydroxymorphinan (Figure 1) [4].

Figure 1: Explains the metabolic pathway of the drug Dextromethorphan.

In one of the reported processes for the preparation of morphinan alkaloids, racemic hydroxy N- methyl morphinan is used as a starting material, an optically inactive isomer and is treated with tartaric acid for resolution to obtain selective one isomer (+) of morphinan. (PATENT- US2676177 (Roche, 1954, CHprior. 1949)) (Scheme 1).

Scheme 1: This scheme explains the reported procedure that uses a racemic hydroxy N- methyl morphinan as a starting material along with the use of solvents.

In a similar procedure reported in PATENT- CN102977021 A, Method for preparation of Dextromethorphan hydro bromide By Cui, Dapeng et al From Faming Zhuanli Shenqing, 102977021, 20 Mar 2013, Raney Nickel as a reducing agent is replaced by KBH4, thus, reducing the cost. Also, resolution is done with R-ibuprofen for the first time. Another advantage is the use of AlCl3 is adopted to replace H3PO4 to cyclize. Overall, it is a low cost, moderate reaction conditions, easy in operation and suitable for industrial production (Scheme 2).

Further, in the search for better preparation methods, which is easier, lesser preparation steps, cost effective, and also using chemicals that are easy to handle and can provide higher yields as well as purity, it has been found that the critical step of Grewe’s cyclization is reported in a paper titled, ‘A Novel synthesis of substituted 1-benzyloctahydroisoquinolines by acid-catalyzed cyclization of N-[2-(Cyclohex-1-enyl]-N-styryl formamides’ [5] (Scheme 3).

Scheme 2: Explains another reported procedure, where alternate reagents like KBH4, R-ibuprofen and AlCl3 have been used to refine the existing method of preparation of Dextromethorphan.

Scheme 3: Explains a reported procedure involving the preparation of Dextromethorphan that involves Grewe`s cyclization.

Scheme 4: Explains a reported procedure of Dextromethorphan preparation, where formylation was done before the cyclization step to improve the yield.

According to this paper, no cyclization of enamide was observed with Lewis acid catalyst (AlCl3, AlEtCl2, TiCl4), Two equivalents of BF3-Et2O was used, and complete conversion was observed. In all cyclization reactions, a side product is formed that is more polar than the octa hydroisoquinolines and N-formyl octa hydroisoquinolines synthesized from N-formyl- 2-phenylethylamines and benzaldehyde. Also, reduction of N-formaldehyde to N-methylated was done using LiAlH4. While going through literature, it was found that formylation before cyclisation avoids ether cleavage as a side reaction and higher yields were obtained than without N-substitution or N-methylation. In this patent, purification/resolution was done using the formation of Brucine salt (US3634429 (Jan 11, 1972) Morphinan derivatives and preparation there of (Scheme 4).

Experimental and Results

All the above-mentioned processes involve the use of solvents. So, in the existent investigation, an endeavor is explored to develop an alternate process wherein use of solvents can be avoided in the synthesis of Dextromethorphan (Scheme 5).

Scheme 5: Explains a greener preparation of Dextromethorphan using an Ionic Liquid.

Preparation of Dextromethorphan Hydrobromide using 1-butyl-3-methyl imidazolium acetate (Ionic liquid) as a solvent

I-step:

a) Stage-IA: In a flask, charge 1-butyl-3-methyl imidazolium acetate under nitrogen atmosphere. Charge (S)-Octa base under nitrogen atmosphere. Cool if required under nitrogen atmosphere. Charge Sodium methoxide solution in methanol under nitrogen atmosphere. Charge Methyl formate. Raise the temperature of the reaction mass to little reflux by using hot water not more than 55oC. Stir and maintain the reaction mass till reaction complies (2 hours). Concentrate the reaction mass u/v (Capacity of vacuum pump should be > 700 mm/Hg) till almost no solvent distills. To the concentrated reaction mass, charge toluene under nitrogen atmosphere and water extraction is done. The extracted toluene layer was concentrated to give N-Formyl octa base and is used as such.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 1) and (Picture 2).

Table 1: s- singlet, m-multiplet, br-broad.

Picture 2:

b) Stage-IB: In another flask, charge Ortho phosphoric acid (~ 85.0 % w/w). Charge Toluene and Raise the temperature of the reaction mass. Reflux and maintain over Dean stark apparatus to remove water azeotropically. Cool the reaction mass under nitrogen atmosphere and Charge Phosphorus pentoxide under nitrogen atmosphere. Reaction is highly exothermic. Charge 1-butyl-3-methyl imidazolium acetate. Slowly add N-formyl octa base and Raise the temperature of the reaction mass under nitrogen atmosphere. Stir and maintain the reaction mass at 65-70oC under nitrogen atmosphere till reaction complies. Concentrate the reaction mass under vacuum to remove toluene. To the concentrated mass, charge ethyl acetate under nitrogen atmosphere and stir. In another flask, charge water, Cool. Charge ethyl acetate reaction mixture reaction mass in to chilled water. Stir, settle and separate the layers. Repeat for back extraction. Wash the organic layer with water again and then a wash of 7% sodium bicarbonate solution is given. Concentrate the organic layer u/v till almost no solvent distills. Degas the concentrate u/v to remove traces of solvents.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 2) and (Picture 3)

Table 2: s- singlet, m-multiplet, br-broad.

Picture 3:

c) Stage-IC: To the concentrate mass, charge 1-butyl- 3-methyl imidazolium acetate and methanol under nitrogen atmosphere. Stir and slowly add sodium hydroxide solution Pre- Cooled ~15oC (Prepare by using 109 g Sodium hydroxide dissolved in 200ml Water). Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~15 hours). Concentrate the reaction mass u/v. To the concentrate mass, charge toluene under nitrogen atmosphere and water workup is done. The extracted toluene layer was concentrated to give N-Nordextromethorphan (Stage-IC).

m/z (M+H+) - 258

NMR chemical shift values tabulated below (Table 3) and (Picture 4):

Table 3: s- Singlet, m-multiplet, br-broad.

Picture 4:

d) Stage-ID: To the mixture of1-butyl-3-methyl imidazolium acetate and N-Nordextromethorphan (Stage-IC), slowly add Formic acid solution (Prepare by using 32.1g Formic acid diluted with 5.7ml water). Charge Formaldehyde solution. Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~2 hours). After the reaction is complete, Charge water and cool the reaction mass if required and then slowly add sodium hydroxide solution Pre-cool (< 15 oC) (Prepared by using 28.0g Sodium hydroxide dissolved in 140ml water), extracted the product into toluene, again charge water, cool, and slowly add Hydrobromic acid. Raise the temperature of the reaction mass to 70-80 oC and Stir and maintain to get clear solution. The organic and aqueous layers separated. Cool the Aqueous layer under stirring to get precipitate and further cooled to 3-6 oC and wash with pre-chilled water. Dry the solid under vacuum, to get Dextromethorphan hydro bromide.

m/z (M+H+) - 272

NMR chemical shift values tabulated below (Table 4) and (Picture 5):

Table 4: s- Singlet, d- doublet, m-multiplet, br-broad.

Picture 5:

a) 1H-1H coupling constants.

Discussion

As of today, chemical manufacturing process of APIs in pharmaceutical industry is handicapped without the use of chemical solvents. However, it is a scientifically known fact that solvents are dangerously damaging chemical entities, mainly of the following reasons:

a) Volatile nature of solvents.

b) Storage and handling risks.

c) Usage requirements in large scale.

Apart from their handling risks to human beings, they also cause significant saturation in chemical pollution levels in the environment; there has been constant research going-on in academic field as well as industries to find their suitable alternative [6].

Ionic liquids are one such alternative that has been found useful to substitute the commonly used bench solvents. Other than their obvious “solvent” property that have been discussed in various publications [7-10], they have also been found to catalyze certain type of reactions in which they participate [11-13]. Moreover, their complete recovery from the reaction is an easy job when juxtaposed with their volatile solvent counterparts. For this reason, an ionic liquid can be re-cycled for multiple batches of reactions.

Another unique property of ionic liquids is that they can be “tailor-made” to suit specific reaction types by playing around with the cation and anion part of them. They are called as “task-specific ionic liquids”. These tailored [14] and specially synthesized ionic liquids have more scope of their application in a chemical reaction than just acting as a green solvent.

Conclusion

A simple, efficient, eco-friendly synthetic route is developed involving the single-step synthesis of Dextromethorphan Hydrobromide that is high on convenience and also a cost-effective procedure. This process is best suitable for the preparation of Dextromethorphan Hydrobromide and is scalable in plant. This synthetic route using an ionic liquid adapts a cleaner chemistry that assures both risk-free handling and reduced environmental pollution, when scaled-up.

Acknowledgement

Our group would like to thank the Department of Scientific and Industrial Research India, Dr. Hari Babu (COO Mylan), Sanjeev Sethi (Chief Scientific Officer Mylan Inc ); Dr Abhijit Deshmukh (Head of Global OSD Scientific Affairs); Dr Yasir Rawjee {Head-Global API (Active Pharmaceutical Ingredients)}, Dr Sureshbabu Jayachandra (Head of Chemical Research) Mr Manoj Pananchukunnath (Head of Global Injectables Scientific Affairs, Product Development) Dr. Suryanarayana Mulukutla (Head Analytical Dept MLL API R & D) as well as analytical development team of Mylan Laboratories Limited for their encouragement and support. We would also like to thank Dr Narahari Ambati (AGC- India IP) & his Intellectual property team for their support.

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