**12. NSAID use after insemination**

In many studies about usage of flunixin meglumine, carprofen and meloxicam in different times after post insemination, decreasing PGF2α release, increasing luteal progesterone level and preventing early embryonic deaths are aimed [72-75].

In some of these studies [74-77], deserved pregnancy rates have been accomplished, on the other hand in some other studies [78-80] pregnancy rates have not changed.

In a study [75], in order to prevent early embryonic deaths in cows which are exposed to transportation stress, flunixin meglumine was given. In the study animals were divided into 3 groups as; control, stress (S) and stress +flunixin meglumine (SFM). After the synchroniza‐ tion of the cows' estrus with MGA - PGF2α, insemination was done by observing the estrus. Animals were exposed to stress 14 days after the insemination. 1.1 mg/kg dose of flunixin meglumine was given to SFM group before transportation. Just transportation stress was formed in S group. When looked at the pregnancy rates (Control 76%, Stress 69% and SFM 84%), it is seen that there is a positive relation between pregnancy rates and flunixin meglu‐ mine application.

**9. Flunixin meglumine**

other animals [49, 62].

**10. Carprofen**

**11. Meloxicam**

Flunixin meglumine is a derivation of nicotinic acid and is also a non-selective cox inhibitor. It is a potent NSAID to keep the inflammation, pain and fever under control. Especially, it is used in visceral pains. In addition to its analgesic effect, it has antiendotoxic and antipyretic effects. Flunixin meglumine's half-life is between 8 and 12 hours in cows, but it is longer in

Flunixin meglumine is used in cows combined with antibiotics to cure illnesses like; joint ill, transit fever, blackleg, superfoul, mastitis, puerperal metritis, vaginal prolapse, pneumonia,

Flunixin meglumine is used in cows in ways like intramuscular, intravenous and peros. When it is used orally, the dose is 1 mg/kg. 1.1-2.2 mg/kg dose is used in intravenous way. The most application way is intramuscular injection and the dose is 1.1 mg/kg. This dose of flunixin meglumine is given once in a day or two times by dividing the dose. Flunixin me‐ glumine can be given in 6-8 hour intervals in 0.25-0.50 mg/kg doses. Average therapy period

Carprofen is a propionic acid derivative NSAID and a selective cox-2 inhibitor. The drugs in this group take –fen suffix (e.g. ibuprofen, ketoprofen). Carprofen is the safest drug in this group because its peripheral prostaglandin inhibition is weak. It is a long effective NSAID with a clinical effect time of 12 hours. Carprofen in cows administered subcutaneous, in

Meloxicam is a selective cox-2 inhibitor. It is an oxicam group NSAID. It has anti-inflamma‐ tory, analgesic and antipyretic effects. Half-life is 13 hours in cows. It is used in cows by in‐ tramuscular, intravenous and subcutaneous ways in single doses of 0.5 mg/kg [65, 70-71].

In many studies about usage of flunixin meglumine, carprofen and meloxicam in different times after post insemination, decreasing PGF2α release, increasing luteal progesterone level

In some of these studies [74-77], deserved pregnancy rates have been accomplished, on the

other hand in some other studies [78-80] pregnancy rates have not changed.

downer cow. Moreover, it is used in pain therapy after small operations [63-64].

is three days and it can be given 5 days maximum [65-69].

80 Success in Artificial Insemination - Quality of Semen and Diagnostics Employed

dose of 1.4 mg/kg to body weight [49, 65, 70-72].

**12. NSAID use after insemination**

and preventing early embryonic deaths are aimed [72-75].

Merrill et al [76] searched the effects of 1.1mg/kg dose of flunixin meglumine administration on embryonic mortality of stressful and unstressed cows. They used 259 heifers and 127 cows. They designed the application groups as; control, control + flunixin meglumine, stress and stress + flunixin meglumine. In the first experiment, they used 259 angus crossbred hei‐ fers. All the heifers were synchronized with Controlled Internal Drug-Release (CIDR®) and PGF2α. In the second experiment, they used 127 angus crossbred cows. All the cows were synchronized with MGA and PGF2α. Applications started 14 days after artificial insemina‐ tion. While pregnancy rate of animals exposed to transportation stress is 62%, unstressed an‐ imals had 64% pregnancy rate. While the pregnancy rate of flunixin meglumine cured animals was 69%, it was 59% in others. In the first experiment they reported that flunixin meglumine given animals had more pregnancy rate than others which were not given. In the second experiment, it was reported that flunixin meglumine applied animals had higher pregnancy rates than others (80% vs. 66%).

In another study, single dose of flunixin meglumine injection (1.1 mg/kg) was done on the 14th day after the insemination to animals which were exposed to transportation stress. The effect of this application on early embryonic deaths and prostaglandin in circulation and cortisol levels were searched. Researchers used 483 beef cows and animals were divided into 4 groups. They designed the groups as; first group transport, second group transport + flu‐ nixin meglumine, third group no transport (n=130) and the last group no transport + flunix‐ in meglumine. After the application, transport + flunixin meglumine group had higher pregnancy rate than flunixin meglumine free group (74% vs. 66%) without looking at trans‐ portation. Just flunixin meglumine administered cows' pregnancy rates were found higher than non-flunixin meglumine cows (71% vs. 61%). Cortisol concentration in cows exposed to transportation stress got increased but pregnancy rate did not change. In flunixin meglu‐ mine given subjects prostaglandin concentration was found lower than not givens. As a re‐ sult researchers came to conclusion that NSAID applications would increase the pregnancy rate [77] .

Odensvik et al [81] have reported that application of flunixin meglumine both orally and pa‐ rentally supports luteal function. They administered 2, 3 or 4 oral doses 2.2 mg/kg flunixin meglumine to heifers. They started the 9 day-therapy period 14-15 days of the estrus. As a result, they have found that estrus cycle is prolonged in groups of 3 and 4 doses administra‐ tion. Luteolysis have taken place when 2 or 3 doses of flunixin meglumine have been ap‐ plied. But in 4 dose give groups luteolysis have been postponed. The first cycle of the animals was evaluated as control and the 2nd cycle was evaluated as therapy cycle. Before the experiment, cycles of the animals were synchronized by PGF2α.

meglumine on 14th, 15th and 16th days after the insemination. In the first experiment, 413 Hol‐ stein-Friesian heifers were used. The cycles of these animals were synchronized with PGF2α and they were inseminated by observing their estrus. 2.2 mg/kg dose of flunixin meglumine was given to therapy group animals after the insemination's 14th-15th days or 15th-16th days. No application was done to animals in the control group. At the end of this experiment, pregnancy rate in the control group was 58.7% and 58.6% in the treatment group. Serum progesterone levels on 14-15days and 21-22 days after insemination were compared in both pregnant and non-pregnant animals. It was observed that on the 21-22 days progesterone levels of pregnant animals were higher. In the second experiment researchers used 380 Hol‐ stein cows and these animals were synchronized by ovsynch protocol. After 16 hours from the second GnRH injection, fixed time artificial insemination was done. 1.4 mg/kg dose of carprofen was given via subcutaneous on the 15th day after the insemination to the treat‐ ment group. No therapy was applied to control group. It was identified that while pregnan‐ cy rate in carprofen given group was 33%, it was 35.5 in control group. Researchers come to

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the idea that NSAID application does not affect the reproductive performance.

therapy had a negative effect on the pregnancy rate.

that the highest pregnancy rates were seen in 4th group.

tion will be harmful to pregnancy [84].

Heuwieser et al. [72] made a study on 970 cows. They divided the animals into three groups. They administered 1.4 mg/kg dose of carprofen subcutaneous following artificial insemina‐ tion. 1.4 mg/kg dose of carprofen was given into the uterus 12-24 hours after the insemina‐ tion to the 2nd group. 3rd group was left as control. After the first insemination the pregnancy rates were found as 42.2%, 38.3% and 45.1%, respectively. As a result they report‐ ed that, subcutaneous carprofen therapy did not affect the pregnancy rate but intrauterine

Amiridis et al. [73] applied flunixin meglumine, ketoprofen and meloxicam to heifers. In the end, they came to conclusion that meloxicam administered animals have the longest estrus cycle and meloxicam is much more potent than other NSAIDs. The same researchers made a study on repeat breeder cows; 1st group was GnRH, 2nd group was progesterone, 3rd group was meloxicam and the 4th group was GnRH + progesterone + meloxicam. They reported

In another study on Holstein heifers, 0.5 mg/kg dose of meloxicam was administered subcu‐ taneous on the 15th day following the insemination. Finally, it was identified that pregnancy rate was 24.3% in meloxicam cured group and 52% in control group. In the light of these data, researchers reported that meloxicam application during the time of maternal recogni‐

In a study aimed at increasing pregnancy rate and progesterone synthesis by inhibiting prostaglandin synthesis, a fixed time artificial insemination was done by synchronising cy‐ cles of Nelore cows. Researchers divided the animals into 8 groups and they designed the groups as follows. 1st group constitutes the control and given saline on 7th and 16th days; to the 2nd group, saline on the 7th day and flunixin meglumine on the 16th day; to the 3rd group, bST on the 7th day and saline on the 16th day, to the 4th group, bST on the 7th day and flunixin meglumine on the 16th day, to the 5th group, hCG on the 7th day and saline on the 16th day, to the 6th group, hCG on the 7th day and flunixin meglumine on the 16th day, to the 7th group, bST + hCG on the 7th day and saline on the 16th day, to the last group, bST + hCG on the 7th

Dogruer et al. [82] synchronized repeat breeder heifers by applying two dose PGF2α. 48 hours after PGF2α, they administered GnRH (buserelin acetate) and after 12 – 14 hours they made fixed time artificial insemination. Then, they divided the heifers into two groups ran‐ domly and they injected a group flunixin meglumine on the 15th and 16th days. They used the other group as control. They made a pregnancy test to animals on the 29th day and in the end, they identified 50% pregnancy rate in therapy group, and 20% in the control group.

Güzeloğlu et al [74] gave GnRH on the 48th hour after synchronisation with PGF2α to 52 Hol‐ stein heifers and they inseminated them after 12-14 hours. Following this application, they administered 1.1 mg/kg dose of flunixin meglumine after artificial insemination on 15th days evening and 16th days morning via intramuscular way. Pregnancy test was done on the 29th day and, 20 pregnant animals in the treatment group and 13 pregnant animals in the control group was found.

In a study by Lucacin et al [78], they administered 1.1 mg/kg dose of flunixin meglumine to animals between the estrus cycle's 11th and 16th days. Saline solution was given to animals in the control group. The estrus cycle of the animals was synchronized by the applications of estradiol benzoate + CIDR + PGF2α and then, fixed time artificial insemination was done. Re‐ searchers did not find any difference between progesterone concentrations and pregnancy rates of treatment group and control group.

Rabaglino et al. [79] synchronized the heifers with Cosynch+CIDR protocol, they gave half of them double dose of flunixin meglumine (400 mg) on the 15th and 16th days after artificial insemination. At the end of this application, 59.4% pregnancy was reached in control group, 59.5% pregnancy rate was reached in Flunixin meglumine given group.

Geary et al. [80] searched the effects of flunixin meglumine on the pregnancy rates in a study done on Angus heifers. In the first experiment they synchronized the animals with MGA and PGF2α. Animals were inseminated 12 hours after the observation of estrus. 13 days after the artificial insemination they injected single dose of flunixin meglumine to ani‐ mals. While pregnancy rate was 72% in control group, it remained 66% in flunixin meglu‐ mine group. In the second experiment, Angus cows were synchronized via Select Synch or Select Synch + CIDR method. After that, they were inseminated by observing estrus. Around 13 days after artificial insemination they were injected flunixin meglumine. In the pregnancy test done on the 47th day, no difference was observed between the control and subject group (57% vs. 58%). In the third experiment both the heifers and the cows were used as materials. While Heifers were synchronized through Select Synch + CIDR protocol, cows were synchronized with Co-Synch + CIDR protocol. Pregnancy test was done on the 29th day; it was confirmed on the 75th day in heifers and 99th day in cows by ultrasound examination. As the conclusion of the experiment, no difference was found between flunixin meglumine and control group (50% vs. 48%).

Kruger and Heuwiser [83] made a study to assess the carprofen and flunixin meglumine's effect on pregnancy rate of dairy cattle. They injected animals with carprofen and flunixin meglumine on 14th, 15th and 16th days after the insemination. In the first experiment, 413 Hol‐ stein-Friesian heifers were used. The cycles of these animals were synchronized with PGF2α and they were inseminated by observing their estrus. 2.2 mg/kg dose of flunixin meglumine was given to therapy group animals after the insemination's 14th-15th days or 15th-16th days. No application was done to animals in the control group. At the end of this experiment, pregnancy rate in the control group was 58.7% and 58.6% in the treatment group. Serum progesterone levels on 14-15days and 21-22 days after insemination were compared in both pregnant and non-pregnant animals. It was observed that on the 21-22 days progesterone levels of pregnant animals were higher. In the second experiment researchers used 380 Hol‐ stein cows and these animals were synchronized by ovsynch protocol. After 16 hours from the second GnRH injection, fixed time artificial insemination was done. 1.4 mg/kg dose of carprofen was given via subcutaneous on the 15th day after the insemination to the treat‐ ment group. No therapy was applied to control group. It was identified that while pregnan‐ cy rate in carprofen given group was 33%, it was 35.5 in control group. Researchers come to the idea that NSAID application does not affect the reproductive performance.

animals was evaluated as control and the 2nd cycle was evaluated as therapy cycle. Before

Dogruer et al. [82] synchronized repeat breeder heifers by applying two dose PGF2α. 48 hours after PGF2α, they administered GnRH (buserelin acetate) and after 12 – 14 hours they made fixed time artificial insemination. Then, they divided the heifers into two groups ran‐ domly and they injected a group flunixin meglumine on the 15th and 16th days. They used the other group as control. They made a pregnancy test to animals on the 29th day and in the end, they identified 50% pregnancy rate in therapy group, and 20% in the control group.

Güzeloğlu et al [74] gave GnRH on the 48th hour after synchronisation with PGF2α to 52 Hol‐ stein heifers and they inseminated them after 12-14 hours. Following this application, they administered 1.1 mg/kg dose of flunixin meglumine after artificial insemination on 15th days evening and 16th days morning via intramuscular way. Pregnancy test was done on the 29th day and, 20 pregnant animals in the treatment group and 13 pregnant animals in

In a study by Lucacin et al [78], they administered 1.1 mg/kg dose of flunixin meglumine to animals between the estrus cycle's 11th and 16th days. Saline solution was given to animals in the control group. The estrus cycle of the animals was synchronized by the applications of estradiol benzoate + CIDR + PGF2α and then, fixed time artificial insemination was done. Re‐ searchers did not find any difference between progesterone concentrations and pregnancy

Rabaglino et al. [79] synchronized the heifers with Cosynch+CIDR protocol, they gave half of them double dose of flunixin meglumine (400 mg) on the 15th and 16th days after artificial insemination. At the end of this application, 59.4% pregnancy was reached in control group,

Geary et al. [80] searched the effects of flunixin meglumine on the pregnancy rates in a study done on Angus heifers. In the first experiment they synchronized the animals with MGA and PGF2α. Animals were inseminated 12 hours after the observation of estrus. 13 days after the artificial insemination they injected single dose of flunixin meglumine to ani‐ mals. While pregnancy rate was 72% in control group, it remained 66% in flunixin meglu‐ mine group. In the second experiment, Angus cows were synchronized via Select Synch or Select Synch + CIDR method. After that, they were inseminated by observing estrus. Around 13 days after artificial insemination they were injected flunixin meglumine. In the pregnancy test done on the 47th day, no difference was observed between the control and subject group (57% vs. 58%). In the third experiment both the heifers and the cows were used as materials. While Heifers were synchronized through Select Synch + CIDR protocol, cows were synchronized with Co-Synch + CIDR protocol. Pregnancy test was done on the 29th day; it was confirmed on the 75th day in heifers and 99th day in cows by ultrasound examination. As the conclusion of the experiment, no difference was found between flunixin meglumine and

Kruger and Heuwiser [83] made a study to assess the carprofen and flunixin meglumine's effect on pregnancy rate of dairy cattle. They injected animals with carprofen and flunixin

59.5% pregnancy rate was reached in Flunixin meglumine given group.

the experiment, cycles of the animals were synchronized by PGF2α.

82 Success in Artificial Insemination - Quality of Semen and Diagnostics Employed

the control group was found.

control group (50% vs. 48%).

rates of treatment group and control group.

Heuwieser et al. [72] made a study on 970 cows. They divided the animals into three groups. They administered 1.4 mg/kg dose of carprofen subcutaneous following artificial insemina‐ tion. 1.4 mg/kg dose of carprofen was given into the uterus 12-24 hours after the insemina‐ tion to the 2nd group. 3rd group was left as control. After the first insemination the pregnancy rates were found as 42.2%, 38.3% and 45.1%, respectively. As a result they report‐ ed that, subcutaneous carprofen therapy did not affect the pregnancy rate but intrauterine therapy had a negative effect on the pregnancy rate.

Amiridis et al. [73] applied flunixin meglumine, ketoprofen and meloxicam to heifers. In the end, they came to conclusion that meloxicam administered animals have the longest estrus cycle and meloxicam is much more potent than other NSAIDs. The same researchers made a study on repeat breeder cows; 1st group was GnRH, 2nd group was progesterone, 3rd group was meloxicam and the 4th group was GnRH + progesterone + meloxicam. They reported that the highest pregnancy rates were seen in 4th group.

In another study on Holstein heifers, 0.5 mg/kg dose of meloxicam was administered subcu‐ taneous on the 15th day following the insemination. Finally, it was identified that pregnancy rate was 24.3% in meloxicam cured group and 52% in control group. In the light of these data, researchers reported that meloxicam application during the time of maternal recogni‐ tion will be harmful to pregnancy [84].

In a study aimed at increasing pregnancy rate and progesterone synthesis by inhibiting prostaglandin synthesis, a fixed time artificial insemination was done by synchronising cy‐ cles of Nelore cows. Researchers divided the animals into 8 groups and they designed the groups as follows. 1st group constitutes the control and given saline on 7th and 16th days; to the 2nd group, saline on the 7th day and flunixin meglumine on the 16th day; to the 3rd group, bST on the 7th day and saline on the 16th day, to the 4th group, bST on the 7th day and flunixin meglumine on the 16th day, to the 5th group, hCG on the 7th day and saline on the 16th day, to the 6th group, hCG on the 7th day and flunixin meglumine on the 16th day, to the 7th group, bST + hCG on the 7th day and saline on the 16th day, to the last group, bST + hCG on the 7th day and flunixin meglumine on the 16th day were administered. It was found out that the group only cured with hCG on the 7th day showed a higher rate of pregnancy [85].

Bulbul et al [92] gave 500 mg flunixin meglumine intramuscular five minutes before embryo transfer in a study done on 39 brown Swiss. As a result of the pregnancy examination on the 30th day by means of ultrasound, they reported that pregnancy rate in the flunixin meglu‐

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Artificial insemination is the first biotechnologic application used in domestic animal. It was first performed by Ivanow in 1899 in Russia on farm animals. This procedure was adopted in 1940s by animal breeders and then it has become prominent all over the world. Such asso‐ ciated technologies as cryopreservation, invitro fertilization and embryo transfer have then started to develop and they have resulted in successful pregnancies (93). NSAID implemen‐ tations have been used in recent years among the assisted reproductive technologies. NSAIDs are applied as a new strategy to increase the pregnancy rates of cows in artificial insemination. Nevertheless, the results obtained from the previous studies conflict with each other. Especially, there are different studies stating that flunixin application increases, does not change or decreases the pregnancy rate. For this reason, NSAIDs relation with interferon tau and endometrial proteins should be investigated in a more detailed way. Thus, from where the difference in pregnancy rates originate can be found and taking of necessary pre‐

\*Address all correspondence to: paksoyland@yahoo.com, huseyindas@hotmail.com

1 Deparment of Veterinary Sciences, University of Gumushane, Gumushane, Turkey

2 Deparment of Veterinary Sciences, University of Gumushane, Gumushane, Turkey

İnfertilite. İkinci Baskı, Ankara: Medisan Yayınevi; 1999. p267-290.

[1] Alaçam E. İnekte İnfertilite Sorunu. In: Alaçam E. (ed.) Evcil Hayvanlarda Doğum ve

[2] Çoyan K and Tekeli T. İneklerde Suni Tohumlama. Birinci Baskı, Konya: Bahçıvanlar

[3] Daşkın A. Sığırcılık İşletmelerinde Reprodüksiyon Yönetimi ve Suni Tohumlama.

mine given group was lower in comparison to control group (50% vs. 52.6%).

**14. Conclusions**

cautions can be possible.

Zahid Paksoy1\* and Hüseyin Daş<sup>2</sup>

Basım San. A.Ş.; 1996.

Ankara: Aydan Web Ofset; 2005.

**Author details**

**References**

Tek et al. [86] searched the effects of flunixin meglumine and oxytetracyclin combinations on the cows diagnosed with subclinical endometritis. They applied intramuscular flunixin meglumine (2 mg/kg) and oxytetracyclin (300 mg). They inseminated the animals in the first estrus seen after the application. When compared with the control group, pregnancy rates were higher in flunixin meglumine and oxytetracyclin administered group (25% vs. 55%).

In another study, animals with puerperal metritis were injected with ceftiofur (CEF) and/or flunixin meglumine. CEF was given to the first group for three days. A single dose of flunix‐ in meglumine (2.2 mg/kg) was given intravenous in addition to CEF to the animals in the second group. At the end of the study, researchers came to a conclusion that flunixin meglu‐ mine application does not have a beneficial effect on clinical recovery and reproductive per‐ formance [87].
